Comprehensive Dermatologic Drug Therapy E-Book
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1626 pages
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Description

Safely and effectively treat a full range of skin disorders with Comprehensive Dermatologic Drug Therapy, 3rd Edition! This trusted dermatology reference provides concise, complete, up-to-date guidance on today's full spectrum of topical, intralesional, and systemic drugs. Dr. Steven E. Wolverton and a team of leading international experts clearly explain what drugs to use, when to use them, and what to watch out for.

  • Consult this title on your favorite e-reader with intuitive search tools and adjustable font sizes. Elsevier eBooks provide instant portable access to your entire library, no matter what device you’re using or where you’re located.
  • Prescribe with confidence thanks to quick-access summaries of indications/contraindications, dosage guidelines, drug interactions, drug monitoring guidelines, adverse effects, and treatment protocols.
  • Assess your knowledge and prepare for certification or recertification with more than 800 review questions and answers throughout.
  • Contain costs and meet patient expectations with purchase information provided for major drugs.
  • Quickly evaluate drug options for each disease discussed using a highly detailed, disease-specific index.
  • Discover the best uses for new biologic therapeutics such as ustekinumab and rituximab, as well as newly improved TNF inhibitors.
  • Offer your patients the very latest in cosmetic procedures, including chemical peels, intradermal fillers, and botulinum toxin.
  • Use the safest and most effective drugs possible with new chapters on irritants and allergens in topical therapeutic agents, plus a new, separate chapter on mycophenolate mofetil.
  • Review drugs recently taken off the market by the FDA, and use that knowledge to improve your current dermatologic drug therapy.

Sujets

Ebooks
Savoirs
Medecine
Botox
Pediculosis pubis
Drug combination
Editorial
Vitamin D
Anthelmintic
SAFETY
Oncology
Herpes simplex
Amoebic liver abscess
Systemic lupus erythematosus
Franceschetti?Klein syndrome
Arthropod
Gingivitis
Acne
Lupus erythematosus
Ulceration
The Only Son
Histamine antagonist
Canakinumab
Patient education
Tumor necrosis factors
Mouth
Belimumab
Ustekinumab
IL-23
Bexarotene
Alitretinoin
Mycophenolate mofetil
Photopheresis
Enzyme inhibitor
Complicity
Cyproheptadine
Alpha hydroxy acid
Long-term care
Venous ulcer
Psoralen
Risedronic acid
Glycolic acid
Carcinogenesis
Octyl methoxycinnamate
Hydroxychloroquine
Adverse event
Tazarotene
Atopic dermatitis
Dermatitis
Interleukin 12
Pregnancy
Insect repellent
Mycosis fungoides
Actinic keratosis
Acitretin
Irritant
Ivermectin
Retinoid
Keratolytic
Alendronic acid
Fatty liver
Urticaria
Mupirocin
Bacitracin
Topical
Hydroxycarbamide
Medical Center
Anti-inflammatory
Pharmacodynamics
Biological agent
Light therapy
Cephalosporin
Anesthetic
Permethrin
Stroke
Ichthyosis vulgaris
Psoriatic arthritis
Itraconazole
Graft-versus-host disease
Antifungal drug
Inhibitor
Glucocorticoid
Mycophenolic acid
Protein isoform
Seborrhoeic dermatitis
B-cell chronic lymphocytic leukemia
Hair coloring
Applause
Photodynamic therapy
Sarcoptes scabiei
H1 antagonist
Cytotoxicity
Sunscreen
Generic drug
Methotrexate
Survey
Immunosuppressive drug
Tetralogy of Fallot
Complete blood count
Androgen
Tired
Demographics
Isotretinoin
Titanium dioxide
Alopecia
Pharmacist
Intravenous therapy
U.S. Patients' Bill of Rights
Local anesthetic
Alopecia areata
Randomized controlled trial
Paste
Ciclosporin
Creativity
Hirsutism
Hypertension
Acne vulgaris
Dermatology
Mucous membrane
Hematology
Crohn's disease
Allergen
Multiple sclerosis
Informed consent
Antiviral drug
Salicylic acid
Risk management
Rheumatoid arthritis
Pharmacology
Pediatrics
Penicillin
Neurology
Major depressive disorder
Chemotherapy
Caesium
Bactericide
Appendix
Ascorbic acid
Allele
Antibacterial
Anxiety
Oxiconazole
Cyclophosphamide
Fluconazole
Finastéride
Ciclosporine
Terbinafine
Doxycycline
Gene
Filler
Hydroquinone
Shampoo
Étanercept
Cholécalciférol
Rituximab
Méthotrexate
Format
Toxin
Desquamation
Cortisone
Lactation
Azathioprine
Electronic
Service
Thalidomide
Lidocaïne
Prednisone
Contact
Cytokine
Dapsone
Psoriasis
Son
Copyright

Informations

Publié par
Date de parution 18 octobre 2012
Nombre de lectures 0
EAN13 9781455738014
Langue English
Poids de l'ouvrage 5 Mo

Informations légales : prix de location à la page 0,0394€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Comprehensive Dermatologic Drug Therapy
Third Edition

Stephen E. Wolverton, MD
Theodore Arlook Professor of Clinical Dermatology, Department of Dermatology, Indiana University School of Medicine
Chief of Dermatology, Roudebush VA Medical Center, Indianapolis, IN, USA
Saunders
Table of Contents
Cover image
Title page
Copyright
List of contributors
Preface
Dedication
Acknowledgements
A dozen suggestions to help the reader optimally utilize this book
Part I: Introduction
Chapter 1: Basic principles of pharmacology
Introduction
Pharmacokinetics – part I (Tables 1-2 and 1-3)
Pharmacodynamics (the drug produces the desired pharmacologic effect)
Pharmacokinetics – part II
Percutaneous absorption
Chapter 2: Principles for maximizing the safety of dermatologic drug therapy
Introduction
Anticipation
Prevention
Diagnosis
Management
Parting thoughts
Chapter 3: Polymorphisms: why individual drug responses vary
Introduction
Evaluating the patient
Factors that influence medication effects (including adverse effects)
Drug metabolism – Phase I reactions
Drug metabolism – Phase II reactions (Table 3-9)
Severe cutaneous adverse drug reactions linked to genetic polymorphisms
Tests for genetic polymorphisms and clinical significance
Conclusions and future directions
Chapter 4: Adherence to drug therapy
Introduction
Measures of adherence
The magnitude of poor adherence in dermatology
Factors that influence adherence behavior
Strategies to improve adherence behavior
Conclusions
Part II: Important Drug Regulatory Issues
Chapter 5: The FDA drug approval process
Introduction
Federal legislation for drug safety and efficacy
Phase I–IV testing
FDA advisory panels
Off-label drug use
Generic drugs
Special drug approval categories
Related issues
Chapter 6: Pharmacovigilance: verifying that drugs remain safe
Introduction
Summary
Chapter 7: Drugs taken off the market: important lessons learned
Introduction
Presentation of benefit–risk in labeling
Product label ‘lifecycle’ changes
RISKS AND BENEFITS: FDA safety information
Drug withdrawal
Part III: Systemic Drugs for Infectious Diseases
Chapter 8: Systemic Antibacterial Agents
Introduction
Penicillins
Cephalosporins
β-lactam and β-lactamases inhibitor combinations
Carbapenems and monobactams
Other systemic agents affecting the bacterial cell wall
Macrolides
Fluoroquinolones
Tetracyclines
Rifamycins
Folate synthesis inhibitors
Lincosamides
Glycyclines
Oxazolidinones
Quinupristin and dalfopristin combination
Daptomycin
Lipoglycopeptides
Summary
Chapter 9: Systemic antifungal agents
Introduction
Conclusion
Chapter 10: Systemic antiviral agents
Introduction
Drugs for human herpes virus infections
Drugs for human immunodeficiency virus infections
Summary
Acknowledgment
Chapter 11: Systemic antiparasitic agents
Ivermectin
Albendazole
Thiabendazole
Alternative agents – doxycycline as antiparasitic agent
Part IV: Systemic Immunomodulatory and Antiproliferative Drugs
Chapter 12: Systemic corticosteroids
Systemic corticosteroids
Pharmacology (Table 12-1)
Systemic corticosteroids chapter update
Chapter 13: Methotrexate
Introduction
Pharmacology
Clinical use
Chapter 14: Azathioprine
Introduction
Pharmacology
Clinical use
Summary
Chapter 15: Mycophenolate mofetil and mycophenolic acid
Introduction
Pharmacology
Mechanism of action
Clinical use
Off-label dermatologic uses
Immunobullous disease
AUTOIMMUNE CONNECTIVE TISSUE DISEASE
Chapter 16: Cyclosporine
Introduction
Summary
Chapter 17: Cytotoxic agents
Introduction
Major subcategories of cytotoxic agents and the cell cycle
Patient education issues
Antimetabolites
Alkylating agents
Chapter 18: Dapsone
Introduction
Pharmacology
Clinical use
Chapter 19: Antimalarial agents
Introduction
Pharmacology
Clinical use
Monitoring guidelines70–72,107
Drug interactions
Therapeutic guidelines
Chapter 20: Systemic retinoids
Introduction and historical perspective
Pharmacology
Clinical use
Acknowldgment
Chapter 21: Interferons
Introduction – interferon
Pharmacology
Clinical use
Acknowledgment
Part V: Drugs Used in Conjunction with Ultraviolet or Visible Light
Chapter 22: PUVA photochemotherapy and other phototherapy modalities
Introduction and drug history
Puva photochemotherapy
Clinical use
Treatment procedure
Narrowband UVB phototherapy
UVA-1 phototherapy
Chapter 23: Extracorporeal photochemotherapy (photopheresis)
Introduction
Treatment delivery and considerations
Pharmacology
Clinical use
Chapter 24: Photodynamic therapy
Introduction
Pharmacology
Part VI: Biological Therapeutics
Chapter 25: Tumor necrosis factor (TNF) inhibitors
Introduction – psoriasis pathogenesis
Etanercept
Infliximab
Adalimumab
Chapter 26: Interleukin 12/23 inhibitors
Introduction
Monoclonal antibody treatments
Interleukin-12/23 therapy
The future: combination therapy and switching
Conclusions
Chapter 27: Rituximab and future biological therapies
Introduction
Part VII: Miscellaneous Systemic Drugs
Chapter 28: Antihistamines
Importance of histamine in skin diseases
Historical overview
First-generation antihistamines
Second-generation H1 antihistamines
Fexofenadine
Loratadine
Cetirizine
Desloratadine
Levocetirizine
H1 antihistamine therapy – special TOPICS
Chapter 29: Vasoactive and antiplatelet agents
Pathophysiology involving cutaneous vasculature
Calcium channel blockers
β-blockers
Aspirin
Dipyridamole
Pentoxifylline
Nitric oxide donors
Phosphodiesterase-5 inhibitors
Iloprost
Antiangiogenesis agents
Chapter 30: Antiandrogens and androgen inhibitors
Introduction
Physiologic role of androgens
Antiandrogens
Androgen inhibitors
Hormone preparations
Gonadotropin-releasing hormone analogs
Herbal remedies
Chapter 31: Psychotropic agents
Introduction
Classification of psychodermatologic disorders
The management of anxiety in dermatology
The management of depression in dermatology
The management of delusional disorders in dermatology
The management of obsessive–compulsive disorder in dermatology
Summary
Chapter 32: Intravenous immunoglobulin therapy
Introduction
Pharmacology
Acknowledgment
Chapter 33: Systemic anticancer agents: dermatologic indications and adverse events
Introduction
Epidermal growth factor receptor inhibitors (EGFRIs)
Multitargeted kinase inhibitors (MKI)
Alkylating agents
Topoisomerase inhibitors
Antimicrotubule AGENTS (TAXANES)
Anthracyclines
Histone deacetylase (HDAC) inhibitors
Miscellaneous
Monoclonal antibodies
Antimetabolites
Biotherapy (immunokines)
BRAF inhibitors
Summary
Chapter 34: Drugs for the skinternist
Introduction
Therapy for corticosteroid-induced osteoporosis
Bexarotene for cutaneous T-cell lymphoma – central hypothyroidism
Therapy for retinoid- OR Cyclosporine-induced hyperlipidemia
Fibric acid derivatives
Corticosteroid-associated peptic ulcer disease
Vitamin D therapy
Acknowledgment
Chapter 35: Miscellaneous systemic drugs
Introduction
Anticholinergic agents – glycopyrrolate and propantheline
Attenuated androgens – danazol and stanozolol
Biotin
Clofazimine
Colchicine
Fumaric acid esters
Gold
Nicotinamide
Non-steroidal anti-inflammatory drugs
Penicillamine
Potassium iodide
Thalidomide
Vitamin E
Zinc sulfate
Part VIII: Topical Drugs for Infectious Diseases
Chapter 36: Topical Antibacterial Agents
Introduction
Drugs used for wound care and minor topical bacterial infections
Drugs used for acne and rosacea
Antiseptics
Acknowledgment
Chapter 37: Topical antifungal agents
Introduction
Polyenes
Azoles
Allylamines and benzylamines
Other topical antifungals
Comparative studies
Chapter 38: Topical and intralesional antiviral agents
Introduction
Viricidal drugs
Immune-enhancing drugs
Cytodestructive drugs
Chapter 39: Topical antiparasitic agents
Introduction
Part IX: Topical Immunomodulatory and Antiproliferative Drugs
Chapter 40: Topical corticosteroids
Introduction
Pharmacology
Clinical use
Chapter 41: Topical retinoids
Introduction
Pharmacology
Clinical use
Acknowledgement
Chapter 42: Topical and intralesional chemotherapeutic agents
Introduction
Topical chemotherapeutic agents
Intralesional chemotherapeutic agents
Chapter 43: Topical contact allergens
Introduction
Mechanism of action in alopecia areata
Mechanism of action in warts
Diphenylcylopropenone
Squaric acid dibutyl ester
Dinitrochlorobenzene
Chapter 44: Topical calcineurin inhibitors
Introduction
Tacrolimus
Pimecrolimus
Chapter 45: Topical Vitamin D 3
Introduction
Pharmacology
Vitamin D analogs
Part X: Miscellaneous Topical Drugs
Chapter 46: Sunscreens
Introduction
Sunscreen options
Clinical use
Summary
Chapter 47: Therapeutic shampoos
Introduction
Dermatoses involving the scalp
Historical perspective
Pharmacology
Clinical use
Therapeutic guidelines
Summary
Chapter 48: α-Hydroxy acids
Introduction
Pharmacology
Clinical use
Formulations
Adverse effects
Summary
Chapter 49: Chemical peels
Introduction
Superficial chemical peels
Medium-depth chemical peels
Deep chemical peels
Chapter 50: Products for the care of chronic wounds
Introduction
Wound healing physiology and ideal wound healing environment
General approach to a patient with chronic wounds
Venous ulcer disease
Systemic and surgical treatments
Chapter 51: Agents used for treatment of hyperkeratosis
Introduction
Chapter 52: Cosmetic therapy
Cosmetic therapy overview
Skin bleaching agents
Skin pigmenting products – dihydroxyacetone
Facial foundations and camouflage cosmetics
Skin cleansers
Moisturizers
Hair shampoos
Hair permanent waving agents
Hair-straightening agents
Hair-dyeing agents
Hair-bleaching agents
Nail polish
Chapter 53: Irritants and allergens: When to suspect topical therapeutic agents
Introduction
Contact dermatitis: the concept
When to suspect contact dermatitis
Final thoughts
Chapter 54: Insect repellents
Introduction
Insect biology
Insect repellents overview
Chemical insect repellents
Biopesticide repellents
Plant-derived repellents
Efficacy of DEET versus botanical repellents
Related issues
Chapter 55: Miscellaneous topical agents
Introduction
Topical antioxidants
Topical agents for hemostasis and hyperhidrosis
Other topical agents
Part XI: Injectable and Mucosal Routes of Drug Administration
Chapter 56: Local anesthetics
Introduction
Injectable local anesthetics
Topical anesthetics
Co-injectable vasoconstrictors
Other agents with local anesthetic effects
Chapter 57: Injectable dermal and subcutaneous fillers
Introduction
Categories of dermal fillers
Fillers on the horizon
Chapter 58: Botulinum toxin injections
Introduction and history
Conclusions
Chapter 59: Oral mucosal therapeutics
Introduction
Review of common terminology
Erosive gingivostomatitis
Herpetic gingivostomatitis
Oral candidiasis
Hairy tongue
Recurrent aphthous stomatitis
Acute necrotizing ulcerative gingivostomatitis
Mucositis (stomatitis)
Xerostomia
Burning mouth syndrome
Part XII: Major Adverse Effects from Systemic Drugs
Chapter 60: Hepatotoxicity of dermatologic drug therapy
Introduction
The liver and drug metabolism
Mechanisms of drug hepatotoxicity
Risk factors for drug hepatotoxicity
Drug information dissemination issues
Classification systems (Table 60-7)
Drug etiologies
Diagnosis
Management
Looking to the future – lessons from the past
Chapter 61: Hematologic toxicity of drug therapy
Introduction
General principles
Major categories of drug-induced hematologic toxicity
Drugs Prescribed by Dermatologists – Risk of Hematologic Toxicity
Treatment of hematologic toxicities
Acknowledgments
Chapter 62: Drug-induced malignancy
Introduction
Assessment of drug causation for malignancy induction
General principles of carcinogenesis
Review of malignancy risk with organ transplantation
Review of malignancy risk with autoimmune diseases
Specific drugs used in dermatology and their potential risk for malignancy
Prevention and detection of possible malignancies
The bottom line
Chapter 63: Neurologic adverse effects from dermatologic drugs
Introduction
General principles
Progressive multifocal leukoencephalopathy
Demyelinating disorders
Pseudotumor cerebri (idiopathic intracranial hypertension)
Drug-induced CNS toxicity and seizures
Peripheral neuropathy/polyneuropathy
Specific drugs
Chapter 64: Dermatologic drugs during pregnancy and lactation
Introduction
General principles
Guide for specific drug use
Summary Q64-8
Chapter 65: Drug interactions
Introduction
General principles of drug interactions
Cytochrome P-450-based drug interactions
Importance of the order of drug administration
Drug interaction risks by drug category
Genetic polymorphisms
Pharmacodynamic mechanisms of drug interactions
Do all drugs in a given class behave in a similar manner?
Summary
Chapter 66: Cutaneous drug reactions with systemic features
Introduction
Drug hypersensitivity syndrome (DHS)
Serum sickness and serum sickness-like reactions
Drug-induced lupus (DIL)
Acute generalized exanthematous pustulosis
Stevens–johnson syndrome and toxic epidermal necrolysis
Anaphylaxis
General discussion
Part XIII: Special Pharmacology and Therapeutic Topics
Chapter 67: Pharmacoeconomics
Introduction
Various cost analyses
Analyzing the various cost analyses
How are pharmacoeconomic analyses used?
Pharmaceutical pricing strategies
Pharmaceutical patient assistance programs
Generic drugs and substitution
Why is pharmacoeconomics important to clinicians?
Chapter 68: Informed consent and risk management
Introduction
Historical perspective
Ethical perspective
Basic legal principles
Components of informed consent
Systemic drugs and informed consent
Optimizing patient understanding
Exceptions to the informed consent requirements
Medicolegal risk management
Dermatology malpractice
Summary
Chapter 69: Compounding in dermatology
Introduction
The ‘compounding triad’
Developing a stable compounding formula
Properly write the prescription
Monitor the patient
Summary
Chapter 70: Dermatologic drug therapy in children
Introduction
General issues
Specific medications used in children
Appendix I – Ten drugs of increasing importance to dermatology
Appendix II – Dapsone patient education and informed consent
Subject Index
Copyright

SAUNDERS is an imprint of Elsevier Inc.
© 2013, Elsevier Inc. All rights reserved.
First edition 2001
Second edition 2007
Third edition 2013
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions .
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
ISBN: 978-1-4377-2003-7
Ebook ISBN: 978-1-4557-3801-4

Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
List of contributors

David R. Adams, MD, PharmD
Associate Professor of Dermatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA

Stephanie S. Badalamenti, MD, PhD, LLC
Fellow, Department of Medicine, Saint Barnabas Medical Center, West Orange, NJ, USA

Mark A. Bechtel, MD
Director of Dermatology, The Ohio State University College of Medicine, Columbus, OH, USA

Brian Berman, MD, PhD
Voluntary Professor of Dermatology and Cutaneous Surgery, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL; Skin and Cancer Associates, LLP and Center for Clinical and Cosmetic Research, Aventura, FL, USA

Tina Bhutani, MD
Clinical Fellow, Psoriasis and Skin Treatment Center, University of California, San Francisco, CA, USA

Robert Bissonnette, MD, FRCPC
Director, Innovaderm Research, Montreal, QC, Canada

Robert T. Brodell, MD
Professor of Internal Medicine; Clinical Professor of Dermatopathology in Pathology; Master Teacher, Northeast Ohio Medical University, Rootstown, OH; Associate Clinical Professor of Dermatology, Department of Dermatology, Case Western Reserve University, Cleveland, OH; Instructor in Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

David G. Brodland, MD
Private Practice; Assistant Clinical Professor, Departments of Dermatology and Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA

Jeffrey P. Callen, MD, FACP
Professor of Medicine in Dermatology; Chief, Division of Dermatology, University of Louisville School of Medicine, Louisville, KY, USA

Charles Camisa, MD, FAAD
Director of Phototherapy and Camisa Psoriasis Center, Riverchase Dermatology, Naples and Fort Myers, FL; Affiliate Associate Professor, Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, FL, USA

Caroline V. Caperton, MD, MSPH
Clinical Research Fellow, Department of Dermatology and Cutaneous Surgery, and Internal Medicine, University of Miami, Miller School of Medicine, FL, USA

Jaehyuk Choi, MD, PhD
Instructor in Dermatology, Yale School of Medicine, New Haven, CT, USA

Richard A. Clark, MD
Director, Burn and Nonscar Healing Program, RCCC Armed Forces Institute of Regenerative Medicine; Professor, Biomedical Engineering and Dermatology, Stony Brook, NY, USA

Kevin D. Cooper, MD
Professor and Chair, Department of Dermatology; Director, Skin Diseases Research Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH, USA

Julio C. Cruz-Ramon, MD
Dermatologist, Private Practice, Buckeye Dermatology, Dublin, OH, USA

Marc A. Darst, MD
Private Practice, Darst Dermatology; Laboratory Director, Charlotte Dermatopathology, Charlotte, NC, USA

Loretta S. Davis, MD
Professor of Dermatology, Division of Dermatology, Georgia Health Sciences University, Augusta, GA, USA

Cynthia M.C. DeKlotz, MD, MASt
Chief Resident in Internal Medicine/Dermatology, Division of Dermatology and Department of Medicine, Georgetown University Hospital; Department of Dermatology and Department of Medicine, Washington Hospital Center, Washington, DC, USA

James Q. Del Rosso, DO, FAOCD
Dermatology Residency Program Director, Valley Hospital Medical Center, Las Vegas, NV; Clinical Professor (Dermatology), Touro University College of Osteopathic Medicine, Henderson, NV; Dermatology and Cutaneous Surgery, Las Vegas Skin and Cancer Clinics, Las Vegas, NV and Henderson, NV, USA

Catherine M. DiGiorgio, MS, MD
Clinical Research Fellow, Center for Clinical Studies, Dermatological Association of Texas, Houston, TX, USA

Zoe D. Draelos, MD
Consulting Professor, Department of Dermatology, Duke University School of Medicine, Durham, NC, USA

William H. Eaglstein, MD
Consultant, IHP Consulting, Inc.; Chairman Emeritus, Department of Dermatology, University of Miami, Miller School of Medicine, FL, USA

Kim Edhegard, MD
Immuno-Dermatology Fellow, Department of Dermatology, Duke University School of Medicine, Durham, NC, USA

Dirk Elston, MD
Managing Director, Ackerman Academy of Dermatopathology, New York, NY, USA

Jason J. Emer, MD
Resident Physician, Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA

Steven R. Feldman, MD, PhD
Center for Dermatology Research, Departments of Dermatology, Pathology and Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Ashley N. Feneran, DO
Internal Medicine Resident, Carilion Clinic, Roanoke, VA, USA

Laura K. Ferris, MD, PhD
Assistant Professor, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA

Seth B. Forman, MD
Private Practice, Forman Dermatology and Skin Cancer Institute, Tampa, FL, USA

Mark S. Fradin, MD
Clinical Associate Professor of Dermatology, University of North Carolina at Chapel Hill, NC, USA

Algin B. Garrett, MD
Professor and Chairman, Department of Dermatology, Virginia Commonwealth University Medical Center, Richmond, VA, USA

Joel M. Gelfand, MD, MSCE
Medical Director, Clinical Studies Unit; Assistant Professor of Dermatology and Epidemiology; Senior Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA

Jennifer G. Gill, PhD, MD
Graduate student, Washington University School of Medicine, St Louis, MO, USA

Michael Girardi, MD
Associate Professor; Residency Director, Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

Tobias Goerge, MD
Assistant Professor of Dermatology, Department of Dermatology, University Hospital Münster, Germany

Cristina Gómez-Fernández, MD
Dermatologist, Department of Dermatology, University Hospital La Paz, Madrid, Spain

Kenneth B. Gordon, MD
Professor of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

Malcolm W. Greaves, MD, PhD, FRCP
Emeritus Professor of Dermatology, Cutaneous Allergy Clinic, St John’s Institute of Dermatology, St Thomas’ Hospital; The London Allergy Clinic, London, UK

Aditya K. Gupta, MD, PhD, MBA/HCM, MA (Cantab), CCI, CCTI, CCRP, DABD, FAAD, FRCPC
Professor, Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada

Anita N. Haggstrom, MD
Associate Professor, Dermatology and Pediatrics, Indiana University, Indianapolis, IN, USA

Kassie A. Haitz, MD
Center for Clinical Studies, Houston, TX, USA

Russell P. Hall, III., MD
J. Lamar Callaway Professor and Chair, Department of Dermatology, Duke University School of Medicine, Durham, NC, USA

Peter W. Heald, MD
Professor of Dermatology, Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

Michael P. Heffernan, MD
Private Practice, Central Dermatology, St Louis, MO, USA

Yolanda R. Helfrich, MD
Assistant Professor, Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA

Adam B. Hessel, MD
Dermatologist, Private Practice, Buckeye Dermatology, Dublin; Clinical Assistant Professor, Division of Dermatology, The Ohio State University College of Medicine and Public Health, Columbus, OH, USA

Whitney A. High, MD, JD, MEng
Associate Professor, Dermatology and Pathology; Vice Chair, Clinical Affairs, University of Colorado Health Sciences Center, Denver, CO, USA

Ginette A. Hinds, MD
Assistant Professor of Dermatology; Director, Ethnic Skin Program; Director, Department of Dermatology, Johns Hopkins Bayview Medical Center, Baltimore MD, USA

Sylvia Hsu, MD
Professor of Dermatology, Department of Dermatology, Baylor College of Medicine; Chief of Dermatology, Ben Taub General Hospital, Houston, TX, USA

Michael J. Huether, MD
Medical Director, Arizona Skin Cancer Surgery Center, Tucson, AZ, USA

Michael S. Kaminer, MD
Assistant Professor of Dermatology, Yale Medical School, New Haven, CT and Dartmouth Medical School, Hanover, NH; Dermatologist, SkinCare Physicians, Chestnut Hill, MA, USA

Swetha Kandula, MD FACP
Resident, Dermatolgy, Indiana University School of Medicine, Indianapolis, IN, USA

Sewon Kang, MD
Noxell Professor and Chairman, Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA

Marshall B. Kapp, JD, MPH
Director, Center for Innovative Collaboration in Medicine and Law; Professor, Department of Geriatrics; Courtesy Professor, College of Law; Florida State University, Tallahassee, FL, USA

Francisco A. Kerdel, MD
Voluntary Professor of Clinical Dermatology, Department of Dermatology, University of Miami School of Medicine; Director, Dermatology Inpatient Services, Cedars Medical Center, Miami, FL, USA

Susun Kim, DO
Adjunct Assistant Professor (Dermatology), Touro University College of Osteopathic Medicine, Henderson, NV; Dermatology and Cutaneous Surgery, Las Vegas Skin and Cancer Clinics, Las Vegas, NV and Henderson, NV, USA

Grace K. Kim, DO
Dermatology Resident, Valley Hospital Medical Center, Las Vegas, NV, USA

Youn H. Kim, MD
Joanne and Peter Haas Jr. Professor for Cutaneous Lymphoma Research; Director, Multidisciplinary Cutaneous Lymphoma Program; Medical Director, Photopheresis Service, Stanford University School of Medicine, Stanford, CA, USA

Melanie Kingsley, MD
Director of Cosmetic Dermatology & Laser Surgery; Assistant Professor of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA

Melanie Kingsley, MD
Director of Cosmetic Dermatology & Laser Surgery; Assistant Professor of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA

Dana M. Klinger, MD
Dermatology Resident, LSU Department of Dermatology, New Orleans, LA, USA

Alfred L. Knable, Jr., MD
Associate Clinical Professor of Dermatology, University of Louisville, Louisville, KY, USA

Sandra R. Knowles, BScPhm
Lecturer, Faculty of Pharmacy, University of Toronto; Drug Safety Pharmacist, Sunnybrook Health Sciences Center, Toronto, Canada

John Y.M. Koo, MD
Professor and Vice Chairman, Department of Dermatology; Director, Psoriasis Treatment Center, University of California Medical Center, San Francisco, CA, USA

Shiva S. Krishnan, PhD
Research Associate, Division of Cancer Epidemiology and Biomakers Prevention, Georgetown University Lombardi Cancer Center, Washington DC, USA

Carol L. Kulp-Shorten, BS, MD
Clinical Professor of Medicine, Division of Dermatology, University of Louisville School of Medicine, KY, USA

Mario E. Lacouture, MD
Dermatologist, Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Megan N. Landis, MD
Dermatology Resident, Department of Dermatology, Mayo Clinic, Jacksonville, FL, USA

Sinéad M. Langan, MRCP, PhD NIHR
Clinician Scientist and Honorary Consultant Dermatologist, London School of Hygiene and Tropical Medicine and St John’s Institute of Dermatology, London, UK

Whitney J. Lapolla, MD
Clinical Research Fellow, Center for Clinical Studies, Houston, TX, USA

Amir Larian, MD
Clinical Instructor, Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA

Sancy A. Leachman, MD, PhD
Professor, Department of Dermatology; Director, Melanoma & Cutaneous Oncology Program, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA

Keith G. LeBlanc, Jr., MD
Chief Resident, Division of Dermatology, Georgia Health Sciences University, Augusta, GA, USA

Mark G. Lebwohl, MD
Professor and Chairman, Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA

Chai S. Lee, MD, MS
Dermatologist, Department of Dermatology, Kaiser Permanente, Milpitas, CA, USA

Samantha M. Lee, BSE
Medical Student, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Katherine B. Lee, MD, MA
Resident Physician, Department of Dermatology, Indiana University Medical Center, Indianapolis, IN, USA

Craig L. Leonardi, MD, FAAD
Clinical Professor of Dermatology, Saint Louis University School of Medicine; Private Practice, Central Dermatology, St Louis, MO, USA

Michelle M. Levender, MD
Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Stanley B. Levy, MD
Adjunct Clinical Professor of Dermatology, Department of Dermatology, University of North Carolina at Chapel Hill; Clinical Associate in Medicine, Duke University Medical School, Durham, NC, USA

Amy B. Lewis, MD, PC
Dermatologist, Private Practice, New York, NY; Clinical Assistant Professor, Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

Andrew N. Lin, MD, FRCPC
Associate Professor, Division of Dermatology and Cutaneous Science, University of Alberta, Edmonton, AB, Canada

Benjamin N. Lockshin, MD
Clinical Instructor, Department of Dermatology, Johns Hopkins University, Baltimore; DermAssociates PC, Silver Spring, MD, USA

Thomas A. Luger, MD
Professor and Chairman, Department of Dermatology, University of Münster, Germany

George D. Magel, MD
Clinical Research Fellow, Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA

Lawrence A. Mark, MD, PhD
Assistant Professor of Dermatology, Department of Dermatology, Indiana University, Indianapolis, IN, USA

Linda F. McElhiney, PharMD, RPh, FIACP, FASHP
Compounding Pharmacy Operations Coordinator, Pharmacy, Clarian Health Partners Inc, Indianapolis, IN, USA

Stephanie Mehlis, MD
Associate Professor of Dermatology, University of Chicago Pritzker School of Medicine, Chicago, IL, USA

Natalia Mendoza, MD
Center for Clinical Studies, Houston, TX, USA

Andrei I. Metelitsa, MD, FRCPC, FAAD
Assistant Professor of Dermatology, Division of Dermatology, University of Calgary, Calgary, AB, Canada

Brent D. Michaels, DO
Dermatology Resident, Valley Hospital Medical Center, Las Vegas, NV, USA

Ginat W. Mirowski, DMD, MD
Adjunct Associate Professor, Departments of Oral Pathology; Medicine; Radiology, Indiana University School of Dentistry, Indianapolis, IN, USA

Anjali V. Morales, MD, PhD
Department of Dermatology, Stanford University Medical Center, Redwood City, CA, USA

Warwick L. Morison, MB, BS, MD, FRCP
Professor, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Kiran Motaparthi, MD
Dermatology Resident, Department of Dermatology, Baylor College of Medicine, Houston, TX, USA

Nico Mousdicas, MBCHB, MMED, MD
Director, Contact Dermatitis Center; Clinical Associate Professor, Dermatology, Indiana University, Indianapolis, IN, USA

Christian Murray, MD, FRCPC, FACMS
Assistant Professor, Division of Dermatology, Department of Medicine, University of Toronto, Women’s College Hospital, Toronto, ON, Canada

Cindy E. Owen, MD
Assistant Professor of Medicine; Assistant Program Director, Division of Dermatology, University of Louisville, Louisville, KY, USA

Timothy J. Patton, DO
Assistant Professor of Dermatology, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA

Rhea M. Phillips, MD
Dermatologist, Department of Dermatology, St Francis Memorial Hospital, San Francisco, CA, USA

Sarika M. Ramachandran, BS, MD
Instructor, Department of Dermatology, New York University, New York, NY, USA

Jaggi Rao, MD, FRCPC
Associate Clinical Professor of Medicine, Division of Dermatology and Cutaneous Sciences, University of Alberta, Edmonton, AB, Canada

Jennifer Reddan, PharmD
Manager, Drug Use Policy/Quality, Clarian Health Partners, Indianapolis, IN, USA

Kathleen A. Remlinger, MD
Associate Professor of Dermatology, Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL; Central DuPage Physician Group, Central DuPage Hospital, Winfield, IL, USA

Elisabeth G. Richard, MD
Assistant Professor, Department of Dermatology, Johns Hopkins University, Baltimore, MD, USA

Alyx C. Rosen, BSofE
Clinical Research Fellow, Department of Medicine, Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Theodore Rosen, MD
Professor of Dermatology, Department of Dermatology, Baylor College of Medicine; Chief, Dermatology Service, Michael E. DeBakey VA Medical Center, Houston, TX, USA

Katherine Roy, MD
Dermatology Resident, Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA

Dana L. Sachs, MD
Assistant Professor of Dermatology, Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA

Naveed Sami, MD
Assistant Professor, Department of Dermatology, University of Alabama, Birmingham, AL, USA

Marty E. Sawaya, MD, PhD
Director, InflamaCore, University of Miami Miller School of Medicine, Miami, FL, USA

Courtney R. Schadt, MD
Clinical Instructor, Department of Medicine, Division of Dermatology, University of Louisville, Louisville, KY, USA

Bethanee J. Schlosser, MD, PhD
Assistant Professor; Director, Women’s Skin Health Program, Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Lori E. Shapiro, MD, FRCPC
Assistant Professor of Medicine, University of Toronto, Staff Dermatology and Drug Safety Clinic, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Neil H. Shear, BASc, MD, FRCPC, FACP
Professor and Chief of Dermatology, University of Toronto and Sunnybrook Health Sciences Center; Professor of Medicine, Departments of Pediatrics, Pharmacy and Pharmacology; Director, Drug Safety Research Group and Drug Safety Clinic,Toronto, Canada

Michael Sheehan, MD
Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA

Pranav B. Sheth, MD, FAAD
Director, Dermatology Research Center of Cincinnati, General Dermatology and Psoriasis Practice; Group Health Associates, Trihealth, Cincinnati, OH; Volunteer Associate Professor, Department of Dermatology, University of Cincinnati College of Medicine, OH, USA

Nowell Solish, MD, FRCP
Assistant Professor of Dermatology, Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada

Najwa Somani, MD
Associate Director of Dermatopathology; Assistant Professor of Dermatology; Departments of Dermatology and Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA

Ally-Khan Somani, MD, PhD, FAAD
Assistant Professor; Director of Dermatologic Surgery & Cutaneous Oncology, Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA

Brandie T. Styron, MD
Private Practice, Associates in Dermatology, Westlake, OH, USA

Eunice Y. Tsai, MD
Associate Physician, Department of Dermatology, Kaiser Permanente, Union City, CA, USA

Stephen K. Tyring, MD, PhD, MBA
Clinical Professor of Dermatology, Microbiology/ Molecular Genetics and Internal Medicine, University of Texas Health Science Center, Houston, TX, USA

Susan J. Walker, MD, FAAD
Director, Division of Dermatology and Dental Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD; Visiting Consultant, National Capital Consortium Dermatology Residency Program, Walter Reed National Military Medical Center, Bethesda, MD, USA

Michael R. Warner, MD
Founder and President, Private Practice, The Cosmetic and Skin Surgery Center, Frederick, MD, USA

Christine H. Weinberger, MD
Mohs Micrographic Surgeon; Assistant Professor, Division of Dermatology, Department of Medicine, The University of Vermont, Fletcher Allen Health Care, Burlington, VT, USA

Stephen E. Wolverton, MD
Theodore Arlook Professor of Clinical Dermatology, Department of Dermatology, Indiana University School of Medicine; Chief of Dermatology, Roudebush VA Medical Center, Indianapolis, IN, USA

Henry K. Wong, MD, PhD
Associate Professor of Medicine, Division of Dermatology, Ohio State University, Gahanna, OH, USA

Blair K. Young, DO
Pre-residential Fellowship, Neuro-ophthalmology, Michigan State University, East Lansing, MI, USA

John A. Zic, MD
Associate Professor of Medicine and Dermatology, Division of Dermatology, Vanderbilt University School of Medicine, Nashville, TN, USA

Matthew J. Zirwas, MD
Assistant Professor, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA

Jeffrey P. Zwerner, MD, PhD
Assistant Professor, Medicine, Division of Dermatology, Vanderbilt University, Nashville, TN, USA
Preface
This third edition of Comprehensive Dermatologic Drug Therapy has been both a challenge and a joy to edit. The challenge has been primarily in keeping up with the rapidly changing landscape of dermatologic therapy. The joy has been the continued refinement of an approach to summarizing vast quantities of information on dermatologic drugs in various formats that have been popular with readers. Furthermore, it is a creative challenge to evolve towards a combination of print and electronic media in medical book publishing (more later on this important area).
Counting the original book, Systemic Drugs for Skin Diseases, published in 1991, the contents have grown from 17 chapters to 50 (first edition of the current title), further increasing to 60 chapters in the second edition of the current title, and now containing 70 chapters in this third edition of Comprehensive Dermatologic Drug Therapy . While continuing to focus on editorial improvements to assist the clinician/learner of dermatologic pharmacology, I will briefly relate how the third edition of Comprehensive Dermatologic Drug Therapy addresses three related questions: ‘What is new?’, ‘What is the same?’, and ‘What is electronic?’
Again in this section, I thank a fantastic group of authors for sharing their knowledge and expertise, their clinical experience, and their creativity in producing the 70 chapters in this book: thanks for a job well done! I trust that all of you will enjoy the product of your hard work and expertise.


What is new?
New chapters : The following chapters are either totally new topics or are derived from earlier chapters divided* to expand topic coverage and emphasis:

Chapter 4Adherence to drug therapy
Chapter 7Drugs taken off the market: important lessons learned
Chapter 11Systemic antiparasitic agents*
Chapter 15Mycophenolate mofetil and mycophenolic acid
Chapter 26Interleukin 12/23 inhibitors
Chapter 27Rituximab and future biologic therapies
Chapter 33Systemic anticancer agents: dermatologic indications and adverse events
Chapter 39Topical antiparasitic agents*
Chapter 49Chemical peels
Chapter 50Products for the care of chronic wounds
Chapter 53 Irritants and allergens: when to suspect topical therapeutic agents
Chapter 57Injectable dermal and subcutaneous fillers
Chapter 63Neurologic adverse effects from dermatologic drugs
Biologic agents in dermatologic therapeutics : New chapters 26 and 27 above, along with Appendix I , continue to expand emphasis on this rapidly evolving and exciting ‘new’ area of dermatologic pharmacology.
Chapters related to dermatologic surgery/procedural dermatology : Chapter 49 (Chemical Peels) and Chapter 57 (Injectable Dermal and Subcutaneous Fillers) are added to expand emphasis on the growing procedural aspects of our field. The addition of Chapter 50 on Products for the Care of Chronic Wounds also supplements earlier chapters on Local Anesthetics and Botulinum Toxin for this growing area of dermatology.
New authors : A total of 12 new senior authors have contributed totally new chapters, with six new senior authors updating earlier chapters.
Important questions : Just under 800 questions (up from roughly 500 in the second edition) located at the beginning of each chapter help to guide the reader towards specific text locations for answers to challenging areas of central importance to our field.

What is the same?
Monitoring guidelines boxes : This tradition of the prominent ‘drug safety’ theme throughout the book is continued and updated.
Drug interactions tables : These tables are derived from Facts and Comparisons, Epocrates, The Medical Letter of Drugs and Therapeutics , and Hansten and Horn’s Top 100 Drug Interactions databases, formatted by (1) similar drug interaction types, and (2) keeping drugs grouped and compared by category.
Indications and contraindications boxes : This theme is another tradition that is continued and yet updated and refined.
General philosophy : I continue to strive to assist authors in providing concise, practical, and relevant information in just under 800 pages of text.
Emphasis on rapid retrieval of information : The continued emphasis on using numerous tables and boxes, coupled with formatting with multiple headings and subheadings, are all of value in this priority for the busy clinician.

What is ‘electronic’?
Maximize utilization of the print version of the book:

• Use handheld electronic device or laptop computer to retrieve information immediately for patient care decisions.
• Search individual diseases or drugs listings in the textbook in a traditional database search format.
‘Value added’ electronic features that will be steadily developed over the upcoming months include (but are not limited to) the following …

• Informed consent documentation forms – similar to dapsone form in the print version of the book; in the coming months there will be online availability of at least 10–12 more consent forms on other systemic drugs.
• Questions at the beginning of each chapter will be indexed and searchable by category (mechanism, clinical use, interactions, etc.) for maximum educational value for clinical use or Boards preparation.
• Newly released drugs – concise summaries in PDF format (similar to Appendix I in the book’s print version) will be released on a regular basis.
• Disease treatment option hierarchies – on a gradual basis we will release in downloadable PDF format structured concise lists of treatment options for common and important dermatoses.
• And many, many other drug information tools …
Enjoy the learning process!

Stephen E. Wolverton, MD
Dedication
This book is dedicated to the following individuals:
To my wife Cheryl, for her support and help over the past 22 months of the book development and the editorial process, let alone our 32 years of marriage.
To our sons Jay Edward (age 26) and Justin David (age 24), now wrapping up their college and postgraduate years, for having a wonderfully diverse set of interests and for being a source of continuing joy – and occasional challenge – over the past 2+ decades.
To my parents Elizabeth Ann (1924–2000) and Dr George M. Wolverton Sr. (1925–2011), for the passion, wisdom, compassion and encouragement provided throughout their lives; these traits continue to have a positive influence on my life on a daily basis.
And to my wonderful (and large) nuclear family with three sisters (Anne, Cynthia, and Pam) and five brothers (George [1951–1996], Greg, Jeff, Doug, and Dan), for their kindness to and consideration for others, and their ongoing camaraderie no matter what challenges we have all faced.
Acknowledgements
I would like to sincerely thank and applaud the following individuals for their energetic and kind support of my journey through the book development and editorial process for the third edition of Comprehensive Dermatologic Drug Therapy . I am indebted to all of you for your efforts.

From the UK (with Elsevier ties)
Martin Mellor (project development editor) for the frequent conference calls over much of the past 18 months and for the plethora of e-mails to authors utilizing his diplomatic assertiveness (and ‘gentle’ persistence) to keep chapters moving through first and second draft phases for all 70 chapters.
Sukanthi Sukumar (project manager) for her remarkable attention to detail and tremendous efficiency, from finding duplicate or incomplete references, to insightful questions on content, to formatting the book in a easy to read fashion.
Belinda Kuhn, and her predecessor Rus Gabbedy (acquisitions editors), for the early book development and oversight and for coordinating the multiple departments involved with the book publication.
WB Saunders (the imprint of this book) and Elsevier for the broader role in oversight from the beginning of the book development through marketing the final product.

From the ‘States’ (with Indiana University Department of Dermatology ties)
My colleagues from Indiana University Department of Dermatology – Nico Mousdicas, Gary Dillon, Lawrence Mark and Joanne Trockman – who provided coverage for a significant number of my clinics and consult duties, enabling the 3-day weekends and entire weeks off so critical for the book editing process.
My colleagues (current and past) from Indiana University Department of Dermatology who contributed chapters: Marc Darst, Anita Haggstrom, Swetha Kandula, Melanie Kingsley, Kathy Lee, Ben Lockshin, George Magel, Lawrence Mark, Ginat Mirowski, Nico Mousdicas, Michael Sheehan, Ally-Khan Somani, Najwa Somani and Brandie Tackett Styron.
The team of four second-year medical students (now fourth-year medical students) at the Indiana University School of Medicine who assisted greatly in the information retrieval on a wide variety of controversies and difficult questions throughout the book. This team included Lina Gordy, Brittany Hedrick, Theresa Tassey and Anthony Zabel, who also helped me with a wide variety of early organizational tasks for the book project.

From the ‘States’ and the World (the authors)
The 132 authors for this edition who responded very, very well to the task of updating earlier chapters and creating totally new ones. These authors responded in a superb fashion to the challenges I set them. In particular, I wish to highlight the following individuals:
The authors who contributed to all four versions of the books I have edited (including the original title Systemic Drugs from Skin Diseases , 1991 edition): Brian Berman, Jeff Callen, Charles Camisa, Loree Davis, Marshall Kapp and Carol Kulp-Shorten.
The international cast of 12 authors from Canada and Europe: Robert Bissonnette, Tobias Goerge, Malcolm Greaves, Aditya Gupta, Sandra Knowles, Andrew Lin, Thomas Luger, Christian Murray, Jaggi Rao, Lori Shapiro, Neil Shear and Nowell Solish.
The authors who contributed to two or more chapters: Andrew Lin (three chapters), plus Jeff Callen, Charles Camisa, Seth Forman, Melanie Kingsley, John Koo, Megan Landis, Chai Sue Lee, Ben Lockshin, Andrei Metelitsa, Katherine Roy and Neil Shear who contributed two chapters each.
Finally, thanks to all remaining authors who took time away from their full-time roles as clinicians and educators while providing fresh ideas along with tremendous personal experience and expertise for the remaining chapters of this third edition of Comprehensive Dermatologic Drug Therapy .
A dozen suggestions to help the reader optimally utilize this book

• If you want general concepts and references concerning drug use for a specific dermatologic condition , there are three related solutions in this book. The Indications and Contraindications boxes, the well-formatted, easy to locate pertinent text sections, and the grouping of references by topic will guide your way for information to treat specific patients.
• If you want to retrieve information or learn about the complicated subject of drug interactions , the Drug Interactions tables will assist in both tasks. Over 30 Drug Interactions tables are continued from the previous edition to summarize four distinct respected databases, formatted for efficient information retrieval and to facilitate understanding general concepts of drug interactions.
• If you want to prepare for pharmacology and therapeutics components of the Dermatology Board Examination or Recertification Examination (let alone efficiently gain a general understanding of drugs utilized in dermatology), the significantly expanded important questions at the beginning of each chapter will assist you in all these goals. The answers for each question are easily found in the text, referenced by page number and marked with a distinctive icon.
• If you want to gain a general understanding of how drugs work , all chapters discussing specific drugs have Mechanism of Action sections. These sections focus on the mechanisms for a drug’s therapeutic benefits and potential adverse effects, with many summarized in table format. In addition, more in-depth knowledge concerning drug mechanisms can be derived from carefully footnoted and highlighted Drug Mechanism figures.
• If you want drug pharmacology concepts and product information in a ‘nutshell’, there are tables for drugs discussed in the chapter and Key Pharmacology Concepts for most systemic drugs and many topical therapies as well.
• If you want to maximize systemic drug safety with appropriate monitoring of laboratory tests, related tests or special examinations for a given drug, the Monitoring Guidelines boxes continue to demonstrate an appropriate standard of care for early detection of the various drugs’ most important potential adverse effects.
• If you want to gain a broad understanding of a given drug or drug group’s adverse effects , each chapter has an Adverse Effects section for each major drug discussed. A substantial number of chapters have an Adverse Effects box summarizing, grouping, and prioritizing important potential drug risks; also, seven of the chapters (Chapters 60–66) focus specifically on important potential drug adverse effects.
• If you want a general understanding of drug structures , particularly in comparing different drugs in the same class, there are roughly 100 drug structures throughout the book to assist your visual understanding of these drugs.
• For drugs recently released (or that have recently gained prominence) after the chapter contents were relatively fixed, Appendix I addresses a number of these drugs in a concise fashion.
• If you would like to evaluate a representative written informed consent form (for dapsone) that likewise serves as a patient information form , Appendix II provides such an example: this will be greatly expanded in the electronic version of this book (see Preface ).
• If you would like to read supplemental information on a given drug or drug group , or a related topic in pharmacology, the Bibliography: Important Reviews and Chapters following the text for each chapter lists about 6–8 relatively recent reviews, chapters and books on the various topics under the chapter title.
• Or, if you just want to learn or relearn any topic covered in Comprehensive Dermatologic Drug Therapy in a complete yet efficient fashion, then the well-formatted chapters with a substantial number of tables, boxes, and figures will maximize the learning (or relearning) process. Just be sure to enjoy the process on this very interesting educational journey!

Stephen E. Wolverton, MD

References for drug interaction tables

CliniSphere 2.0 CD-ROM. Facts & Comparisons. St. Louis. 2006.
The Medical Letter Adverse Drug Interactions Program 2005. The Medical Letter of Drugs and Therapeutics. New Rochelle, NY. 2005.
E-pocrates Online Premium Reference. Epocrates. San Mateo, CA. 2006.
Hansten PD, Horn JR. The top 100 drug interactions: a guide to patient management. Freeland, WA: H & H Publications, 2006.
Part I
Introduction
1 Basic principles of pharmacology

Stephen E. Wolverton


 Questions

Q1-1 What are the simplest definitions of ‘pharmacokinetics’, ‘pharmacodynamics’, and ‘pharmacogenetics’? (Pg. 1, Table 1-1 )
Q1-2 What are several drugs or drug families for which the absorption may be altered by (a) food, (b) cations such as iron, calcium, and magnesium, and (c) variations in gastric pH? (Pg. 2)
Q1-3 What are some of the pros and cons to the decision of whether to calculate drug dose on (a) actual body weight, (b) ideal body weight? (Pg. 2)
Q1-4 What are several examples in which sustained exposure to a drug may give reduced positive or negative pharmacologic effects at the drug receptor level? (Pg. 4, Table 1-4 )
Q1-5 What are several of the most important agonists and antagonists at the level of specific receptors? (Pg. 4, Table 1-5 )
Q1-6 What are several of the most important examples in which drugs inhibit specific enzymes? (Pg. 5, Table 1-6 )
Q1-7 What are several important examples of active drug and active metabolite relationships? (Pg. 8, Table 1-9 )
Q1-8 What are several of the most important examples of prodrug and active drug relationships? (Pg. 8, Table 1-8 )
Q1-9 Pertaining to drug excretion, (a) what are three important routes of drug excretion, and (b) what is the overall general change in the active drug properties that makes excretion possible? (Pg. 8)
Q1-10 What are 5 of the most important basic components that determine percutaneous absorption of topical medications? (Pg. 9)
Q1-11 What are the some of the additional cutaneous properties and therapeutic maneuvers that alter the degree of percutaneous absorption in individual patients? (Pg. 10, Table 1-10 )

Introduction
This chapter is a relatively brief overview of basic principles of pharmacology, intended as a primer to maximize understanding of the remaining chapters of the book. There is by design some overlap with other chapters in the book, in order to address relevant issues from a number of vantage points. Of particular relevance to this chapter are the following: Chapter 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy; Chapter 60 Hepatotoxicity of Dermatologic Drug Therapy (contains detailed information on hepatic metabolism of drugs); and Chapter 65 Drug Interactions. The reader is encouraged to pursue further detailed information and references (cited in the respective chapter for specific drugs) for drug examples used to illustrate basic principles of pharmacology in this chapter. In this chapter only a bibliography format for references on pharmacologic general principles is used.
The primary focus of this chapter will be on pharmacologic principles related to systemic drugs. A relatively brief section on percutaneous absorption will conclude the chapter. The basic goal of this chapter (and for the rest of the book) is to describe and illustrate pharmacologic principles that will enable the clinician to maximize the efficacy and minimize the risk (adverse effects, drug interactions) of dermatologic drug therapy. It is my hope that this chapter will provide a broad foundation for true understanding of pharmacology to enable clinicians to achieve:

1. More efficient assimilation of new information on medications,
2. Adaptability to the many unpredictable responses of patients to medications, and
3. Better long-term retention of important information on all aspects of drug therapy.

Outline for the chapter
Q1-1 Traditionally, discussions on basic pharmacology divide the topic into two domains ( Table 1-1 ): pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body). As a relatively novel way of presenting this information, I will discuss topics in sequence as seen through the ‘eyes’ of the drug as it progresses through the human body. In broad strokes, the sequence will be:

1. Pharmacokinetics (part I – absorption, distribution, bioavailability): the drug must enter the body, travel to, and be ‘available’ at the site of desired pharmacologic action;
2. Pharmacodynamics: the drug interacts with a receptor/effector mechanism, producing both desirable and undesirable effects; and
3. Pharmacokinetics (part II – metabolism, excretion): the drug and/or its metabolites must leave the body.
Table 1-1 Three ‘entry level’ definitions Term Definition Pharmacokinetics What the body does to the drug – from entry into the body until excretion of the drug and/or its metabolites Pharmacodynamics What the drug does to the body – once at site of action; from receptor binding through the definitive effect (desired or adverse) Pharmacogenetics Interindividual genetic alterations that produce variations in both pharmacokinetic and pharmacodynamic aspects of drug therapy
Each of the above steps has a number of variables (with both predictable and unpredictable components) for which the clinician should have at least a baseline working knowledge. These variables will be presented and illustrated under each chapter heading that follows.

Pharmacokinetics – part I ( Tables 1-2 and 1-3 )

Drug absorption (The drug has to be absorbed and enter circulation)
The routes of drug administration most pertinent to dermatology, in order of descending frequency of use, are topical, oral, intramuscular, and intralesional. Intravenous drug administration is uncommonly ordered by the dermatologist. Typically, drugs must be relatively lipophilic (non-ionized, non-polar) to ‘enter’ the body by topical or oral routes, whereas relatively hydrophilic (ionized, polar) drugs can still ‘enter’ by intramuscular and intravenous routes. Upon absorption, drugs still must traverse other cell membranes in order to reach the intended destination(s). Again, a drug with lipophilic qualities is rewarded by the ability to traverse these lipid bilayers in order to arrive at the site of desired pharmacologic action.
Table 1-2 Pharmacokinetics – major components * Component Most important issues Absorption Relatively lipophilic drugs are more optimally absorbed through the GI tract; lipophilic or hydrophilic drugs are relatively equal for parenteral absorption Distribution Body compartments to which the drug is dispersed; important subcomponents include fatty tissues and blood–brain barrier Bioavailability Percentage of administered drug reaching circulation; also relates to free (active) versus protein-bound drug Metabolism Lipophilic drugs are converted to more hydrophilic metabolites to enable excretion Excretion The above conversion to hydrophilic metabolites allows renal or biliary excretion; other synonyms – clearance, elimination
* These components as related to oral (enteral) or parenteral administered drugs.
Table 1-3 Definitions and concepts central to understanding pharmacokinetics Term Definition Bioactivation Either (a) conversion of prodrug to any active drug, or (b) conversion of the active drug to a reactive, electrophilic metabolic intermediate Bioequivalence * Generally referring to overall ‘equal’ bioavailability between two comparable drugs; usually between generic and trade name formulations of a drug Biotransformation In general, the metabolic change of a lipophilic drug to a more hydrophilic metabolite allowing renal or biliary excretion Blood–brain barrier Protective mechanism for brain neurons; due to tight junctions (and lack of intercellular pores) in brain capillaries; highly lipophilic drugs may ‘overcome’ this barrier Detoxification The metabolic conversion of a reactive, electrophilic intermediate to a more stable, usually more hydrophilic, compound Enteral Gastrointestinal administration of a drug Enterohepatic recirculation Sequence of initial GI absorption of drug followed by hepatic excretion into bile and small bowel, followed by subsequent GI reabsorption First-pass effect Drugs which have significant metabolism in the liver, prior to widespread systemic distribution – occurs after GI absorption, by way of portal vein to liver Half-life Duration of time for 50% of the absorbed and bioavailable drug to be metabolized and excreted Parenteral Literally ‘around enteral’; either intravenous, intramuscular, or subcutaneous administration Pharmacogenetics The inherited aspects of drug pharmacokinetics and pharmacodynamics which alter the likelihood of various pharmacologic effects (positive or negative) Prodrug A pharmacologically inactive precursor of the biologically active ‘drug’ Steady state A balance between the amount of drug being absorbed and the amount being excreted; in general the time to reach steady state is 4–5 ‘half-lives’ Terminal elimination Elimination/clearance of drug from all body compartments to which the drug is distributed Therapeutic index The ratio of (a) the drug dose required to give a desired pharmacologic response to (b) the drug dose which leads to significant adverse effects Therapeutic range Range of circulating drug levels deemed to give optimal efficacy and minimal adverse effects Tissue reservoirs Body locations to which a given drug is distributed, from which the drug is very slowly released – includes sites such as fatty tissues, stratum corneum
* The US FDA definition for ‘bioequivalence’ requires that the bioavailability of the proposed generic drug must have a 95% confidence interval between 80% and 120% of the trade name drug’s bioavailability.
Several other variables may affect the absorption of drugs by oral administration. Q1-2 Certain drugs are absorbed less efficiently in the presence of food. In descending order the impact of food on tetracycline family drug absorption is as follows: tetracycline > doxycycline > minocycline. Divalent and trivalent cations in milk (calcium), various traditional antacids (aluminum-, magnesium-, calcium-containing), and iron-containing products can reduce the absorption of the above tetracyclines, as well as fluoroquinolone antibiotics. Gastric pH is yet another variable that influences drug absorption. An example would be the necessity for a relatively low gastric pH for ketoconazole and itraconazole to be optimally absorbed, whereas gastric pH is not a critical determinant for fluconazole absorption. The above absorption variables are the basis for a number of drug interactions that do not involve the cytochrome P-450 (CYP) system.
A few other points are worth considering under this heading. Some drugs have negligible absorption with oral administration, yet can have a pharmacologic value in the GI tract. Several examples would be the use of oral cromolyn sodium (Gastrochrome) for the GI manifestations of mastocytosis, as well as the use of nystatin for reduction of bowel Candida levels. A number of medications are available in sustained-release preparations, in which the drug vehicle is modified to allow a steady, slow rate of drug absorption. Finally, the addition of a vasoconstrictor (epinephrine) to local anesthetics will slow absorption of the anesthetic and therefore prolong the duration of anesthesia after intralesional injection of the anesthetic.

Distribution (The drug has to travel to the site of intended action or to a reservoir)
This somewhat mundane component of pharmacokinetics has several applications in dermatologic therapeutics. With oral administration of drugs for dermatologic purposes, there are at least four compartments of great interest to which a drug can be distributed:

1. Circulation: important to widespread drug effects, both desirable and adverse;
2. Cutaneous: logically of central importance to the desired pharmacologic effects;
3. Fatty tissue: at both cutaneous and internal sites; very important to highly lipophilic drugs, creating a ‘reservoir’ for prolonged release of the drug (as with etretinate); and
4. Past the ‘blood–brain barrier’: of importance to dermatology primarily for lipophilic drugs with the potential for sedation or other central nervous system adverse effects (first-generation H 1 antihistamines, sedation; minocycline, dizziness).
Fortunately, there are alternatives to the above drugs which do not readily cross the blood–brain barrier (second-generation H 1 antihistamines; doxycycline, tetracycline).
Q1-3 Many systemic drugs discussed in this book have dosages based on body weight. Included are drugs with doses calculated per kilogram of body weight (isotretinoin, etretinate) and dose calculated per meter squared (bexarotene – Targretin). The question arises as to what to do with dosage calculations for very obese patients. There are both drug cost implications and potential adverse effect implications for very high drug doses. I tend to calculate dosages based more on ‘ideal weight’ for several reasons. Aside from treatment of panniculitis, there are virtually no indications for which the site of desired pharmacologic effect is in fatty tissue. Highly lipid-soluble drugs are readily distributed to fatty tissues, but when a steady state is reached there is steady release back into the circulation. When considering efficacy, risk, and cost, all three point toward maximizing the dosage using calculations based on ideal (or close to ideal) body weight (IBW), perhaps allowing for a small ‘fudge factor’ on the high side for very heavy patients who do not respond to traditional doses. One set of formulas from the life insurance industry for calculating ‘ideal weight’ is as follows: (1) females IBW = 100 lb for 5 ft tall + 5 lb/inch over 5 ft, and (2) males IBW = 106 lb for 5 ft tall + 6 lb/inch over 5 ft, and (3) an upward ‘adjustment’ up to 10% based on a ‘large frame’.
Conceptually, there are three drug ‘reservoirs’ of significant interest to dermatology. The first is in systemic circulation, in the form of drug–protein binding. The bound drug is pharmacologically inactive, whereas the unbound drug = free drug = pharmacologically active drug. Acidic drugs are most commonly bound to albumin, whereas basic drugs bind preferentially to α-1 acidic glycoprotein. There are noteworthy exceptions regarding lipophilic drugs with intracellular physiologic receptor–effector systems such as corticosteroids and retinoids. There is a large circulatory reservoir for highly protein-bound drugs such as methotrexate. Sudden increases in the free drug levels due to displacement of methotrexate from circulatory protein-binding sites by aspirin, non-steroidal anti-inflammatory drugs, and sulfonamides can markedly increase the risk for pancytopenia (although the body can adjust to this drug displacement over time). The second drug reservoir of interest is in various fatty tissues (including, but not limited to, subcutaneous fat) for highly lipophilic drugs, as discussed in the preceding paragraph. The third drug reservoir (the stratum corneum) pertains just to percutaneous absorption for topically applied medications. In all three settings the free drug and the drug in the reservoir are in equilibrium. As the free drug is metabolized and excreted, corresponding amounts of the drug in these tissue and circulatory reservoirs are released into the free/active drug fraction.

Bioavailability (The drug has to be ‘available’ at the site of intended action)
Bioavailability is expressed as the percentage of the total drug dose administered that reaches the circulation. For a drug taken orally, the ‘first-pass effect’ of hepatic metabolism reduces bioavailability. The bioavailability calculations include both free and bound forms of the drug. A systemic drug with a relatively low bioavailability is acyclovir; the prodrug for acyclovir, valacyclovir, has at least three times greater bioavailability. At the other end of the spectrum are the fluoroquinolones, for which oral absorption (and resultant bioavailability) is so complete that the oral and intravenous doses for many members of this drug group are identical. A more optimal method (if it were more practical) would be to calculate bioavailability at the site of intended action; for drugs discussed in this book, it would be based on tissue levels at the site of intended action, the various skin structures. At present such ‘ideal’ bioavailability calculations are not routinely available.
For most chapters in this book that discuss systemic drugs there are tables that present data for the following: (1) % bioavailable and (2) % protein binding. The ‘% bioavailable’ is typically factored into ideal oral drug dosage calculations, which will produce circulating drug levels in a reasonably safe and effective ‘therapeutic range.’ The ‘% protein binding’ is important to the subject of drug interactions as previously discussed, with methotrexate an important example. Changes in albumin levels in disease states such as severe liver or renal disease will often necessitate drug dosage adjustments for drugs (such as methotrexate) that are highly protein bound.
Creating drug formulations with a more optimal bioavailability is a daunting task for the pharmaceutical industry. In the past two decades there have been updated formulations of older drugs with higher bioavailability, more predictable bioavailability, or both. For drugs with a relatively narrow therapeutic index (cyclosporine, methoxsalen), improved predictability of the drug absorption and resultant bioavailability are very important. The release of Neoral (in place of the previous cyclosporine formulation, Sandimmune) is an example for both improved % bioavailability and more predictable bioavailability of the newer formulation. Likewise, Oxsoralen Ultra demonstrates improvement in both of the above parameters. In a separate example, the need for improved efficacy from griseofulvin led to the progression from the original griseofulvin formulations → microsize formulations → ultramicrosize formulations. Each step of this progression resulted in improved bioavailability and smaller griseofulvin dosages required for an adequate therapeutic response.

Pharmacodynamics (the drug produces the desired pharmacologic effect)
The subject of pharmacodynamics is very complicated. In essence, this topic is the ‘basic science’ behind drug mechanisms of action. Considering all the diverse mechanisms of actions discussed in this book (let alone the diversity of drug mechanisms the whole of medicine), it is not possible to summarize general principles behind all of them. In contrast, it is possible to cover a few areas of central importance to understanding pharmacodynamics. These include the concepts of drug receptors, enzyme inhibition by drugs, signal transduction, and transcription factors.

Definitions ( Table 1-4 )
In general, the definitions used in pharmacodynamics tend to be less familiar to most clinicians than the comparable terms in pharmacokinetics. These terms overall tend to relate to factors that:

1. Address aspects of drug binding to receptor (ligand, affinity);
2. Relay the drug ‘signal’ to the definitive effector mechanism (signal transduction, second messenger);
3. Increase the desired pharmacologic response (drug agonists, partial agonists);
4. Reduce an undesirable physiologic or pharmacologic response (drug antagonists or receptor blockers); or
5. Q1-4 Result in a loss of a desirable or undesirable pharmacologic response through repeated use (tolerance, cross-tolerance, refractoriness, downregulation, tachyphylaxis).
Table 1-4 Definitions and concepts central to understanding pharmacodynamics Term Definition Active metabolite A drug metabolite which retains the same/similar pharmacologic properties as the parent drug Affinity (binding) A physical measurement which reflects the attraction of the drug ligand to a given receptor molecule Agonist Drug which binds to a given receptor initiating an effector mechanism → pharmacologic response Antagonist Drug which binds to a receptor, but fails to activate the effector mechanism Cross tolerance (see tolerance) Reduced pharmacologic effect when exposed to a new, chemically-related drug Down regulation Reduced receptors number/availability, presumably due to a negative feedback mechanism Inverse agonist Drug which stabilizes receptors which have some constitutive activity to an inactive conformation Ligand Any molecule (drug) which binds to the drug receptor; binding can be by hydrogen bonds, ionic forces, or covalent forces Partial agonist Drug which binds to a receptor and weakly initiates an effector mechanism and resultant response Receptor The molecule to which the drug (ligand) binds to initiate its effector response; location can be cell membrane, cytosolic, or intranuclear Refractoriness (synonyms – desensitization, tachyphylaxis) Temporary lack of responsiveness to a drug Second messenger Biochemical mediator (commonly calcium or cyclic AMP) that serves to relay the signal initiated by the receptor/effector in signal transduction Signal transduction Cellular biochemical pathways which relays a second messenger ‘signal’ from the receptor to the effector mechanism Tachyphylaxis A diminished pharmacologic response after repeated drug administration; can be due to down regulation or receptor sequestration (transiently ‘unavailable’ to the drug) Tolerance Diminished effect (generally adverse effect) after repeated drug administration (most common is tolerance to sedating drugs such as antihistamines)
Only a proportion of these concepts can be realistically addressed in the remainder of this section on pharmacodynamics.

Drug receptors
The broadest definition of a drug receptor is given in Table 1-4 . In this definition, any molecule to which a drug binds, thus initiating an effector mechanism leading to a specific pharmacologic response, is a drug receptor. In contrast, proteins involved in drug ‘protein binding’ are merely drug storage (reservoir) or transportation sites, and thus, are not receptors.
The drug receptor subtypes that are easiest to characterize are cell surface receptors for endogenous neurohormonal ligands. Similar receptors are operant for various growth factors and other cytokines. Q1-5 Such ‘drug’ receptors are common targets in current therapeutic strategies and in drug development. In addition, lipophilic drugs easily absorbed through cellular membranes may have cytosolic drug receptors. Common examples using these cytosolic physiologic receptors include both systemic and topical versions of corticosteroids and retinoids. The ‘catch’ regarding receptors for these two drug categories is that both desirable (therapeutic effects) and undesirable (adverse effects) effects are mediated through the same physiologic receptor. A ‘dissociation’ of the drug receptors for the therapeutic anti-inflammatory benefits of methotrexate (such as methionine synthetase) and adverse effects (dihydrofolate reductase, DHFR) is of interest. Folic acid (folate) supplementation can competitively antagonize the DHFR inhibition of methotrexate and minimize the adverse effects of methotrexate without compromising therapeutic benefits. A few examples of drugs that are either antagonists or agonists at well-defined cellular receptors are given in Table 1-5 .
Table 1-5 Pharmacodynamics – selected receptor antagonists and agonists Drug Receptor affected Biologic outcome Receptor antagonists (receptor ‘blockers’) H 1 antihistamines H 1 antihistamine receptor Antagonize histamine effects via receptor – vasodilation, increased vascular permeability, etc. H 2 antihistamines H 2 antihistamine receptor Antagonize histamine effects via receptor – decreased gastric acid secretion, suppressor T-cell effects Spironolactone, flutamide Androgen receptor * Antagonize testosterone and dihydrotesterone effects via receptor – variable hair effects depending on scalp or face location; also reduced sebum secretion Selective serotonin reuptake inhibitors Serotonin transport protein Antagonize serotonin reuptake mechanism (net effect increased persistence of serotonin as neurotransmitter) Hormonal receptor agonists Corticosteroids Corticosteroid receptor Augment both the desirable pharmacologic effects and the adverse effects mediated through same receptor Calcipotriene Vitamin D 3 receptor Augment vitamin D 3 effects via receptor – include keratinocyte and fibroblast differentiation Retinoids Retinoic acid receptor (RAR) Retinoid X receptor (RXR) Augment various vitamin A mediated effects via gene response elements
* Primary pharmacologic (diuretic) effects of spironolactone are mediated through the mineralocorticoid receptor; anti-androgen effects are mediated via the androgen receptor for dihydrotestosterone and testosterone.
Few drugs are ideally specific for a given drug receptor molecule. The ability of both tricyclic antidepressants (such as doxepin) and first-generation H 1 antihistamines (such as diphenhydramine, hydroxyzine) to also bind muscarinic anticholinergic receptors can produce objectionable anticholinergic adverse effects such as dry mouth, blurred vision, and orthostatic hypotension. Relatively selective drug receptor binding was achieved in later ‘generations’ of related drug groups. Selective serotonin reuptake inhibitors (such as fluoxetine, sertraline) and second-generation H 1 antihistamines (such as fexofenadine, loratadine) have had a significant improvement in the adverse effect profile due to much more selective drug receptor binding. It is of interest to note that ‘tolerance’ to the sedative adverse effects can occur with prolonged use of the first-generation H 1 antihistamines.

Enzyme systems inhibited by drugs
Q1-6 For comparison purposes, a number of specific examples for drugs that selectively inhibit an enzyme system are listed in Table 1-6 . Drugs that inhibit enzyme systems of importance to nucleotide synthesis have significant potential for use in neoplastic diseases or as immunosuppressants in autoimmune dermatoses. A number of drugs representing antimicrobial agents for bacterial, viral, and fungal infections capitalize on vital enzyme systems, which are more readily inhibited in the infectious organism than in the human host. Finally, a number of drugs inhibit enzyme systems that contribute important downstream mediators to an inflammatory response. For all three categories of enzyme listed in this table, the drug receptor may be the enzyme itself (methotrexate and DHFR) or may work indirectly through another receptor/effector mechanism (as with corticosteroid inhibition of phospholipase A 2 , probably mediated through lipomodulin-1).
Table 1-6 Pharmacodynamics – selected examples of enzymes that specific drugs inhibit Drug Enzyme inhibited Biologic outcome Enzymes important to DNA synthesis Methotrexate Dihydrofolate reductase Reduced formation of fully reduced folate precursors for purine and thymidylate synthesis Mycophenolate mofetil Inosine monophosphate dehydrogenase Inhibition of de novo pathway for purine (guanosine) nucleotide synthesis – preferentially affects various WBC subsets (other cells can utilize salvage pathway) Enzymes important to microbial growth and survival Sulfonamides, dapsone Dihydropteroate synthetase Affects bacterial version of this enzyme far more readily than the mammalian enzyme; first step of two enzyme pathway essential for folate reduction Trimethoprim, methotrexate Dihydrofolate reductase Affects bacterial version of this enzyme far more readily than the mammalian enzyme; second step of two enzyme pathway essential for folate reduction Itraconazole, fluconazole Lanosterol 14-α demethylase Triazole inhibition of this enzyme inhibits formation of ergosterol, an essential component of fungal cell wall Terbinafine, naftifine Squalene epoxidase Allylamine inhibition of this enzyme decreases ergosterol, and increases squalene accumulation Acyclovir, valacyclovir, famciclovir DNA polymerase Triphosphorylated forms of these drugs * preferentially inhibit viral DNA polymerase >> human version of enzyme Other enzymes of importance to inflammatory response Retinoids Ornithine decarboxylase This is rate-limiting enzyme in polyamine pathway, which is initiated by protein kinase C (PKC) activation Dapsone Myeloperoxidase This enzyme in neutrophils and macrophages is essential to microbial killing by these cells (also in eosinophils) Cyclosporine, tacrolimus Calcineurin This calcium-dependent signal transduction enzyme is key to increased IL-2 production dependent on NFAT-1 † Corticosteroids Phospholipase A 2 Inhibition probably mediated through lipomodulin-1; net effect is reduced prostaglandins, leukotrienes, and other eicosanoids which are important to inflammatory responses
* See Table 1-8 regarding prodrug and active relationship of these drugs.
† NFAT-1 (nuclear factor activated T-cells) is a transcription factor essential to increased T-cell production of IL-2 and upregulation of IL-2 receptors.

Signal transduction and transcription factors
These two aspects of pharmacodynamics have a number of conceptual similarities, albeit with very distinctive mechanisms of action. Signal transduction is a series of intermediary steps in relaying a drug-initiated signal or message to the definitive effector mechanism. Tremendous details on the various receptor/signal transduction categories (6 main families) are beyond the scope of this chapter but are available in the Bibliography. This definitive effector mechanism is commonly accomplished through DNA transcription and subsequent new protein translation. In many cases the signal transduction ‘passes through’ a DNA transcription factor. This sequence and the resultant overlap of topics is best illustrated by the so-called ‘signal one’ in activated T-cells upon T-cell receptor binding to antigen, which is amplified by subsequent IL-2 binding to the IL-2 receptor. The rough sequence of steps is as follows: (1) T-cell receptor binding to antigen, (2) CD3 molecule-based T-cell activation, and (3) calcineurin-based production of NFAT-1, a DNA transcription factor important to IL-2 upregulation. Cyclosporine and tacrolimus both interfere with this signal transduction pathway through inhibition of calcineurin activity, with a resultant decrease in activity of the transcription factor NFAT-1.
Second messengers are also important to this discussion. Probably the two most important second messengers pertinent to pharmacology are calcium and cyclic AMP (cAMP). Calcium is an important component of the above T-cell signal transduction system in two locations; calcineurin is a calcium-dependent enzyme, with a calcium-binding protein (calmodulin) playing an important role as well. Although not directly related to dermatology, the role of cAMP as a second messenger in the beneficial effects of β-agonists in therapy of asthma is of interest. The concept of tachyphylaxis as defined in Table 1-4 has been well characterized for β-agonists used in this setting.
Two more examples of important drugs and their effects on signal transduction (retinoids) and transcription factors (corticosteroids) can be presented. The polyamine pathway creates a process known as inflammatory hyperplasia, which is an important component of the pathogenesis of both psoriasis and various malignancies. Retinoids inhibit the activity of ornithine decarboxylase, the rate-limiting enzyme in the polyamine pathway. This signal transduction enzyme inhibition is important to the benefits of systemic retinoids in both psoriasis therapy and retinoid chemoprevention of cutaneous malignancies in transplantation patients.
Corticosteroids inhibit the actions of the transcription factor, nuclear factor κB (NFκB) by two mechanisms. Corticosteroids both increase production of the inhibitor of NFκB (known as IκB) and directly bind to and inactivate NFκB. This transcription factor is pivotal in the upregulation of a multitude of cytokines of central importance in the inflammatory response to a wide variety of stimuli. There is tremendous amplification potential of the inflammatory response through this NFκB pathway. Likewise, a major portion of the anti-inflammatory benefits of corticosteroids (topical or systemic) are probably accomplished through the inhibition of this important transcription factor. It is unclear whether the relatively common occurrence of tachyphylaxis noted with class I topical corticosteroids relates to downregulation of receptors involved in this particular pathway.

Pharmacokinetics – part II

Metabolism (The drug becomes more hydrophilic to favor renal and biliary excretion)
This topic is extensively discussed in Chapter 60 on Hepatotoxicity of Dermatologic Drug Therapy. A relatively brief synopsis will be presented here. Most drugs are metabolized by phase I (oxidation reactions) and phase II (conjugation and detoxification reactions). The initial oxidation reactions in phase I are accomplished by various CYP isoforms, which are largely present in the liver (but also available in many other organ sites, including the skin). The result of these enzymes is a somewhat more hydrophilic (water-soluble) metabolite, which may provide a site of attachment for subsequent conjugation reactions. To complicate matters, reactive electrophilic intermediates are often created, which in the absence of adequate phase II detoxification systems may induce important metabolic or immunologic complications ( Table 1-7 ). Phase II conjugation reactions (glucuronidation, sulfonation, acetylation) and the various detoxification systems (such as glutathione and epoxide hydrolase) will generally accomplish the production of both significantly increased hydrophilicity of the drug metabolites and stabilization of the aforementioned reactive intermediates, respectively. Q1-7 It is important to note here that many drug metabolites retain the parent drug’s pharmacologic activity ( Table 1-8 ). An example of this principle would be the itraconazole metabolite hydroxyitraconazole, which also has significant antifungal activity. In the great majority of drugs metabolism renders the drug inactive.
Table 1-7 Definitions related to adverse effects Term Definition Adverse effect Negative or undesirable effect from a drug (either at toxic or pharmacologic drug doses) Idiosyncratic Unexpected adverse effect from a drug Immunologic idiosyncrasy Unexpected adverse effect from a drug occurring on an immunologic basis (usually due to hypersensitivity) * Metabolic idiosyncrasy Unexpected adverse effect from a drug occurring due to a metabolic byproduct (reactive intermediate) Pharmacologic effect Positive or negative effect from a drug, expected at normal doses and/or drug levels Side effect Synonym for adverse effect (prefer to use ‘adverse effect’ to address undesirable quality of drug effect) Toxicity/toxic effect Undesirable effects expected from a drug due to excessive doses and/or drug levels
* Confusing reality is that immunologic hypersensitivity may occur due to excessive quantities of a reactive metabolite, rendering immunogenic a previously normal endogenous protein (see Chapter 60 – Hepatotoxicity).
Table 1-8 Some examples of prodrugs important to dermatology Prodrug Active drug Antiviral agents Valacyclovir Acyclovir Famciclovir Penciclovir Corticosteroids Prednisone Prednisolone Cortisone Hydrocortisone (cortisol) Other immunosuppressants Azathioprine 6-mercaptopurine → 6-thioguanine Mycophenolate mofetil Mycophenolic acid Cyclophosphamide Phosphoramide mustard Antihistamines Terfenadine Fexofenadine
The topic of pharmacogenetics largely addresses genetically based variations in the above metabolic enzyme systems. At times these genetic alterations can explain idiosyncratic adverse effects of medications. Examples pertinent to the above phase I and phase II metabolic systems include the following genetic polymorphisms:

1. CYP2D6 polymorphisms with at least 50-fold variation in activity of this important isoform: One result is unexpected profound sedation from various antidepressants (including doxepin) and other sedating medications in ‘poor metabolizers.’
2. ‘Slow acetylators’: One result of this polymorphism is more frequent occurrence of drug-induced lupus erythematosus.
3. Glutathione depletion (which in part may be acquired due to malnutrition or HIV infections): This results in markedly increased risk of hypersensitivity to sulfonamide medications in these populations.
The key research agenda for this important topic is the development of predictive tests to anticipate which patients are at increased risk for important adverse effects from drugs. These tests would be analogous to the baseline G6PD determinations for dapsone patients and baseline thiopurine methyltransferase determinations for azathioprine patients, which in both cases enables better prediction of patients at risk for important adverse effects. Genetic predictive testing for polymorphisms of CYP2D6, 2C9, and 2C19 are currently commercially available.
The most important numerical parameter under the heading of drug metabolism is the drug ‘half-life.’ The discussion of the multiple subtypes of drug half-life, such as terminal elimination half-life, is beyond the scope of this chapter. A given drug’s half-life is important in determining the time to reach a steady state once drug therapy is initiated (4–5 half-lives) and the time for virtually complete drug clearance after drug therapy is discontinued (likewise 4–5 half-lives).
Q1-8 One flaw of the linear model presented here for discussing pharmacodynamics between the two sections on pharmacokinetics relates to prodrugs ( Table 1-9 ). These prodrugs are pharmacologically inactive until ‘metabolic’ conversion to the active drug, typically through hydrolysis of an ester or amine linkage. The conversion of prednisone (prodrug) to prednisolone (active form) is dependent on a hepatic-based enzyme, which in end-stage liver disease may not produce therapeutically adequate quantities of the active drug form prednisolone. Once the prodrug is metabolized to the active drug, the principles of interest follow through the distribution, bioavailability, and pharmacodynamics sections as with other drugs already in active form once absorbed.
Table 1-9 Some examples of active drug, active metabolite relationships Active drug Active metabolite(s) Antihistamines Hydroxyzine Cetirizine → levo-cetirizine Loratadine Desloratadine Antidepressants Doxepin Nordoxepin Citalopram Escitalopram Antifungal Itraconazole Hydroxyitraconazole

Excretion (The hydrophilic drug metabolites must leave the body)
Q1-9 Conceptually there are three common routes by which systemically administered medications leave the body. These are (1) renal excretion, (2) biliary excretion of a more hydrophilic metabolite through the GI tract, and (3) orally administered medications may in part be excreted through the GI tract after failing to be absorbed. The excreted drug can be the parent drug, drug metabolites, or combinations of both. Relatively hydrophilic drugs can be excreted unchanged through the kidney. An example would be fluconazole, which because of its relatively hydrophilic properties has a significant portion of the administered drug excreted through the kidney unchanged. Relatively lipophilic drugs typically must be rendered more hydrophilic by the aforementioned phase I and II metabolic steps, before excretion is possible through renal or biliary routes. In particular, greater hydrophilicity favors renal excretion, which has a much larger overall capacity for drug excretion than the hepatobiliary route.
In reality, the drugs discussed in this book are frequently excreted by several of the above routes, both as free drug and as a variety of metabolites. Refer to the various ‘Pharmacology Key Concepts’ tables used for systemic drugs in this book for illustrations of this point. The reader should also be aware that many drugs conjugated in the liver, and excreted into bile, will subsequently undergo hydrolysis in the small intestine and be reabsorbed (enterohepatic recirculation) through many cycles; eventually the definitive excretion may be through the kidney.
It is very important to recognize that disease-induced or age-dependent reduction in renal function should prompt the clinician to significantly reduce dosages of drugs with significant renal clearance. An example would be the increased risk for pancytopenia and other complications with methotrexate when standard doses are administered to patients with either disease- or age-related reduction in renal function. Likewise, drugs that have significant liver metabolism and excretion should have dosage reductions with advanced liver disease.

Percutaneous absorption

General principles
There is a wealth of scientific and practical information in Tables 1-10 and 1–11 . Q1-10 Probably the 5 most important determinants of percutaneous absorption of topical dermatologic products are:

1. Stratum corneum thickness and integrity of ‘barrier function’;
2. Drug partition coefficient – the ability of the drug to ‘depart from’ the specific vehicle and enter the stratum corneum;
3. Drug diffusion coefficient – the ability of the drug (due to innate molecular properties) to penetrate through all layers of skin once in the stratum corneum;
4. Drug concentration – the specific drug concentration of a given topical product; and,
5. Superficial dermal vascular plexus – site of systemic absorption for topically applied drugs.
Table 1-10 Percutaneous absorption variables Variable Biologic result Drug variables Concentration PCA is directly related to concentration, and not volume of topical medication applied to a specific skin site Lipophilicity Most topically effective drugs are at least somewhat lipophilic Molecular size Most effective topical medications have a molecular weight < 600 (tacrolimus greater topical absorption than cyclosporine due to lower molecular weight) Vehicle variables (see Table 1-11 ) Lipid content Ointment is strongest vehicle due to most optimal partition coefficient in transferring drug to stratum corneum lipids (solution typically weakest vehicle) Irritancy Irritating vehicles will alter skin barrier function and may ↑ PCA Innate skin variables Stratum corneum thickness Rate-limiting site for PCA; thickness of stratum corneum is inversely related to PCA Cutaneous vasculature Increased cutaneous vasculature can increase both local and systemic drug effects Area of absorptive surface Increased surface area to which drug is applied will ↑ PCA total overall, but not ↑ PCA at a specific site (concentration most important variable at a specific site) Mucosal surfaces Far less innate barrier function, generally less well developed stratum corneum; consider that any mucosal route of administration can produce systemic effects Diseased skin variables Inflamed skin Overall ↑ PCA, due both to altered barrier function and increased vasodilation Ulceration Topical application responds as if systemic administration of medication (bacitracin anaphylaxis risk after application to a leg ulcer) Other variables Additional skin hydration Hydrating skin (by various means) prior to application of topical medication will ↑ PCA Occlusion of medication Topical occlusion locally (food wrap) or widespread (‘sauna suit’) with marked ↑ PCA; conceptually transdermal application of ‘systemic medications’ utilizes somewhat similar process Age of patient Increased total body surface area to body volume ratio in infants and young children; therefore, increased risk of systemic effects from topical therapy due to relatively high absorptive surface
PCA = percutaneous absorption.

Table 1-11 Clinical comparisons of various vehicles – generalities
Q1-11 Measures that increase percutaneous absorption can always be considered a ‘two-edged sword.’ The desired pharmacologic result is enhanced by these measures. For instance, use of a high-potency topical corticosteroid in an ointment base, after skin hydration, and with total body occlusion, will do wonders for extensive psoriasis. The counterpoint is that all of these measures will markedly increase systemic absorption of the topical corticosteroid, potentially giving a net prednisone-like effect from the topical corticosteroid. For a short period of time there will be relatively few trade-offs. After 2–3 weeks or more, important systemic adverse effects such as weight gain, fluid retention, hypertension, hypokalemia, and cushingoid changes are all possible with this undesirable long-term approach to topical corticosteroid administration. It is important to note here that all topical drug absorption occurs via passive diffusion.
Topical medications applied in several clinical settings can produce immediate hypersensitivity (Coombs–Gell type I) reactions. In particular, topical application to ulcerated skin can give the applied medication almost immediate access to systemic circulation. There have been reports of anaphylaxis to topical bacitracin or neomycin in this setting. Likewise, mucosal applications of medications (such as eyedrops, vaginal suppositories, and rectal foam or suppositories) can result in significant systemic levels of various drugs and freedom from ‘first-pass effect’ due to the small intestine and liver. Although the risk from topical application of medications to these above sites is usually small, the clinician should always be mindful of this systemic absorption potential.

Vehicles
Much of the art and science of dermatology revolves around choosing the appropriate vehicle for topical medications ( Table 1-11 ). In general, the choice of vehicle is just as important as choosing the proper active ingredient. Two common consequences of certain vehicles are the following:

1. Irritancy: most notably from high concentrations of propylene glycol; other ‘alcohols’ or certain acidic vehicle ingredients also may be irritants, particularly when applied to diseased skin with altered barrier function.
2. Contact allergy/sensitization: common with preservatives in various water-based (creams, lotions, solutions) topical products, and include various parabens along with ‘formalin releasers’ (such as quaternium-15, imidazolidinyl urea, and diazolidinyl urea).
The astute clinician will be mindful of the potential adverse effects of the vehicle, particularly if the patient fails to improve or worsens with topical therapy. The simplest and safest way to minimize the risk of these vehicle-induced adverse effects is to choose topical products that lack the most common potential irritants and allergens. See Chapter 40 on Topical Corticosteroids and Chapter 53 Irritants and Allergens: When to Suspect Topical Therapeutic Agents for additional information on this topic.

Tachyphylaxis
In my experience tachyphylaxis is a relatively common clinical event with very high-potency (class I) topical corticosteroids. (See Chapter 4 Adherence with Drug Therapy for some ‘counterpoints’ on this controversial topic.) The measures previously discussed, which can produce excessive systemic absorption, also predispose to diminished therapeutic benefit from the topical drug over time. The clinician should be aware that continued daily or twice-daily application of a class I topical corticosteroid to minimally inflamed skin (without any other maneuvers to increase percutaneous absorption) commonly leads to tachyphylaxis after 2–4 weeks of continuous therapy. The good news is that this is an easily reversible process, particularly if the clinician is mindful of the potential for tachyphylaxis. Weekend-only or alternate-day applications of these high-potency topical products typically prevents tachyphylaxis; a week or so off therapy altogether allows upregulation of the corticosteroid receptor molecules and a resultant return of the desired therapeutic benefit upon resumption of the topical corticosteroid.

Transdermal medication formulations
One final routine of topical administration of medications that is tangentially related to dermatology deserves mention here. The potential for certain drugs to have reduced bioavailability through excessive hepatic and small intestine first-pass metabolism can be circumvented by transdermal administration. An excellent example would be transdermal estrogen administration, which allows the drug to be absorbed directly into systemic circulation. This avoids the significant first-pass metabolism typical of orally administered estrogens, with resultant improved drug bioavailability. There are numerous other medications that can be administered in various transdermal delivery systems for steady, continuous percutaneous delivery of the active ingredient.
Given the central importance of understanding percutaneous absorption, the interested reader is encouraged to pursue further information on this subject from the chapters listed in the Bibliography. Hopefully through the principles, clinical examples, and tables presented on this subject, all readers can achieve an adequate basic understanding of the most important concepts of percutaneous absorption and the importance of the drug vehicle to the optimal clinical response. Each chapter in the three major book sections on topical medications ( Chapters 36 – 55 ) will expand on and illustrate these principles of percutaneous absorption.

Bibliography: important reviews and chapters

Systemic drugs
Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Chabner BA, Knollman BC. Goodman and Gilman’s the pharmacologic basis of therapeutics . 12th ed. New York: McGraw Hill; 2011:17–39.
Blumenthal DK, Garrison JC. Pharmacodynamics: molecular mechanisms of drug action. In: Brunton LL, Chabner BA, Knollman BC. Goodman and Gilman’s the pharmacologic basis of therapeutics . 12th ed. New York: McGraw Hill; 2011:41–72.
Gonzales FJ, Coughtrie M, Tukey RH. Drug metabolism. In: Brunton LL, Chabner BA, Knollman BC. Goodman and Gilman’s the pharmacologic basis of therapeutics . 12th ed. New York: McGraw Hill; 2011:123–143.
Relling MV, Giacomina KM. Pharmacogenetics. In: Brunton LL, Chabner BA, Knollman BC. Goodman and Gilman’s the pharmacologic basis of therapeutics . 12th ed. New York: McGraw Hill; 2011:145–168.

Percutaneous absorption
Burkhart C, Morell D, Goldsmith L. Dermatogic pharmacology. In: Brunton LL, Chabner BA, Knollman BC. Goodman and Gilman’s the pharmacologic basis of therapeutics . 12th ed. New York: McGraw Hill; 2011:1803–1832.
2 Principles for maximizing the safety of dermatologic drug therapy

Stephen E. Wolverton


 Questions

Q2-1 What four words characterize the overall approach to maximizing drug safety, and what general concepts are represented by these words? (Pg. 12)
Q2-2 How are the ‘standards of care’ for drug therapy determined? (Pg. 13)
Q2-3 What are several of the typical characteristics of the most worrisome adverse effects to systemic drug therapy (Pg. 13)
Q2-4 In general, what are the most important issues to discuss with a patient prior to initiating systemic drug therapy which has a significant element of risk? (Pg. 14)
Q2-5 What are three broad categories for mechanisms for drug interactions, which can assist clinicians in anticipating important potential drug interactions? (Pg. 15)
Q2-6 What are three to four examples of major drug risks ‘discovered’ many years after the drug’s release? (Pg. 15)
Q2-7 When considering a ‘teamwork’ approach to maximize drug safety, name at least five different ‘individuals’ with a key role in this drug safety process for a given patient. (Pg. 17)
Q2-8 What are the most important common clinical scenarios which require more frequent (compared to normal monitoring frequencies) laboratory monitoring? (Pg. 18)
Q2-9 What are some important examples of ‘thresholds of concern’ and ‘critical values’ for laboratory tests commonly utilized in drug monitoring? (Pg. 18)
Q2-10 What are several important options available for a specific abnormal lab value? (Pg. 18)
Q2-11 In the event a potentially serious complication of drug therapy does occur, what are some of the most important management options available to clinicians? (Pg. 19)

Introduction
This chapter is unique in the context of the entire book. The principles that follow are a blend of science, literature reports, personal experience, and common sense. Rather than provide references for the principles and examples used in this chapter, the reader is encouraged to selectively pursue more detailed information and literature references pertaining to examples cited here in the various chapters devoted to the respective drug or drug category. Most of the examples provided deal with systemic drug therapy in dermatology, given that the systemic drugs commonly prescribed pose a significantly greater potential risk to the patient than topical or intralesional therapeutic options.
Q2-1 Four words summarize the proactive approach to maximizing the safety of dermatologic drug therapy discussed in this chapter: anticipation, prevention, diagnosis, and management . The primary goals of maximizing drug safety are:

1. Anticipation of which patients (comorbidities and other drugs the patient receives) and which drug regimens are at risk for various important adverse effects;
2. Prevention of adverse effects of potential concern by taking appropriate safety measures;
3. Diagnosis at an early, reversible stage should an adverse effect occur; and
4. Management of the adverse effect in a safe and effective manner.
I will present a number of general principles regarding how to maximize the safety and efficacy of systemic drug therapy. Each principle will be illustrated with several pertinent drug examples.
Unlike many medical specialties, dermatologists in general must take greater precautions with systemic drug therapy, for the following reasons. Systemic drugs used in this field have typically been developed for specialties such as rheumatology, oncology, infectious diseases, and transplantation surgery. These specialties in general care for patients with more serious, possibly life-threatening, illnesses than the majority of conditions for which dermatologists prescribe the various systemic drugs. Clinicians in any field are obliged to avoid creating a greater risk with drug therapy than the innate risk (in that specific patient) of the underlying disease to be treated. This statement is the underlying principle behind the need for careful monitoring of systemic drug therapy in dermatology. It is essential to maximize the safety and minimize the risk of this drug therapy.
How to optimally anticipate , prevent , diagnose , and manage specific drug adverse effects in order to maximize drug safety is a central theme of this chapter and of the book as a whole. This is a broader viewpoint than merely ‘monitoring’ for adverse effects. The goals of this broader approach are to (1) maximize overall drug safety for the patient, (2) improve the ‘comfort’ of systemic drug therapy for the patient and physician, and (3) follow the appropriate ‘standards of care’ in order to minimize medicolegal risk. These overlapping goals are interdependent. For example, when appropriate standards of care are followed, the patient safety is the focus of these standards. In addition, when the patient’s safety and emotional comfort during drug therapy are truly of central importance to the physician, the medicolegal risk is negligible. This is particularly true if the patient assumes an active role in all aspects of any systemic drug therapy regimen, in turn forming a ‘therapeutic partnership’ with the prescribing physician.
It is somewhat challenging to define the definitive sources of these so-called ‘standards of care.’ Q2-2 In general, such standards come from one or more of the following sources:

1. Specialty-based formal guidelines such as the American Academy of Dermatology ‘Guidelines of Care’;
2. Individual pharmaceutical company guidelines for specific drugs, such as the therapeutic guidelines and informed consent packet for isotretinoin (iPLEDGE) in women of childbearing potential;
3. FDA Advisory Committee recommendations, such as those guidelines proposed in the early 1980s for monitoring the hematologic complications of dapsone;
4. Consensus conference publications, such as the consensus guidelines published in 2004 for isotretinoin therapy in acne patients; and
5. ‘Dear Health Care Professional’ letters (formerly ‘Dear Doctor’ letters) from pharmaceutical companies, with careful oversight by the FDA, updating physicians and other healthcare providers nationally regarding recent findings on specific adverse effects.
The reality is that the standards of care for a given drug are often a blend of several of these sources, with a certain amount of ambiguity as would be expected from such a mix.
Historically, these standards of care were based on local practices in the ‘community’ in which the physician practiced. Currently the realities of the ‘information age’ in which we practice tend to create a trend towards national, if not global, standards of care. Such standards should be considered guidelines, and not mandates, with room for flexibility as the patient’s individual circumstances and scientific ‘evidence’ justify.
As far as possible, special efforts must always be made to ensure that the most serious adverse effects ‘never’ occur. Q2-3 Characteristics of the most serious adverse effects given the highest priority in this chapter, and throughout the book, include at least several of the following: (1) a sudden, precipitous onset, (2) no early warning symptoms, (3) no predictive laboratory tests, (4) potentially irreversible, and (5) a potentially serious outcome. Examples of such high-priority adverse effects include (1) hematologic complications (pancytopenia from azathioprine or methotrexate, agranulocytosis from dapsone), (2) isotretinoin teratogenesis, (3) corticosteroid osteonecrosis, and (4) opportunistic infections from TNF (tumor necrosis factor) inhibitors. Principles to minimize the likelihood of these and other complications follow in the four major sections of this chapter.
First, a few ‘baseline concepts.’ No matter how careful a physician may be, sooner or later ‘bad things’ will happen to a patient from drug therapy that he or she initiates. No medical risk reduction system is perfect, given the unpredictabilities of the human body. If the patient and physician can form a strong therapeutic partnership, and if the physician continues to work with the patient to promptly diagnose and manage any drug-induced complications, there can be a number of positive results: (1) the patient’s medical outcome is optimized, (2) the physician’s ethical obligations are met, and (3) the medicolegal risk is minimized. Nevertheless, the physician must take a ‘lifelong learner’ approach to any such unexpected complications, carefully analyzing the events leading to the specific drug complication, and learning how to minimize the likelihood of a similar therapeutic outcome in the future.
On the following pages of this chapter, 33 ‘principles’, with over 80 specific drug therapy examples, are used to illustrate principles for maximizing the safety of dermatologic drug therapy.

Anticipation
This section is broken down into five subsections: (1) patient selection, (2) patient education, (3) baseline laboratory and related tests, (4) concomitant drug therapy – drug interactions, and (5) evolving guidelines – risk factors.

Patient selection

Principle #1
Carefully compare the ‘risk’ of the disease to be treated with the ‘risk’ of the drug regimen planned (in that particular patient); thus a ‘risk – risk’ assessment.

• The risk of high-dose systemic corticosteroids in severe pemphigus vulgaris versus the risk from the same corticosteroid regimen in patients with either pemphigus foliaceus or localized epidermolysis bullosa acquisita.
• The risk of 6–12 months of cyclosporine for a patient with limited plaque-type psoriasis versus the risk of the same regimen in a patient with debilitating and extensive pyoderma gangrenosum.

Principle #2
Choose patients who can comprehend and comply with important instructions for preventing and monitoring the most serious potential complications of systemic drug therapy. Examples in which this principle is most important include the following:

• The importance of avoiding abrupt cessation of long-term, high-dose prednisone therapy – risk of HPA axis complications such as an addisonian crisis.
• The pregnancy prevention measures which are of central importance in isotretinoin therapy for women of childbearing potential.
• The importance of avoiding significant amounts of alcohol with long-term methotrexate therapy for severe psoriasis or in women of childbearing potential on long-term acitretin therapy for psoriasis.

Principle #3
All patients are not ‘created equal’ regarding the risk for various adverse effects. Examples of patients at significantly increased risk for the following adverse effects (beyond the specifics of the drug regimen) include:

• Methotrexate hepatotoxicity: obesity, alcohol abuse, diabetes mellitus, renal insufficiency.
• Corticosteroid osteoporosis: postmenopausal women, especially those who are thin and inactive.
• Corticosteroid osteonecrosis: recent significant local trauma, alcohol abuse, cigarette smoking, and presence of underlying hypercoagulable conditions.
• TNF inhibitor use in patients with a personal or family history of multiple sclerosis.
The bottom line is that individual patients must be carefully ‘matched’ with the safest and most effective drug regimen for the unique presentation of their dermatosis. This ‘match’ hinges on the various risk factors and demographic variables with which a specific patient presents. Perhaps the best example is the lesson provided by the specialty of rheumatology regarding the apparent lesser risk of methotrexate in rheumatoid arthritis (RA) patients compared to the historical risk of the same methotrexate therapy in psoriasis patients. This risk reduction was accomplished by (1) more careful patient selection of patients by rheumatologists, and (2) by the much lower risk of ‘metabolic syndrome’ in RA patients than in psoriasis patients.

Patient education
The multiple variables regarding a given course of systemic drug therapy are often very difficult for physicians to master. Thus, it should come as no surprise that the specific drug regimens and risks of these various therapies discussed are much more difficult for patients (who typically lack medical training) to understand. Q2-4 The patient needs to understand at least the following information: (1) how to take the medication, specifically the correct dose and timing, (2) the expected adverse effects, (3) what symptoms to report, and (4) the specific monitoring using laboratory and related diagnostic tests. Particularly when significant risks to important organs or body systems are discussed, the understandable emotional reaction of most patients makes long-term retention very difficult. The above points and other concepts form the basis of the following principles.

Principle #4
Careful and reasonably thorough patient education is essential to truly ‘informed consent’ (see Chapter 68 ).

• Patients need to be active participants in therapeutic decision-making, which requires physicians to present the information in an understandable fashion.
• In addition, the patient must be provided the opportunity to ask questions and be given adequate time to consider the therapeutic options presented.

Principle #5
Use patient handouts, written at a very understandable level, to reinforce important information and instructions concerning the drug therapy chosen.

• The physician must emphasize the key information contained in the handout, but handouts are never a substitute for appropriate physician–patient communication.
• The patient should be instructed to notify the physician if there are any questions pertinent to the handout provided.
• The patient should be instructed to report any significant new symptoms that may develop subsequently (even if they are not sure these symptoms are due to the specific drug).
• Sources for these handouts include National Psoriasis Foundation (major systemic therapies for psoriasis, including biologics), various pharmaceutical companies (acitretin/Soriatane), and the American Medical Association (corticosteroids and many others). Consider creating your own personalized patient education handouts regarding specific drugs you commonly prescribe.

Principle #6
Educate your patients regarding groups or clusters of symptoms, which together are important for the detection of potentially serious drug-induced complications. The grouping of these symptoms may not be emphasized in the above-mentioned handouts.

• Corticosteroid osteonecrosis: focal, significant joint pain (especially hip, knee, shoulder) with decreased range of motion of the affected joint.
• Isotretinoin pseudotumor cerebri: headache, visual change, nausea and vomiting.
• TNF inhibitor opportunistic infections: fever plus localizing symptoms such as a cough.
• Dapsone hypersensitivity syndrome: fever, fatigue, sore throat, adenopathy, and morbilliform rash.
A ‘two-way street’ of open communication between patient and physician is essential in maximizing the safety of systemic drug therapy. Any extra time the physician spends in this communication process should pay great dividends with regard to improved therapeutic outcomes.

Baseline laboratory and related tests
Any organ system with potential for drug-induced complications requires a baseline evaluation before initiating therapy. There are very few exceptions to this principle. It stands to reason that existing pathology in an organ system, for which a given drug has the potential to induce abnormalities, will increase the likelihood of further injury to this organ system.

Principle #7
Assess the baseline status of any potential target organ or site of excretion for a given drug. Similarly, if a drug can induce a metabolic abnormality, check for baseline presence of this metabolic defect if such testing is currently available.

• Baseline liver function tests and hepatitis viral serology: methotrexate hepatotoxicity (methotrexate ‘target’ organ).
• Baseline renal function assessment; at least testing serum creatinine, and possibly creatinine clearance: methotrexate hepatotoxicity or pancytopenia (site of methotrexate excretion).
• Baseline eye examination for presence of cataracts: PUVA therapy (PUVA ‘target’ organ).
• Baseline testing for hyperglycemia or hyperlipidemia: prednisone therapy (metabolic abnormalities aggravated by prednisone).

Principle #8
Use the most optimal tests that predict which patients are at increased risk for a specific adverse effect. Typically such tests are ordered only at baseline. (Ideally many more of these predictive tests will be available in the future.)

• Baseline G6PD level: predicts magnitude of risk for dapsone hemolysis. (This test does not predict which patients are at risk for dapsone agranulocytosis or dapsone hypersensitivity syndrome.)
• Baseline thiopurine methyltransferase level: predicts risk for azathioprine hematologic complications as well as guiding optimal drug dosing. (This test does not predict azathioprine hepatotoxicity or hypersensitivity syndrome reactions.)
There are a few select tests for which a baseline determination is not required. Near the end of long-term high-dose prednisone therapy, an AM cortisol determination (usually ~ 8AM) may be of value in assessing HPA (hypothalamopituitary axis) function; a baseline determination is virtually never indicated. Some tests may require a delayed baseline determination. I request a ‘delayed baseline’ ultrasound-guided liver biopsy for methotrexate patients after 6–12 months of therapy, once it is clear that the patient tolerates the drug, benefits from the drug, and requires long-term methotrexate therapy. Still, overall the general rule holds: if you plan on monitoring a specific test during therapy with a given systemic drug, it is prudent to determine the baseline status of that specific test.

Concomitant drug therapy – drug interactions
Chapter 65 is devoted entirely to the subject of drug interactions of importance to the dermatologist and other physicians using similar medications. However, a few principles must still be addressed in this setting. The vast majority of drug interactions can be anticipated, and thus prevented. Truly life-threatening drug interactions are quite uncommon and virtually always have been well publicized. Q2-5 The following are principles dealing with three categories of drug interactions of central importance to maximizing the safety of systemic drug therapy.

Principle #9
Anticipate (and avoid) drug combinations that have overlapping target organs of potential toxicity.

• Tetracycline or minocycline plus isotretinoin: pseudotumor cerebri.
• Hydroxychloroquine plus chloroquine: antimalarial retinopathy. (It is acceptable practice to combine quinacrine with either of these two drugs, as quinacrine alone does not induce a retinopathy.)
• Methotrexate and a second-generation retinoid (previously etretinate, now acitretin): probably an increased risk for hepatotoxicity.

Principle #10
Anticipate interactions involving two drugs that alter the same metabolic pathway.

• Methotrexate and trimethoprim/sulfamethoxazole: increased risk for pancytopenia, given that these drugs inhibit folate metabolism.
• Azathioprine and allopurinol: increased risk for hematologic complications, as these drugs affect parallel purine metabolic pathways.

Principle #11
Anticipate (and avoid) drug combinations metabolized by the same cytochrome P-450 (CYP) pathway, particularly if there is a narrow therapeutic index for one of the drugs involved.

• Rifampin (CYP3A4 enzyme inducer) plus hormonal contraceptives: loss of efficacy of the contraceptive with the potential for an unintended pregnancy.
• Ketoconazole or erythromycin (CYP3A4 enzyme inhibitors) plus cyclosporine: increased risk for renal toxicity due to increased cyclosporine blood levels.
This area of medicine is very complicated and it is very difficult to stay ‘current’ (see Chapter 65 ). At times recently released drugs have important, potentially life-threatening interactions which are discovered only years later. The potential for torsades de pointes with life-threatening cardiac arrhythmias from terfenadine, astemizole, or cisapride (elucidated several years after the drugs’ release) in the presence of certain CYP enzyme inhibitors illustrates this point. Do your best to stay current: liberally use the numerous electronic resources for information on drug interactions. Frequent use of your hospital’s drug information pharmacists is highly recommended in order to more effectively deal with this challenging area of medicine.

Evolving guidelines – risk factors
Typically, with the passage of time the magnitude of risk for various systemic drugs becomes clarified. The level of concern can go in one of two directions: over time there is either increased concern or decreased concern about various risks subsequent upon the publication of new data. Furthermore, specific new risk factors can be elucidated as new scientific information is reported.

Principle #12
Q2-6 Certain risks or risk factors for systemic therapies may be discovered many years after a specific drug is released. It is imperative to ‘stay tuned’ regarding standards of care, as discussed in the Introduction.

• PUVA therapy: an increased risk for squamous cell carcinoma of the male genitalia (specific risk factor – male gender, without clothing protection for the groin region during PUVA treatments).
• PUVA-induced melanoma: probably an increased risk in patients receiving more than 250–350 treatments over a lifetime (specific risk factor – very large number of PUVA treatments).
• Minocycline hypersensitivity syndrome or minocycline-induced lupus erythematosus: the magnitude of risk for these complications was not clarified until over a decade after the drug’s release.
• Ketoconazole hepatotoxicity: magnitude of risk overall and potential for fatal outcomes were not clarified until several years after the drug’s release.

Principle #13
In contrast, the perceived magnitude of risk for a particular adverse effect may decrease over time as new scientific evidence accumulates.

• Antimalarial retinopathy: markedly lower risk than originally perceived, largely due to more careful antimalarial dosing schemes, and perhaps also to greater use of hydroxychloroquine rather than chloroquine.
• PUVA cataracts: primarily a risk in patients who fail to comply with current regimens regarding UVA-protective wraparound sunglasses.
• Prednisone bursts and osteonecrosis risk: although this issue is still cloudy in the legal system, the scientific evidence ‘rules against’ there being a true risk of this bone complication with short courses (‘bursts’) of systemic corticosteroids.

Principle #14
In many clinical scenarios, physicians must make decisions about measures to prevent important potential drug risks before all necessary information is published concerning whether there truly is an increased risk of a specific complication.

• TNF inhibitors (etanercept, adalimumab, infliximab) and TB risk: at least ordering a baseline PPD (and selectively ordering a chest X-ray in higher-risk patients) prior to initiating therapy.
• TNF inhibitors (etanercept, adalimumab, infliximab) and risk of demyelinating diseases: at least check personal and family history closely for multiple sclerosis and related demyelinating disorders prior to initiating therapy.
As challenging as it may be, physicians are obliged to stay ‘current’ with the latest published information on the magnitude of risk from the drugs we use. Truly important ‘new risks’ tend to be widely and repeatedly disseminated to physicians, with the so-called ‘Dear Health Care Professional’ letters from the FDA being a common vehicle for the dissemination of such information.

Prevention
This section of the chapter will be divided into three subsections as follows: (1) patient measures to reduce risks, (2) therapeutic interventions to minimize drug risk, and (3) timing of risk and medication errors.

Patient measures to reduce risks

Principle #15
Patients should take all reasonable protective measures to prevent important adverse effects.

• Prevention of squamous cell carcinoma of male genitalia due to PUVA therapy: wearing a ‘jockstrap’ or underwear during a PUVA treatment.
• Prevention of cataracts in PUVA therapy: wearing opaque goggles during the PUVA treatment and wearing wraparound UVA-protective sunglasses when exposed to outdoor light, at least until sundown the day of the PUVA treatment.

Therapeutic interventions to minimize drug risk
There are many occasions in which the patient would benefit from a specific systemic drug, yet there are worrisome risk factors for a given adverse effect. If the drug regimen is essential for the patient, concomitant medical therapy to reduce the negative impact of the adverse effect is logical and appropriate in most cases.

Principle #16
Use all reasonable adjunctive therapeutic measures to minimize the risk of various adverse effects.

• Daily folic acid therapy in patients receiving methotrexate: prevention of GI adverse effects and minimization of pancytopenia risk. (Ideally, folic acid should be used in all methotrexate patients.)
• Calcium, vitamin D, and possibly estrogens, bisphosphonates, PTH analogs or nasal calcitonin: use in patients receiving long-term systemic corticosteroid therapy at or above physiologic doses. (Use a greater number of these preventative therapies in higher-risk patients.)

Timing of risk and medication errors
The prevention of many adverse effects requires either heightened awareness with more frequent monitoring (drugs with a specific timing of greatest risk) or careful patient education (for potentially serious medication errors). In either setting a proactive physician style is preferred to maximize safety.

Principle #17
For the most potentially serious adverse effects of systemic drugs, learn the timing of greatest risk for the drug-induced complication while monitoring the patient most carefully during this period.

• Dapsone agranulocytosis or dapsone hypersensitivity syndrome: both are primarily an issue between weeks 3 and 12 of therapy. (Minocycline hypersensitivity syndrome: timing of greatest risk is roughly in the same interval, particularly in the first 2 months of therapy.)
• Methotrexate or azathioprine pancytopenia: the risk is greatest primarily in the first 4–6 weeks of therapy, unless a drug interaction is a precipitating factor later in the course of therapy.
• Prednisone osteonecrosis: the risk begins to increase substantially by months 2–3 of pharmacologic dose corticosteroid therapy. (This risk tends to parallel the overall development of cushingoid changes in the patient.)

Principle #18
Medication errors are largely preventable with careful patient education and, if necessary, cross-checks on potentially unreliable patients. These medication errors can be due to either dose omissions or dose duplications.

• Methotrexate weekly dosing scheme: the literature has many reports of pancytopenia due to inadvertent daily dosing of methotrexate. If necessary, another caregiver or family member should place the drug in the slot for just one specific day each week in a weekly pill container, particularly for older patients.
• Hormonal contraceptives and isotretinoin or thalidomide: pregnancy prevention is critical in women of childbearing potential. Omission of oral contraceptives for even a day can be hazardous in patients prescribed these potent teratogens.

Diagnosis
This section is divided into five subsections as follows: (1) evolving guidelines for monitoring, (2) a teamwork approach for maximizing the safety of drug therapy, (3) use of the most optimal diagnostic tests, (4) higher-risk scenarios, and (5) efficient and thorough record keeping.

Evolving guidelines for monitoring
As discussed under the section ‘Anticipation’, newer scientific evidence commonly leads to new or revised guidelines for standards of care. As before, the level of concern can increase or decrease over time with the release of this new scientific information.

Principle #19
Stay current with changing guidelines for diagnosing important complications of systemic drug therapy at an early, reversible stage.

• Methotrexate chest X-rays for pneumonitis: pneumonitis from methotrexate is a significant risk in rheumatoid arthritis patients. In contrast, the negligible risk for this complication in psoriasis patients led to elimination of a previous yearly requirement for chest X-rays in more recent methotrexate guidelines.
• TNF inhibitors (etanercept, adalimumab, infliximab) and tuberculin skin test or interferon-γ releasing assays (IGRA): the recent overall resurgence in incidence of tuberculosis and the TNF-α role in stabilizing granulomatous responses leads to this guideline for screening patients for TB prior to initiating therapy.

A teamwork approach for maximizing the safety of drug therapy
Despite recent trends in managed care to fragment care and limit access to various medical specialties in the name of cost savings, a teamwork approach for risk reduction is imperative. Q2-7 A ‘team’ consisting of the prescribing physician, the patient, and, in many cases, the patient’s primary physician or another specialist, is of central importance. In addition, pharmacists and members of the physician’s office staff have key roles in this ‘team.’ Each member of the team has an important role in maximizing the safety of systemic drug therapy.

Principle #20
In addition to the importance of patient awareness to report symptoms suggesting the early phases of selected complications, the patient often has a role in home monitoring for selected complications.

• Cyclosporine or corticosteroids and hypertension: with a growing number of patients using home blood pressure cuffs or electronic blood pressure monitoring devices, this is a relatively easy area of home surveillance for adverse effects. The patient merely needs to be told what levels of blood pressure elevation should be reported to the prescribing physician and/or primary physician.
• Corticosteroids and home glucose monitoring: even though the history of diabetes mellitus should lead to careful scrutiny regarding the necessity of systemic corticosteroids, there are many circumstances in which prednisone therapy is essential in diabetic patients. Home glucose monitoring provides for relatively easy surveillance and follow-up.
• Corticosteroids and weight gain: the simple bathroom scale can provide useful information on the progression of cushingoid changes or for signs of increasing fluid overload in patients with previously well-compensated congestive heart failure.

Principle #21
The prescribing physician’s examination is essential for detection or verification of important early signs of various drug complications.

• Full skin examination for PUVA or patients on systemic immunosuppressive therapy: detection of melanoma, squamous cell carcinoma, and basal cell carcinoma (and precursors thereof).
• Neurologic examination (screening style) for dapsone motor neuropathy or thalidomide sensory neuropathy: screening done by the prescribing physician, possibly verified by a consultant.
• Morbilliform eruption and related hypersensitivity syndrome findings due to dapsone, minocycline, or azathioprine: reported by the patient but verified by the prescribing physician.

Principle #22
Co-management with another consultant is commonly an essential part of this ‘teamwork’ approach to maximizing the safety of systemic drug therapy.

• Interventional radiologist: for ultrasound-guided liver biopsies with long-term methotrexate therapy.
• Ophthalmologist: integral part of monitoring guidelines for PUVA and antimalarial therapy.
• Primary physician: for management decisions regarding elevated blood glucose or blood pressure with corticosteroid therapy or for management of hyperlipidemia in patients on long-term systemic retinoid or cyclosporine therapy.

Use of the most optimal diagnostic tests

Principle #23
Stay current regarding the most optimal diagnostic tests that have improved sensitivity and precision for early diagnosis of important adverse effects at a reversible stage.

• Corticosteroid osteonecrosis diagnosis: magnetic resonance imaging is far superior to conventional X-rays for early diagnosis, and can allow timely performance of core decompression to salvage the affected bone or joint.
• Corticosteroid osteoporosis diagnosis: dual-energy X-ray absorptiometry (Dexascan) has much greater sensitivity than conventional X-rays for early recognition of bone density loss.
• Methotrexate hepatotoxicity diagnosis: ultrasound-guided liver biopsies give much greater technical precision to avoid trauma to large vessels and bile ducts, thus providing greater safety for liver biopsies.

Principle #24
Realize that many diagnostic tests provide complementary information for the clinician.

• Transaminase values and liver histology for methotrexate hepatotoxicity: one method of testing (transaminases) assesses hepatocellular toxicity, whereas the other method (liver biopsy/histology) assesses the potential for slow progression from fatty liver changes to focal fibrosis to cirrhosis; both tests in combination are essential for proper hepatic monitoring.
• Ordering both transaminases (SGOT/AST and SGPT/AST) for detection of dapsone, azathioprine, and methotrexate hepatotoxicity: improved sensitivity and specificity when ordering both tests; subsequently, tests for hepatobiliary obstruction (bilirubin, alkaline phosphatase, GGT) can be useful adjuncts if significant transaminase elevation has already occurred.

Higher-risk scenarios
As discussed earlier, patients are not all created equal when it comes to risk factors for adverse effects from systemic drug therapy. The more a physician knows about relatively high-risk clinical scenarios (with corresponding increased surveillance for adverse effects in these settings), the more that physician can maximize the safety of the drug therapy in that particular patient.

Principle #25
Q2-8 Laboratory monitoring and related diagnostic tests should be performed more frequently with (1) higher-risk patients, (2) abnormal test results, and (3) at high-risk periods – typically early in therapy.

Principle #26
Q2-9 Become familiar with thresholds of concern (levels at which to consider dose reduction and/or more frequent monitoring) and ‘critical values’ (levels at which therapy should be stopped, possibly indefinitely) for various laboratory tests and related monitoring procedures. (First value listed below is the ‘threshold of concern,’ the second on right is the ‘critical value.’)
• WBC count <3500 <2500–3000 • Hemoglobin 10–11 <10 • Platelet count <100 000 <50 000 • Triglycerides <400–500 >700–800 • Creatinine 30% increase >40–50% (increase from the baseline value) • AST/ALT 1.5–2.0 times >2.5–3.0 times increase (increase above the upper normal value) • Dexascan T-score – 1.0 to −2.5 T-score < −2.5
Q2-10 It is of tremendous importance for the reader to realize that the above test result ranges are merely rough guidelines for clinicians to use. The rapidity of change and the overall trend of the laboratory values are of at least equal importance to recognize. Regardless of the actual laboratory test abnormality or the rapidity of change, the clinician should be mindful of four possible options (depending on the clinical circumstances in an individual patient):

1. Discontinue the drug therapy temporarily or indefinitely;
2. Reduce the drug dose;
3. Increase the frequency of test monitoring; and
4. Treat the adverse effect while carefully continuing the therapy.
These are not mutually exclusive options: generally, several of the above steps are instituted simultaneously. Again, the key is to know which circumstances constitute a high-risk clinical scenario, and subsequently to proceed therapeutically with greater caution in these clinical settings.

Efficient and thorough record keeping
It is quite difficult to stay ‘current’ regarding scientific advancements related to dermatologic therapeutics. It is at least an equal challenge to keep track of the following aspects of medical record keeping for the five general steps of maximizing safety presented in this chapter. The issues here include (to name a few):

1. Documenting informed consent discussions;
2. The changing frequency of laboratory tests any given patient should have, depending on the stage of therapy and the dose of the drug;
3. Keeping track of which patients did not get laboratory tests done when scheduled;
4. Notifying patients about laboratory test results, particularly abnormal results, and the resultant algorithm regarding how to respond to these abnormal results; and
5. How to efficiently document steps ‘2’ through ‘4’ above.
What is a busy practitioner to do?
Fortunately, the electronic/information era in which we practice has provided some solutions. I previously kept written test result flow sheets on patients I followed in the 1980s, but through the 1990s and into the 21st century most laboratories are capable of printing computer-generated flow sheets of test results. Similarly, most electronic medical records (EMR) can provide a summary of test results over time. If a clinician can readily find the last 2–3 sets of test results, most decision-making proceeds without much difficulty.
There should be a cross-check system regarding missed appointments and missed laboratory tests for patients on systemic drug therapy. In general, it is helpful to have a patient call about test results (in a specified time frame) if not previously notified about test results by mail or a phone call from the physician’s office. A less time-consuming step is a policy that only abnormal test results require notification to the patient. The reality is that even with normal test results, the physician (or physician’s staff) must commonly contact the patient regarding drug dose changes, and hence the need to document and to communicate this decision.
A few principles need to be listed, some of which overlap with other chapters (such as Chapter 68 , ‘Informed Consent and Risk Management’).

Principle #27
An important medicolegal dictum states that ‘if it was not written, it was not done.’ An individual physician needs to find a balance of thoroughness and efficiency. Personally, I believe that dictated chart notes more readily allow this optimal balance – I believe voice recognition software is the most efficient manner of documenting important informed consent discussions.

Principle #28
When possible, with relatively high-risk medications, create backup systems in case the patient, the physician, the office staff, or the laboratory personnel have (hopefully rare) oversights.

Principle #29
Use any electronic means available to keep track of important information needed to maximize the safety of systemic drug therapy.

Management
This section of the chapter will be divided into two subsections as follows:

1. What to do if problems arise – relatively minor complications; and
2. What to do if problems arise – potentially serious complications.

What to do if problems arise – relatively minor complications
The vast majority of complications from systemic drug therapy are relatively minor and are fixable. Provided that communication channels are kept open, the physician remains non-defensive and a solutions-based approach to these complications is used, keeping the patient’s best interests in mind, serious medical complications and adverse medicolegal outcomes are relatively unlikely. This relatively brief section will address a general approach to managing adverse effects if the ‘anticipation’ and ‘prevention’ steps are not fully successful. Parenthetically, these same principles also apply to any complication of topical or intralesional therapy.

Principle #30
When in doubt, have the patient stop the drug in question if a potentially serious adverse effect has occurred. The physician generally has at least a few days (subsequent to discontinuation of the drug) to consider the management options, and to communicate with the necessary consultants. Important factors in this decision-making process include:

• The severity of the underlying disease being treated.
• The magnitude of risk from the adverse effect the patient experienced, particularly if the complication can worsen precipitously with continued use of the responsible drug.
• Whether the drug in question is uniquely effective for the disease being treated.
• Whether there is a significant risk due to abrupt discontinuation of the responsible drug – most notably the risk of abrupt cessation of high-dose long-term systemic corticosteroid therapy and the potential for an addisonian crisis.

Principle #31
With less serious medical complications in the setting of a systemic drug essential for the patient, specific medical therapy directed at this complication is quite acceptable.

• Retinoid or corticosteroid hyperlipidemia: concomitant treatment with ‘statins’ or gemfibrozil.
• Corticosteroid or cyclosporine hypertension: any of a wide variety of medical options for blood pressure control. One should be mindful that the therapeutic choice for cyclosporine-induced hypertension needs to preserve optimal renal blood flow as well.

What to do if problems arise – potentially serious complications

Principle #32
Q2-11 More serious complications generally have a specific remedy, although frequently these management steps come at significant cost or present a lifelong risk to the patient.

• Corticosteroid osteonecrosis: core decompression (if diagnosed relatively early) or joint replacement surgery (if there is more advanced osteonecrosis).
• Methotrexate pancytopenia: if recognized early, ‘Leucovorin rescue’ will be quite effective, as is routine for high-dose methotrexate therapy in oncology settings.
• Methotrexate, ketoconazole, dapsone liver failure: worst-case scenario is that the patient may require a liver transplant.
• Corticosteroid or PUVA cataracts: this outcome is far less catastrophic than even a decade or two ago, given the availability of safe and reliable lens implants after cataract extraction.

Principle #33
A few complications cannot be ‘fixed’ and should be avoided at all costs.

• Retinoid or thalidomide teratogenesis: absolute and complete pregnancy prevention is essential.
• Antimalarial retinopathy: although therapeutic and monitoring approaches used in the current era minimize the likelihood of this complication.

Parting thoughts
The bottom line is as follows: it would be an ideal goal that physicians reading this chapter, and who used the principles presented, never had a patient suffer a major complication from systemic drug therapy in their respective careers. In reality, this is not likely. The mindset that is more realistic goes as follows:

1. The physician should thoroughly learn the measures necessary to anticipate the most important risk factors and strive to prevent important complications of systemic drug therapy.
2. When important adverse effects rarely occur, which is inevitable despite meticulously following all principles discussed in this chapter, the clinician should move quickly to diagnose the condition at an early and reversible stage.
3. Once diagnosed, management of these complications of therapy should proceed in an efficient manner, using appropriate consultants when necessary; the patient’s best overall wellbeing is always first and foremost a guide to medical decision making.
4. The more potentially serious and less reversible the complication, the greater the efforts should be sure that this complication never occurs (retinoid or thalidomide teratogenesis as examples).
5. With a proactive mindset for the prevention of and monitoring for adverse effects, and forming a true therapeutic partnership with the patient, the medicolegal risks of systemic drug therapy becomes quite negligible.
6. Should an important drug complication occur (virtually inevitable in any physician’s career) the most successful and professional approach has three parts:
(a) ‘Stand by’ and work with the patient’s management, regardless of the circumstances.
(b) For future patients’ benefit, learn everything possible from the undesirable therapeutic outcome.
(c) Focus on the numerous patients who have benefited from (and will continue to benefit from) the same drug or therapeutic approach throughout your career.
The gratification that patients and physicians alike receive from successful outcomes of carefully planned and appropriately monitored systemic drug therapy is immense. Please use the principles discussed in this chapter carefully and effectively, reinforced by additional strategies detailed in specific chapters throughout this book, and look forward to the numerous safe and successful therapeutic results for your patients.

Bibliography: important reviews and chapters

Wolverton SE. Systemic drugs for psoriasis. The most critical issues. Arch Dermatol . 1991;127:565–568.
Wolverton SE. Monitoring for adverse effects from systemic drugs used in dermatology. (CME Article). J Am Acad Dermatol . 1992;26:661–679.
Wolverton SE. Major adverse effects from systemic drugs: defining the risks. Curr Probl Dermatol . 1995;7:1–4.
3 Polymorphisms
why individual drug responses vary

Cynthia M.C. DeKlotz, Stephen E. Wolverton, Benjamin N. Lockshin


 Questions

Q3-1 How are ‘polymorphism’ and ‘variability’ defined in the most basic sense? ( Pg. 21 )
Q3-2 Regarding the CYP isoforms discussed in this chapter, (a) which 5 isoforms are most important to drug interactions, and (b) which of these 5 isoforms have polymorphisms? ( Pg. 22 )
Q3-3 Which 3 CYP isoforms are most important for drug metabolism based on the percentage of drugs metabolized by the respective isoform? ( Pg. 22, Table 3-2 )
Q3-4 What are the terms regarding the rate of drug metabolism (and their respective abbreviations) for the 4 major groups in various populations, given that a polymorphism is present? ( Pg. 22 )
Q3-5 Regarding the CYP2C9 isoform, what are (a) the frequency of polymorphisms in various populations, and (b) the key alleles affecting drug metabolism (and the clinical result)? ( Pg. 23 , Table 3-4 , Table 3-5 )
Q3-6 Regarding the CYP2C19 isoform, what are (a) the frequency of polymorphisms in various populations, and (b) the key alleles affecting drug metabolism (and the clinical result)? ( Pg. 23 , Table 3-6 , Table 3-7 )
Q3-7 Regarding the CYP2D6 isoform, what are (a) the frequency of polymorphisms in various populations, and (b) the key alleles affecting drug metabolism (and the clinical result)? ( Pg. 24 , Table 3-8 )
Q3-8 Regarding thiopurine methyltransferase, what are (a) the frequency of polymorphisms in various populations, and (b) the net clinical effect of the polymorphisms? ( Pg. 26 , Table 3-10 )
Q3-9 Regarding N -acetyl transferase (NAT 2 ), what are (a) the frequency of polymorphisms in various populations, and (b) the net clinical effect of the polymorphisms? ( Pg. 28 , Table 3-11 )
Q3-10 Regarding glucose-6-phosphate dehydrogenase (G6PD), what are (a) the frequency of polymorphisms in various populations, and (b) the net clinical effect of the polymorphisms? ( Pg. 29 Table 3-12 , Table 3-13 )

Introduction
This chapter focuses on the intrinsic and extrinsic factors that affect systemic medications. Adverse drug reactions (ADR) often are associated with drug toxicity, but ADR can also account for decreased drug efficacy. An understanding of drug interactions and drug metabolism is imperative for selecting the appropriate medications.
ADR occur frequently and result in a substantial cost burden on the healthcare system. In a prospective study of over 18 000 patient admissions by Pirmohamed and associates, 1 ADR were responsible for 6.5% of all admissions. Furthermore, it has been speculated (in a very controversial study) that 100 000 deaths each year in the United States are due to ADR. 2
Given that the primary focus of this chapter is on polymorphisms, it is important to provide a clear-cut definition of the terms variability and polymorphism. Q3-1 The definitions can relate to receptor affinity/avidity and a variety of other biologic properties, although for the purposes of this chapter the definitions will be applied to activity for phase I and phase II enzymes important for drug metabolism. Conceptually, ‘variability’ is defined by a single ‘bell-shaped curve,’ whereas ‘polymorphism’ is defined by two or more distinct ‘bell-shaped curves.’ Genetically this correlates with specific mutations of a single allele (SNP, single nucleotide polymorphism). A ‘polymorphism’ is a variation that occurs in more than 1% of the studied population. 3

Evaluating the patient
Initial patient evaluation should include a detailed history with focus on the patient’s demographics, comorbidities, current medications, and allergies. Renal function declines with age, accounting for decreased clearance of many medications. In addition to evaluating renal function, any presence of liver dysfunction or disease must be determined prior to administration of most medications. Ethnicity can occasionally help predict genetic variability in enzyme levels responsible for drug metabolism. A complete list of the patient’s prescription medications along with all vitamins, herbals, and over-the-counter (OTC) medications is imperative. When seeking information on a given patient’s drug allergies, inquire if there are any medications that the patient cannot take, and what specifically happens when the medication is taken. This will help distinguish between potential life-threatening ADR and drug intolerances.

Factors that influence medication effects (including adverse effects)
There can be considerable variability in virtually every point along a medication’s course from absorption to excretion. It is important to be aware of many factors that can ultimately affect the patient’s medication tolerability and treatment outcomes.

Absorption

Gastrointestinal tract
Extrinsic and intrinsic factors can result in altered absorption in the gastrointestinal (GI) tract. Antacids alter the stomach’s pH, which can influence medication absorption. Ketoconazole is a classic example of a medication which is better absorbed in an acidic milieu ( Table 3-1 ). 4 Other medications can act as binding resins in the GI tract, and thus inhibit absorption. There is evidence that iron will bind mycophenolate mofetil, thereby inhibiting its absorption ( Table 3-1 ). 5 GI transit times are thought to play only a small role in drug absorption variability. 4 Anticholinergic agents can slow down transit times, whereas some medical conditions such as Crohn’s disease and ulcerative colitis can markedly increase transit times.
Table 3-1 Absorption of important dermatologic drugs 4, 5 Drug Absorption location Take home point Ketoconazole GI tract Improved absorption in an acidic environment Mycophenolate mofetil GI tract Do not give with iron: binds with iron, which inhibits absorption Cyclosporine PGP Affects bioavailability

P-glycoprotein
P-glycoprotein (PGP), a membrane-bound transport protein, affects drug absorption in the GI tract. Functioning as part of the ‘first-pass effect’ in the gut, PGP acts as a pump to remove drugs from the cell by active ATP hydrolysis. 6 Cyclosporine is just one example of a medication in which PGP can affect drug bioavailability ( Table 3-1 ). 4 High levels of PGP are also found in the kidneys and liver, where it functions in drug elimination.

Phase I and Phase II drug metabolism
Drug metabolism is a process that facilitates drug clearance by (1) increasing solubility, or (2) being responsible for converting prodrugs to their active drug form (along with the formation of potentially toxic metabolites). 4 Classically, drug metabolism is divided into two general components, designated phase I and phase II reactions. Despite what the nomenclature suggests, there is no order in which these reactions take place. Phase I reactions involve intramolecular modifications: oxidation, reduction, and hydrolysis. Phase II reactions result in conjugation of the drug with an endogenous substance by acetylation, glucuronidation, sulfation (also called sulfonation), and methylation. Most commonly, the phase I oxidative reactions create a site for subsequent attachment of larger polar side chains in phase II reactions. Both phase I and II reactions function to make the drug more water soluble, thereby facilitating renal or hepatobiliary excretion.

Drug metabolism – Phase I reactions

Cytochrome P-450 enzyme system overview
The cytochrome P-450 (CYP) enzyme group plays a paramount role in drug metabolism. Various CYP enzymes are responsible for catalyzing 70–80% of all phase I reactions. 7 These enzymes are located within the endoplasmic reticulum of most cells, but are found in variable concentrations. As expected, hepatocytes have the greatest concentration of CYP enzymes.

Nomenclature
CYP enzymes are classified by a hierarchical nomenclature system. The first number represents the enzyme family followed by a letter designating the subfamily. The final number is for the individual gene. There is at least 40% homology in amino acid sequences within a family, whereas subfamilies have 77% or more homology.
Q3-2 Although there are more than 50 families of CYP enzymes, only 6 CYP isoforms (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) appear to play a significant role in drug metabolism ( Table 3-2 ). 7 Of these 6 isoforms, all but CYP2E1 play a prominent role in drug interactions important to dermatologists. CYP1A2, 2C9, 2C19, and 2D6 all have polymorphisms. 7 Q3-3 Based on the percentage of drugs metabolized by the respective isoforms, CYP2C9, 2D6, and 3A4 are most important for drug metabolism ( Table 3-2 ). 7
Table 3-2 Fraction of drugs metabolized by various CYP isoforms 7 CYP isoform Percentage of all drugs metabolized by isoform CYP1A2 * † 5 CYP2A6 2 CYP2B6 2–4 CYP2C8 1 CYP2C9 * † 10 CYP2C19 * † 5 CYP2D6 * † 20–30 CYP2E1 2–4 CYP3A4 * 40–45 CYP3A5 <1
* CYP isoforms most commonly involved in drug interactions
† CYP isoforms with polymorphisms

CYP polymorphisms
Q3-4 Many CYP isoforms show significant genetic polymorphism. Approximately 40% of human CYP-dependent drug metabolism is carried out by polymorphic CYP enzymes. 8 This can translate into variable enzyme activity between individuals. Depending on the enzyme activity, individuals are designated as:

1. ‘Poor metabolizers’ (PM) if they have very low to no enzyme activity;
2. ‘Intermediate metabolizers’ (IM) if there is reduced activity;
3. ‘Extensive metabolizers’ (EM) if there is average enzyme activity; or
4. ‘Ultrarapid metabolizers’ (URM) if there is exceptionally high enzyme activity. 4, 7
This has important clinical relevance for medications that have a narrow therapeutic index. If a clinician can predict that a patient is a PM of a specific medication, a relatively low starting dose would be indicated to avoid unwanted adverse effects. On the other hand, if the patient was an URM, a clinician could more aggressively up-titrate a medication to reach a therapeutic level with a greater assurance that the patient could safely tolerate the more aggressive dosing.
Aside from genetic variability of the CYP isoforms, drug metabolism can be influenced by other medications as well as physical factors. Medications can affect the various CYP isoforms by either inhibition or induction of enzyme activity.

Drug inhibition or induction of CYP isoforms
Drug-induced inhibition of various CYP isoforms plays an important role in many ADR. Inhibition reduces the metabolizing effects of the affected cytochrome. In turn, CYP inhibition increases drug levels and toxicity. This can occur after just 1–2 doses of a medication, with maximal inhibition being observed once the steady state is achieved. 4 This inhibition is typically competitive. However, few drugs are non-competitive inhibitors that result in CYP alteration, inactivation, or destruction.
Induction of a CYP isoform causes an increase in its metabolic activity by increasing either the enzyme level or its activity. This is a much slower (up to a week or more) process than CYP enzyme inhibition, because induction relies on synthesis of additional CYP enzyme. Once an inducing agent is removed, the duration of enzyme induction is dependent on the degradation of the newly formed enzyme.

CYP1A2 polymorphism
CYP1A2 functions primarily to metabolize several antipsychotic medications and theophylline. Environmental and genetic factors are shown to influence the activity of CYP1A2. These can account for up to a 60-fold difference in activity. Tobacco byproducts produced from smoking and oral contraceptive steroids have been well established as CYP1A2 inducers. 9 Caffeine is a common substrate of CYP1A2. 9 Polymorphisms have been observed in the gene encoding CYP1A2, accounting for 16 known alleles. These genetic factors account for approximately 35–75% of the variation in CYP1A2 activity. 9 The frequency of these polymorphisms varies between different ethnic groups. A lower CYP1A2 activity has been found in Asian and African populations than in Caucasians. Among non-smokers, the frequency of poor metabolizers was found to be 5% in Australians, 14% in Japanese, and 5% in Chinese. 9

CYP3A4 variability
CYP3A4 is responsible for 40–45% of all phase I reactions and accounts for up to 70% of gastrointestinal CYP activity. 4, 7 CYP3A4 is co-expressed with P-glycoprotein in the liver and intestine. 10 Despite little genetic variability between populations, there appears to be as much as a 20-fold interindividual ‘variability’ of enzyme activity. 4 CYP3A4*1B appears to be the most common variant allele ( Table 3-3 ) and is associated with decreased CYP3A4 activity. 10 Obesity has been shown to reduce CYP3A4 activity, resulting in increased substrate activity. A number of medications and supplements can influence the activity. Importantly, ivermectin is a known substrate for CYP3A4. 10 See Chapter 65 on Drug Interactions for additional details on CYP3A4 substrates, inhibitors, and inducers.
Table 3-3 Prevalence of CYP3A4 variant alleles 10 Population CYP3A4*1B CYP3A4*3 Caucasian (%) 4–9 2 African (%) 69–82 0 Ghanaian (%) 71 0

CYP2C9 polymorphism
Overall, 10% of drug metabolism is carried out by CYP2C9. Q3-5 Although there have been over 100 SNP identified, only 2 allelic variants (CYP2C9*2 and CYP2C9*3) have been shown to significantly reduce substrate affinity through inhibiting CYP activity ( Table 3-4 ). Only the homozygote CYP2C9*3/*3, comprising 0.5% of most populations, is considered to have marked clinical significance with very low CYP2C9 activity. 11 The CYP2C9*3 variant may also play a role in phenytoin-induced cutaneous adverse drug reactions (see ADR section below) . 12 With regard to the activity of CYP2C9, the *1/*1 genotype demonstrates normal activity; the *1/*2 genotype has a minor reduction in activity; and, the *2/*2, *1/*3, and *2/*3 genotypes all show moderately reduced activity ( Table 3-4 ). 11 Epidemiologic studies show varying prevalences of the different CYP2C9 genotypes among different ethnic populations ( Table 3-4 and Table 3-5 ). Caucasians show marked variability in CYP2C9, with *2 being the most common mutant allele, whereas people of African and Asian descent have predominantly normal activity with the presence of the *1/*1 genotype. 15, 16 There are no allelic variants known to be inducers. Warfarin is the most clinically significant substrate for CYP2C9. Fluconazole inhibition of CYP2C9 can result in markedly elevated levels of warfarin, with a resultant risk of hemorrhage.

Table 3-4 CYP2C9 polymorphism activity: frequency in various populations 11, 13, 14

Table 3-5 Prevalence of CYP2C9 genetic polymorphisms 15 – 17

CYP2C19 polymorphism

General issues
Proton pump inhibitors and numerous anticonvulsants are the primary substrates metabolized by the CYP2C19 isoform. This isoform comprises approximately 5% of all drug metabolism.

Specific alleles of importance
Q3-6 There are several allelic variants 18 (CYP2C19*2–8) that show no enzymatic activity, which translates into a PM phenotype. This phenotype is observed in 1–23% of persons, with Asians having the highest incidence and African-Americans and Caucasians having the lowest ( Table 3-6 ). 19 Detailed prevalence of some of the CYP2C19 genotypes may be seen below, where *2/*2, *2/*3, and *3/*3 are the poor metabolizers ( Table 3-7 ). 16, 17
Table 3-6 CYP2C19 poor metabolizer frequency in various populations 19 Population # Studied PM % Japanese 399 19.5 Korean 309 12.1 Filipino 52 23.1 Chinese 538 15.6 Middle East 537 3.0 African 684 3.9 Whites – European 2291 2.9 African American 291 1.4 Whites – American 422 2.6

Table 3-7 Prevalence of CYP2C19 genetic polymorphisms 16, 17
In addition to acting as a strong CYP3A4 inhibitor, ketoconazole inhibits the CYP2C19 isoform, although it is not a substrate of this isoform. This dual inhibition is important, given that many medications metabolized by the CYP2C19 isoform are also metabolized by CYP3A4. 19

CYP2D6 polymorphism

General issues
CYP2D6 shows significant pharmacogenetic variation (polymorphism) and is integral in the metabolism of numerous medications, especially psychiatric and cardiac mediations. Q3-7 With over 90 documented allelic variants reported, CYP2D6 displays remarkable polymorphism. Overall, 20–30% of drugs are metabolized through this pathway ( Table 3-2 ) 4, 7 and because of these important issues CYP2D6 has been extensively studied. 20 In contrast to CYP2C9, CYP2D6 alleles that alter enzymatic activity are common. The enzymatic activity can vary up to 1000-fold between allele types. 7 Clinically this translates to at least a 50-fold difference in drug doses tolerated between various individuals; this principle is illustrated by the wide dosing range of the CYP2D6 substrate doxepin.

Specific alleles of importance
CYP2D6 polymorphisms are classified according to level of activity: PM, IM, EM, and URM. 21 The EM phenotype, which is expressed by the majority of the population, is considered the norm. In Europeans, four alleles, CYP2D6*3, *4, *5, and *6, are most closely associated with the reduced enzyme, also known as PM phenotypes. 20, 22 These PM phenotypes are seen in 1.5–10% of Caucasians, but in only 0–1.2% of many Asian populations (Thai, Chinese, Japanese) ( Table 3-8 ). Importantly, 6% of Caucasians lack the CYP2D6 enzyme altogether as a result of the presence of two null alleles. 3

Table 3-8 CYP2D6 polymorphism frequency in various populations 20, 21, 23 – 27
Many individuals, particularly those in certain African and East Asian regions, have the IM genotype. 22 Among those with IM, CYP2D6*10 is common in East Asians and CYP2D6*17 is common among African populations. 22

Gene duplication
Gene duplication occurs with the CYP2D6*2 allele, which generally confers an URM phenotype, resulting in very low drug levels with standard drug dosing. Population studies reveal considerable variation in the prevalence of CYP2D6*2 gene duplication. Genotypic studies of CYP2D6*2 gene duplication in various European countries demonstrate a prevalence of 1–10%, depending on the country studied. Up to 29% of black Ethiopians and 21% of Saudi Arabians have CYP2D6*2 gene duplication. 20

CYP2D6 testing
Despite the fact that CYP2D6 polymorphisms have been known for over 30 years, genotyping still has not entered routine clinical practice. 22

Sources for additional information on CYP-based interactions
Physicians should be cognizant of potential CYP-based drug interactions when prescribing systemic medications. The website www.drug-interactions.com is a valuable reference tool evaluating for CYP-based interactions. 28 It has a comprehensive list of medications that are substrates, inducers, or inhibitors for the major CYP isoforms of clinical significance. 28 This website links the reader to pertinent references for the interactions listed. 28
On the horizon, commercially available testing (see section on Tests for Genetic Polymorphisms) is likely to be available on a widespread basis for the major CYP isoforms with polymorphisms. Currently, this is primarily available only at certain reference laboratories.

Dihydropyrimidine dehydrogenase
Another example of phase I drug metabolism involves the metabolism of 5-fluorouracil (5-FU). 29 5-FU is a chemotherapeutic agent used to treat solid tumors, with topical formulations designed to treat some cutaneous premalignant lesions (actinic keratoses) and nonmelanoma skin cancers. Treatment can be limited by unwanted ADR. A number of functional genetic variants are present in the main enzyme that metabolizes 5-FU, dihydropyrimidine dehydrogenase (DPD), and in the target of 5-FU, thymidylate synthase (see below section for details on thymidylate synthase polymorphisms). 30, 31
As more than 80% of a given dose of 5-FU is rapidly metabolized by DPD, it is not surprising that patients with DPD deficiency have been reported to have severe neurotoxicity from 5-FU treatment. 30 Severe gastrointestinal and hematological toxicity has been reported in a DPD-deficient patient who applied topical 5-FU to the scalp. 32 As a result, topical 5-FU is contraindicated in patients with DPD deficiency. 33
Many genetic variants in the DPD gene have been described. The most common polymorphism is a splice site mutation, recognized as the DPD*2A allele, which leads to an enzymatically deficient DPD. 30 The DPD*2A allele is associated with 5-FU-induced toxicity, specifically leukopenia and mucositis. 30 In a study, this effect depended strongly on gender, given that heterozygosity for DPD*2A was associated with FU-induced toxicity in men, but not in women. 30
Genetic testing for the DPD*2A allele may be performed in many laboratories. Additionally, a DPD enzyme deficiency test may be carried out in specific laboratories. One example is the DPD enzyme assay performed by ITT laboratories, which cost $450 US in 2009 ( www.ittlabs.com ). 34 Approximately 1% of the population is heterozygous for the DPD polymorphism; 29 however, the clinical relevance or indications for DPD genetic testing remain unclear at present. Currently, routine screening for DPD enzyme deficiency is not standard of care prior to the topical application of 5-FU.

Drug metabolism – Phase II reactions ( Table 3-9 )

P-Glycoprotein

General issues
Permeability-glycoprotein (P-glycoprotein, PGP), an ATP-activated pump, has gained increased attention in the past few years because of its role in multidrug resistance, in particular to chemotherapeutic agents. Essentially, PGP involves pumping molecules from intracellular to extracellular spaces, counteracting the effects of passive diffusion, most notably in the gastrointestinal tract, with a resultant decrease in net drug absorption. 35 This has been shown to have a greater effect on drug absorption than clearance.

Table 3-9 Polymorphisms of phase II enzymes 3, 8, 30, 34, 37, 39, 42, 40, 49, 53, 58, 59, 61

Polymorphisms of PGP
Genetic polymorphisms have been identified in the multidrug resistance-1 (MDR1) gene that encodes PGP. Various alleles have been linked to lower PGP expression in the small intestine. This decreased PGP expression correlated with increased drug concentration when digoxin was administered in a study by Hoffmeyer and co-workers. 36
Ethnic variability has been demonstrated in the MDR1 gene. Testing for MDR1 gene expression may help identify populations who are at increased risk for PGP drug interactions. 37

Clinical importance of PGP polymorphisms
There appears to be significant overlap of substrate specificity between PGP and CYP3A4. 38 This overlap has complicated assessment of the role of PGP polymorphisms and drug interactions. Although evidence suggests that PGP likely has a significant role in drug–drug interactions, this currently appears to be of limited clinical application.

Thiopurine methyltransferase

General issues
Q3-8 Thiopurine methyltransferase (TPMT) functions as a catalyst for the metabolism and inactivation of azathioprine, 6-mercaptopurine (6-MP), and thioguanine. The enzyme functions by converting 6-mercaptopurine to inactive methylmercaptopurine nucleotides and by converting 6-thioguanine to inactive metabolites ( Figure 3-1 ). 39, 42 Decreased TPMT activity results in increased 6-thioguanine levels, leading to increased toxicity. 40 Specifically, high levels of accumulated 6-thioguanine nucleotides (6-TGN) seen in patients with TPMT deficiency appear to be associated with myelosuppression. 41 Conversely, TPMT deficiency leads to a decreased amount of 6-methyl mercaptopurine (6-MMP) nucleotides because TPMT is not available to convert 6-MP to 6-MMP. Since 6-MMP is correlated with azathioprine-induced hepatotoxicity, TPMT-intermediate and -deficient patients are at a lower risk for developing hepatotoxicity. 41 For these reasons, it is important to determine TPMT activity prior to dosing these immunosuppressive agents. This is recommended to ensure therapeutic drug levels and to reduce the risk of potentially life-threatening adverse reactions.

Figure 3-1 Azathioprine metabolic pathways.
With permission from el-Azhary RA. Azathioprine: current status and future considerations. Int J Dermatol 2003;42:335–41.

Polymorphism of TPMT
TPMT displays genetic polymorphism accounting for variable phenotypes. Approximately 89–90% of the general Caucasian population has high (normal) TPMT activity, which corresponds with homozygous expression of TPMT*1. 3, 42 Approximately 17 allelic variants of TPMT have been identified. 43 Of these, three mutant alleles (TPMT*3C, *3A, and *2) account for over 95% of individuals with decreased TPMT activity. TPMT*3A is the predominant mutant allele in Caucasians, whereas TPMT*3C is the most common mutant allele in Asians and Africans. 42 Heterozygous expression of any of these alleles, along with TPMT*1, results in intermediate TPMT activity. 42 Approximately 10–11% of the general population falls into this intermediate category. 3 Low to no TPMT activity is seen in approximately 0.3% of the Caucasian population. These persons are either homozygous or heterozygous with two mutant alleles with decreased enzyme activity and are at high risk for severe bone marrow suppression during treatment with azathioprine. 3, 42 Epidemiologic studies show these percentages to vary significantly among various ethnic groups ( Table 3-10 ). 43 - 48

Table 3-10 Thiopurine methyltransferase polymorphisms in various populations 43 – 48

Specific testing methods for TPMT polymorphism and clinical applications
Patient evaluation is becoming more accessible to community physicians. There are a number of reference laboratories performing TPMT evaluation. Two general testing methods are available: (1) TPMT phenotypes can be assessed by measuring the TPMT activity in erythrocytes, through peripheral red blood cell lysates, 40 and (2) DNA-microarray studies can be performed, which have resulted in more rapid and cost-effective TPMT genotyping. TPMT assays based on enzyme activity or genotype are both valuable screening tools that are available in selected laboratories; 8 however, each has drawbacks and limitations. Enzyme activity can be influenced by physiological or environmental factors: medications, recent blood transfusions, tobacco use, and impaired renal function all can cause an inaccurate result. 43 TPMT genotyping studies have shown some discordance between phenotype and genotype, which was most commonly observed in the intermediate activity groups. Studies have noted concordance rates from 76% to 99%. With DNA-microarrays including an increasing number of less common alleles, genotyping studies appear to be better correlated with phenotype testing. 43 Also, newly introduced rapid genetic polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) TPMT*3A and *3C allele tests are likely available in standard laboratories. 49 It is thought that these tests should allow more widespread screening of TPMT polymorphisms to be performed prior to treatment with azathioprine.
Recommended doses of azathioprine have been determined based upon the patient’s genetic TPMT polymorphisms. If a patient is homozygous for the wild type, TPMT*1, then a standard dose of 2–2.5  mg/kg/day may be administered. 42 In patients who are heterozygous with one TPMT*1 allele and one mutant allele (intermediate activity), the dose of azathioprine should be reduced by 15–50%. Limited case reports have demonstrated both improved efficacy and safety in treating severe atopic dermatitis in heterozygote TPMT-deficient children with azathioprine at 50% reduced doses. 41 For patients found to have two ‘mutant’ alleles with known associated markedly decreased TPMT activity (TPMT*3A, *3C, or *2), it is recommended that they not be treated with azathioprine or, if they must be treated, treatment should be at a dose reduced by 90% (see also Chapter 14 – Azathioprine). 42

N -Acetyltransferase

General issues
N -Acetyltransferase-2 (NAT 2 ) is responsible for acetylation of numerous xenobiotic substances. The addition of an acetyl group to a parent compound increases the drug’s water solubility, facilitating drug elimination.

Polymorphism of NAT 2
In the 1950s, high variability in individual rates of excretion of isoniazid was found among patients being treated for tuberculosis. 3 This was later determined to be caused by polymorphisms in NAT 2 , which metabolizes isoniazid.
Q3-9 At least 25 allelic variants of the NAT 2 gene have been identified, some being correlated with altered enzyme activity that varies in prevalence among different ethnic populations ( Table 3-11 ). 50, 51 NAT 2 enzyme activity is often reported as rapid , intermediate , or slow (analogous to EM, IM, PM). Rapid acetylation is seen in persons who are homozygous for NAT2*4, NAT2*12, and NAT2*13. 3 Rapid acetylators require higher doses of medications to minimize the likelihood of treatment failure. NAT2*5, *6, *7, *14S comprise virtually all of the alleles associated with slow or intermediate acetylation. 3 These slow acetylators are more likely to develop toxic adverse effects, including drug-induced lupus from procainamide and hydralazine, neuropathy from isoniazid, and toxic epidermal necrolysis from sulfonamides. 3 Studies have also demonstrated that slow acetylators may have an increased risk for certain solid tumors and for some IgE-mediated food allergies seen in children. 52 However, as approximately 40–70% of Caucasians are slow acetylators, and as severe adverse drug reactions (ADR) are rare, there are likely other underlying factors that contribute to these associations and ADR. 8 Hence, the practicality of testing for these NAT 2 polymorphisms is questionable in daily clinical practice.

Table 3-11 N -acetyl transferase (NAT 2 ) polymorphisms in various populations 51

Glucose-6-Phosphate dehydrogenase

General issues
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first reaction in the pentose phosphate pathway (PPP), leading to the reduction of NADP to NADPH throughout the body. NADPH plays an important role in reducing glutathione, which is central to preventing cellular damage by oxidative stress. 53 Since erythrocytes lack mitochondria, the PPP is the only source of NADPH, thus making G6PD-deficient erythrocytes exquisitely sensitive to oxidative stressors, resulting in significant hemolysis. This became clinically evident when primaquine caused hemolysis in some patients with malaria.

Polymorphism of G6PD
In the 1950s, polymorphisms of the G6PD gene on the X chromosome were noted to be the genetic cause for anemia, occurring in a certain subset of African patients taking primaquine. Affected individuals had low levels of the functioning activity of the G6PD enzyme. 3 The cause of this decreased activity was found in a single base substitution, asparagine to aspartic acid, resulting in hemolytic anemia.
Q3-10 Although there are over 400 identified variants, only 30 SNP mutations are associated with altered G6PD function. 54 Epidemiologic studies have identified higher incidences of G6PD deficiency in areas where malaria is endemic, because of its protective role against this infection ( Table 3-12 ). 55 – 57
Table 3-12 Glucose-6-phosphate dehydrogenase (G6PD) deficiency in various populations 55 – 57 Population # Studied Deficiency African Americans 6366 11.4% males 2.5% females Kuwait 1080 6.5% United Arab Emirates 496 9.1% Mexican 4777 0.71% Indian 3166 10.5% Caucasian Italians 85,437 0.9% Nigeria (Yoruba Tribe) 721 23.9% males 4.6% women

Specific drugs of importance to G6PD
Approximately 2 dozen drugs have been shown to cause varying degrees of hemolysis in G6PD-deficient patients ( Table 3-13 ). 53 This is germane to dermatologists who use sulfones (particularly dapsone) and sulfonamides, as these drugs rely on G6PD for phase II metabolism. Although primaquine causes hemolysis in G6PD-deficient patients, there appears to be minimal hemolysis with other antimalarial medications used in dermatology (chloroquine and hydroxychloroquine). See Chapter 19 on Antimalarials.
Table 3-13 Drugs with phase II metabolism altered by G6PD deficiency 53 Drug category Specific examples Antimalarials Primaquine Sulfonamides

Sulfanilamide
Sulfacetamide
Sulfapyridine
Sulfamethazole Other antimicrobial agents

Nitrofurantoin
Spiramycin Sulfones

Dapsone
Triazolesulfone Other drugs

Acetanilide
Furazolidone
Glibenclamide
Isobutylnitrite
Niridazole
Phenylhydrazine
Phenazopyridine Related chemicals

Aniline dyes
Methylene blue
Naphthalene (mothballs)
Toluidine blue
Urate oxidase
Fava beans, infections, and physiological stressors have also been noted to induce hemolysis in G6PD-deficient persons.

Specific G6PD testing methods and limitations
Screening for G6PD deficiency has become regular practice before starting dapsone and other medications that increase oxidative stress on erythrocytes. Quantitative evaluation is the most common method of screening for a G6PD deficiency. G6PD activity is measured by its ability to reduce NADP to NADPH in erythrocytes. 58 The fluorescent spot test, which allows for direct visualization of a fluorescently tagged NADPH, is the most commonly employed testing method. However, inaccurate G6PD test results can occur in certain patient populations. For example, because of chromosome X inactivation, women with a heterozygous G6PD mutation can have two populations of erythrocytes, one with and the other without G6PD activity. 58
In contrast to the fluorescent spot test, which measures the activity in a population of erythrocytes, methemoglobin or Nile blue sulfate reduction studies are more accurate because they evaluate individual erythrocytes. 58 Nonetheless, recent hemolysis and blood transfusions can both yield inaccurate results. In these situations, G6PD determination can be made by testing family members; they can function as a reliable surrogate, as there are very low rates of spontaneous mutations in the G6PD gene. Another option is to genotype the patient. This is reliable in all patient populations provided the mutation is already known. 58

Glutathione S -transferase
Glutathione S -transferase is an enzyme involved in the detoxification of carcinogenic derivatives of coal tar. 8 Approximately 50% of European Caucasians have low or absent activity of glutathione S -transferase (GST) owing to the presence of the GSTM1-null genotype. 8 After applying 2% coal tar topically to the skin, GSTM1-null individuals were found to have twice the amount of urinary 1-hydroxypyrene excreted as individuals with normal enzyme activity. 8 Hence, when GSTM1-null individuals are treated with topical coal tar, they have a greater mutagen exposure. 8 Genotyping for GSTM1 may be performed via PCR analysis in selected research laboratories. 59

Thymidylate synthase and other polymorphisms in the folate pathway
Methotrexate, a drug frequently used in dermatology, is a structural analogue of folic acid which competitively inhibits dihydrofolate reductase (DHFR). 60 Methotrexate also directly inhibits thymidylate synthase (TS). Via downstream effects of DHFR, methotrexate also influences the activity of methylene tetrahydrofolate reductase (MTHFR), which converts homocysteine to methionine. Methotrexate-associated ADR, including hepatotoxicity, gastrointestinal symptoms, and acute myelosuppression, result in up to 30% of patients discontinuing therapy. 60, 61 These ADR have been associated with polymorphisms of TS and MTHFR.
Evidence suggests that a polymorphism in the promoter region of the TS gene may affect methotrexate metabolism and clinical response. 61 The thymidylate synthase (TS) 5′-untranslated region (UTR) 3R/3R homozygous genotype has been significantly linked with ADR in psoriasis patients taking methotrexate when folic acid is not administered. 40, 61 Additionally, the TS 5′-UTR 3R allele has been associated with a poor therapeutic response to methotrexate. 61 The TS 3′UTR 6 bp deletion allele has also been associated with increased methotrexate-induced toxicity, 40, 61 including up to an 8-fold increased risk of developing elevated ALT transaminase levels in the absence of folic acid supplementation. 61 The importance of folic acid administration was confirmed as patients not receiving it were twice as likely to discontinue methotrexate, and many of the ADR attributed to these polymorphisms were attenuated or resolved with folic acid supplementation. 61
5-FU is a chemotherapeutic medication that strongly inhibits thymidylate synthase (TS), which is considered to be its major drug target. 30 In contrast to methotrexate, the TS 2R/3R or 3R/3R genotypes have been associated with a lower risk for 5-FU-induced ADR, specifically diarrhea. 30 The TS 2R/2R genotype, on the other hand, has been reported to increase the risk for 5-FU-induced toxicity. 30
The C677T polymorphism of MTHFR, observed in 8% of the normal population, leads to a thermolabile variant subsequently reducing its activity to about 30% of the wild type. 60 The C677T polymorphism has been associated with an increased risk of discontinuing methotrexate because of ADR, mainly elevated liver enzymes, 60 postulated to be related to increased homocysteine levels. 60 However, different studies have yielded conflicting results, some which show no association between MTHFR C677T and methotrexate toxicity. 61
Additionally, studies on the effects of MTHFR polymorphisms in regards to treatment with fluorouracil have yielded varying clinical results. Some studies suggest that MTHFR 677C>T is correlated with better clinical response to FU; however, the impact of MTHFR polymorphisms on severe FU-induced toxicity seems negligible based on prospective data. 30
Because methotrexate interacts with the folate pathway, studies analyzing the effects of reduced folate carrier (RFC) polymorphisms have been performed. The RFC 80A allele has recently been associated with methotrexate-induced toxicity. 61

Severe cutaneous adverse drug reactions linked to genetic polymorphisms
For many clinicians the future of ‘personalized medicine’ brings great hope, with the ideal future allowing physicians both to increase the efficacy of medicines and to reduce unwanted side effects and adverse reactions. In fact, ADR cause approximately 6% of hospitalizations and over 100 000 deaths per year in the United States. 40 Causes of ADR are likely multifactorial, and individual responses can be affected by age, renal and hepatic function, drug–drug interactions, as well as genetic polymorphisms that influence drug metabolism thereby altering drug efficacy and toxicity. 40
Recent studies and advances have increased our understanding of these genetic risks. Currently some genetic tests are commercially available that can be used to determine the risk. Some of the genetic variations now associated with ADR include specific HLA alleles ( Table 3-14 ). In a drug-specific manner, HLA-B*1502 has been associated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrosis (SJS/TEN) among Han Chinese patients. 40, 62, 63 However, HLA-B*1502 is not associated with the more benign morbilliform eruption or hypersensitivity syndrome triggered by carbamazepine. 40 Additionally, the HLA-B*1502 associated carbamazepine-induced SJS/TEN is ethnically specific, being found in Asians, specifically Han Chinese, but not in Caucasians. 40, 62, 63
Table 3-14 HLA genetic markers for severe cutaneous adverse drug reactions Drug Genetic marker for severe ADR Ethnic associations Carbamazepine HLA-B*1502 Han Chinese 38, 62 Allopurinol HLA-B*5801 Han Chinese 64 Abacavir HLA-B*5701, HLA-DQ3, HLA-DR7 62   Nevirapine HLA-B*3505 (rash) HLA-DRB1*0101 (hypersensitivity syndrome ± rash) 66 HIV-infected Thai (B*3505) 65
Additionally, the HLA-B*5801 allele was found to be present in 100% of 51 Han Chinese patients experiencing allopurinol-induced severe cutaneous ADR, but was only present in 15% of 135 allopurinol-tolerant patients. 64 Unfortunately, HLA testing is expensive at present, which can limit routine screening. 62
Similarly, the HLA-B*5701 allele has been associated with abacavir hypersensitivity. 40 The combination of HLA-B*5701, HLA-DQ3, and HLA-DR7 is 100% predictive of an abacavir-associated hypersensitivity reaction. 62
Nevirapine, an inexpensive nonnucleoside reverse transcriptase inhibitor, is often prescribed in resource-limited countries to treat HIV infection. 65 There are data to suggest that HLA-B*3505 is a predictor for all types of nevirapine-induced cutaneous drug reactions in Thai patients. 65 Additionally, data suggests an association of HLA-DRB1*0101 with nevirapine hypersensitivity involving combinations of hepatitis, fever, and/or rash, but not with isolated rash. 66 These nevirapine-induced ADR occur more frequently in patients with higher pre-treatment CD4 levels. 65, 66 It is thought that CD4-positive T lymphocytes must be present in a high enough number to induce the associated ADR. 65 It is now recommended that nevirapine be avoided in women with CD4 counts > 250 cells/µL and in men with CD4 counts > 400 cells/µL. 67
Other genetic markers are being evaluated for possible associations with severe cutaneous ADR. In studies of Japanese patients, Toll-like receptor 3 gene polymorphisms, certain Fas ligand polymorphisms, and IL-13 gene polymorphisms were found to be associated with SJS/TEN. 68 - 70
Phenytoin, also known as diphenylhydantoin, is known to be a cause of severe cutaneous ADR. In recent years, a study on a small group of patients with phenytoin-induced cutaneous ADR found a possible association with the CYP2C9*3 variant, 12 a known poor metabolizer. 28 From a practical standpoint, one might consider testing for the CYP2C9*3 variant prior to prescribing phenytoin in an attempt to help avoid severe ADR.
As previously mentioned, slow acetylators of NAT 2 may be at higher risk of sulfonamide-induced TEN and SJS. 3, 8

Tests for genetic polymorphisms and clinical significance
Testing for specific polymorphisms could help address ADR in approximately 10–20% of patients. 40 Although many of the tests for such polymorphisms are not widely accessible, several have become more readily available in recent years ( Table 3-9 and Table 3-15 ). A DNA microarray analyzing genetic polymorphisms of CYP2D6 has also been developed in recent years. 62 In 2008, the FDA issued a safety warning to all healthcare professionals that ‘serious and sometimes fatal hypersensitivity reactions (HSR) caused by abacavir therapy are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701.’ The name of the pharmacogenetics test for the HLA-B*5701 polymorphism is the ‘HLA-B5701 test’. 31
Table 3-15 Clinically relevant available tests for genetic polymorphisms Genetic polymorphism Test CYP2D6 polymorphisms DNA-microarray analysis 62 General HLA polymorphisms PCR-based HLA typing 63 Sequence-based typing 63 Specific HLA polymorphisms HLA-B*5701 polymorphism HLA B*1502 Specific HLA typing HLA-B5701 test 31 HLA B*1502 ‘carbamazepine sensitivity’ test Thiopurine methyltransferase (TPMT) Phenotyping : measures TPMT activity in erythrocytes though peripheral red blood cell lysates 40 Genotyping 8 DNA-microarray study PCR, ‘Prometheus TPMT Genetics’ ( www.mayomedicallaboratories.com ) Genetic allele testing: rapid PCR-RFLP TPMT*3A and *3C allele testing 49 Dihydropyrimidine dehydrogenase (DPD) polymorphisms Genetic testing for DPD*2A allele; e.g., ‘TheraGuide® 5-FU’ test (full sequencing of DPD , and analysis of TYMS gene ( www.myriadtests.com ) 71 DPD enzyme deficiency test, e.g., the DPD enzyme assay performed by ITT laboratories (cost $450 in 2009) ( www.ittlabs.com ) Glucose-6-phosphate dehydrogenase (G6PD) Fluorescent spot test, measures G6PD activity in population of erythrocytes 58 Methemoglobin or Nile blue sulfate reduction G6PD studies, evaluate individual erythrocytes 58 G6PD genotyping 58
The FDA has issued similar recommendations for other medicines, including azathioprine, where it was recommended on the Imuran (azathioprine) drug label that genotype or phenotype for TPMT should be considered in patients. 31 Testing for TPMT may be performed in several ways. One method is to order a test called ‘Prometheus TPMT Genetics.’
Additionally, on the Efudex (topical 5-FU) drug label there is a warning that the medicine ‘should not be used in patients with dihydropyrimidine dehydrogenase (DPD) deficiency’. 31 The dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms may be tested by ordering the ‘TheraGuide® 5-FU’ test. 71 Testing for DPD deficiency is described in the above section on DPD.
There is also a warning on the Tegretol (carbamazepine) label stating that genetically at-risk patients should be screened for HLA-B*1502 prior to starting treatment. 31 Specifically, the FDA has concluded that Asian patients should be screened before initiating treatment with carbamazepine. This may be done by ordering an ‘HLA B*1502 carbamazepine sensitivity’ test.
It is our hope that similar genetic tests for all polymorphisms will become readily available in the near future so that future ADR may be minimized. Until this becomes a commonplace reality, clinicians must focus on family and personal histories as a means of screening patients that might be at high risk for ADR. 62 Additionally, although costs remain high, clinicians must optimize the use of available genetic tests primarily in high-risk patients.

Conclusions and future directions
An understanding of drug metabolism and drug interactions is of paramount importance in an era when many patients are taking multiple medications. This chapter presents a brief overview of how genetic factors can alter the likelihood of various drug interactions and related adverse effects in the absence of drug interactions. New information on drug metabolism, including polymorphisms, is constantly being accrued. New tests that have clinical application are being developed and commercialized at a staggering pace. Electronic and print sources for this information are essential for all clinicians. A general understanding of how drugs are metabolized, along with recognition of the genetic and environmental factors that can influence drug metabolism, and their clinical effects, will prove to be an invaluable asset when choosing appropriate systemic and topical medications.
Pharmacogenomics is an emerging field that applies information and technology gained from the Human Genome Project towards the goals of optimizing drug efficacy, minimizing ADR, facilitating drug development, and reducing healthcare costs. 40 For ethical and legal reasons, pharmacogenomic profiling should only predict patients’ responses to drugs and not test specifically for disease-causing genetic mutations. 8
Although pharmacogenomics is important for future drug development, its applications in drug approval processes are still being debated. Currently, authorities in the USA (FDA), Europe (EMEA), and Japan (MHLW) have issued guidelines for new drug development that address the genetic heterogeneity of target patient populations. 40 In particular, the Food and Drug Administration (FDA) has approved modifications on 58 drug labels that contain pharmacogenetic information. 31 Additionally, since March 2008, through the Public Law No. 110–85, 121 Stat. 823, the FDA has the power to mandate that a genetic test be performed as part of a plan to optimize safety or efficacy of a new drug. 31
Expect an exciting future as the medical applications of pharmacogenomics, and the specific testing for various polymorphisms, gradually unfold.

Bibliography: important reviews and chapters

Correia Maria A. ‘Chapter 4. Drug Biotransformation’ (Chapter). Katzung BG: Basic & Clinical Pharmacology, 11e http://www.accessmedicine.com/content.aspx?aID=4515730
Crettol S, Petrovic N, Murray M. Pharmacogenetics of phase I and phase II drug metabolism. Curr Pharm Des . 2010;16(2):204–219.
Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther . 2007;116(3):496–526.
Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicology–with emphasis on cytochrome p450. Toxicol Sci . 2011 Mar;120(1):1–13.
Wecker: Brody’s Human Pharmacology, 5th ed. Chapter 2–Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination Mosby. 2009.
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev . 2009;41(2):89–295.

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56 Zaffanello M, Rugolotto S, Zamboni G, et al. Neonatal screening for glucose-6-phosphate dehydrogenase deficiency fails to detect heterozygote females. Eur J Epidemiol . 2004;19:255–257.
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58 Beutler E. G6PD deficiency. Blood . 1994;84:3613–3636.

Glutathione S -transferase
59 Davies MH, Elias E, Acharya S, et al. GSTM1 null polymorphism at the glutathione S-transferase Ml locus: phenotype and genotype studies in patients with primary biliary cirrhosis. Gut . 1993;34:549–553.

Thymidylate synthase
60 Warren RB, Griffiths CEM. The potential of pharmacogenetics in optimizing the use of methotrexate for psoriasis. Br J Dermatol . 2005;153:869–873.
61 Campalani E, Arenas M, Marinaki AM, et al. Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol . 2007;127:1860–1867.

Severe cutaneous drug reactions linked to genetic polymorphisms
62 Pereira FA, Mudgil AV, Rosmarin DM. Continuing medical education: toxic epidermal necrolysis. J Am Acad Dermatol . 2007;56:181–200.
63 Yang G, Deng YJ, Qin H, et al. HLA-B*15 subtypes distribution in Han population in Beijing, China, as compared with those of other populations. Int J Immunogenet . 2010 Jun;37(3):205–212.
64 Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A . 2005;102:4134–4139.
65 Chantarangsu S, Mushiroda T, Mahasirimongkol S, et al. HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients. Pharmacogenet Genomics . 2009 Feb;19(2):139–146.
66 Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS . 2005;19:93–99.
67 Martin A, Nolan D, Almeida CA, et al. Predicting and diagnosing abacavir and nevirapine drug hypersensitivity: from bedside to bench and back again. Pharmacogenomics . 2006;7:15–23.
68 Ueta M, Sotozono C, Inatomi T, et al. Toll-like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome. Br J Ophthalmol . 2007;91:962–965.
69 Ueta M, Sotozono C, Inatomi T, et al. Association of Fas Ligand gene polymorphisms with Stevens-Johnson syndrome. Br J Ophthalmol . 2008;92:989–991.
70 Ueta M, Sotozono C, Inatomi T, et al. Association of combined IL-13/IL-4R signaling pathway gene polymorphism with Stevens-Johnson syndrome accompanied by ocular surface complications. Invest Ophthalmol Vis Sci . 2008 May;49(5):1809–1813.
71 https://www.myriadpro.com/test-offerings/chemotherapy-management/theraguide , 2012.

References *

3 Lowitt MH, Shear NH. Pharmacogenomics and dermatological therapeutics. Arch Dermatol . 2001;137:1512–1514.
4 Shapiro LE, Shear NH. Drug interactions: Proteins, pumps, and P-450s. J Am Acad Dermatol . 2002;7:467–484. quiz 485–6
6 Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side effects. N Engl J Med . 2003;348:538–549.
7 Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci . 2004;25:193–200.
8 Ameen M, Smith CH, Barker JNWN. Pharmacogenetics in clinical dermatology. Br J Dermatol . 2002;146:2–6.
9 Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J . 2009;3:481–494.
12 Lee A-Y, Kim M-J, Chey W-Y, et al. Genetic polymorphism of cytochrome P450 2C9 in diphenylhydantoin-induced cutaneous adverse drug reactions. Eur J Clin Pharmacol . 2004;60:155–159.
17 Yang ZF, Cui HW, Hasi T, et al. Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Mongolian population in China. Genetics and Molecular Research . 2010;9(3):1844–1851.
21 Bernard S, Neville KA, Nguyen AT, et al. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist . 2006 Feb;11(2):126–135.
22 Daly AK. Pharmacogenetics and human genetic polymorphisms. Biochem J . 2010;429:435–449.
28 Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2009). http://medicine.iupui.edu/clinpharm/ddis/table.aspx . (
30 Schwab M, Zanger UM, Marx C, et al. Role of genetic and non-genetic factors for fluorouracil treatment-related severe toxicity: A prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol . 2008;26:2131–2138.
31 Flockhart DA, Skaar T, Berlin DS, et al. Clinically Available Pharmacogenetic Tests. Clin Pharmacol Ther . 2009;86:109–113.
40 Pincelli C, Pignatti M, Borroni RG. Pharmacogenomics in dermatology: from susceptibility genes to personalized therapy. Exp Dermatol . 2009;18:337–349.
62 Pereira FA, Mudgil AV, Rosmarin DM. Continuing medical education: toxic epidermal necrolysis. J Am Acad Dermatol . 2007;56:181–200.
63 Yang G, Deng YJ, Qin H, et al. HLA-B*15 subtypes distribution in Han population in Beijing, China, as compared with those of other populations. Int J Immunogenet . 2010 Jun;37(3):205–212.
65 Chantarangsu S, Mushiroda T, Mahasirimongkol S, et al. HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients. Pharmacogenet Genomics . 2009 Feb;19(2):139–146.
66 Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS . 2005;19:93–99.

* Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com .
4 Adherence to drug therapy

Michelle M. Levender, Steven R. Feldman


 Questions

Q4-1 What is the most basic definition of adherence in clinical practice? ( Pg. 34 )
Q4-2 What is the estimated cost to the US healthcare system of poor adherence in terms of (a) percentage of hospital admissions, and (b) total monetary cost? ( Pg. 34 )
Q4-3 How is the ‘medication possession ratio’ defined? ( Pg. 34 )
Q4-4 How are the following terms defined (a) acceptance, (b) persistence, and (c) quality of execution? ( Pg. 35 )
Q4-5 What are several important ‘internal’ factors affecting patient adherence? ( Pg. 35 , Table 4-1 )
Q4-6 What are several important ‘external’ factors affecting patient adherence? ( Pg. 36 , Table 4-1 )
Q4-7 What are some of the most important (a) office environmental factors, and (b) physician behavior characteristics, that affect patient adherence? ( Pg. 36x2 , Box 4-1 )
Q4-8 How does the physician’s explanation of treatment options, choice of vehicle for topical medications, and complexity of treatment affect patient adherence? ( Pg. 37x3 , Box 4-2 )
Q4-9 How does the real or perceived risk of adverse effects affect patient adherence? ( Pg. 37 )
Q4-10 How do (a) written instructions, (b) motivational interviewing techniques, and (c) measures to allow the use of pre-existing habits improve medication adherence? ( Pg. 37, 38x2 )

Introduction
This book describes the panoply of medications available to treat a broad array of skin diseases. The outcomes of these treatments are not entirely predictable. In clinical trials, treatment response varies among research subjects. This variability is even greater in the clinic setting and has resulted in the development of the field of Pharmacogenomics; but, a key underlying and often under-appreciated determinant of the outcome of dermatologic treatment is simply how well patients use their medications, a concept subsumed under the term ‘adherence.’ Q4-1 Adherence (previously known as ‘compliance’) is the degree to which a patient’s behavior coincides with the recommendations of their healthcare provider. 1
Poor adherence is ubiquitous across all fields of medicine. Q4-2 Improving patients’ adherence behavior may be a quick, low-cost effective way to improve medical outcomes. Non-adherence to medication regimens is responsible for 10% of all hospital admissions and costs the US healthcare system $100–300 billion annually. 2 – 4
The problem of non-adherence manifests in many ways in the treatment of dermatologic disease, particularly with chronic topical treatment. The well-known problem of tachyphylaxis (‘the more you use the medicine, the less it works’) is commonly a manifestation of poor adherence (‘the less you use the medicine, the less it works’). Other phenomena that are best explained by patients’ adherence (or lack of adherence) include the resistance of scalp psoriasis to topical treatment and the tendency of children with atopic dermatitis previously ‘resistant’ to topical treatment to clear rapidly – in just 2 or 3 days – with topical treatment administered in the hospital setting.
This chapter will (1) describe how adherence is measured, (2) examine the magnitude of the problem of adherence, (3) describe the variables that influence adherence behavior, and (4) identify principles and practical strategies to improve patients’ adherence to treatment.

Measures of adherence
Assessing adherence can be challenging. Self-reporting of adherence is not a particularly reliable methodology. 5, 6 A more objective measure to monitor adherence is blood test monitoring for drug levels, but even this approach often overestimates adherence because patients tend to be better about using their medications around the time of an office visit, a phenomenon called ‘white coat compliance’ (one of the best examples of this phenomenon is the tendency for people to floss more before going to the dentist). 7
In the past, studies on adherence in dermatology relied on surveys, pill counts or medication weights. In an anonymous survey of psoriasis patients, roughly 40% reported non-adherence to their treatment regimen; we suspect most of the other 60% simply were not completely honest. 8, 9 Counting pills or weighing a topical medication may appear to be a more objective way to assess adherence, but patients are wily and may dump their medication to hide their poor adherence behavior. Some creativity may help. To encourage honest responses, the physician may ask, ‘It can be hard to use the medicine every day. How often are you missing doses: every day or every other day?’ To improve the reliability of pill counts, instead of prescribing 60 tablets for a bid dosing and having the patient return in a month, either prescribe 70 tablets or prescribe 60 but have patients come back before the month is over. That way, if the bottle is empty, the physician can distinguish a bottle that has been emptied due to good adherence from one that was emptied to hide poor adherence. 10
Other approaches have been used to more reliably assess patients’ use of their medications in research studies. Q4-3 Pharmacy data can be used to tell whether patients filled a prescription. Combined with data on refills, pharmacy data can establish an upper limit on patients’ use of medication by describing how many days’ worth of medication the patient obtained over the course of treatment. The standard metric for this is the ‘medication possession ratio’. The medication possession ratio is calculated as the number of days of supply for dispensed prescriptions divided by the number of days between prescription refills.
Pharmacy data are useful for determining whether patients procure medication, but they are a step removed from whether the patient uses the treatment. Q4-4 Objective electronic monitors in the caps of medication containers – such as the Medication Electronic Monitoring System (MEMS) – provide more direct information on patients’ use of medication. These devices record the data and time each time the bottle or tube is opened. Electronic monitoring of adherence can be used to elucidate the various patterns of poor adherence. The initial phase of adherence is acceptance, when the patient fills and begins treatment. Patients with poor ‘acceptance’ may not fill the medication, or may begin taking it after some delay. ‘Persistence’ refers to how long patients stay on therapy. Poor persistence implies that patients discontinued their treatment early. During the period when patients are using their medication, ‘quality of execution’ refers to how well the patient is using the medication. Patients may skip doses at regular intervals, take drug holidays, or over-treat. The typical patient probably is doing some combination of all of these.

The magnitude of poor adherence in dermatology
Electronic monitors and prescription refill data have opened up new vistas in our understanding of how well patients use the medication we prescribe. Pharmacy data reveal that many prescriptions are never filled. A groundbreaking Danish study found that 4 weeks after the doctor visit, 30% of dermatologic prescriptions had not been filled; 50% of the psoriasis prescriptions had not been filled. 11 In a study population of North Carolina Medicaid patients (for whom the costs for procuring medication were very low), the medication possession ratio was only 35% for non-biologic psoriasis treatments. 12 For biologics, the medication possession ratio was considerably better, at 66%, but this indicates that on average those patients missed taking at least one-third of recommended doses.
Studies of pharmacy data inform us about how much medication the patient received; electronic monitors reveal how often medication was used. In a study of patients with psoriasis, adherence to twice daily 6% topical salicylic acid was measured over 8 weeks using self-report diaries, medication weights, and MEMS caps. While the subjects reported adherence rates of 90–100% in their treatment diaries and medication weights, the MEMS caps revealed an overall average adherence of only 55%, with a drop in adherence of approximately 20% every 5 weeks. 7 Electronic medication monitors have revealed that patients’ adherence behavior is far worse than previously thought.
Certain patient populations are notoriously non-adherent, particularly teenagers. In one small study of teenage acne patients, electronically monitored adherence to a once-daily treatment regimen was 82% on day 1, dropping to 45% at the end of 6 weeks. 13 In a study of children with atopic dermatitis, electronic monitors were used to assess adherence to topical triamcinolone over 8 weeks. Mean adherence was an abysmal 32%, with a drop of 60–70% in adherence over the first 3 days of the study. 14
Much of the data on adherence come from patients who are knowingly enrolled in studies of adherence (though they usually do not know how adherence is being measured). Thus, patients in these studies are probably motivated to be more adherent than they would under normal circumstances. Yet, even in these clinical studies, lasting no more than a few weeks to months, adherence rates are suboptimal. 15 One can imagine just how poor adherence must be in regular dermatology practice, particularly among patients with chronic diseases who require daily medications, not just for a few weeks or months, but for a lifetime.

Factors that influence adherence behavior
Adherence behavior is affected by many interacting variables. There is a complex relationship between adherence behavior, treatment and outcome. Q4-5 The factors that affect adherence can be classified as internal and external ( Table 4-1 ). A major internal factor affecting adherence is the patient’s motivation to get better. Some patients may not be particularly motivated to get better, or they may not be bothered by their condition. Other patients may be seeking secondary gain from their condition. One might expect that patients with severe disease would be very motivated to use their medications, but in fact patients with worse quality of life are less likely to be adherent. 16 Perhaps these patients feel hopeless and simply resign themselves to the realities of their condition. Sometimes patients want to get better but may not have understood the medication instructions, or they may be forgetful or unable to physically apply the medication.
Table 4-1 Factors contributing to poor adherence Internal factors External factors

Age
Poor motivation to get well
Secondary gain from illness
Feeling of hopelessness/resignation about condition
Poor understanding of the disease
Unrealistic or inaccurate expectations of treatment
Psychiatric comorbidities
Lack of trust in the doctor
Lack of trust in or fear of the treatment
Fear of adverse effects

Weak physician–patient relationship
Complex treatment regimen (frequent dosing and/or multiple agents)
Poorly tolerated vehicle
Adverse effects and toxicities
Slow-acting medication
Cannot afford treatment
Limited access to treatment
Inadequate instructions provided on how to use medications
Long interval between follow-up visits
Patients may have psychiatric comorbidities such as depression that interfere with their ability to carry out their treatment. Age is another important factor, as children and teenagers are less likely to adhere to treatment. Additionally, patients’ understanding of their disease and the expectations for treatment significantly affect their adherence behavior, as does their understanding of the treatment itself, in particular expectations about adverse effects. Of profound importance is the patient’s trust in their doctor and the quality of the physician–patient relationship. Overall, 70% of adherent patients reported that they were using their medication because they believed their provider was a compassionate advocate. 17
Q4-6 External factors affecting adherence behavior include (1) complexity of regimen, (2) cost of and access to treatment, (3) vehicle choice in topical medications, and (4) adverse effects. In addition, (5) the time it takes a medication to work is critical, as is (6) the patient’s response to treatment. For example, if a medication takes weeks to work but the patient is expecting a ‘quick fix,’ then that patient may stop using the medication, thinking that it failed. Conversely, if the patient has rapid initial success with a particular treatment, he or she may be more likely to continue using it. Other important considerations over which physicians have considerable control include the quality of the physician–patient relationship, plans for follow-up visits, and clarity of instructions provided.

Strategies to improve adherence behavior

The physician–patient relationship
In finding ways to improve adherence it is helpful to consider the many steps involved in a patient using their medication ( Figure 4-1 ). Breakdowns may occur anywhere along the way. A strong physician–patient relationship provides the foundation for medical practice. The physician–patient relationship will influence whether the patient voices concerns with choice of treatment when the treatment is initially selected, fills the prescription, uses the medication, and accurately reports back to the physician on their experience with the medication.

Figure 4-1 Steps necessary to achieve and maintain adherence.
Q4-7 Patients should feel they are seeing a caring, trustworthy doctor. 18 Patients’ perceptions of their doctor are influenced by their experience of the initial contact with the office. Front desk staff should be friendly and professional. The general appearance of the office is important, and it should be tidy and pleasant. Posted signs can send subtle (and not so subtle) messages to patients about the priorities of the physician. If the only signs in view are in regard to making payments, returned check policies and the like, patients may believe their doctor is more concerned about making money than patients’ wellbeing. Instead, office signs can show that a practice values service and may help to reinforce a feeling of caring in the practice, thanking patients for referrals or wishing them a nice day.
Q4-7 When meeting a patient, the physician should make eye contact, smile, and shake their hand. The patient should feel cared for and not rushed. Overall, 72% of physicians interrupt patients an average of 23 seconds into giving their history; uninterrupted, patients require only an additional 6 seconds to complete their opening monologue. 19 By simply allowing patients to tell their story, physicians send a strong message that caring for the patient is their number one priority. Body language during an encounter is important too. Patients perceive a visit as lasting longer if the provider is sitting down. 17 Active listening and empathetic statements further reinforce the patient’s perceived sense of being taken care of. Summarizing a patient’s story and telling it back to them, or asking questions to reflect understanding, help the patient to see their physician is paying close attention.
Patients want to know they received a thorough examination. Laying hands on a patient is an integral component of the encounter that has important therapeutic value. Touching the patient’s skin during an examination helps convey that the physician is performing a careful examination; a lighted magnifier is another prop that can be used to reinforce this perception. The encounter offers an opportunity to educate patients about their condition and plans for treatment. Use language that the patient can understand and take the time to solicit additional questions. 20 Finally, it is helpful to provide contact information in case patients have questions later. This serves a practical purpose and reinforces the message that the priority is caring for patients. Incorporating these basic steps into practice helps provide the foundation of a strong physician–patient relationship, which in turn facilitates good adherence and good patient outcomes ( Box 4-1 ).

Box 4-1
Ways to strengthen the physician–patient relationship

• Office staff should be friendly and professional
• Office is clean and well-maintained
• Posted signs convey message that patient care is the priority
• Make eye contact, smile, and shake hands with the patient
• Sit down during the encounter
• Do not interrupt the patient’s opening monologue
• Be an active listener
• Show empathy
• Touch the patient’s skin during examination
• Solicit patient input and questions
• Give patients contact information

Choice of treatments
Once a diagnosis has been made, a treatment plan should be developed that takes patients’ preferences into consideration. A variety of treatment factors have an impact on adherence ( Box 4-2 ). Q4-8 Treatment options should be clearly explained and the patient should be an active participant in choosing among those options. Their opinion should be solicited directly, in a non-judgmental way. Some patients may prefer their doctor to choose the medicine, but other patients may have past experiences that have left them with strong ideas about a particular treatment.

Box 4-2
Treatment considerations to maximize adherence

• Explain all treatment options clearly
• Involve the patient in choice of treatment
• Solicit the patient’s opinion and beliefs about treatment options
• Choose a vehicle that the patient will use
• Create a simple treatment regimen: use less frequent dosing and combination products when possible
• Explain side effects and use them to advantage when possible
• Be aware of the cost of medicines and do not prescribe medications that the patient cannot afford
• Ensure the patient can access the treatment
Q4-8 In the case of topical medications, selection of the appropriate vehicle is essential. 21 Patients should be involved in this decision. Past teaching suggested that ointments are the most effective vehicles for dry skin conditions such as psoriasis; the most effective vehicle, however, is usually the one the patient is most willing to use. Newer, less messy non-ointment vehicles are highly effective psoriasis treatments. 22, 23 Testing samples of different products may help patients decide which vehicle is best for them.
Q4-8 The complexity of treatment is also an issue. Greater adherence will be achieved with once- or twice-daily dosing than with more frequent dosing schedules. Combination products that include two or more medications in one product can help improve adherence. Streamlining treatment is particularly important for patients with refractory disease. Although our instinct with these patients may be to add penetration enhancers or switch to more potent and risky treatments, the opposite approach may be more effective. As the lesson of the dramatic effect of hospitalization in children with severe AD teaches us, poor adherence is usually the culprit in patients with seemingly refractory disease. Using riskier medications may be counterproductive if the patient did not use the first treatment because of perceived risks. Adding additional medicines to a treatment regimen may be counterproductive if poor adherence was caused by the complexity and time-consuming nature of the initial treatment. For many patients the treatment should be simplified as much as possible, paring it down to a single medication for once- or twice-daily use. Remarkably, patients may achieve rapid improvement using a treatment that had previously been ‘ineffective’. 10
Q4-9 Adverse effects of treatment, both real and perceived, are important to consider. This is a particularly common issue in the treatment of infants and young children. Patients may have very specific ideas or concerns about the adverse effects of a particular medication, perhaps due to something they read or learned from a friend. Sometimes, for example in the case of topical calcineurin inhibitors, there may be little or no scientific basis for a particular concern. The strength of the physician–patient relationship may help overcome these fears. A simple discussion with a trusted physician can reassure the patient that the proposed medication is safe enough to use.
Some medications have very real adverse effects and potential toxicities that warrant discussion. These risks should be put into perspective to help minimize anxiety. Unexpected adverse effects can quickly lead to discontinuation of a medication. For example, forewarning patients that burning or dryness is a normal reaction to the medication and will subside with use – or better yet, that such a reaction is ‘a sign the drug is working’ – may keep patients from discontinuing treatment. While telling a patient ‘a burning sensation is a sign the medication is working’ may be a stretch, it is true that if the patient is experiencing such an adverse effect, it means he or she is using the medication, and so it probably is working. 17
Cost and availability are important considerations that may be overlooked by the physician, but can potentially represent very real obstacles to adherence. If an expensive medication is used, discuss the cost with the patient. Warn patients if a particular medication is not widely available.

Stress good initial adherence
If patients do not see that their treatment is working well, they may be discouraged and discontinue it. In order to ensure that treatment does work well and quickly, securing good initial adherence is essential. There are a variety of techniques that can be used to help attain a high level of initial adherence ( Box 4-3 ). A fast-acting medicine should be used. If a slow-acting medication is necessary, perhaps it can be paired with a fast-acting medication, at least at the start of treatment, to help secure good initial adherence. Much in the same way that first impressions are important, seeing good results early on will help the patient to trust their doctor, to trust in their medication and to continue using the treatment long term, thus achieving better long term adherence.

Box 4-3
Techniques to improve initial adherence

• Use fast-acting medications; if a slow-acting medication is being used, pair it with a fast-acting medication initially
• Provide written instructions on treatment
• Educate the patient about their condition and provide realistic expectations for treatment outcome
• Schedule an early follow-up visit
• Use motivational interviewing techniques
• Help the patient to identify memory aids to help them remember to use the medicine
Q4-10 Patients need to know how to use their medicines. Instructions for the use of medication can quickly get complicated, especially in the case of multiple medications. Most verbal directions given in a patient encounter are forgotten by the time the patient gets home. 24 Ideally, physicians should provide clear written instructions explaining how to use all medications. Whenever possible, having written materials available for patients is helpful. If a specific handout is unavailable, the Internet can be a great resource for information.
An especially powerful tool to promote good initial adherence is ‘white coat compliance.’ Adherence improves around the time of office visits. 6, 7 An early follow-up visit, ostensibly to check on how well the medication is working, can dramatically improve how well patients use their treatments. Scheduling a quick follow-up visit improves initial adherence and improves short-term outcomes, which in turn helps to secure good long-term adherence. The many follow-up visits in clinical trials are likely a strong contributor to the tendency for medications to work better in clinical trials than they do in clinical practice.
Q4-10 Motivational interviewing techniques can be used to improve adherence. The physician should express empathy and acknowledge that it can be challenging to use the medication as prescribed. They should praise the patient for good adherence behavior: positive reinforcement goes a long way. The physician can ask the patient if they feel adherence is important, and if it is, what things the patient might do that would improve their adherence to treatment.
Q4-10 Incorporating a new habit into everyday life can be challenging. It is easy for even the most motivated individual to forget to use their medicine. Simple memory aids can help patients maintain good adherence. A common suggestion is to tie the medication to an already established habit. This could mean taping a topical acne medication to the toothpaste tube, or placing topical antifungal medication on top of the shoes.

Achieving adherence in special groups
Several patient populations present unique challenges in adherence ( Table 4-2 ). These include children, teenagers, and adherence-resistant patients. In children with chronic skin diseases all the usual barriers to adherence exist, along with additional challenges. The child is often not a motivated participant, and especially in the case of topical medications may be very uncooperative in the application of the medication, which is typically done by the parent. A daily battle may ensue, which over time can whittle away at the parent’s motivation to apply the medicine. Work and other social demands on caregivers may leave little time or energy for treating the child. Also, in households with two caregivers, each might think the other is responsible for treatment. On top of all this, parents may be particularly fearful of the potential adverse effects of treatment on their child. 10
Table 4-2 Techniques to improve adherence in special populations Children Teenagers Especially adherence-resistant patients

Keep the burden of treatment low
Limit the time horizon of treatment by scheduling an early follow-up visit
Avoid the use of anxiety-inducing language when discussing treatment (’topical anti-inflammatory’ rather than ‘steroid’)
Create reward systems
Use written action plans

Acknowledge the teenager before the parent
Speak directly to the teenager
Use fast-acting medications
Capitalize on the desire to fit in
Use memory aids
Avoid using parental reminders, which may reduce adherence

Take the responsibility for treatment out of the hands of the patient
Utilize home health services
Add a daily phototherapy session to the treatment plan, then apply the topical medication in-office after each session
For oral medications, consider switching to an office-administered weekly injection
To address these concerns it is important to keep the apparent burden of treatment low by limiting the time horizon of treatment. An early return visit will help in this regard. The risk of treatment should be put into perspective. It may help to let parents know that the child will be treated with a ‘topical anti-inflammatory’ rather than subject them to unwarranted fears of the effects of evil ‘steroids.’ Children are particularly motivated by reward systems and praise. Sometimes just a simple weekly calendar, in which the child gets to apply a star or sticker for each successful medication application, works wonders. A written action plan (WAP) can be used to empower the child and their caregivers. 25
Teenagers represent a challenging population because they are at a developmental stage in which they are becoming, but are not yet fully, independent. Relationships with parents are strained and there is often a strong desire to rebel. Teenagers may struggle with delayed gratification, and so fast-acting medications should be used when possible. 17 Teenagers have a strong desire to fit in with other teenagers, which can be used to improve adherence. In treating acne, the physician can simply state that the recommended medicine is one that most teenagers use to control their acne. On the other hand, telling a teenager, ‘most teenagers aren’t compliant with the treatment,’ is likely to be counterproductive. Finally, the role of the parent in treatment can be tricky, as parental reminders may reduce use of the medication in some patients. 10, 17
Some patients are particularly resistant to using their medications, such that taking the responsibility for treatment out of the hands of the patient may be the best approach. Success can often be achieved with physician-administered treatments. Home health services may be possible. Patients on methotrexate can be given a weekly injection. For patients with psoriatic plaques that are unusually resistant to topical agents, consider adding daily office-based phototherapy; the nurse can apply the topical medication at the light treatment visits (if the office does not offer standard phototherapy, using a Woods lamp to provide the ‘phototherapy’ may be a sufficient). While the implementation of provider-administered treatment can be challenging, it is often possible to find creative ways to get the treatment to the patient and the improvements in outcomes can be great.

Conclusions
There is a wealth of evidence to demonstrate that adherence is suboptimal across all fields of medicine, and especially in dermatology. Patients’ adherence to treatment should be considered at every visit, and it may be best to assume that patients are not completely adherent. Adherence behavior is complex, affected by numerous internal and external factors, with many potential pitfalls. With a better understanding of the factors affecting adherence and by employing creative strategies, physicians can exert a great degree of control over patients’ adherence. Key elements include (1) the establishment of trust in the physician–patient relationship, (2) considering patients’ preferences in the choice of treatment, and (3) timing the return visit to encourage good initial adherence. Rather than spending time and money developing new medications, energy should be focused on finding new ways to get patients to use the medications we already have.

Bibliography: Important reviews and chapters

Baldwin HE. Tricks for improving compliance with acne therapy. Dermatol Ther . 2006;19(4):224–236.
Chisolm SS, Taylor SL, Balkrishnan R, et al. Written action plans: potential for improving outcomes in children with atopic dermatitis. J Am Acad Dermatol . 2008;59(4):677–683.
Feldman SR, Horn EJ, Balkrishnan R, et al. International Psoriasis Council. Psoriasis: improving adherence to topical therapy. J Am Acad Dermatol . 2008;59(6):1009–1016.
Gupta G, Mallefet P, Kress DW, et al. Adherence to topical dermatological therapy: lessons from oral drug treatment. Br J Dermatol . 2009;161(2):221–227.
Thiboutot D, Dréno B, Layton A. Acne counseling to improve adherence. Cutis . 2008;81(1):81–86.
Yan AC, Treat JR. Beyond first-line treatment: management strategies for maintaining acne improvement and compliance. Cutis . 2008;82(2 Suppl 1):18–25.

web References

Introduction
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3 Bender BG, Rand C. Medication non-adherence and asthma treatment cost. Curr Opin Allergy Clin Immunol . 2004;4(3):191–195.
4 Vermeire E, Hearnshaw H, Van Royen P, et al. Patient adherence to treatment: three decades of research. A comprehensive review. J Clin Pharm Ther . 2001;26(5):331–342.

Measures of adherence
5 Greenlaw SM, Yentzer BA, O’Neill JL, et al. Assessing adherence to dermatology treatments: a review of self-report and electronic measures. Skin Res Technol . 2010;16(2):253–258.
6 Carroll CL, Feldman SR, Camacho FT, et al. Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial: commonly used methods of measuring adherence to topical therapy overestimate actual use. J Am Acad Dermatol . 2004;51(2):212–216.
7 Feldman SR, Camacho FT, Krejci-Manwaring J, et al. Adherence to topical therapy increases around the time of office visits. J Am Acad Dermatol . 2007;57(1):81–83.
8 Richards HL, Fortune DG, O’Sullivan TM, et al. Patients with psoriasis and their compliance with medication. J Am Acad Dermatol . 1999;41(4):581–583.
9 Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol . 2006;55(4):607–613.
10 Feldman SR. Practical Ways to Improve Patients’ Treatment Outcomes . Winston Salem, North Carolina: Medical Quality Enhancement Corporation; 2009.

Magnitude of poor adherence in dermatology
11 Storm A, Andersen SE, Benfeldt E, et al. One in 3 prescriptions are never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol . 2008;59(1):27–33.
12 Bhosle MJ, Feldman SR, Camacho FT, et al. Medication adherence and health care costs associated with biologics in Medicaid-enrolled patients with psoriasis. J Dermatol Treat . 2006;17(5):294–301.
13 Yentzer BA, Alikhan A, Teuschler H, et al. An exploratory study of adherence to topical benzoyl peroxide in patients with acne vulgaris. J Am Acad Dermatol . 2009;60(5):879–880.
14 Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth monitoring of adherence to topical medication: adherence is very poor in children with atopic dermatitis. J Am Acad Dermatol . 2007;56(2):211–216.
15 Yentzer BA, Yelverton CB, Pearce DJ, et al. Adherence to acitretin and home narrowband ultraviolet B phototherapy in patients with psoriasis. J Am Acad Dermatol . 2008;59(4):577–581.

Factors that influence adherence behavior
16 Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol . 2004;140(4):408–414.
17 Baldwin HE. Tricks for improving compliance with acne therapy. Dermatol Ther . 2006;19(4):224–236.

Strategies to improve adherence behavior
18 Uhas AA, Camacho FT, Feldman SR, et al. The relationship between physician friendliness and caring, and patient satisfaction: Findings from an Internet-based survey. The Patient . 2008;1(2):91–96.
19 Marvel MK, Epstein RM, Flowers K, et al. Soliciting the patient’s agenda: have we improved? JAMA . 1999;281(3):283–287.
20 Feldman SR, Horn EJ, Balkrishnan R, et al. Psoriasis: improving adherence to topical therapy. J Am Acad Dermatol . 2008;59(6):1009–1016.
21 Wilson R, Camacho F, Clark AR, et al. Adherence to topical hydrocortisone 17-butyrate 0.1% in different vehicles in adults with atopic dermatitis. J Am Acad Dermatol . 2009;60(1):166–168.
22 Warino L, Balkrishnan R, Feldman SR. Clobetasol propionate for psoriasis: are ointments really more potent? J Drugs Dermatol . 2006;5(6):527–532.
23 Feldman SR. Approaching psoriasis differently: patient-physician relationships, patient education and choosing the right topical vehicle. J Drugs Dermatol . 2010;9(8):908–911.
24 Ong LM, de Haes JC, Hoos AM, Lammes FB. Doctor-patient communication: a review of the literature. Soc Sci Med . 1995;40(7):903–918.
25 Chisolm SS, Taylor SL, Gryzwacz JG, et al. Health behavior models: a framework for studying adherence in children with atopic dermatitis. Clin Exp Dermatol . 2010;35(3):228–232.

References *

1 Gupta G, Mallefet P, Kress DW, et al. Adherence to topical dermatological therapy: lessons from oral drug treatment. Br J Dermatol . 2009;161(2):221–227.
6 Carroll CL, Feldman SR, Camacho FT, et al. Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial: commonly used methods of measuring adherence to topical therapy overestimate actual use. J Am Acad Dermatol . 2004;51(2):212–216.
8 Richards HL, Fortune DG, O’Sullivan TM, et al. Patients with psoriasis and their compliance with medication. J Am Acad Dermatol . 1999;41(4):581–583.
9 Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol . 2006;55(4):607–613.
10 Feldman SR. Practical Ways to Improve Patients’ Treatment Outcomes . Winston Salem, North Carolina: Medical Quality Enhancement Corporation; 2009.
11 Storm A, Andersen SE, Benfeldt E, et al. One in 3 prescriptions are never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol . 2008;59(1):27–33.
14 Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth monitoring of adherence to topical medication: adherence is very poor in children with atopic dermatitis. J Am Acad Dermatol . 2007;56(2):211–216.
16 Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol . 2004;140(4):408–414.
17 Baldwin HE. Tricks for improving compliance with acne therapy. Dermatol Ther . 2006;19(4):224–236.

* Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com .
Part II
Important Drug Regulatory Issues
5 The FDA drug approval process

William H. Eaglstein


 Questions

Q5-1 In the broadest sense, what are the general areas of oversight by the US FDA? (Pg. 41)
Q5-2 Concerning the Food Drug and Cosmetic Law of 1938 and the Kefauver–Harris Drug Amendment of 1962, what is (a) the scope of the laws, and (b) the key impetus for passage of each? (Pg. 41x2)
Q5-3 Of drugs reaching clinical trials, what percent pass (a) phase I, (b) phase II, (c) phase III, and (d) receive an approved New Drug Application (NDA)? (Pg. 42)
Q5-4 What is involved in defining a drug ‘label’ and the related ‘off-label use’? (Pgs. 42, 43)
Q5-5 How does the pharmacovigilance process after drug release for marketing differ in the US versus several European countries? (Pgs. 43, 44)
Q5-6 What are the most important elements of the Prescription Drug User Fee Act of 1992? (Pg. 43)
Q5-7 Concerning a given FDA Advisory Panel, what is (a) the composition of members, (b) its primary purpose, and (c) its role in approving drugs or taking drugs off the market? (Pg. 43)
Q5-8 What general changes were allowed by the FDA Modernization Act of 1997? (Pg. 43)
Q5-9 Concerning bioequivalence testing for generic products and product reformulations, what are the testing requirements for (a) systemic drugs, (b) topical corticosteroids, and (c) other topical drugs? (Pgs. 44x2)
Q5-10 What are some issues regarding FDA regulation of ‘compassionate use’ (or ‘compassionate treatment’) IND? (Pg. 44)

Introduction
Q5-1 The US Food and Drug Administration (FDA) is the federal agency charged with regulating all of our foods, human and veterinary drugs, medical devices, biologicals, and cosmetics. Although the general public assumes that physicians know a great deal about the FDA, in fact physicians actually receive little education about the FDA in medical school, residency, or other postgraduate training. This may be partly because most FDA efforts deal largely with legal issues or social policy. However, science and medical research information is fundamental to carrying out the FDA’s missions, and the agency’s policies have a tremendous impact on public health and on the practice of medicine. The FDA regulatory jurisdiction (direct and indirect control) is estimated to encompass an enormous 25 cents of every dollar Americans spend. The FDA is part of the Health and Human Services Department, which is in the executive branch of the federal government. Thus, the FDA Commissioner is appointed by the President, with advice from and the consent of Congress. Until the 1992 imposition of ‘user fees,’ the FDA budget for the drug approval process was almost totally derived from Congress, which also has oversight responsibility for the FDA. The FDA now spends about $290 million on approving, labeling and monitoring drugs, with more than 2000 people throughout the agency involved in this process. This amount compares favorably with the $47 million spent in 1992, before the prescription drug user fees were instituted. Overall, the fiscal year 2010 FDA budget request was $3.2 billion (including $828 million in user fees), with approximately 11 000 employees. Clearly the FDA budget is too small, with too few employees to actively make or supervise all of the decisions affecting 25% of the gross national product. The system therefore depends on a great deal of voluntary self-regulation from the pharmaceutical industry. This chapter focuses primarily on the approval process for prescription drugs, although much of the information is also applicable to biologicals and devices.

Federal legislation for drug safety and efficacy

Food drug and cosmetic law
Q5-2 The first federal Food Drug and Cosmetic Act was enacted in 1938 ( Table 5-1 ). Considerable credit for its passage is given to the author, Sinclair Lewis, whose books describing conditions in the meat packing industry are said to have led to public outrage, and finally, congressional action. Physicians, however, were also active in promoting and creating federal standards. Prior to the 1938 Act there were no federal standards regarding drug safety or efficacy. This was the era of ‘snake oil’ and elixirs. However, the original Act only required that drugs be proved safe. It was assumed that doctors and patients could work out which drugs were effective, and that market forces would assure the success of only efficacious drugs. The current high cost of drug development has led some to call for a reversion to this standard by approving all safe drugs and allowing clinical experience and market forces to pick out those indications for which the drugs are truly effective.
Table 5-1 Timeline for major pharmaceutical legislation in the US Year Legislation regulating pharmaceutical industry 1938 Food Drug and Cosmetic Act 1962 Kefauver–Harris Amendment 1983 Orphan Drug Act 1984 Drug Price Competition and Patent Restoration Act 1992 Prescription Drug User Fee Act 1997 Food and Drug Administration Modernization Act (FADAMA)

Kefauver–harris drug amendment
Q5-2 Although thalidomide was never approved by the FDA and was never sold in the US, the birth defects the drug caused alarmed the US population so much that in 1962 Congress passed a comprehensive FDA reform bill known as the Kefauver–Harris Drug Amendment. This Amendment added the requirement that drugs also be proved effective before they could be marketed. Since then, all potential drugs have been required to be proved both safe and effective before approval for marketing (premarket approval).

General testing required prior to marketing
To satisfy the premarketing requirements, sponsors (usually pharmaceutical companies) test drugs by a variety of methods, including bioassays, animal models, and finally, human trials ( Table 5-2 ). The process is quite costly (from $600 million to $900 million) and takes about 15 years (which is double the time needed in 1964). The wide range in development costs reflects not only the variations inherent in the type of drug and the sponsor’s efficiency, but also a variety of accounting methodologies. For example, the cost of ‘losers’ (drugs that fail at some point in the development process) is typically added as a cost of developing the ‘winners.’ Other factors accounting for the wide range of drug development costs include whether the cited cost is in pre-tax or after-tax dollars, and whether the lost interest income on the dollars invested in the development process is included.
Table 5-2 FDA approval process Drug development stage Description Average # years – Laboratory and animal studies 6.5 * File IND with FDA – Clinical studies   Phase 1 Pharmacological profile 1.5 Phase 2 Safety and limited efficacy 2.0 Phase 3 Extensive trials 3.5 File NDA with FDA – FDA review and approval 1.5   Total for drug development process 15.0
* Patents usually issue relatively early in this time period.

Phase I–IV testing
Q5-3 For every 5000 pharmaceutical compounds evaluated or screened, 5 reach the stage of clinical trials, and only about 1 of these 5 actually reaches the market after FDA approval (see Table 5-2 ). Of those compounds reaching clinical trials, 70% pass Phase I, 33% pass Phase II, 27% pass Phase III, and 20% (1 in 5) receive an approved New Drug Application (NDA). The sponsors conduct and pay for those studies needed to prove safety and efficacy. The FDA evaluates and judges the test results, but rarely does drug testing. However, the FDA is involved in the sponsor’s test plans, especially those concerning human testing. As potential new drugs have not been proved safe and effective, they may not be given as therapy. The sponsor may give the investigational drug to patients for evaluation (testing) only after submitting an Investigative New Drug (IND) exemption.

Phase I testing
FDA guidelines for human testing divide the premarket testing process into three phases: I, II, and III. In Phase I, patients or healthy volunteers receive the drug in order to study its safety, along with metabolic and pharmacologic profiles. Usually, Phase I testing involves 20–80 subjects and the safety testing is general as well as specific, depending upon the toxicities detected in animal studies. Phase I is intended to give enough pharmacokinetic and pharmacologic information to allow the design of controlled clinical studies to be used in Phase II.

Phase II testing
In Phase II studies the drug is tested for safety and efficacy to determine the optimal dose or duration to be used in Phase III. Phase II usually involves several hundred subjects with the targeted condition.

Phase III testing
Phase III studies involve larger numbers of patients, usually several hundred to several thousand, most often in randomized controlled trials (RCT), to evaluate efficacy and safety in a larger, well-controlled setting. Q5-4 Phase III studies will also provide sufficient data to allow the development of a benefit–risk relationship and the development of a ‘label.’ FDA considers any written, printed, or graphic matter that is affixed to, or appears on, a drug or its package to be a label. Labels are required on all drugs involved in interstate commerce or held for sale after shipment or delivery in interstate commerce. Each word of a drug’s label has been scrutinized and often negotiated by both the FDA and the sponsor. The Physician’s Desk Reference is largely a collection of drug labels. Use of a drug for a condition or in a manner not described on the label gives rise to the phrase ‘off-label use.’ For totally new drugs (new molecular entities, NME), efficacy and safety must be demonstrated in at least two RCT. In RCT, patients receive either the drug being tested (the ‘active drug’) or the control drug (frequently a placebo). Usually RCT are double-blinded, which means that neither the patients nor the investigators know which agent – active or control – a given patient is receiving. All human (and animal) testing is approved by institutional review boards (IRB) at each investigative site.

Pharmacovigilance process
Q5-5 At the end of Phase III testing a new drug has usually been received by 1000–3000 patients. Given these numbers, it is not surprising that uncommon adverse effects are often not discovered until a drug has been on the market for several years. (See also Chapter 6 on Pharmacovigilance.)
Overall, 51% of approved drugs have serious adverse effects not detected before FDA approval. It is interesting to note that some other countries (unlike the US) have the post-marketing safety monitoring done by an organization separate from the organization that gives initial approval to a drug. For example, in the UK, drug approval and safety monitoring processes are entirely separate. The safety monitoring unit may order changes in product labeling or the outright withdrawal of a marketed drug. France has a well-developed network of regional pharmacovigilance centers, a national database for practitioners, and a drug safety journal. The recent FDA action severely restricting the use of the blockbuster diabetes drug rosiglitazone indicates a serious intent toward enhancing the response to post-marketing safety findings.

Phase IV studies
Occasionally the FDA approves a drug but requires additional studies or reporting. These studies are referred to as post-marketing, or Phase IV, studies. Until recently many of these post-marketing or post-approval studies were never carried out, but recent FDA action has resulted in far better compliance. In a related action FDA has developed a mandatory system for public reporting of all FDA-approved study results.

Prescription Drug User Fee Act
Q5-6 The Prescription Drug User Fee Act of 1992 was passed to help shorten the time needed for FDA to review New Drug Approval applications. By requiring sponsors to pay the FDA a fee (‘user fee’) to have their mandated studies evaluated, this law provided designated money with which FDA hired 600 new staff, mostly aimed at drug review, and reduced the time required for evaluation of NDA to between 12 and 18 months. The Prescription Drug User Fee Act was renewed in 1997 for a second 5-year period, and again in 2002. User fees have also been applied to the approval process for devices (2002) and animal drugs (2003).

FDA advisory panels
In order to assist in reaching decisions on a drug’s safety, efficacy, and benefit–risk ratio, the FDA often asks for advice from its standing, or ad hoc, advisory panels. Q5-7 These panels are composed of experts who are not full-time government employees. They are usually physicians, scientists, and statisticians who are special government employees for the time they serve, which is usually 1–2 days, once or twice a year. The panel members individually review the written information before their formal public meeting. At the FDA Advisory Panel meetings participants hear from the sponsor, the FDA, and other interested parties. The panels are convened to answer specific questions posed by the FDA about the drug application. The questions almost always include the broad issue of whether the sponsor has demonstrated safety and efficacy for the intended drug use. The FDA is not required to follow the advice of the advisory panels, but usually does. The panels’ conclusions are often mentioned in the popular press, leading patients to the misunderstanding that a new drug has been approved and is on the market. FDA Advisory Panels are not required for all new drugs.

Off-label drug use

General principles
Q5-4 Traditionally, once a drug was approved, it could only be marketed/promoted for the disease indication studied (intended use). Other uses are called ‘off-label’ because the FDA-approved written instructions and information (‘label’) are based on information just for the uses formally studied. Off-label treatment is fully legal and is very commonly used. For example, most pediatric treatments are off-label because few drugs have been developed and studied in populations of children. Even changing the total dosage or frequency of drug administration can make its use off-label. Many of the combination chemotherapy regimens used in oncology have not been approved by FDA, are not described on the label, and are often considered off-label. Examples of off-label uses common in dermatology include cyclosporine for atopic dermatitis and pentoxifylline for venous ulcers. Congress has been clear in its intent that the FDA should not interfere with the practice of medicine. As long as the physician is prescribing an approved drug for an off-label use to help the wellbeing of an individual patient, and has a reasonable scientific basis for expecting success, the off-label use is within the appropriate context of the practice of medicine. Such therapy may be referred to as innovative therapy. It should be noted that on occasion sponsors do seek label changes, and toward that end studies are submitted to FDA for approval. FDA approval of cyclosporine for use in psoriasis and Botox for hyperhidrosis are examples pertinent to dermatology.

Food and Drug Administration Modernization Act
Q5-8 In 1998, the Food and Drug Administration Modernization Act (FADAMA) of 1997 was changed, allowing pharmaceutical companies to promote (teach about and recommend to physicians) off-label uses of an approved drug. Typically this role is in the domain of ‘Medical Science Liaisons’ for pharmaceutical companies. Such off-label use promotion is allowed only if there are significant published data supporting the drug’s off-label use as both safe and effective, and showing that the sponsor is committed to conducting further studies of the drug for the off-label use. In addition to the changes on the promotion of off-label uses, the new Act allowed companies to advertise directly to consumers for approved prescription drugs. Some critics believe that direct-to-consumer advertising has reduced drug safety by expanding the number of people using drugs for marginal indications.

Generic drugs

Systemic drugs bioequivalence
Q5-9 When patents on the brand-name or pioneer drugs expire, generic formulations become available at prices generally much lower than those for brand-name drugs. Originally, generics were produced and sold by so-called generic drug companies. Recently, generic drugs have also been manufactured (and marketed by) the brand-name producers. Generic drugs must also be approved by FDA before being marketed. As noted earlier, to secure FDA marketing approval the pioneer drug must be shown to be safe and effective in clinical trials. However, after marketing, the pioneer drugs are often reformulated. The FDA standard for reformulated pioneer drugs and for generic drugs is that they must be shown to be the bioequivalent of the pioneer drug formulation. Bioequivalence is assumed to equal therapeutic equivalence. Bioequivalence is demonstrated by showing similar peak serum concentrations and area-under-the-curve values after a single oral dose of the generic or reformulated drug.

Topical drug testing required
Q5-9 As topical drugs usually do not have significant serum values, generic topical products and formulations, even if identical to the brand-name or pioneer drug, must be tested in clinical trials similar to those needed for pioneer drug approval. For generic topical corticosteroids, the Stoughton vasoconstrictor assay has been approved as a surrogate endpoint sufficient to allow marketing approval. No serious therapeutic differences between brand-name original (pioneer) drugs and FDA-approved generics have been reported for topical products.

Special drug approval categories

Compassionate use regulations
Q5-10 Treating patients with drugs under investigation, but not approved, for marketing in the US for any indication is very complicated. Regulations developed since the acquired immunodeficiency syndrome (AIDS) epidemic make it possible for patients to ‘import’ non-approved drugs for personal use under a physician’s care. ‘Compassionate use’ (also known as ‘compassionate treatment’) IND (as compared to study IND) are typically limited to patients who have received the test drug under protocol and who still need it after completion of the protocol. Drugs sold under a treatment IND are priced to recover only ‘costs’ rather than to achieve a profit.

Drug Price Competition and Patent Restoration Act
Many other laws have indirect, but important, general effects on the drug development and approval process. For example, because proving safety and efficacy is so time-consuming, the Drug Price Competition and Patent Restoration Act of 1984 gives the sponsor back some of the patent protection time consumed by meeting the premarketing approval requirements.

Orphan Drug Act
Similarly, the Orphan Drug Act of 1983 offers tax and other incentives to encourage companies to prove the safety and efficacy of drugs whose potential market (number of potential patients) is too small to allow recovery of their drug development costs.

Related issues

Regulation of over the counter drugs, biologicals, and generics
It is important to recognize that the approval process for devices, biologicals, and over-the-counter (OTC) drugs is similar to, but somewhat different from, the approval process for prescription drugs. For example, OTC drug status is dependent upon a much higher level of safety and a need for patients to be able to recognize independently when the drug is indicated. Also, many OTC products are marketed based on complying with an OTC monograph (for a drug group) requirement, rather than being based on conducting extensive premarket testing. Biologicals have not been subject to generic competition because of the many chemical and other technical differences between these large molecules and the traditional small molecular drugs. However, in very near future the FDA intends to define a pathway for the development of generic biological drugs, also known as biosimilars.

Regulation of combination products
The advent of agents composed of a device and a drug (such as vascular stents that release antithrombosis drugs) have led to the creation of an FDA office of combination products, which assigns such combination products to the proper reviewing authority within the FDA. Furthermore, physicians should recognize that there is not an FDA regulatory process for surgery.

Comparisons of FDA regulation with other countries
Q5-5 It should also be noted that the FDA’s drug regulatory process is considerably different from the drug regulatory process used in many other countries. For example, in some countries a non-governmental organization evaluates the data and submits a recommendation, which the government usually accepts. In other countries only safety data are required. However, the FDA processes are highly regarded by other countries, some of which use US FDA approval as the basis for their own country’s approval of a given drug. The FDA is proud of the fairly low number of approved drugs subsequently recalled or taken off of the market. At the same time, critics often lament the ‘drug lag’ that results in many drugs being available in other countries significantly before release in the US.

Some final thoughts
Finally, it is important to recognize that the laws governing the drug-approval process are drafted to meet broad public health and social policy considerations. The regulations developed to implement these laws quickly become complicated and are constantly fine-tuned to meet new circumstances and specific situations. In addition to Federal ‘Regulations,’ the FDA also issues ‘Guidances.’ Unlike Regulations, which are legally binding, Guidances represent the FDA’s current thinking and recommendations, but are not legally binding.

Common abbreviations utilized in this chapter FADAMA Food and Drug Administration Modernization Act FDA Food and Drug Administration IND Investigative new drug IRB Institutional review board NDA New drug application NME New molecular entity OTC Over the counter RCT Randomized controlled trial(s)

Bibliography: important reviews

eMedicinehealth. FDA Overview [Online]. http://www.emedicinehealth.com/script/main/art.asp?articlekey=59287&pf=3&page=1 , 22 September 2010.
FDA How Drugs are Developed and Approved. [Online] http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved.htm , 12 August 2010.
FY 2010 Summary of the FDA’s FY 2010 budget. [Online] http://www.fda.gov/aboutfda/reportsmanualsforms/reports/budgetreports/ucm153154.htm , 16 September 2010.
Okie S. Reviving the FDA. New Engl J Med . 2010;363(16):1492–1494.
6 Pharmacovigilance
verifying that drugs remain safe

Joel M. Gelfand, Sinéad M. Langan


 Questions

Q6-1 How is pharmacovigilance defined? ( Pg. 46 )
Q6-2 What are some recent examples of drugs removed from the market by the FDA as a result of the pharmacovigilance process (as well as the reason for the drug being removed)? ( Pg. 47 )
Q6-3 What are the three main categories of adverse effects used in pharmacovigilance? ( Pg. 47 )
Q6-4 What are some of the most important limitations of randomized controlled trials in generating drug safety data? ( Pg. 47 )
Q6-5 What is the public health impact of drug adverse effects? ( Pg. 48 )
Q6-6 Why are ‘new’ adverse effects of medications so frequently discovered after a drug has already been approved for marketing as safe and effective? ( Pg. 49 )
Q6-7 How is a ‘signal’ defined, regarding an important potential adverse effect due to a drug; likewise, how are these ‘signals’ generated in the pharmacovigilance process? ( Pg. 50 )
Q6-8 What are registries and how can they be used to monitor drug safety? ( Pg. 51 )
Q6-9 What are the advantages and disadvantages of meta-analyses in analyzing drug safety? ( Pg. 52 )
Q6-10 What are the key concepts for interpreting safety studies under the following headings (a) statistical issues, (b) study design, (c) outcomes analysis, and (d) assessing causality? ( Pg. 52 , Table 6-3 )

Do not be the first to prescribe a new medication, and do not be the last to prescribe an old one.
Sir William Osler

Introduction
Q6-1 Pharmacovigilance is defined as, ‘…the activities involved in the detection, assessment, understanding, and prevention of adverse effects or any other drug related problems…’. 1 All drugs have the capacity to cause adverse effects and no drug is completely safe. Medication safety is of particular concern for dermatologists, as most treatment indications involve diseases that are not life-threatening and are often chronic, requiring years of medical therapy. Although skin diseases can create substantial morbidity, physicians, regulatory agencies and society generally have less tolerance for risk when treating skin diseases. This chapter reviews the 8 key principles related to interpreting information related to drug safety. Knowledge of these principles is fundamental to making informed treatment decisions and to aid in the discussion of risk with patients.


Principle #1
The history of drug safety is marked by numerous examples of public health crises related to medical products initially thought to be safe when approved for use in humans.
The most dramatic events have resulted in a major regulatory response from government. Drugs previously thought to be ‘safe’ often have unknown adverse effects that only become apparent after years of use. Safety issues are particularly difficult to discover if they are rare or delayed in onset (e.g. cancer). The discovery of previously unknown serious adverse effects after a drug has been approved for marketing is common. 2 Therefore, it is very important that physicians scrutinize the safety of medications they prescribe and be aware of new safety information as it becomes available. Instructive examples of drug safety issues include:

• In 1937, 107 deaths, many in children, occurred in the United States from the use of a cough syrup that used diethylene glycol as a solvent. This event led to the 1938 Food Drug and Cosmetic Act, which for the first time required proof of safety prior to marketing.
• In 1955, over 40 000 children developed abortive polio (51 of whom were permanently paralyzed) and 5 died from a polio vaccine made by Cutter Laboratories that was not effectively inactivated during manufacturing. The incident also sparked a polio epidemic in the families and communities of those immunized with the defective vaccine, leading to an additional 113 people who were paralyzed and 5 more deaths. In ensuing lawsuits it was determined that pharmaceutical companies could be held liable for harm from their products even if there was no negligence (e.g. liability without fault). 3
• In 1961, over 10 000 children worldwide developed severe birth defects (phocomelia) related to in utero exposure to thalidomide. In the United States this event led to the Kefauver–Harris Amendment, which strengthened the requirements for safety testing and for the first time required proof of efficacy prior to a drug being marketed. This public health disaster also spurred the development of formal spontaneous reporting systems for pharmcovigilance which are still the primary method of identifying safety issues in approved medications.
• In the 1970s it was discovered that diethylstilbestrol caused clear cell adenocarcinoma of the cervix and vagina in women exposed in utero decades earlier.
• In 1984, PUVA was definitively linked to an increased risk of squamous cell carcinoma, approximately 10 years after the first description of PUVA therapy for psoriasis. 4 It took over 20 years to establish a link between PUVA and melanoma, which remains controversial. 5
• Over the past 4 decades more than 130 medications have been withdrawn from the market because of safety concerns. One-third of drug withdrawals occur within 2 years of being approved for marketing, and half occurred within 5 years of marketing. 7 Q6-2 Recent examples (since 1997) of prescription drugs removed from the market include classes of medications that are commonly prescribed, such as antihistamines (e.g. astemizole, terfenadine), non-steroidal anti-inflammatory agents (bromfenac, valdecoxib), antibiotics (trovafloxacin), lipid-lowering medications (cerivastatin) and an immunosuppressant for the treatment of psoriasis (efalizumab – progressive multifocal leucoencephalopathy). 6
• 51% of approved drugs have serious adverse effects not detected prior to approval.

Principle #2
Adverse reactions to medications are divided into three classes. Q6-3 These categories are based on whether the adverse effect is: (1) pharmacologic – type A, (2) idiosyncratic or allergic – type B, or (3) an effect that increases the risk of new morbidities over time – type C.
Type A effects are those related to pharmacological effects of the drug. Type A effects are usually common, dose related, and can be mitigated by using doses that are appropriate for the individual patient. An example would be cheilitis related to isotretinoin. Type A effects are generally well described by the time a drug is approved for marketing. Type A effects may be difficult to identify if they occur in only a very few patients (i.e. bone marrow suppression from azathioprine in patients with thiopurine methyltransferase deficiency), or when the phenomenon is trivial or the mechanism is unclear. An example would be flushing with alcohol intake in patients treated with topical tacrolimus.
Type B effects are those which are often idiosyncratic or allergic and typically are rare (<1 in 1000 people). Type B effects are often not detected before a drug is approved. Type B effects are usually discovered through spontaneous reports to pharmaceutical companies and the Food and Drug Administration (FDA). Because type B effects are very rare and often occur in close proximity to the initiation of a new medication, spontaneous reports of such events often offer compelling evidence that the drug caused the observed adverse reaction.
Type C effects are those that introduce new morbidities by altering the risk of diseases that occur over time. For example, chronic PUVA therapy increases the risk of squamous cell carcinoma. Type C effects can often have a substantial impact on public health. However, because they are relatively rare and often delayed, they are often not detected before a drug is approved for marketing. Type C effects typically require analytic studies in order to investigate the association of the drug with the effect in question.

Principle #3
Drugs are approved for marketing based on data from preclinical animal studies and randomized controlled trials (RCT) in patients. Although RCT are the gold standard for proving the efficacy of a medication, they have several important limitations with respect to defining the safety of a medication.
Q6-4 The limitations of safety data generated from the RCT used to approve a drug for marketing must be considered when interpreting safety data.

• RCT typically are short term , whereas real-world exposure to the medication may occur over a period of many years. For example, clinical trials of systemic psoriasis medications are typically 2–3 months in duration; however, in clinical practice these medications are used for much longer periods. 8 Therefore, adverse effects that may be delayed in onset, or that may be related to duration of exposure, are unlikely to be uncovered by short-term RCT.
• RCT typically occur in highly selected patient groups of individuals who have minimal comorbidities. Therefore, the safety of using medications in patients with comorbidities such as coronary artery disease, diabetes, chronic obstructive pulmonary disease, cancer, or the young or elderly or in pregnancy, is not well defined.
• RCT typically occur in relatively small populations of patients. When a drug is approved for marketing, typically 500–3000 patients have been treated for a short time (weeks to months) in RCT. Additionally, another 1000–2000 patients may be treated in uncontrolled confirmatory studies prior to a drug being approved. As a result, RCT used to approve medications for marketing usually can only clearly describe adverse event rates that occur in about 1% of patients, and often cannot begin to detect rare adverse events (those occurring in <1/1000).
• RCT typically evaluate a single drug , with limitations on other medications the enrolled patient may be taking. Subsequently, the drug used in clinical practice may be given to patients receiving multiple medications, allowing the possibility of drug interactions not previously recognized.
The RCT is the gold standard study design for proving causality. However, RCT are limited by the generalizability of the results. Therefore, caution is advised when prescribing a medication for a patient who is not typical of patients in the RCT. Importantly, adverse drug reactions have been observed to occur at increased frequencies in populations not well represented in clinical trials, such as children and the elderly, and those with hepatic and renal impairment. 9 Additionally, the incidence of adverse events may vary by ethnicity and gender. 9 Also, as RCT are typically of short duration (e.g. months) they provide minimal information on the safety of long-term exposure to a medication. This limitation is a particular problem for defining type C effects, such as cancer, which may have a prolonged latency period from exposure to the development of the adverse effect. Finally, RCT as conducted for the current drug approval process are generally designed to define just relatively common adverse effects (e.g. those affecting at least 1% of patients).

Principle #4:
A study that does not observe an adverse effect does not necessarily mean the medication does not cause the adverse effect in question. Large studies are necessary to identify adverse effects that, although rare, can be of public health importance.
The statistical power of a study to detect the adverse event of interest is also a major limitation of many safety studies. This limitation particularly applies to rare adverse effects, which typically occur at rates of about 1 in 1000. Unfortunately, many serious adverse effects that are of concern are ‘rare’. Table 6-1 demonstrates that adverse events that have been concerning to dermatologists (e.g. suicide associated with isotretinoin, lymphoma associated with immunosuppressive therapy for psoriasis) occur less frequently than 1 in 1000 people per year. To adequately investigate risks that occur at 1 in 1000 patients, approximately 3000 patients exposed to the medication need to be studied. 10
Table 6-1 Incidence rates of various causes of death or serious health outcomes 26 – 28 Cause of death Rate per 100 000 people per year All causes 847.3 Heart disease 241.7 Cancer 193.2 Acute myocardial infarction 62.3 Chronic lower respiratory disease 43.3 Motor vehicle accidents 15.7 Suicide 11 Lymphoma 8.1 Homicide 6.1 HIV 4.9 Skin cancer 2.6 Medical and surgical treatment 1 Commercial airline accident 0.032 Lightening strike 0.015 Serious health outcome Rate per 100 000 people per year Lymphoma 21.7 Melanoma 17 Toxic epidermal necrolysis (TEN) 0.05–0.19 TEN from antibacterial sulfonamides 0.45 per 100 000 exposures
If a study does not observe an adverse effect, it is critical to know the statistical power of the study to detect the adverse effect if the medication truly was associated with it. Statistical power is defined as the probability of observing an association, given that one truly exists. By examining the 95% confidence interval (CI) of a relative risk or odds ratio, one can determine whether the sample size was adequate to rule out a potentially important association. For example, in a study of 1252 patients with psoriasis treated with cyclosporine for an average of 1.9 years, no statistically significant risk of lymphoma was observed (incidence ratio 2.0, 95% CI 0.2–7.2). 11 However, because of the small sample size, this study could not rule out a 7-fold increased risk of lymphoma based on the confidence interval. Additionally, the ‘rule of threes’ can be used to carefully scrutinize studies that do not observe an adverse event. To use this rule, one takes the reciprocal of the number of patients in the study and multiplies it by 3 to determine the range of results that could be statistically consistent with the observed findings based on a 95% CI. In other words, if the study was repeated 100 times, 95% of the results would occur within the 95% CI. In this approach the statistics report a range of results that could be consistent with the findings, in contrast to the method in the previous paragraph, in which the statistics report approximate numbers.
For example, if a study followed 300 patients on methotrexate for 1 year and observed no cases of lymphoma, then the study would be 95% certain that the true rate of lymphoma was no greater than (1/300) × (3) = 1/100 per person-year. However, the baseline risk of lymphoma is approximately 1/5000 per person-year. Therefore, such a result could be consistent with a 50-fold relative risk of lymphoma, demonstrating that in this example the study would lack statistical power to determine the risk of lymphoma in methotrexate-treated patients. This example also demonstrates that the individual clinician cannot rely on their own experience to determine whether a drug is associated with a rare adverse effect, and therefore must rely on large long-term studies in order to fully capture information on the safety of medications they prescribe.

Principle #5
Although rare adverse effects may be unlikely to affect the individual patient, they are of public health importance because millions of patients may potentially be exposed to the drug. It can take years to definitively prove the relationship between a drug and an adverse effect, which further compounds the public health impact.
Q6-5 Some important statistics to consider regarding this principle are:

• Patients in the US received 3.1 billion prescriptions in 2004, 60% more then a decade earlier. 10 Because medications are used by such a large population, rare adverse effects have the ability to affect many individuals.
• Overall, 4% of patients in ambulatory medical practices experience serious adverse effects from medications. 12
• 1.5 million people are hospitalized annually for adverse drug reactions, comprising 5% of all admissions. 13
• An estimated 100 000 Americans die each year ( no doubt a controversial study ) from adverse drug reactions. 13
An important example of this principle is the impact of cyclooxygenase-2 (COX-2) inhibitors on public health. When rofecoxib was approved in 1999 it was noted that, based on biologic actions, it could theoretically increase the risk for thrombosis. 14 Although an increased rate of thrombotic events was seen in short-term RCT, these findings were not statistically significant as the sample size (about 2200 people) was inadequate to provide sufficient statistical power. In 2004, a series of large long-term RCT of COX-2 inhibitors definitively linked them to the risk of myocardial infarction. Although myocardial infarction is statistically uncommon, millions of patients were exposed to COX-2 inhibitors. For rofecoxib alone, it is estimated that 88 000–140 000 excess cases of myocardial infarction occurred during the 5-year period when this drug was on the market. 15

Principle #6
Q6-6 The drug approval process rigorously defines the efficacy of an agent. However, when a drug is approved, safety issues such as adverse events which are uncommon, delayed in onset, or occur at higher frequencies in subpopulations, are not well defined.
The drug approval process represents a trade-off between minimizing delays in access to new medications with delays in fully defining the safety of a medication. Therefore, pharmacovigilance is a critical component of ensuring that drugs approved for marketing remain ‘safe’ when used in large populations of patients. Figure 6-1 summarizes the process of investigating drug safety in the United States from the point of initial development to post-approval surveillance.

Fig. 6-1 Overview of investigation into drug safety in the United States.
Pharmacovigilance occurs primarily through physicians and patients voluntarily reporting adverse effects to pharmaceutical companies and regulatory agencies, such as the FDA. Since 1968 the FDA has collected data on over 8000 drugs and biologic products, cumulating in over 2.5 million reports. 14 The FDA receives about 370 000 reports annually: only 10% of these are submitted directly to the FDA and 90% are initially submitted to pharmaceutical companies. Physicians can report adverse reactions to medications, biologics, and cosmetics through the FDA-sponsored MedWatch program by telephone or via the web, http://www.fda.gov/medwatch/index.html . Physicians are particularly encouraged to report serious adverse events (those that result in death, hospitalization, disability , a congenital anomaly , or are life-threatening or require intervention to prevent permanent impairment of damage) even if they are not certain there is a causal relationship with the medication in question. The FDA maintains spontaneous reports in the Adverse Event Reporting System (AERS) database. Additionally, formal spontaneous reporting systems exist in over 60 countries worldwide, with pharmacovigilance efforts coordinated by the World Health Organization. 16
Important advantages of spontaneous report programs include:

• Capture data on all prescribers, drugs, patients, and dispensers;
• Relatively inexpensive;
• Can be useful for detecting novel adverse effects.
Reports of adverse events by physicians can be critical in identifying previously unknown reactions to medications. Dermatologic adverse events can herald important drug safety issues, as demonstrated by practolol-induced oculomucocutaneous syndrome and L -tryptophan-induced eosinophilic myalgia syndrome, both of which were identified through spontaneous reports. 17, 18
Important disadvantages of spontaneous reporting include:

• Adverse effects from medications are seriously under-reported, studies having suggested that only about 1% of adverse reactions are reported. 9, 18
• The number of people exposed to a medication in a population captured by spontaneous reporting systems is not well defined (thus, lacks denominator data).
• Spontaneous reporting systems such as AERS cannot be used to determine the true incidence or risk of an adverse effect, since the number of true cases and the number of individuals exposed are poorly defined.
• There is substantial bias in the reporting of adverse events. Adverse event reporting is more likely to occur within the first 2 years of drug approval or if there is media attention related to a particular adverse event. 19
• Spontaneous reporting systems generate case report and case series data, and as a result, the causal nature of these reports usually cannot be determined.

Principle #7
Q6-7 Case reports of adverse events are used as part of signal generation. A signal is defined as a set of data constituting a hypothesis that is relevant to the rational and safe use of a drug in humans. 20
Signals can be generated by spontaneous case reports, epidemiologic studies, clinical trials, and in vitro and animal studies. Signals are typically identified by expert clinical reviewers of spontaneous reports. Additionally, new computer programs using bayesian statistical algorithms are being used to mine spontaneous reporting databases for potential safety signals. 21 Case reports provide particularly compelling signals when the adverse reaction regresses with discontinuation of the drug and recurs if the drug is reintroduced. Spontaneous reports are also compelling if the event is very rare. 22 For example, in 2009 efalizumab was withdrawn from the market after 3 confirmed and 1 suspected case of progressive multifocal leukoencephalopathy (PML) after more than 46 000 people had been exposed to the drug. 6 Despite the limitations of case reports, they are the most frequently used form of evidence to withdraw a medication from the market or alter a product’s label. 23 Recent examples of safety signals identified by spontaneous reporting in dermatology include isotretinoin and suicide, biologics and lymphoma, and topical immune modulators (pimecrolimus, tacrolimus) and lymphoma. In each of these examples no definitive drug causation has been established.

Principle #8
An observed association or ‘signal’ does not necessarily mean causation. A breadth of scientific data is necessary to test the hypothesis generated by a ‘signal’ to determine whether drug ‘causation’ is likely.
Study designs used to investigate drug safety as part of pharmacovigilance are summarized in Table 6-2 . 24, 25 Case reports, case series, cross-sectional studies, secular trends and ecologic studies are considered descriptive studies which are best used to generate hypotheses. Case–control, cohort, case–crossover, and clinical trials are analytic studies which are designed to test hypotheses. Case–control and cohort studies are often performed using existing patient databases, which allows for efficiency in the conduct of these studies. 18 Figure 6-2 details the calculation of measures of association from case–control and cohort studies. Case–control studies generate odds ratios as a measure of association, whereas cohort studies (and clinical trials) generate relative risks. Odds ratios may overestimate the relative risk if the outcome being studied is common (e.g. occurs in more than 10% of patients). Cohort studies and clinical trials also allow one to calculate the attributable risk (also called risk difference), which provides information on the excess risk of disease in those exposed compared to those unexposed. To better understand the magnitude of risk one can also calculate the number needed to ‘harm,’ which is the number of patients clinicians need to expose to the factor in order to observe 1 excess case related to that exposure. Owing to the limitations of spontaneous reporting the FDA often requires a commitment to undertaking post-marketing safety studies as a condition of approval; however, the proportion of completed Phase IV studies has dropped from 62% in 1970 to 24% in 1998. 26 The 2007 FDA Administration Amendments Act increased the power of the FDA, enabling them (1) to require post-marketing studies and to fine companies if these studies are not completed, and (2) to order changes in a drug’s label after approval of that drug. 27 Although RCT are the gold standard for causality, case–control and cohort studies are often more appropriate to address the hypotheses generated by case reports and other forms of signal generation.

Table 6-2 Overview of pharmacoepidemiology study designs

Fig. 6-2 Measures of association from analytic studies.
Data from analytic studies are typically analyzed using a 2 × 2 table, as shown above. Case–control studies yield odds ratios, whereas cohort studies and clinical trials yield relative risks. The magnitude of risk can be measured by calculating the attributable risk and the number needed to harm.
Two increasingly used modalities for pharmacopidemiology studies are registries and meta-analyses. Q6-8 Briefly, a registry is a roster of people with a common characteristic, either a disease or a drug exposure, where systematic data are collected. An example in dermatology is the registries established to study the safety of topical calcineurin inhibitors, based on signals from animal studies and data relating to oral ingestion of these agents. 28 Registries have the advantage of yielding a well-defined ‘numerator’ of adverse events and a ‘denominator’ of those exposed to the medication, which can aid in signal detection. Registries require appropriate controls and statistical adjustment in order to test hypotheses raised by safety signals.
Q6-9 Meta-analyses are used to overcome the lack of power of individual RCT and the lack of a control group that affects many registry designs. Meta-analyses combine data from different studies quantitatively to determine an overall estimate of relative risk. However, there are some critical issues related to the methodology of meta-analysis that investigators using this technique need to be aware of. 29 These include (1) heterogeneity between study populations and designs, (2) publication bias, (3) need for appropriate statistical techniques when analyzing rare outcomes, (4) lack of access to original source data for inclusion, and (5) incomplete retrieval of published studies.
All studies, whether observational (e.g. case–control or cohort) or experimental (e.g. clinical trials), have important limitations that must be considered. Q6-10 Table 6-3 summarizes the key methodological issues that must be considered when interpreting studies related to the safety of a medication. If an association is not due to statistical error (e.g. chance) or issues related to the design of the study (e.g. confounding or bias) then a causal relationship may be considered.
Table 6-3 Summary of factors to consider when interpreting safety studies Q6-10 Factor to be scrutinized Question to be addressed Statistical issues Chance (type I error, α error) Were the observed findings due to chance? A P value of 0.05 implies that there is a 5% probability that the observed finding was due to chance. Studies looking at multiple outcomes (e.g. cohort studies) may be more prone to finding statistically significant findings by chance alone due to multiple comparisons. Power (type II error, β error) If the study was negative (no effect), what was the probability of detecting an effect if one was truly present. What magnitude of effect was the study powered to detect? Precision How precise is the estimate of effect? What was the range of results statistically consistent with the observed finding (e.g. 95% confidence interval)? Did the study’s confidence interval include/exclude the relative risk that is important to detect? Study design Confounding Is there a third factor that is associated with the exposure of interest and, independent of the exposure, is a risk factor for the outcome being studied? Was it controlled for? Confounding by indication Is the disease being treated a risk factor for the outcome independent of the medication? Information bias Was the exposure and outcome measured the same way in both groups? Selection bias Were the two groups enrolled in the study similar with respect to important determinants of outcome except for the exposure of interest? Sensitivity analyses Are the findings robust to changes in the definition of exposure or outcome? What degree of potential confounding or bias would be necessary to remove the observed association? Generalizability Was your patient well represented in the study? Do the results apply to your patient? Outcome Magnitude of risk What is the magnitude of the increased risk (above the background risk) associated with the exposure? This can be determined through calculation of the attributable risk and number needed to harm ( Figure 6-2 ). Risk vs. benefit Does the magnitude of risk associated with the treatment outweigh the benefit for the patient? Assessing causality Time sequences of events Studies need to clearly demonstrate that the adverse effect occurred after the initiation of the medication.   The biologic plausibility of the association Understanding the mechanism by which a drug induces an adverse effect is helpful in establishing a causal relationship. However, biologic plausibility is not necessary to establish causation.   Dose response Evidence that a higher dose of a medication is associated with a higher rate of the adverse event provides compelling evidence of a causal relationship.   Strength of study design Analytic studies are more compelling then descriptive studies. Randomized controlled trials are the gold standard for assessing causality. However, RCT have important limitations for studying safety endpoints (as described above) and are often impractical.   Strength of association High relative risks or odds ratios (e.g. >2 or 3) from cohort studies or case–control studies provide more compelling information in support of a causal relationship.   Consistency with other studies Multiple studies with similar findings provides information supporting a causal relationship.

Summary
Tremendous progress has been made in the pharmaceutical treatment of dermatologic disorders. In recent years we have seen an explosion of new topical and systemic medications that can dramatically improve the quality of life of patients living with skin disease. As a result, more patients than ever are being treated with medications on a long-term basis for diseases that are not life-threatening or do not have a risk of permanent disability. Therefore, the principles of pharmacovigilance are particularly relevant to the current practice of dermatology. As new safety information becomes available, prescribers need to consider the scientific validity and limitations of such information and the potential risk versus benefit in making treatment decisions with the patient.

Common abbreviations used in this chapter AERS Adverse Events Reporting System COX-2 Cyclooxygenase-2 FDA Food and Drug Administration PML Progressive multifocal leukoencephalopathy RCT Randomized controlled trial(s)

Bibliography: important reviews and chapters

Hennekens CH, Buring JE. Epidemiology in Medicine, Chapter 6 . Little, Brown and Company; 1987.
Rothman KJ, Greenland S. Case control studies. Rothman KJ, ed. Modern epidemiology, 2nd ed, Philadelphia: PA Lippincott-Raven, 1998.
Strom B, ed. Pharmacoepidemiology. New York: John Wiley and Sons, Ltd, 2000.

Web references

History of drug safety: principle #1
1 World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products . Geneva: WHO Uppsala Monitoring centre; 2002.
2 Routledge P. 150 years of pharmacovigilance. Lancet . 1998;351(9110):1200–1201.
3 Offit P. The Cutter incident, 50 years later. N Engl J Med . 2005;352(14):1411–1412.
4 Stern R, Nijsten T, Njisten T. Insuring rapid and robust safety assessment. J Invest Dermatol . 2004 Mar;122(3):857–858.
5 Stern R, Nichols K, Väkevä L. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med . 1997;336(15):1041–1045.
6 Tsintis P, La Mache E. CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications. Drug Saf . 2004;27(8):509–517.
7 Seminara N, Gelfand J. Assessing long-term drug safety: lessons (re) learned from Raptiva. Semin Cutan Med Surg . 2010;29(1):16–19.

Categorization of adverse reactions: principle #2 (no references)
Preclinical trials: principle #3
8 Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis 1977-2000: the EDEN survey. J Invest Dermatol . 2003;120(5):738–741.
9 Khong TK, Singer DR. Adverse drug reactions: current issues and strategies for prevention and management. Expert Opin Pharmacother . 2002;3(9):1289–1300.

Statistical power to detect rare adverse event: principle #4
10 Okie S. Safety in numbers–monitoring risk in approved drugs. N Engl J Med . 2005;352(12):1173–1176.
11 Paul C, Ho V, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol . 2003;120(2):211–216.

Public health importance rare adverse events: principle #5
12 Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med . 2003;348(16):1556–1564.
13 Strom B. What is Pharmacoepidemiology. In: Strom B, ed. Pharmacoepidemiology . New York: John Wiley and Sons, LTD; 2000:3–16.
14 Psaty BM, Furberg CD. COX-2 inhibitors–lessons in drug safety. N Engl J Med . 2005;352(11):1133–1135.
15 Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet . 2005;365(9458):475–481.

Safety issues remainig after drug approval: principle #6
16 Olsson S. The role of the WHO programme on International Drug Monitoring in coordinating worldwide drug safety efforts. Drug Saf . 1998;19(1):1–10.
17 Venning GR. Identification of adverse reactions to new drugs. II (continued): How were 18 important adverse reactions discovered and with what delays? Br Med J (Clin Res Ed) . 1983;286(6362):365–368.
18 Rodriguez EM, Staffa JA, Graham DJ. The role of databases in drug postmarketing surveillance. Pharmacoepidemiol Drug Saf . 2001;10(5):407–410.
19 Kennedy DL, Goldman SA, Lillie RB. Spontaneous Reporting in the United States. In: Strom B, ed. Pharmacoepidemiology . New York: John Wiley and Sons, Ltd; 2000:151–174.

Drug safety signals: principle #7
20 Meyboom RH, Egberts AC, Edwards IR, et al. Principles of signal detection in pharmacovigilance. Drug Saf . 1997;16(6):355–365.
21 Hauben M. A brief primer on automated signal detection. Ann Pharmacother . 2003:37. (7-8):1117–23
22 Begaud B, Moride Y, Tubert-Bitter P, et al. False-positives in spontaneous reporting: should we worry about them? Br J Clin Pharmacol . 1994;38(5):401–404.
23 Arnaiz JA, Carne X, Riba N, et al. The use of evidence in pharmacovigilance. Case reports as the reference source for drug withdrawals. Eur J Clin Pharmacol . 2001;57(1):89–91.

Assessing drug causation: principle #8
24 Etminan M, Samii A. Pharmacoepidemiology I: a review of pharmacoepidemiologic study designs. Pharmacotherapy . 2004;24(8):964–969.
25 Barzilai DA, Freiman A, Dellavalle RP, et al. Dermatoepidemiology. J Am Acad Dermatol . 2005;52(4):559–573.
26 Psaty B, Charo R. FDA responds to institute of medicine drug safety recommendations–in part. JAMA . 2007;297(17):1917–1920.
27 Schultz W. Bolstering the FDA’s drug-safety authority. N Engl J Med . 2007;357(22):2217–2219.
28 Kapoor R, Hoffstad O, Bilker W, Margolis D. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis. Pediatr Dermatol . 2009;26(6):682–687.
29 Hennekens C, Demets D. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA . 2009;302(21):2361–2362.

References *

1 World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products . Geneva: WHO Uppsala Monitoring centre; 2002.
3 Offit P. The Cutter incident, 50 years later. N Engl J Med . 2005;352(14):1411. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)2
4 Stern R, Nijsten T, Njisten T. Insuring rapid and robust safety assessment. J Invest Dermatol . 2004 Mar;122(3):857. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)8
6 Tsintis P, La Mache E. CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications. Drug Saf . 2004;27(8):509. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)17
7 Seminara N, Gelfand J. Assessing long-term drug safety: lessons (re) learned from Raptiva. Semin Cutan Med Surg . 2010;29(1):16–19.
9 Khong TK, Singer DR. Adverse drug reactions: current issues and strategies for prevention and management. Expert Opin Pharmacother . 2002;3(9):1289. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)300
10 Okie S. Safety in numbers–monitoring risk in approved drugs. N Engl J Med . 2005;352(12):1173. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)6
11 Paul C, Ho V, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol . 2003;120(2):211. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)6
12 Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med . 2003;348(16):1556–1564.
14 Psaty BM, Furberg CD. COX-2 inhibitors–lessons in drug safety. N Engl J Med . 2005;352(11):1133. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)5
17 Venning GR. Identification of adverse reactions to new drugs. II (continued): How were 18 important adverse reactions discovered and with what delays? Br Med J ( Clin Res Ed ) . 1983;286(6362):365. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)8
19 Kennedy DL, Goldman SA, Lillie RB. Spontaneous Reporting in the United States. In: Strom B, ed. Pharmacoepidemiology . New York: John Wiley and Sons, LTD; 2000:151. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)74
20 Meyboom RH, Egberts AC, Edwards IR, et al. Principles of signal detection in pharmacovigilance. Drug Saf . 1997;16(6):355. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)65
24 Etminan M, Samii A. Pharmacoepidemiology I: a review of pharmacoepidemiologic study designs. Pharmacotherapy . 2004;24(8):964. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)9
29 Hennekens C, Demets D. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA . 2009;302(21):2361. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)2

* Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com .
7 Drugs taken off the market
important lessons learned

Stephen E. Wolverton, Susan J. Walker


 Questions

Q7-1 Concerning product labeling for a specific drug, (a) what are the 4 components of the ‘label’, (b) what is the purpose of the label, and (c) what are ways that some flexibility is built into the process? (Pg. 54)
Q7-2 What is the individual purpose of each of following sections of the product label: (a) clinical studies, (b) adverse reactions, (c) warnings and precautions, and (d) contraindications? (Pgs. 54, 55)
Q7-3 How are the strongest possible warnings and strategies concerning drug risks communicated through (a) boxed warnings, and (b) risk evaluation and mitigation strategies (REMS)? (Pg. 55)
Q7-4 Concerning ‘Elements to Assure Safe Use’ strategies, what is (a) the purpose of these strategies with respect to REMS, and (b) a specific example pertinent to the daily practice of dermatology? (Pg. 55)
Q7-5 How do the concepts of ‘signals’ and ‘labeling changes’ relate to FDA Adverse Events Reports? (Pg. 55)
Q7-6 What are 5–6 of the online sources for ‘electronic’ information from the FDA concerning drug safety information? (Pg. 55)
Q7-7 What are several of the most important issues that the FDA may consider regarding a potential drug withdrawal? (Pg. 56)
Q7-8 What are several of drugs of potential central or peripheral significance to dermatology that have been taken off the market in association with (a) liver toxicity ( Table 7-1 ) , (b) cardiac arrhythmias ( Table 7-2 ) , (c) other cardiovascular toxicity ( Table 7-3 ) , and (d) neurologic toxicity ( Table 7-4 ) ?
Q7-9 What ‘lessons’ can be ‘learned’ from issues leading to drug withdrawal of products listed in the above 4 tables. (See ‘Principles’ #1 through #13 starting Pg. 56)

Introduction
The goal of drug development is to provide safe and effective pharmaceutical products for use in the treatment of clinical diseases and conditions. The vast majority of approved drug products remain on the market, with routine revisions to labeling as needed. In some instances new safety information may provide a basis for significant safety labeling changes or considerations for market withdrawal. This chapter will focus on tools that can be used to communicate risk and benefit, and provide examples of products whose risks were considered to outweigh the benefits.
Q7-1 Product (drug) labeling (including the physician package insert, patient package insert, carton/container labeling, medication guide) is a summary of the essential scientific information needed for the safe and effective use of the drug. The approval of original New Drug Applications (NDA) and Biologics Licensing Applications (BLA) results in product labeling intended to define and describe the conditions under which the product has been determined to be safe and effective, with the benefits outweighing the risks. This original labeling provides a baseline for continued risk management activities for the product. As new indications are proposed for marketing approval, or as new safety information becomes known, the risks and benefits of the product may change. Drug product labeling is dynamic and intended to be amended via supplemental labeling applications that keep abreast of new safety and efficacy information. This capacity for labeling changes allows new information regarding product risks and benefits to be provided for physicians and patients.

Presentation of benefit–risk in labeling
Product labeling describes the conditions under which a product has been determined to be ‘safe and effective:’ in other words, it describes the conditions under which the product has been determined to provide a reasonable balance of risks and benefits. Although considerations of risk–benefit assessment are ultimately informed by the totality of available information, product labeling provides safety information in discrete sections with levels of interest. Q7-2 The Clinical Studies section contains primarily efficacy information describing the adequate and well-controlled studies that provided the primary support for effectiveness, including the study design and efficacy outcomes, without an emphasis on safety information. The Adverse Reactions section is intended to contain information that would be useful to healthcare providers making treatment decisions, monitoring and advising patients, including adverse events where a causal relationship exists, and also rare serious reactions unusual in the absence of drug therapy. Exhaustive lists of every reported adverse event, including those not plausibly related to drug therapy, are not considered relevant in this section, as such lists are not informative and tend to obscure more clinically meaningful information. Warnings and Precautions sections include adverse reactions that are serious or otherwise clinically significant relevant to the indication, events that may require discontinuation of the drug or dosage adjustment, or may interfere with a laboratory test. Unobserved yet expected adverse reactions based on pharmacology, chemistry or animal data or related to unapproved uses may be included in this section.
Q7-2 The Contraindications section describes instances in which risks clearly outweigh any possible benefit and is intended to capture known hazards only, not theoretical possibilities.
Q7-3 Two additional instruments, the ‘Boxed Warning’ and a Risk Evaluation and Mitigation Strategy (REMS), may be implemented to address a safety concern. Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required to be presented in a boxed warning. The Boxed Warning (traditionally known as a ‘black box warning’) ordinarily must be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. 1 This warning is intended to highlight for prescribers an event that is (1) so serious with regard to the potential benefit from the drug (i.e. a fatal, life-threatening or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using the drug; or (2) there is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation). Boxed Warnings may be updated as new information becomes available. In mid-2011 the FDA Adverse Event Reporting System (AERS) database and published medical literature provided post-marketing information on the tumor necrosis factor-α (TNF-α) blockers (infliximab, etanercept, adalimumab, certolizumab, golimumab) to inform a revision of the Boxed Warning to include the risk of infection from the bacterial pathogens Legionella and Listeria .
In some instances REMS may also be necessary to ensure that the benefits of a drug outweigh the risks. Q7-4 These programs (REMS) are intended to provide for continued availability of products that have been determined to have significant risks that must be mitigated in order to continue marketing of the product. Isotretinoin is marketed with a REMS, including Elements to Assure Safe Use (ETASU), implemented as the iPledge program. A summary of Elements to Assure Safe Use may be required if a drug has been shown to be effective but is associated with a serious adverse event, and can be approved only if, or would be withdrawn unless, such elements are required as part of a strategy to mitigate the specific serious risk(s) listed in the labeling of the product. Elements to Assure Safe Use may be required for approved products when an assessment and Medication Guide, patient package insert, or communication plan are not sufficient to mitigate these risks. The goals of the iPledge program are to (1) prevent fetal exposure to isotretinoin, and (2) inform prescribers, pharmacists, and patients about isotretinoin serious risks and safe-use conditions.

Product label ‘lifecycle’ changes
In order to change existing labeling, the drug company submits a supplemental application to the FDA for approval. There are various types of supplements, but generally these are either (1) efficacy supplements (intended to add a new indication for an already marketed product), or (2) safety/labeling supplements. An applicant may submit labeling supplements for review at any time and without prior notification to the FDA; however, the FDA was recently given the authority 2 to require safety-related labeling changes based on new safety information (such as information derived from a clinical trial, adverse event report(s), peer-reviewed literature, or other scientific data)that becomes available after product approval. Q7-5 Adverse Events Reports (spontaneous case reports) have proved to be a primary mechanism by which drug regulatory agencies detect ‘signals’ regarding emerging post-marketing safety concerns. Generally, applicants will work voluntarily with FDA to incorporate labeling changes related to new safety information, and the appropriate labeling changes will be proposed by the application holder and approved by the agency. Important safety information will be communicated to physicians and patients by the agency, and the FDA currently uses one safety communication, the ‘Drug Safety Communication’, to provide the public with easy access to important drug safety information. These communications also provide recommendations for action that can be taken by patients or caregivers to avoid or minimize the potential for harm from a drug, and are issued when FDA has information that would help doctors and patients make better treatment choices. This type of communication is part of FDA efforts to communicate early with the public when the agency is still evaluating data and has not reached a conclusion. FDA shares information in the interest of informing doctors and patients about the issues under review, and when FDA experts anticipate completing their review. Prior to ordering a safety labeling change, FDA would generally form a multidisciplinary team to evaluate the information. If the safety information is relevant to more than one member of a drug class, the affected class would be identified and the review staff in all relevant review divisions and offices would participate. Team discussions and evaluations of new safety information may include internal FDA meetings, Drug Safety Oversight Board, or FDA Advisory Committee meetings. Public meetings and safety communication venues are used by FDA to outline available data, obtain public input, and explain the FDA decision-making process.

RISKS AND BENEFITS: FDA safety information
Q7-6 FDA provides information regarding drug safety in multiple venues. Some examples of physician and patient communications for drug safety information include:

1. An online 3 ‘Index to Drug Specific Information’ includes only drugs that have been the subject of a Drug Safety Communication or equivalent (previously known as Early Communication/Health Care Professional Information Sheet), and provides direct access to the content of each communication.
2. MedWatch Alerts 4 contain actionable information that may affect both treatment and diagnostic choices and provide timely medical product information. The MedWatch gateway 3 provides opportunities to sign up for MedWatch email updates, subscribe to RSS Feed safety alerts, and follow MedWatch on Twitter.
3. Daily Med, 5 a website developed with the National Library of Medicine, gives physicians and patients electronic access to FDA-approved drug labels. The presentation includes a ‘tabbed’ format, providing quick access to specific portions of product labeling, including reproductions of the carton and container.
4. Drugs@FDA 6 , an online database of approved drug products, allows a search for information regarding drugs and biologic products by drug name or active ingredient. Electronic links to the product approval history, approval letters, reviews and related documents, labeling information, REMS information and medication guides are provided.
5. Complete transcripts of FDA Advisory Committee meetings, and schedules of upcoming meetings and agendas, are available online. 7
6. Please also see the Bibliography for various links for additional drug safety information.
The Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) 8 is convened to obtain independent expert advice on scientific, technical and policy matters. The committee convenes to discuss approval of new molecular entities proposed for use in dermatology, and has provided substantial input and advice concerning risk management programs for isotretinoin and thalidomide.

Drug withdrawal
In rare cases FDA may need to reassess and change its approval decision on a drug. A conclusion that a drug should no longer be marketed is based on the nature and frequency of the adverse events and how the drug’s risk–benefit balance compares with treatment alternatives. Considerations regarding risk may include assessments of whether the benefits outweigh the risks for some defined population, and whether this can be addressed in labeling. Q7-7 Discussions concerning risk–benefit and the decision to keep a drug on the market could include:

• What is the magnitude of the benefit compared to known therapy or to alternatives?
• Does the drug add to existing therapy?
• Is there a subgroup of high responders?
• Is the product effective for patients who failed other therapies?
• Is the product tolerated by patients who cannot tolerate other treatments?
• Is there a substantial convenience factor (frequency, dosage, administration)?
When FDA believes that a drug’s benefits no longer outweigh its risks, the agency will ask the manufacturer to withdraw the drug. Q7-8 Specific examples of drugs withdrawn and the associated category of complication are given in Tables 7-1 through 7-4 .

Table 7-1 Drugs off the market – liver toxicity

Table 7-2 Drugs off the market – cardiac arrhythmias (torsades de pointes)

Table 7-3 Drugs off the market – other cardiovascular adverse events

Table 7-4 Drugs off the market – (neurologic) progressive multifocal leukoencephalopathy

General principles concerning drug withdrawal decisions Q7-9

Principle #1
At times, the FDA (or a similar agency is other countries) mandates a drug removal; in other circumstances the pharmaceutical company (sponsor) undertakes voluntary drug withdrawal.

• Mandated withdrawal by FDA – rofecoxib (Vioxx)
• Voluntary withdrawal by pharmaceutical company – valdecoxib (Bextra), efalizumab (Raptiva).

Principle #2
At times drugs taken off the market are a ‘business decision’ by the pharmaceutical company:

• Valdecoxib (Bextra) was voluntarily ‘taken off’ the market even though the FDA Drug Advisory Committee involved voted to allow the drug to stay on the market.
• Celecoxib (Celebrex; produced by the same pharmaceutical company as Bextra) stayed on the market; this drug is a less selective COX-2 inhibitor with less thrombosis risk.
• Within a company, decisions may include re-evaluation of the portfolio, considering future potential medicolegal risks, market competitors and related expenses; two examples include the above decision, as well as the recent decision to take the original brand name isotretinoin (Accutane) off the market.

Principle #3
New drugs which are safer and/or more efficacious than a prior drug in the same drug category may prompt the previous drug with significant risks to be taken off market:

• Once pioglitazone and rosiglitazone were released as suitable ‘alternatives’, troglitazone was promptly taken off market because of significant liver toxicity; these drugs were all thiazolidinediones (‘insulin sensitizers’).
• In contrast, isotretinoin provides unique efficacy in the treatment of severe nodular acne vulgaris and remains on the market, at least partly because no suitable ‘alternative’ is available.

Principle #4
In general, clinicians must ‘learn from history’ for drugs in same group as the drug taken off the market; issues to emphasize include (1) improved patient selection, (2) drug interactions to avoid, and (3) improved monitoring guidelines.

• FDA communications concerning terfenadine and astemizole prior to withdrawal from the market emphasized the need for clinicians to avoid combining the above medications with ketoconazole or erythromycin (among others), which increased the risk of torsades de pointes.
• In general, physicians need to markedly improve awareness and cooperation with strong FDA suggestions such as the above to minimize patient risk and preserve the availability of various drugs, including similar warnings with drugs currently available.

Medical principles – specific examples

Principle #5
Not all drugs in a given class have similar risk profiles:

• Statins – cerivastatin off market; others in this drug group have a much lower risk of rhabdomyolysis.
• Second-generation antihistamines – terfenadine, astemizole were taken off the market due to torsades de pointes; all remaining second-generation H 1 antihistamines lack significant QT prolongation and have no significant risk for torsades de pointes.

Principle #6 (CYP = cytochrome P-450)
Concerning any drug with the potential to prolong the QT interval, clinicians should be very cautious about potential drug interactions; examples are listed below involving these CYP3A4 substrates, which were taken off the market due to torsades de pointes, and the CYP3A4 inhibitors which were commonly involved in these life-threatening interactions:

• CYP3A4 substrates – terfenadine, astemizole, cisapride
• CYP3A4 inhibitors – erythromycin, clarithromycin, ketoconazole, itraconazole.

Principle #7
Any drug which upon release has at least 3 – 5% of patients in clinical trials with ‘minor, transient transaminase elevations’ should be followed very carefully from a liver toxicity standpoint; some examples of this principle that were taken off the market for liver toxicity include:

• Troglitazone
• Trovafloxacin ( very limited availability ).

Principle #8
Be very cautious with a drug which has a risk for toxicity involving a target organ in patients with abnormality in that target organ at baseline:

• Cerivastatin – risk of rhabdomyolysis was much greater with pre-existing renal disease.

Principle #9
Be cautious with aggressive dosing regimens when dose relationships to high-risk adverse effects have been established:

• A recent example limiting the maximum dose to 40 mg is for atorvastatin (prior maximum dose 80 mg) in order to minimize the risk of rhabdomyolysis which is more common with the prior maximum dose.

Principle #10
Strong CYP enzyme inducers or inhibitors frequently have a greater risk of liver toxicity:

• CYP inducers – troglitazone and rifampin
• CYP inhibitor – ketoconazole innately with a significant risk for liver toxicity (independent of drug interactions).

Principle #11
Drugs may need to have strategies to mitigate risk in order to be allowed on the market or to stay on the market:

• A drug that was previously taken off the market was reintroduced under a special distribution program – natalizumab (for multiple sclerosis).
• Original US approval included risk management strategy – thalidomide.
• REMS intended to minimize teratogenicity risk (prevent fetal exposure and inform providers) – isotretinoin.
• Still available, but on a very limited basis – trovafloxacin.

Medical principles – general issues

Principle #12
We recommend using a new drug gradually until the ‘real world’ risks are clarified over the next few years:

• Drugs with risks that occur in 1 in 1000 patients or less are commonly not detected in premarketing clinical trials.
• Highly ‘controlled’ nature of preclinical trials may limit potential drug interactions, liver or kidney abnormalities.
• With the above realities in mind, many important significant drug risks are not detected until at least 2–3 years later, when use of the drug is widespread and ‘uncontrolled.’

Principle #13
Pay very careful attention to the following publications by FDA:

• Drug Safety Communications give strong ‘advice’ on potential drug interactions, patient selection, and monitoring required; such communications may precede drug withdrawal.
• Risk Evaluation and Mitigation Strategies (REMS); widespread clinician attention to details in these programs may allow specific drugs to stay on the market.

Abbreviations used in this chapter AERS Adverse Event Reporting System BLA Biologics Licensing Applications COX-2 Cyclo-oxygenase 2 CYP Cytochrome P-450 DODAC Dermatologic and Ophthalmic Drugs Advisory Committee ETASU Elements to Assure Safe Use NDA New Drug Applications NSAID Nonsteroidal anti-inflammatory drug(s) REMS Risk Evaluation and Mitigation Strategy TNF-α Tumor necrosis factor-alpha

Bibliography: important reviews and websites for supplemental information

General information link
FDA ‘Guidance for Industry’ www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances

Specific links
Guidance for Industry: Warnings and Precautions, Contraindications, Boxed Warnings. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075096.pdf , October 2011.
Guidance for Industry: Safety Labeling Changes (FDAAA). Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM250783.pdf , October 2011.
Guidance for Industry: Adverse Reactions Section: Labeling. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075057.pdf , October 2011.
Guidance for Industry – Risk Evaluation and Mitigation Strategies. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf , October 2011.

Link to list of approved risk evaluation and mitigation strategies
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm , October 2011.

Reviews
Issa AM. Drug withdrawals in the United States: a systematic review of the evidence and analysis of trends. Curr Drug Saf . 2007;2:177–185.
Temple RJ, Himmel MH. Safety of newly approved drugs. JAMA . 2002;287(17):2273–2275.
Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002. Arch Intern Med . 2005;165:1363–1369.

References

1 21 CFR 201.57(c)(1)
2 Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(o)(4)) added by section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA)
3 www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111085.htm .
4 www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ .
5 dailymed.nlm.nih.gov/dailymed/about.cfm .
6 Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ .
7 www.fda.gov/AdvisoryCommittees .
8 www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs .
Part III
Systemic Drugs for Infectious Diseases
8 Systemic Antibacterial Agents

Susun Kim, Brent D. Michaels, Grace K. Kim, James Q. Del Rosso


Questions

Q8-1 What are some dermatologic indications of antibiotic use in chronic inflammatory skin disorders, based on their anti-inflammatory properties? (Pgs. 61, 81x3)
Q8-2 Which antibiotic classes have significant alterations in bioavailability due to foods and divalent cations? (Pgs. 63, 66, 75, 76, 79x2, 88, 90)
Q8-3 Which members of the penicillin family of drugs most frequently induce hypersensitivity reactions? (Pgs. 63, 64)
Q8-4 What are some of the drugs with the potential for a cross-reaction in patients allergic to penicillins, and what is the true risk (frequency and magnitude) of such cross-reactions? (Pgs. 64, 67, 68, 69x2)
Q8-5 What are antibacterial agents with a risk of antibiotic-associated colitis due to Clostridium difficile ? (Pgs. 64, 67, 89, 92, 94x2)
Q8-6 What two drugs discussed in this chapter can induce a serum sickness-like reaction? (Pgs. 67, 84)
Q8-7 What are 3–4 of the mechanisms by which bacteria develop resistance to antibacterial agents? (Pgs. 69x2, 78, 88, 93, 95)
Q8-8 What are 2 relatively unique cutaneous ‘hypersensitivity’ reactions to vancomycin? (Pg. 69)
Q8-9 Which drugs/drug groups mechanism is to interfere with bacterial ribosome subunits (a) 30S, (b) 50S, and (c) 23S portion of the 50S subunit? (Pgs. 70, 77, 93, 94, 95x2)
Q8-10 What are several antibiotic classes with significant anti-inflammatory activity, and what are several of the mechanisms for this anti-inflammatory activity? (Pgs. 70, 77, 78)
Q8-11 Concerning macrolides and azalides, what are some important differences in (a) infections most effectively treated, and (b) CYP–drug interactions? (Pgs. 71x3, 72)
Q8-12 What are several of the bacterial enzymes inhibited by antibacterial agents discussed in this chapter? (Pgs. 75, 87, 92)
Q8-13 Concerning community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, what are (a) several of the best oral antibiotic choices, and (b) several antibiotics with a trend towards increasing resistance? (Pgs. 75, 81, 88, 89, 92, 93, 94, 95)
Q8-14 Which drugs discussed in this chapter are most likely to induce photosensitivity reactions? (Pgs. 76, 83)
Q8-15 What are several relatively unique hypersensitivity and autoimmune reactions due to minocycline? (Pgs. 84x2, 85)
Q8-16 Which two drug groups discussed in this chapter are listed as pregnancy category D? (Pgs. 85, 95)
Q8-17 What is the scientific basis for various antibacterial groups possibly reducing the effectiveness of hormonal contraceptives? (Pgs. 85, 90)

Introduction
Systemic antimicrobial agents, especially antibiotics, play a vital role in dermatology, with oral antibiotic prescriptions estimated to represent approximately 20% of all prescriptions written by dermatologists annually in the outpatient setting. 1 – 5 Dermatologists in ambulatory practice in the United States (US) accounted for approximately 8 – 9 million oral antibiotic prescriptions per year over the period 2001 – 2005, and at least 5 million oral antibiotic prescriptions written annually by dermatologists have been attributed to acne vulgaris treatment. 1, 5 As a basis for comparison, the total number of oral antibiotic prescriptions written by all physician specialties in the US was approximately 250 million per year between 2001 and 2005, predominantly for treatment of infectious disorders. 1 The chronic use of this drug category raises potential concerns about the emergence of resistant bacterial strains, sometimes with the development of cross-resistance among antibiotics. 1, 4, 5
Q8-1 In addition to their antibacterial properties, many antibiotic agents, such as tetracycline and macrolide groups, possess significant anti-inflammatory activities which have led to their use for the treatment of both infectious and non-infectious skin diseases. 2, 3 The biologic effects of several antibiotics, unrelated to their antibiotic or antimicrobial properties, appear to correlate at least partially with their efficacy in the treatment of inflammatory dermatoses, including acne vulgaris and rosacea. 1, 2 Owing to the increased prevalence of uncomplicated skin and soft tissue infections (USSTI) caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), the overall pattern of oral antibiotic use in outpatient dermatology practices has evolved. Such changes in prescribing patterns have been characterized by increased use of doxycycline, minocycline (immediate-release formulations), and trimethoprim-sulfamethoxazole, and a decrease in the use of oral cephalosporin therapy owing to higher rates of CA-MRSA infection. 1, 4 – 8
Rational antibiotic selection for dermatologic disorders warrants consideration of multiple important factors to optimize both therapeutic outcome and safety. These factors include:

1. Host-related properties (age, comorbidities, allergy status, pregnancy status, breastfeeding status);
2. Nature of the disease state to be treated (infection vs. inflammatory disease, severity, affected sites);
3. Microbiologic factors if applicable (suspected or confirmed pathogen, virulence, antibiotic sensitivity and resistance profiles);
4. Applicable antibiotic options (efficacy, adverse reactions, drug interactions);
5. Antibiotic-specific pharmacokinetic (PK) properties (route of administrations, oral formulation differences, sites of infection); and
6. Additionally, specific adverse reactions to some antibiotics may be more common and more severe in immunocompromised patients. 9
This chapter emphasizes the oral antibacterial agents used primarily for skin and soft tissue infections, with reference to use in inflammatory dermatoses such as acne vulgaris and rosacea, where applicable.

Penicillins
Penicillin G (benzylpenicillin) is produced naturally by the fungus Penicillium chrysogenum . Subsequent to the discovery in 1928 of penicillin G, many semi-synthetic penicillins have been developed ( Table 8-1 ). The first advance was the development of penicillin V (phenoxymethyl penicillin), which is more stable in the presence of gastric acid and is better absorbed from the gastrointestinal (GI) tract than penicillin G. The safety and efficacy of the penicillins have been established overall in the pediatric population ( Table 8-1 ). The penicillins are rated as category B for use in pregnancy, and penicillin G should be used with caution during lactation, as the excretion of low concentrations of penicillins in breast milk has been reported. 11 Sensitization of infants has been associated with ampicillin use in nursing mothers. 12

Table 8-1 Currently available FDA-approved penicillins

Pharmacology

Antimicrobial activity
Both penicillin G and penicillin V are categorized as natural first-generation penicillins. Although penicillin V generally exhibits lower antibacterial potency than penicillin G, both agents share the same antimicrobial spectrum against Gram-positive cocci and rods, Gram-negative cocci, and anaerobes. Importantly, methicillin-sensitive S. aureus (MSSA) and MRSA are almost uniformly resistant to penicillin G and penicillin V. 5, 7
Subsequent generations of penicillins include: 10

1. Penicillinase-resistant first-generation penicillins ( isoxazolyl penicillins), including the oral agents dicloxacillin and oxacillin (related to parenteral methicillin), exhibit activity against most strains of MSSA and other Gram-positive cocci, but MRSA developed subsequently.
2. Extension of the antimicrobial spectrum of penicillins which includes inhibition of Gram-negative bacilli is seen with the second-generation agents ( aminopenicillins ), ampicillin and amoxicillin, which may be administered orally, and
3. The third-generation extended-spectrum penicillins ( carboxypenicillins ) such as carbenicillin, and the fourth-generation penicillins ( ureidopenicillins ) such as piperacillin, are both parenteral and exhibit anti-pseudomonal activity (piperacillin > carbenicillin), especially when combined with an aminoglycoside antibiotic.
Unfortunately, hydrolysis by β-lactamases renders these drugs ineffective against S. aureus or the many Enterobacteriaceae species that produce β-lactamases. 10 In addition, some β-lactams have been combined with a β-lactamase inhibitor to produce resistance of the antibiotic to degradation by β-lactamase (see section on β-lactamase and β-lactamase inhibitor combinations). 10

Pharmacokinetics
Of the β-lactamase-resistant penicillins available for oral use, dicloxacillin exhibits very favorable pharmacologic and pharmacokinetic (PK) properties. It can be given in doses exceeding 4 g daily; however, a dose of 2 g daily is easily adequate for the majority of staphylococcal pyodermas not caused by MRSA. Q8-2 Because of its vulnerability to gastric acid degradation, GI absorption is optimized by administration 1 h before or after a meal. 10 Of the aminopenicillins, amoxicillin is superior to ampicillin, exhibiting greater GI absorption, a lower incidence of diarrhea, and comparable efficacy. Amoxicillin can also be taken with food. 10 The elimination half-lives for most penicillins are short (<1.5 h). All β-lactams are excreted renally with the exception of nafcillin, oxacillin, and piperacillin, which are eliminated predominantly through the biliary system. 10

Clinical use

Dermatologic uses ( Table 8-2 )

Antibacterial indications
Isoxazolyl penicillins show good coverage for Streptococcus pyogenes and MSSA, and may be used for a wide range of uncomplicated skin infections, including erysipelas, cellulitis, impetigo, folliculitis, furunculosis, bacterial paronychia, and ecthyma. 10 Intramuscular (IM) penicillin administered weekly has been used successfully to prophylactically inhibit recurrent erysipelas, with the risk of recurrence to pre-treatment levels after discontinuation of therapy. 12 Parenterally administered nafcillin may be used in the management of toxin-induced staphylococcal scalded skin syndrome. Some sexually transmitted diseases (STD), such as syphilis and chlamydial infections, are susceptible to penicillins. Penicillins have also been used for the treatment of erysipeloid, scarlatina, cutaneous anthrax, Lyme disease, actinomycosis, listeriosis, gas gangrene, gingivostomatosis, and leptospirosis (Weil’s disease). 10 In the clinical setting, individual selection among the penicillins is highly dependent on the diagnosis and causative organism, with substantial variability of activity based on the drug chosen.
Table 8-2 Commonly used oral penicillins * – dosage guidelines Generic name Tablet/capsule sizes (mg) Adult dosage Amoxicillin 250, 400, 500, 875 500–875 mg bid † Amoxicillin/clavulanate 250, 500, 875, 1000 500–875 mg bid † Ampicillin 250, 500 250–500 mg qid Dicloxacillin 250, 500 125–500 mg qid ‡ Oxacillin 250, 500 500–1000 mg Q4–6h Penicillin V 250, 500 250–500 mg qid
* All of the drugs in this table have either liquid or suspension formulations available.
† These two drugs can also be dosed at 250–500 mg tid.
‡ Dicloxacillin can also be dosed at 250–500 mg tid for uncomplicated skin infections.

Non-specific penicillin benefits
There are scant data for use of penicillins for their ‘non-specific’ properties. Penicillin G has been used with some success to treat dermal fibrosis in patients with circumscribed and systemic sclerosis, hypothesizing the role of Borrelia burgdorfer i in the development of scleroderma. 10 Penicillin has been used for pityriasis rubra pilaris, although its efficacy is questionable. 10 The addition of benzanthine penicillin therapy (IM) once every 3 weeks to colchicine therapy reduced the frequency of oral and genital aphthae and benefited erythema nodosum-like lesions in patients with Behçet’s disease compared to monotherapy with colchicine. 14 A systematic review of the literature has concluded that there is no evidence that administration of anti-streptococcal antibiotics, including penicillins, improves guttate psoriasis. 15, 16

Adverse effects

Hypersensitivity reactions
Q8-3 β-lactams are among the group of drugs that have been more commonly associated with drug-induced hypersensitivity reactions. 17 The first β-lactam reported to cause a hypersensitivity reaction was benzylpenicillin, with amoxicillin noted to be the most commonly implicated agent more recently. 17 Not surprisingly, hypersensitivity reactions are the most common diverse effects associated with penicillins, with the severity of these reactions ranging from morbilliform eruptions to urticarial to fatal anaphylaxis. 18 - 21 A skin eruption that is not truly allergic in origin may arise when ampicillin is given to patients with infectious mononucleosis or lymphocytic leukemia, and is also seen when ampicillin is co-administered with allopurinol. The eruption is generalized, maculopapular, and pruritic, and typically manifests within 7–10 days after the initiation of the antibiotic, with usual persistence for up to 1 week after ampicillin is discontinued. This unique ampicillin eruption is not believed to be a contraindication to treatment with other penicillins at a later date. 12

Cross-reaction potential
Q8-4 For practical purposes it should be assumed that all of the penicillins cross-react, and that if a patient has a true allergic reaction to one form of penicillin they may react to all penicillins, and possibly to cephalosporins as well. 22 Therefore, in patients with a history of severe and life-threatening allergic reaction to a penicillin or cephalosporin, avoidance of the other drugs in these two general categories is advised. Q8-3 The aminopenicillins appear to be associated with a higher incidence of allergic reactions than other penicillins. 23 Intradermal testing with benzylpenicillin G and penicilloyl polylysine (Pre-Pen) may be helpful. If an immediate cutaneous reaction does not occur on administration of penicillin, it is highly unlikely that an immediate or accelerated reaction will occur. On the other hand, a positive reaction to penicillin testing requires either the use of an alternative antibacterial agent or desensitization. It should be noted that Pre-Pen (penicilloyl polylysine) was temporarily and voluntarily removed from the market in 2004; however, legal rights were subsequently obtained by Allerquest. According to the Allerquest website, Pre-Pen is now available on the market after full FDA approval in 2009. 24, 25

Other important adverse effects
Q8-5 GI disturbances, including nausea and antibiotic-associated diarrhea are not uncommon, and C. difficile colitis can occur with use of penicillins. 10 Yogurt or other means of Lactobacillus ingestion may be a helpful adjuvant to prevent diarrhea-related complications due to alterations in normal gut flora. Other untoward reactions to penicillins are unusual with oral penicillin forms. Hemolytic anemia, neutropenia, platelet dysfunction, seizures, and electrolyte disturbances, when seen, are associated with very large doses given via parenteral formulations. 26 Shore nails (transverse leukonychia and onychomadesis following drug-induced erythroderma) have been seen with dicloxacillin, and onychomadesis and photo-onycholysis have been noted following cloxacillin use. 27 Cholestasis associated with β-lactams, including penicillins, is uncommon overall. 28 Local skin reactions, phlebitis, myositis, and even vasospasm have been seen with parenteral and intramuscular formulations of penicillins. 10

Drug interactions
Few clinically significant drug interactions are noted with the penicillins. Probenecid prolongs the renal excretion of penicillins. Oral antibiotics, including β-lactams, may potentially alter the anticoagulant effects of warfarin, warranting closer monitoring of International Normalized Ratio (INR) values. The controversial topic of whether or not oral antibiotics reduce the efficacy of oral contraceptives is reviewed below under the Drug Interactions sections for both tetracyclines and rifamycins.

Dosage
Table 8-2 contains dosage guidelines for commonly used oral penicillins. It is suggested that infections with β-hemolytic streptococci should be treated for 10 days because of possible complications such as acute glomerulonephritis and rheumatic fever. Scarlatina (formerly known as scarlet fever) may be treated with a 10-day course of oral penicillin V or a single injection of benzanthine penicillin G. A single intramuscular injection of 2.4 × 10 6  U of penicillin G is used to treat primary or secondary syphilis, although latent syphilis of more than 1 year (or of indeterminate) duration requires 3 weekly injections of this same dose. For penicillin-susceptible Neisseria gonorrhoeae , one of the aminopenicillins may be given as single-dose treatment (ampicillin 3.5 g or amoxicillin 3 g) along with probenecid. For other Gram-negative infections such as Haemophilus influenzae , ampicillin in daily doses of 2–4 g, divided into three or four doses, is given with probenecid if higher blood levels are needed.

Cephalosporins

Cephalexin and many others
Most cephalosporins are antibiotics produced and derived as byproducts of the mold Cephalosporium acremonium . Cephalosporins have a basic structural core consisting of a 4-membered β-lactam ring attached to a 6-membered dihydrothiazine ring, and therefore are β-lactams. The two-ring combination gives the cephalosporin structure inherent resistance to β-lactamase enzymes. 29, 30 Penicillins, on the other hand, differ from cephalosporins in that they are composed of a 5-membered thiazolidine ring. Most cephalosporins, especially oral cephalosporins, are considered safe in children. Cephalosporins are generally pregnancy category B, with a low likelihood of congenital malformations when used during the second and third trimesters. 11 Caution is suggested in women who are breastfeeding, as the small quantities of cephalosporins in breast milk have been associated with reports of diarrhea, candidal infections, and skin eruptions in the nursing infants. 11

Pharmacology

Antimicrobial activity
The cephalosporins have been grouped into ‘generations’ based on their general spectrum of antimicrobial activity ( Table 8-3 ). There are currently 5 generations of cephalosporins.

Table 8-3 Currently available FDA-approved cephalosporins

First generation
The first-generation cephalosporins are the most active of all the cephalosporins against staphylococci and non-enterococcal streptococci. Typically resistant organisms include MRSA, penicillin-resistant Streptococcus pneumonia , and Gram-negative organisms including H. influenzae and enterococci. 30 The first-generation cephalosporins are not indicated when Pseudomonas spp , Hemophilus influenzae, and nosocomial Gram-negative infections are present. 30 They are active against many of the oral anaerobes, except the Bacteroides fragilis group. The in vitro antibacterial spectrum among the first-generation agents is almost identical, with cefdinir likely to exhibit greater activity against MSSA. 30

Second generation
Second-generation cephalosporins in general demonstrate increased Gram-negative and decreased Gram-positive activity overall. 30 Individual agents vary greatly in their spectrum of activity. These agents are often classified into two groups, (1) the true cephalosporins, and (2) the cephamycins (cefoxitin, cefotetan). The true cephalosporins have increased activity against H. influenzae , Moraxella catarrhalis , Neisseria meningitidis , N. gonorrhoeae, and some Enterobacteriaceae. The cephamycins have inferior activity against staphylococci and streptococci, but are effective against strains of B. fragilis. 30

Third generation
Third-generation cephalosporins demonstrate less consistent activity against Gram-positive organisms and an increased spectrum of Gram-negative activity due to greater β-lactamase stability. 31 Agents such as ceftazidime, cefepime, and cefoperazone have antipseudomonal coverage. Cefditoren has a broad spectrum of coverage, including against an assortment of Gram-positive and Gram-negative organisms, but does not provide activity against Pseudomonas aeruginosa. 32 Ceftazidime has the greatest activity against Pseudomonas aeruginosa, but is not active against S. aureus. Cefdinir has good coverage against both S. aureus and S. pyogenes , making this antibiotic effective for USSTI. 30

Fourth generation
Cefepime is the only fourth-generation cephalosporin approved in the US, is administered parenterally, and has a broad antibacterial spectrum. Its coverage includes activity against MSSA and non-enterococcal streptococci, as well as Gram-negative organisms including P. aeruginosa . Cefepime is not effective against B. fragilis .

Fifth generation
There are two newer fifth - generation cephalosporins: ceftobiprole, which is currently seeking FDA approval, and ceftaroline, which received FDA approval on October 29, 2010. 33 Importantly, ceftaroline has shown activity against multidrug-resistant S. aureus , including MRSA, vancomycin-intermediate S. aureus (VISA), heteroresistant vancomycin-intermediate S. aureus, (hVISA), and vancomycin-resistant S. aureus (VRSA), in addition to MSSA and coagulase-negative staphylococci . 34 Ceftaroline has shown weak coverage against Pseudomonas spp. and is indicated for acute skin infections caused by S. aureus (including MRSA), S. pyogenes, S. agalactiae, E. coli and Klebsiella. 34 Ceftobiprole has also shown activity against MRSA, in addition to S. pneumoniae, Pseudomonas spp and enterococci.
On the horizon, a new antipseudomonal cephalosporin, CXA-101 (previously designated FR264205) has been shown to have activity against carbapenem-resistant and multidrug-resistant P. aeruginosa clinical strains. 35

Pharmacokinetics
Q8-2 The absorption properties of the currently available cephalosporins vary greatly, with peak serum concentrations dependent on their administration in relation to food intake. 30 Cefaclor, cefadroxil, cephalexin, and cephradine are best absorbed from an empty stomach. Conversely, the bioavailability of cefuroxime axetil is increased when taken with food. 36 First- and second-generation cephalosporins are excreted primarily by the kidneys; thus, dosage adjustments are recommended for patients with significant renal insufficiency. Cefoperazone and ceftriaxone undergo predominantly hepatic metabolism and excretion, so renal insufficiency does not generally necessitate dosage adjustments. 37 The half-life of most parenterally administered cephalosporins varies between 0.5 and 2 hours, although the 6–8-hour half-life of ceftriaxone permits once-daily dosing. The newer fifth-generation cephalosporin, ceftaroline, is administered intravenously as the inactive prodrug, ceftraline fosamil, and is subsequently converted to the active metabolite, ceftaroline, with a short half-life of 0.19–0.43 hours and primarily renal excretion. 34, 38

Clinical use

Dermatologic indications
Oral cephalosporins are used primarily in ambulatory dermatologic practice to treat USSTI such as impetigo, folliculitis, furuncles, carbuncles, acute bacterial paronychia, cellulitis, ecthyma, erysipelas, and postoperative wound infections. Severe infections such as complicated cellulitis and necrotizing fasciitis require intravenous antibacterial agents. 30, 37 Additional special uses of individual cephalosporins include selected STDs, diabetic foot infections and Lyme disease. 30 See Table 8-3 for list of cephalosporins classified by generation, and Table 8-4 for dosage guidelines for oral cephalosporins.
Table 8-4 Commonly used oral cephalosporins – dosage guidelines Generic name Tablet/capsule sizes * (mg) Adult dosage First generation Cefadroxil 500, 1000 500 mg to 1–2 g/day (qd or bid) Cephalexin 250, 500 250–500 mg qid Cephradine** 250, 500 250–500 mg qid Second generation Cefaclor † 250, 375 ‡ , 500 250–500 mg tid Cefprozil 250, 500 250–500 mg/day (qd or bid) Cefuroxime axetil 125, 250, 500 250–500 mg bid Loracarbef ** 200, 400 200–400 mg bid Third generation Cefixime 200, 400 200 mg bid or 400 mg qd Cefpodoxime proxetil 100, 200 100–400 mg bid Ceftibuten 400 400 mg qd
* All of the drugs listed in this table have either liquid or suspension formulations available.
** These antibiotics are currently not available in the United States.
† For uncomplicated skin infections, cefaclor 500 mg bid has been used.
‡ Extended release formulation for 375-mg size of cefaclor.

First generation
The most commonly used first-generation oral cephalosporin since its inception is cephalexin. It is indicated for USSTI caused by MSSA and S. pyogenes . Although twice-daily dosing has been suggested, the short half-life (≤1 h) may be associated with bacterial resistance. More frequent dosing, i.e., three to four times daily, is generally recommended. Cefadroxil, another first-generation cephalosporin, has a longer half-life and may be dosed twice daily. 13

Second generation
Second-generation agents have been efficacious in treating Gram-negative cellulitis caused by H. influenzae or Enterobacteriaceae. Both cefprozil and cefaclor are available in oral formulations. Cefuroxime axetil can be used to treat selective cases of Lyme borreliosis and gonorrhea. 30, 39

Third generation
Third-generation cephalosporins have also been used in the treatment of soft tissue abscesses and diabetic foot ulcers. 40 One of the newer oral cephalosporins in this generation, cefditoren, can also be used for USSTI. A single intramuscular injection of ceftriaxone is an effective treatment for uncomplicated gonorrhea, as are single oral doses of cefpodoxime and cefixime. Ceftriaxone may also be used for the treatment of acute Lyme disease complicated by meningitis, as well as for the later stages of the disease. Ceftazidime has been effective in the treatment of P. aeruginosa infections, including ecthyma gangrenosum, diabetic foot ulcers, and infections in burn patients. 40 ( Note: fourth-generation cefapime has no specific dermatologic clinical use. )

Fifth generation
Most recently, ceftaroline, a fifth-generation agent, has been approved for the treatment of acute bacterial skin and skin structure infections, including those caused by MRSA. 34, 38, 41 Additionally, ceftobiprole, another fifth-generation cephalosporin, has also shown promise for the treatment of skin and soft tissue infections. However, although ceftobiprole is approved in Switzerland and Canada, it is still seeking FDA approval in the US for CSSTI, including diabetic foot infections. 42 Ceftobiprole may be used as monotherapy for the treatment of CSSTI that have required combination therapy in the past. 43, 44

Adverse effects
Q8-5 GI toxicities are relatively frequent with cephalosporin use, presenting commonly as nausea, vomiting, or diarrhea. 30, 37 Antibiotic-associated colitis is much less common. Mild elevation of liver transaminaes may occur, but serious hepatic injury is rare. 30, 37 Ceftriaxone has been associated with biliary sludge formation, which is usually asymptomatic, except in children receiving high doses of prolonged therapy. 30, 45 The most common adverse effects associated with the fifth-generation cephalosporin ceftaroline include diarrhea, as well as nausea, skin eruption, headache and insomnia. 34, 38

Hypersensitivity reactions and cross-reaction potential
Hypersensitivity reactions, reported in 1–3% of treated individuals, include cutaneous findings such as urticaria, maculopapular eruptions, and pruritus. 30
Q8-4 Potential cross-reactivity of cephalosporins with penicillins has been traditionally stated to occur in approximately 5–10% of penicillin-allergic patients. The degree of this cross-reactivity likely depends on the generation of cephalosporin, and very likely is due to structural differences in side chains among individual cephalosporins. 46, 47 Early first-generation cephalosporins sometimes contained trace amounts of penicillins, and this may explain an increased estimation of cross-reactivity between pencillins and cephalosporins. 47 With the above in mind, the true incidence of cross-reactivity is likely from 1% to 7%. 30 One report stated that the risk of a reaction to a cephalosporin in a pencillin-allergic patient is no greater than the risk of developing a cephalosporin reaction by itself. 24 Another study concluded that cephalosporins can be considered for patients with penicillin allergy and that the risk of serious adverse events, and specifically anaphylaxis, was 0.001%. 48 Although this issue remains controversial, 49 there are data to show that cephalosporin-allergic reactions occur more commonly in patients with a history of penicillin allergy versus those without a penicillin allergy. 30 Thus, it is recommended that cephalosporin use be avoided in patients with a history of an immediate or accelerated reaction to penicillin (IgE-mediated or severe type IV delayed hypersensitivity reactions). 18 Cephalosporin skin testing is much less reliable than penicillin skin testing to evaluate hypersensitivity reactions. 47

Other adverse effects
Other potential adverse effects related to cephalosporin use include vaginal infections from overgrowth of Candida spp, hematopoietic changes, mental and sleep disturbance, and liver function test alterations. 24 Q8-6 Among the cephalosporins, serum sickness-like reaction has been reported almost exclusively with cefaclor, used more commonly in the past for otitis media in children. 50 The cefaclor-induced serum sickness-like reaction, presenting as urticaria, fever, and arthralgias, with or without lymphadenopathy or eosinophilia, has also been suspected in one case with cefprozil. 30, 50 A Jarisch–Herxheimer reaction occurring during the treatment of Lyme disease has been noted with cefuroxime axetil, with an estimated incidence between 12% and 29%. 24 Local reactions such as thrombophlebitis or pain at injection sites have been described in up to 5% of cephalosporin-treated patients undergoing parenteral administration. 30 Nail changes have been described following treatment with cephalexin (acute paronychia) and cephaloridine (onychomadesis and photo-onycholysis); the latter is no longer available. 27

Hematologic effects
With regard to hematopoietic changes, despite a reported rate of 3% Coombs’ antibody positivity, hemolytic anemia is rare in cephalosporin-treated patients. 30, 51, 52 The cephalosporins most often associated with drug-induced immune hemolytic anemia are cefotetan, ceftriaxone, and pipercillin, with cefotetan suspected to be the most common cause. 51 Hypoprothrombinemia may occur with cephalosporins, cefotetan and cefoperazone, which contain an N -methylthiotetrazole (NMTT) ring. Eosinophilia and neutropenia have also been reported. 53

Nephrotoxicity
Nephrotoxicity is rare, although a reduction in the dosage of most cephalosporins is recommended in patients with significant renal insufficiency. 30

Drug interactions
Some of the most important drug interactions for cephalosporins include the following:

1. Cephalosporins (such as cefotetan) which contain an NMTT ring have been reported to induce disulfiram-like reactions with alcohol ingestion. 54
2. The NMTT ring can also prolong prothrombin times as it inhibits production of vitamin-K clotting factors, which is a consideration in patients on anticoagulation therapy. 12, 55
3. Probenecid competes with renal tubular secretion of some cephalosporins. This may increase and prolong the plasma levels for cephalosporins.
4. Some cephalosporins may increase the risk of nephrotoxicity when co-administered with aminoglycosides or potent diuretics. 12, 56
5. H 2 antihistamine, oral antacids and possibly proton pump inhibitors may reduce the plasma levels of cefditoren. 57
6. The controversial topic of whether or not oral antibiotics decrease the efficacy of oral contraceptives is reviewed under the Drug Interactions sections for both tetracyclines and rifamycins.
7. To date, there are no known drug interaction studies that have been conducted with the newer cephalosporin ceftaroline. 34, 38 Ceftaroline appears to exhibit minimal interaction with the cytochrome P-450 (CYP) system. 34, 38

Dosage
Table 8-4 lists dosage guidelines for oral cephalosporins.

β-lactam and β-lactamases inhibitor combinations

Amoxicillin/clavulanate and others
β-lactamase enzymes render β-lactam antibiotics inactive by irreversibly hydrolyzing the amide bond of the β-lactam ring. The production of a β-lactamase is controlled by either chromosomal or plasmid genes, and transferability of these genetic capabilities among bacterial organisms is possible. 58 β-lactamase inhibitors, when combined with a β-lactam antibiotic, act in concert to inhibit β-lactamase produced by Enterobacteriaceae, S. aureus , and Gram-negative anaerobes. 59 In the US, clavulanate, sulbactam, and tazobactam are the β-lactamase inhibitors approved for clinical use. Combination β-lactam antibiotic and β-lactamase inhibitor formulations include (1) amoxicillin–clavulanate, (2) ampicillin–sulbactam, (3) ticarcillin–clavlanate, and (4) piperacillin–tazobactam (trade names in Table 8-1 ).

Antibacterial activity
β-lactamase inhibitors alone do not possess relevant antibacterial activity, but when they are combined with a β-lactam antibiotic they act by inhibiting plasmid-mediated β-lactamase, thereby restoring the spectrum of activity of the β-lactams. 31, 60 Significant activity against β-lactamase produced by MSSA, Haemophilus spp, Klebsiella spp., E coli , Proteus spp., and B. fragilis has been noted. However, the β-lactamase inhibitors have not been found to provide effective inhibition of β-lactamases produced by Pseudomonas aeruginosa , Enterobacter and Citrobacter spp. 31

Pharmacokinetics
When clavulanate is given orally with amoxicillin (Amox/Clav), it is rapidly absorbed, with peak concentrations reached 40–60 minutes after ingestion, and bioavailability not significantly affected by food. 60, 61 Ampicillin–sulbactam (Amp/Sulb), ticarcillin–clavulanate (Ticar/Clav) and piperacillin–tazobactam (Pip/Tazo) are administered intravenously. Amp/Sulb can also be administered intramuscularly. In patients with renal impairment, it has been found that the half-life of the β-lactam/β-lactamase combination of drugs is prolonged and blood levels are elevated, thus warranting dosage adjustment in some cases. 31

Clinical use

Dermatologic indications
The broad-spectrum antimicrobial coverage provided by Amox/Clav, Amp/Sulb, Ticar/Clav, and Pip/Tazo makes these agents useful for the treatment of polymicrobial infections. The recommended oral agent for treatment of animal or human bites infected by combined aerobic and anaerobic pathogens is Amox/Clav. 58 Ticar/Clav and Pip/Tazo exhibit an even broader antibacterial spectrum, and are effective in treating CSSTI such as diabetic foot ulcers, infected decubiti, and burn wounds. 63, 64

Adverse effects
Adverse effects most often associated with Amox/Clav and Pip/Tazo are GI complaints, most commonly diarrhea. 59 Diarrhea appears to occur less frequently when Amox/Clav is administered with food. Q8-4 Hypersensitivity reactions from the β-lactam/β-lactamase inhibitor combinations are similar to those seen from the β-lactams alone. Ticarcillin and piperacillin can prolong bleeding times and cause platelet aggregation dysfunction. 65 Hypernatremia has been reported with both ticarcillin and piperacillin administration. 59 Transient elevation of transaminases, positive Coombs’ test, thrombocytopenia, neutropenia, and eosinophilia have also been reported with these agents. 66 Cholestatic injury has been reported in up to 1 in 100 000 prescriptions of Amox/Clav, but not with amoxicillin alone. 28 Sulbactam has been associated with pain at the intramuscular injection sites. 67

Drug interactions
When administered concomitantly with β-lactam/β-lactamase inhibitor combinations, oral probenecid slows the rate of renal tubular secretion of the β-lactam agent, resulting in an increase in serum concentration and delayed renal excretion. 68, 69 The controversial topic of whether or not oral antibiotics reduce the efficacy of oral contraceptives is reviewed below under the Drug Interactions sections for both tetracyclines and rifamycins.

Dosage
Amox/Clav is administered orally. The adult dosage is 250–500 mg every 8 hours, although the 875 mg formulation twice daily is increasingly used. The tablets and suspension contain either a 2 : 1 or a 4 : 1 ratio of the drugs. Table 8-2 contains dosage guidelines for oral penicillins.

Carbapenems and monobactams
Both of these drug groups have limited applicability in dermatology as they are available only in parenteral forms.

Carbapenems 70 – 77

1. Imipenem, the first carbapenem available in the US, is combined with cilastatin, a natural inhibitor of renal dehydropeptidase enzyme responsible for the metabolism, and provides renal toxicity protection. 70
2. Other carbapenems include meropenem and ertapenem. 70, 71
3. Overall, carbapenems probably demonstrate the most complete range of antibacterial coverage of any antibiotic class. 70 – 74 They are active against most aerobic and anaerobic Gram-negative bacteria, including most P. aeruginosa strains, and anaerobic organisms including the B. fragilis group. 72, 73
4. Q8-4 Skin test studies have shown a high degree of cross-reactivity between carbapenems and penicillin. The incidence of allergic-type reactions to a carbapenem was 5.2 times greater in patients who were reportedly allergic to penicillin. 76, 77
5. Carbapenems may lower the seizure threshold, and should be administered with caution in a patient with a history of seizures.

Monobactams 78 – 82

1. Aztreonam, the only monobactam currently available in the US, exhibits an antimicrobial spectrum of activity limited to aerobic Gram-negative organisms. 78 – 80
2. The drug has been employed as a sole agent in treating Gram-negative cutaneous infections, including postoperative wounds, ulcers, burns, and ecthyma gangrenosum, and in conjunction with other drugs that inhibit Gram-positive or anaerobic flora. 80
3. Aztreonam has an adverse effect profile similar to that of other β-lactam antibacterial agents, including rare cases of erythema multiforme, toxic epidermal necrolysis, urticarial, and exfoliative dermatitis. 81
4. Q8-4 Patients who are allergic to penicillin can be safely given aztreonam. 82

Other systemic agents affecting the bacterial cell wall

Vancomycin
Vancomycin, a glycopeptide antibiotic, was isolated in 1956 from the actinomycetes Streptomyces orientalis , and approved by the US FDA in 1958. 83 It inhibits the synthesis of the bacterial cell wall via a mechanism different from that of the β-lactams. Vancomycin is pregnancy category C, is excreted in breast milk, and is approved for use in children.

Pharmacology

Antibacterial activity
Vancomycin is structurally classified as a tricyclic glycopeptide. It is effective only against Gram-positive organisms, exhibiting ‘slow’ bactericidal activity against staphylococci and streptococci, and bacteriostatic activity against most enterococci. 83 – 85 One of the most important clinical applications of vancomycin is in the treatment of staphylococcal infections that are resistant to several more conventional antibiotics, such as those caused by MRSA and methicillin-resistant coagulase-negative staphylococci. 93, 84
Q8-7 Resistance to vancomycin is reportedly mediated by a plasmid that reduces the permeability of the drug, and reduces binding of vancomycin to receptor molecules in the bacterial cell wall. 83 Over 3 decades of use pathogens resistant to vancomycin have emerged, including vancomycin-resistant staphylococci and streptococci. 84, 85 Increasing numbers of therapeutic failures have been observed with vancomycin for MRSA infections, due in large part to increases in minimum inhibitory concentrations (MIC) of vancomycin for many Gram-positive pathogens, including MRSA. 85 Other organisms showing increasing resistance to vancomycin, predominantly in the hospital setting, include vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRS), and vancomycin-resistant enterococci (VRE).

Pharmacokinetics
Vancomycin is administered parenterally because of its minimal absorption from the GI tract, and is used orally only for the treatment of C. difficile diarrhea. 86 Owing to its lack of extensive metabolism, 90–100% of vancomycin is excreted by glomerular filtration. The serum half-life of vancomycin is 4–8 hours after intravenous injection with normal renal function, with the need for dosage modification in patients with marked renal insufficiency.

Clinical use

Dermatologic indications
Vancomycin is used for the treatment of SSTI caused by MRSA and methicillin-resistant coagulase-negative staphylococci. It is mostly used for the treatment of hospital-acquired MRSA (HA-MRSA), but may be indicated for the treatment of fulminant and deeply invasive CA-MRSA infections. Q8-7 In general, CA-MRSA derives its resistance pattern via staphylococcal cassette type IV chromosome mec element (SCC-MEC IV). Most CA-MRSA infections seen in dermatologic practice cause USSTI that are susceptible to incision and drainage (when presenting as abscesses) and oral therapy with minocycline, doxcycycline, clindamycin, or TMP-SMX; however, exceptions exist and the patterns of resistance to vancomycin, such as strains of S. aureus , are among the most common infections treated in hospitals today, often presenting as CSSTI. 88 The increasing prevalence of this resistance to major pathogens, such as S. aureus and VRE, has prompted the development of multiple new antibiotic classes that are currently under investigation. 89 Some of these lipoglycopeptides, fluoroquinolones, oxazolidinones, and dihydrofolate inhibitors are discussed later in this chapter.

Adverse effects

Cutaneous reactions and hypersensitivity
Q8-8 Red man syndrome and shock secondary to histamine release can be caused by rapid transfusion of vancomycin. Rarely, toxic epidermal necrolysis (TEN) has been reported; however, differentiation of TEN from a variant presentation of linear IgA bullous dermatosis (LABD) caused by vancomycin is warranted. 83, 90 – 95 Vancomycin is one of the most common causes of drug-induced LABD, developing after the initiation of vancomycin and also upon rechallenge. 83, 90, 91 Multiple cases of vancomycin-induced LABD mimicking TEN have been reported. 92 – 95 In some cases, vancomycin-induced LABD has presented as morbilliform eruption without blistering. 96 Although the target antigens in idiopathic LABD are believed to be heterogeneous, IgA antibodies to LAD285 and dual response antibody formation (IgA and IgG) to BP180 have been reported in 2 cases of vancomycin-induced LABD. 97

Other adverse effects
Dose-related hearing loss has been reported in patients with renal failure, likely due to the accumulation of vancomycin. Nephrotoxicity can occur, particularly when administered along with aminoglycoside antibiotics. 83 Other adverse effects include fever, neutropenia, thrombocytopenia, and phlebitis at the infusion site.

Drug interactions
Concurrent administration of vancomycin with aminoglycosides increases the risk of nephrotoxicity. Vancomycin may enhance the activity of non-deporlarizing muscle relaxants. 12

Macrolides

Erythromycin, azithromycin, and clarithromycin
Macrolide antibiotics contain a macrocyclic lactone ring structure and are either products of actinomycetes (soil bacteria) or semi-synthetic derivatives of these bacteria. Q8-9 Unlike β-lactams, macrolides are bacteriostatic antibiotics which bind reversibly to the large (50S) subunit of the bacterial ribosome, inhibiting RNA-dependent protein synthesis. 98 – 100 Q8-10 Macrolides have also been reported to demonstrate specific anti-inflammatory properties, unrelated to their antibiotic activities, which may potentially contribute to their therapeutic benefit in inflammatory facial dermatoses such as acne and rosacea. 101 – 103 Macrolides, azalides, and ketolides are listed in Table 8-5 .

Table 8-5 Currently available FDA-approved macrolides, azalides, and ketolides


Traditional macrolides
Erythromycin is the prototype macrolide, available for either oral or parenteral use. In the past, erythromycin was a consistently good substitute for penicillins in patients who are allergic to β-lactams; however, the emergence of widespread S. aureus resistance to erythromycin, as well as some resistant streptococcal strains, has significantly limited the clinical utility of this drug in both adults and children. 1, 4, 5 In the management of acne vulgaris, the use of oral erythromycin has markedly declined in the US and other countries due to widespread emergence of resistant P. acnes strains, with resistance rates as high as 50%. 1, 4, 5 Additionally, oral erythromycin is associated with other clinically relevant drawbacks, including erratic oral bioavailability, a short half-life requiring frequent administration, and the frequent development of GI adverse effects, such as nausea and abdominal discomfort. 104 Finally, the use of erythromycin is sometimes prevented by its relatively strong inhibition of CYP3A4 and 1A2, leading to reduced clearance and increase risk of toxicity to a wide variety of drugs (see Drug Interactions section for details). 105

Azalides
The azalide antibiotics, based on a structural modification of the macrolide nucleus, include clarithromycin and azithromycin. 104 These azalide agents exhibit a broad range of clinical uses, including for a variety of cutaneous infections.

Ketolides
Another group structurally similar to macrolides, called the ketolides, incorporates substitutions on the 14-membered macrolide ring. The first ketolide introduced in the US was telithromycin, with reported benefits for penicillin- and macrolide-resistant strains of S. pneumoniae . Telithromycin had not been adequately studied in the treatment of skin infections at the time of its release in the US. 106, 107 Major safety issues with telithromycin have since emerged, including symptomatic hepatotoxicity, including several deaths, prolongation of the QTc interval, and the need to avoid use in patients with myasthenia gravis (see Adverse Effects section). 108 - 110 Cethromycin is a newer ketolide submitted for FDA approval in 2008 for treatment of mild to moderate community-acquired pneumonia (CAP) that exhibits inhibition of both Gram-positive and Gram-negative respiratory organisms. 111 – 112 Interestingly, cethromycin was granted ‘orphan drug’ status for the prevention of post-exposure anthrax. CEM-101 is the newest ketolide for which the structure of telithromycin has been modified somewhat, with enhanced activity against telithromycin-resistant organisms. 113

Pharmacology

Antimicrobial activity
Macrolide antibiotics are effective against most Gram-positive organisms, with the notable exceptions of MRSA and enterococcus. Q8-11 Compared to erythromycin, clarithromycin is 2–4 times more potent than erythromycin against Gram-positive organisms such as staphylococci and streptococci. 114 Although the in vitro activity of azithromycin against Gram-positive organisms is 2–4 times less than that of erythromycin, its efficacy is enhanced by its ability to achieve high levels in several tissues. Unlike erythromycin, clarithromycin and azithromycin possess increased activity against several Gram-negative pathogens, including H. influenzae . 115 Azithromycin has activity against E. coli , N. gonorrhoeae , Haemophilus ducreyi , Ureaplasma urealyticum , and Chlamydia trachomatis . 116 Azithromycin also has activity against organisms contacted via animal bites, including Pasturella multocida and human bites such as Eikenella corrodens . 117 Both clarithromycin and azithromycin are effective against atypical mycobacteria such as Mycobacterium avium-intracellulare , Mycobacterium leprae , and Mycobacterium chelonei . 118 – 120 Clarithromycin is the most active macrolide against M. leprae . Both clarithromycin and azithromycin demonstrate activity against Toxoplasma gondii , Treponema pallidum, and B. burgdorferi . 121 – 123

Pharmacokinetics
Erythromycin, the azalides, and the ketolides may be given orally. Unless administered in an enteric-coated form, erythromycin base is vulnerable to gastric acid inactivation and must be taken on an an empty stomach. Erythromycin is also available as an acid-stable salt (stearate), ester (ethyl succinate and propionate), or salt of an ester (estolate). 116 The stearate must be taken on an empty stomach, whereas the other formulations may be taken without regard to food ingestion. Erythromycin and azithromycin are also available in parenteral forms.
The azalides have improved oral bioavailability, 104 with clarithromycin equally well absorbed with or without food, although azithromycin absorption is decreased with food (best taken 1–2 hours before a meal). Renal elimination is significant route of excretion for clarithromycin and less so for erythromycin, with dosages for both drugs warranting modification in significant renal failure. As azithromycin is primarily metabolized by the liver, no adjustments are required in renal disease. The elimination half-life of azithromycin initially is 11–14 hours, followed by a more prolonged half-life of 68 hours.

Clinical use

Dermatologic indications

Indications for cutaneous infections
Q8-11 The macrolides are effective in the treatment of various skin and soft tissue infections, with an overall favorable safety profile; erythromycin has been used since 1952. These agents, especially oral formulations, have been used for several types of USSTI, including pyodermas, abscesses, infected wounds, infected ulcers, and erysipelas; however, erythromycin use is no longer optimal in many cutaneous infections owing to the marked increase in bacterial resistance to this agent, especially with S. aureus and some streptococcal strains. 1, 4 – 7 , 124 – 126 MRSA is not responsive to treatment with macrolide or azalide antibiotics. 6, 7 Other potential mucocutaneous indications for erythromycin include Lyme disease, erythrasma, anthrax, erysipeloid, rheumatic fever, non-gonococcal urethritis, syphilis, chancroid, and lymphogranuloma venereum. 116 Data exist to overall support the efficacy for most of these indications with azalides as well.
Q8-11 Among the azalide subcategory of macrolides, azithromycin has been shown to be effective in the treatment of donovanosis, cat-scratch disease, toxoplasmosis, and Mediterranean spotted fever. 116 Additionally, the high activity against N. gonorrhoea and C. trachomatis renders a single dose of azithromycin effective for treatment of uncomplicated urethritis or cervicitis. Azithromycin is an excellent choice for infections associated with animal and human bites, given its activity against Pasteurella and Eikenella spp. Clarithromycin has been shown to be effective in the treatment of leprosy, as well as the atypical mycobacterial skin infections with M. chelone i, M. simiae , M. avium complex (MAC), M. kansasii , and M. intracellulare . 127

Indications for inflammatory dermatoses
Erythromycin, and to a much lesser extent azithromycin, has been used for the treatment of inflammatory facial dermatoses with an infectious component, including acne vulgaris, rosacea, and perioral dermatitis. 1, 4, 128 – 132 Owing to the high prevalence of erythromycin-resistant P. acnes , the use of erythromycin for the treatment of acne has waned in the US and several other countries. 1, 4, 5 Selective use of azithromycin for acne vulgaris and rosacea may be helpful in some patients who are intolerant to tetracycline agents, with azithromycin shown to be as effective as tetracycline in one study for rosacea. 128, 129 Owing to the long elimination half-life and persistent tissue levels with azithromycin, various intermittent dosing regimens have been used, such as 250 mg three times weekly, after an initial ‘tissue load,’ with daily dosing for 5 days. 128 – 132 Data on oral macrolide use for perioral dermatitis are limited. 133
As with penicillins, a systematic review of the literature has concluded that there is no evidence that administration of anti-streptococcal antibiotics, including macrolides, improves guttate psoriasis. 15, 16 Macrolides have been used successfully to treat confluent and reticulated papillomatosis. 116 A few reports have suggested efficacy of erythromycin in the treatment of pityriasis rosea. 134, 135

Adverse effects

Common adverse effects
The most common adverse effects of erythromycin are nausea, abdominal pain, and diarrhea, reported to occur in 15–20% of patients, depending on the oral formulation used. 136 Erythromycin binds to motilin receptors throughout the GI tract, releasing motilin, which stimulates migrating digestive contractions, thus inducing a higher incidence of GI disturbance than with the azalide and ketolide subcategories. 137, 138 Erythromycin has also been reported to be a rare cause of skin eruptions and allergic reactions ranging from mild to severe, as well as reversible hearing loss at high doses. 116 Ototoxicity was reported at higher doses or in patients with hepatic or renal dysfunction. 136 Cardiac conduction abnormalities have been associated with macrolide use. 116, 139 One study reviewed the cardiac safety profile of macrolides and found that erythromycin carried the greatest risk of QT prolongation and torsades de pointes compared to other macrolides, with the risk of cardiotoxicity increased with advanced age, higher dosages, rapid administration, and history of cardiac diseases. 139 Clarithromycin may cause a metallic or bitter taste, fixed drug eruption, leukocytoclastic vasculitis, and hypersensitivity reactions. Azithromycin has been associated with irreversible deafness, angioedema, photosensitivity, hypersensitivity syndrome, and contact dermatitis. Telithromycin has been implicated in cases of symptomatic hepatotoxicity, including acute hepatic failure and liver injury, and exacerbation of myasthenia gravis. 108 – 110 ,140 ,141 Overall, macrolide antibiotics have rarely been associated with cholestatic hepatitis. 116

Use in infants
Macrolides are excreted into breast milk, and therefore infant exposure to these drugs during lactation has been reported to increase the risk of hypertrophic pyloric stenosis. 142, 143 An increased risk of cardiovascular malformation and pyloric stenosis in infants who were exposed to erythromycin in utero has been noted. 11, 144 However, a more recent prospective controlled observational study of 55 infants exposed to macrolides via lactation found no association with pyloric stenosis or any other serious adverse reacton. 145 Larger prospective studies are required to substantiate these findings.

Use in pregnancy
In general, most clinicians consider oral erythromycin to be safe in pregnancy as only low concentrations cross the placenta. Even so, the safety of chronic use in pregnancy for acne vulgaris, rosacea, or perioral dermatitis has not been adequately addressed. Short-term use of macrolides in the latter trimesters of pregnancy should be considered a different risk–benefit analysis. The following are some factors to consider with regard to prolonged administration of oral erythromycin during pregnancy. With oral erythromycin use in pregnancy, fetal concentrations of the drug are low, given some placental crossing of erythromycin. Fetal levels are reported to increase after multiple doses. 147 – 148 Also, the estolate salt of erythromycin used for longer than 3 weeks in pregnancy has been associated with maternal hepatotoxicity, with approximately 10% of 161 pregnant women treated with oral erythromycin in the second trimester developing elevated transaminase levels, which returned to normal after therapy was discontinued. 11, 149
The observation that erythromycin may be rarely associated with cardiotoxicity raises additional concerns regarding prolonged use of erythromycin in pregnancy. 116, 139 A case–control study designed to assess oral erythromycin use in early pregnancy and possible association with fetal cardiac abnormalities evaluated outcomes from 3 Swedish health registries. 150 The findings were compared between infants with cardiac defects unrelated to genetic causation (n=5015) and a control group consisting of all infants born in Sweden between 1995 and 2001 (n=577 730). ‘Potential’ associations between cardiac defects and the use of a variety of drugs, including erythromycin, were noted. There were a total of 1588 erythromycin exposures, with 27 cases of cardiac defects in infants noted, although it is uncertain whether erythromycin was causative. 150 Lastly, a surveillance study conducted in Michigan evaluated 229 101 pregnant women who were Medicaid recipients, with 6972 newborns exposed to oral erythromycin during the first trimester. 151 Major birth defects occurred in 4.6% of infants exposed to erythromycin, compared to an expected rate of 4.0%. Cardiovascular abnormalities were noted in approximately 1.0% of erythromycin-exposed newborns, which was the same as the expected rate in this population. It remains wise to minimize erythromycin exposure in pregnancy for non-infectious indications. 152 Erythromycin has been evaluated in the third trimester of pregnancy to safely reduce maternal and infant colonization with group B β-hemolytic streptococcus, and to reduce rates of pregnancy loss and low-birthweight infants in women with genital mycoplasma infections. 151

Drug interactions
Q8-11 Erythromycin, and to a lesser extent clarithromycin, inhibits the hepatic and intestinal (‘first-pass’) CYP system, primarily CYP3A4, leading to decreased metabolic clearance of a number of drugs, often relatively rapidly after initiation of erythromycin/clarithromycin therapy. 105, 153 These two macrolide agents (erythromycin > clarithromycin) inhibit the metabolism, raise plasma levels, and prolong the clearance of many drugs that are administered chronically, including ( Table 8-6 ):

1. Carbamazepine and phenytoin; 153 – 155
2. Theophylline;
3. Certain benzodiazepines (i.e., triazolam, midazolam);
4. Warfarin, with potential for severe bleeding complications;
5. Cyclosporine, with potential for renal toxicity and HBP;
6. Drugs with potential for QT prolongation and torsades de pointes 153, 156, 157 (terfenadine, astemizole, cisapride, and pimozide; all but pimozide have been withdrawn from the market); and
7. Some HMG-CoA reductase inhibitors or ‘statins’ (i.e., atorvastatin, simvastatin, lovastatin), thereby enhancing their risk for toxicity such as rhabdomyolysis. 105, 153, 154
8. Clarithromycin may reduce the absorption of zidovudine (AZT) by 20% and may also reduce the serum levels of didanosine (ddI). 158, 159
9. In contrast, clarithromycin may significantly increase linezolid serum concentrations when co-administered. 160
10. Several cases of macrolide antibiotic-induced digoxin toxicity have been reported, including with the azalide and ketolide subcategories, possibly due to alterations in gut flora or via telithromycin alterations of P-glycoprotein. 161 – 167
Table 8-6 Drug interactions – macrolides, azalides, and ketolides Interacting drug group Examples and comments These drugs may ↑ serum levels (and potential toxicity) of erythromycin, clarithromycin – CYP3A4 inhibition Antiarrhythmic agents Amiodarone Antidepressants – SSRI Fluoxetine, fluvoxamine Antifungal – azoles Ketoconazole >> itraconazole > fluconazole (also voriconazole) Calcium channel blockers Diltiazem, verapamil; only these two drugs are CYP3A4 inhibitors Foods and beverages Grapefruit, grapefruit juice HIV drugs – other Delavirdine HIV drugs – protease inhibitors Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir Immunosuppressive agents Cyclosporine These drugs ↓ serum levels (loss of efficacy) of macrolides and azalides – CYP3A4 induction Antibacterial – rifamycins Rifampin, rifabutin, rifapentine Anticonvulsants Carbamazepine, oxcarbazepine, phenobarbital, phenytoin Miscellaneous drugs Nevirapine Retinoids (‘rexinoid’) Bexarotene Erythromycin and clarithromycin ↑ serum levels (and potential toxicity) of these drugs – CYP3A4 substrates Alzheimer’s disease drugs Donepezil Antiarrhythmic agents † Amiodarone, disopyramide, dofetilide, flecainide, propafenone, quinidine; risk for arrhythmias including QT prolongation (torsades de pointes) Anticoagulants † Warfarin; ↑ anticoagulant effect ( risk of hemorrhage), also a 1A2 substrate Anticonvulsants † Carbamazepine, ethosuximide, felbamate, oxcarbazepine, valproate; check levels Antidepressants Buspirone, maprotiline, nefazodone, trazodone, venlafaxine, various tricyclics, including amitriptyline, imipramine Antipsychotic agents Aripiprazole, haloperidol, pimozide, quetiapine, risperidone Calcium channel blockers † All calcium channel blockers are substrates of CYP3A4 Chemotherapeutic agents † Bortezomib, docetaxel, geftanib, imatinib, paclitaxel, vinblastine, vincristine Corticosteroids Budesonide, fluticasone (inhaled), methylprednisolone, mometasone (inhaled) Diabetes drugs Glipizide, glyburide, metformin, pioglitazone, tolbutamide; monitor glucose Erectile dysfunction drugs † Silderafil, tadalafil, vardenafil HIV drugs – other † Delavirdine, efavirenz, nevirapine Hormonal contraceptives Oral, transdermal, injectable forms – may ↑ risk of intrahepatic cholestasis Immunosuppressive agents † Cyclosporine, tacrolimus – ↑ risk for nephrotoxicity, neurotoxicity, ↑ BP Miscellaneous drugs Aprepitant, bromocriptine, cinacalcet, colchicine, digoxin, mifepristone Narcotics † Alfentanil, buprenorphine, fentanyl, meperidine, methadone, sufentanil; monitor for excessive sedation Retinoids (‘rexinoid’) † Bexarotene; monitor lipids, amylase, TSH, transaminases Sedatives – benzodiazepines Alprazolam, midazolam, triazolam; monitor for excessive sedation Statins † Atorvastatin, lovastatin, simvastatin; ↑ risk of myopathy, rhabdomyolysis, hepatotoxicity, ↓ cholesterol Erythromycin can ↑ the serum levels (and potential toxicity) of these drugs – CYP1A2 subtrates Antiarrhythmic agents † Mexiletine; risk for arrhythmias including QT prolongation (torsades de pointes) Bronchodilators – xanthine † Theophylline – risk of CNS toxicity particularly important Chemotherapeutic agents Erlotinib; also a CYP3A4 substrate Foods and beverages Caffeine; this ‘drug’ used in preclinical studies for assessing 1A2 metabolism Lipoxygenase (5-LO) inhibitor † Zileuton; risk for hepatotoxicity
Note : Risk for interactions involving CYP3A4 greatest with erythromycin, moderate with clarithromycin, negligible with azithromycin; CYP1A2 inhibition primarily by erythromycin (clarithromycin, azithromycin are azalides ).
*Astemizole, cisapride, grepafloxacin, terfenadine withdrawn from US market due to torsades de pointes, ↑ risk in presence of CYP3A4 inhibitors such as clarithromycin, erythromycin; also cerivastatin withdrawn due to rhabdomyolysis.
† Drug interactions with CYP3A4 and 1A2 substrates with a ‘narrow’ therapeutic index leading to a greater risk of toxicity.
Adapted from Facts & Comparisons, The Medical Letter Drug Interactions Program, E-pocrates, Hansten and Horn – references on pg. xxii.
Azithromycin does not significantly affect CYP isoenzymes, and so may be safely co-administered with other drugs. 153, 168 ,169 However, there have been reports of toxicity related to co-administration of azithromycin and lovastatin, warfarin, cyclosporine, disopyramide, and theophylline. 170, 171 The controversial topic of whether or not oral antibiotics reduce the efficacy of oral contraceptives is reviewed below under the Drug Interactions sections for both tetracyclines and rifamycins.

Dosage
The dosing schedule of the various macrolide antibiotics for treatment of cutaneous infections varies significantly depending on the specific drug ( Table 8-7 ). The usual adult dosing schedule for erythromycin base is 250–500 mg every 6–12 hours, and for erythromycin ethyl succinate 400–800 mg every 6–12 hours. The adult dosage of clarithromycin is 250–500 mg every 12 hours, though a newly available XL formulation (500 mg) permits once-daily dosing. For azithromycin, the adult dosage is 500 mg given as a single dose on the first day of therapy, followed by 250 mg once daily for 4 additional days. For the treatment of uncomplicated chlamydial infections azithromycin is administered as a single 1- g dose. Localized gonococcal infections may be treated with a single 2- g oral dose. Azithromycin is available in 250, 500, 600 mg tablets, a 2 g extended-release oral suspension, a 250 mg/5 mL pediatric liquid preparation, and an intravenous formulation. Table 8-7 gives dosage guidelines for commonly used oral macrolides and related drugs.
Table 8-7 Commonly used oral macrolides – dosage guidelines Generic name Tablet/capsule sizes (mg) Adult dosage Azithromycin * 250, 500, 600 500 mg day 1, then 250 mg qd 3 4 † Clarithromycin * 250, 500 250–500 mg bid Erythromycin base 250, 333, 500 250–500 mg qid ‡ Erythromycin ethyl succinate * 400 400 mg qid
* These drugs are available in either suspension or liquid formulations.
† Azithromycin PO QD for 3 days is also an approved dosage schedule (product also supplied in 250-mg tablets 36 tablets or 500-mg 33 tablets).
‡ Enteric-coated formulations are available.

Fluoroquinolones
There are many fluoroquinolones (FQ) currently available in the US ( Table 8-8 ), with those used more commonly in dermatology reviewed in more detail below. The ‘modern day’ FQ exhibit a broader spectrum of concentration-dependent bactericidal activity than older quinolones, such as nalidixic acid, and their longer serum half-lives allow for once- or twice-daily administration in most instances. Other advantages of FQ include high oral bioavailability (except in the presence of certain metal cations), and extensive tissue penetration into human cells, resulting in antimicrobial activity against intracellular pathogens. 172 Q8-12 FQ interfere with bacterial DNA replication via inhibition of DNA gyrase (bacterial topoisomerase II), an enzyme that regulates supercoiling of bacterial DNA, and topoisomerase IV, an enzyme that allows separation of the topologically linked daughter chromosomes during DNA replication. 173

Table 8-8 Currently available FDA-approved oral fluoroquinolones
The FQ are pregnancy category C and are excreted in breast milk. 11 They have been found to impair cartilage formation in immature animals, and therefore are usually not recommended for use in children. 174, 175 This issue will be covered in detail in the Adverse Effects section for FQ.

Pharmacology

Antimicrobial activity
The FQ are effective against most Gram-negative organisms, particularly the Enterobacteriaceae, and in vitro are active against some Gram-positive bacteria, such as S. aureus , including MRSA. FQ are generally applicable as oral agents for treatment of USSTI caused by susceptible pathogens, although some exceptions do exist in clinical practice. 5 – 7 Ciprofloxacin, the first oral FQ antibiotic agent brought to market in the US, has remained overall the most active of the FQ against P. aeruginosa , although some strains have become ciprofloxacin-resistant over time. 176
FQ show variable efficacy against Gram-positive organisms, with emergence of ciprofloxacin-non-susceptible S. pyogenes isolated from a healthy pediatric population. 177 Levofloxacin and moxifloxacin are reported to be efficacious against S. aureus and S. pyogenes . Q8-13 Importantly, although some FQ exhibit high activity in vitro against MRSA, including CA-MRSA strains, there are increasing reports of treatment failure due to FQ-resistant staphylococci. 5 – 7 ,178 ,179 Therefore, FQ are not considered first-line agents for USSTI caused by CA-MRSA, but may be used in selected cases when other options are limited by specific circumstances. Ciprofloxacin is also active against Bacillus anthrax . The FQ possess minimal anaerobic activity. Ciprofloxacin, ofloxacin, and levofloxacin are active against Mycobacterium spp, including M. tuberculosis , M. fortuitum , and M. kansasii . 180 – 183

Pharmacokinetics
Q8-2 With the exception of norfloxacin, the oral bioavailability of the FQ is excellent and minimally affected by food, except in the presence of some metal ions co-administered in high concentration, such as in antacids, and vitamin/mineral supplements. 105, 173 Half-lives of FQ vary from 3 to 13 hours. 184 Except for moxifloxacin, FQ are mainly excreted renally, and thus require dosage adjustment in patients with significantly impaired renal function. 185

Clinical use

Dermatologic indications
Because of high drug levels in the skin and its appendages, the oral FQ are ideal agents for treating USSTI caused by Gram-negative bacteria, including those caused by multiresistant organisms such as folliculitis, abscesses, cellulitis, infected ulcers, and wound infections. 173 FQ can be used as an alternative to penicillins or β-lactams to treat USSTI caused by susceptible organisms in patients allergic or hypersensitive to penicillins or other β-lactams. 186 These agents are also useful in treating Gram-negative toe web-space infections, infected diabetic foot ulcers, and puncture wounds. Single doses of ciprofloxacin or ofloxacin are effective in the treatment of gonorrhea caused by FQ-susceptible strains; however, caution is advised as FQ-resistant strains of N. gonorrhoeae are emerging in the US. Fluoroquinolones are effective against donovanosis and chancroid. Ciprofloxacin is a treatment of choice for cutaneous anthrax. 173
Although there have been a limited number of reports suggesting efficacy of FQ for acne vulgaris, the use of FQ for this indication is not generally recommended. 128, 129, 152 Rare exceptions may include brief use for highly refractory cases. Prolonged administration of FQ is not suggested in order to preserve the utility of oral FQ for indications where they are regularly depended upon for efficacy. 128, 129, 152 Oral FQ may be helpful in some cases of Gram-negative folliculitis, including persistent ‘hot tub folliculitis’ caused by Pseudomonas spp. In patients with Gram-negative folliculitis other than the ‘hot tub’ variety, treatment with oral FQ is sometimes curative, with antibiotic selection optimally based on bacterial culture and sensitivity results. However, treatment with oral isotretinoin may be needed for refractory cases and/or recurrences.

Adverse effects

Common adverse effects
The most common adverse reactions associated with FQ involve the GI tract, such as nausea, vomiting, and diarrhea. 173 – 187 Common central nervous systemic (CNS) adverse effects range from milder reactions such as headaches, dizziness, agitation, and sleep disturbances to more severe reactions including seizures, psychotic reactions, hallucinations, and depression. 173 – 187 ,188 The mechanism of at least some CNS reactions may relate to FQ antagonism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). 173

Use in children – cartilage formation alteration
As discussed above, based on animal studies FQ may impair cartilage formation, and therefore these agents are generally avoided in children except for selected cases with extenuating circumstances. 174, 175, 189
A retrospective observational study completed through an automated database identified patients <19 years of age, 6124 of whom were treated with at least 1 of 3 FQ, receiving ciprofloxacin, levofloxacin, or ofloxacin (active study group) and 15 073 who were treated with azithromycin. 174 Potential cases of tendon or joint disorders (TJD) occurring within 60 days of a prescription for one of the study antibiotics were identified based on diagnosis coding and were verified. The incidence of verified TJD diagnosed within 60 days of prescribing either an FQ antibiotic or azithromycin was <1% in both study groups. Despite this information, cautious prescribing of FQ in children is wise, particularly when other drug categories are equally effective. 175
Tendinitis and tendon rupture have been observed with FQ, and may be delayed in onset after initiation of FQ use. 173, 190, 191 Risk factors for FQ-induced tendinopathy and tendon rupture are corticosteroid use, patient age, sports participation, history of renal failure, diabetes mellitus, hyperparathyroidism, rheumatic disease, gout, and a history of tendinopathy. 190, 191

Hypersensitivity and photosensitivity reactions
Hypersensitivity reactions and photosensitivity have also been reported, and photo-onycholysis has been described. 17, 192, 193 Q8-14 In order of decreasing photosensitivity potential, these agents include lomefloxacin, ciprofloxacin, norfloxacin, and ofloxacin. 192 Evening dosing of these agents may minimize phototoxic potential. 193 Blue-black pigentation of the legs similar to minocycline dyschromia, with demonstration of iron particles within the cytoplasm of dermal macrophages, has been reported with perfloxacin therapy. 194
As a class, quinolones are generally well tolerated; however, more serious anaphylactoid or anaphylactic reactions have been reported with ciprofloxacin use. 195 Patients may present with edema of the face, difficulty breathing, hypotension, tachycardia, fever, pruritus, and/or diffuse erythroderma, with the reactions tending to occur up to 3 days following the initial dose of IV or oral ciprofloxacin therapy. 195

Liver and other major toxicity
Trovafloxacin has been associated with hepatic injury and is available in the US just on a very limited basis. 28 Gatifloxacin and moxifloxacin are associated with QTc interval prolongation, with gatifloxacin withdrawn from the US market in 2006 owing to reports of serious dysglycemia in older adults. 188, 196

Use in pregnancy and lactation
Although congenital anomalies associated with FQ use during pregnancy are inconsistent, FQ are not suggested during pregnancy, especially as a first-line therapy, although accidental exposure is not a definitive indication for medical abortion. 11

Drug interactions ( Table 8-9 )
Q8-2 Essentially all FQ show decreased bioavailability when administered with calcium-, aluminum-, or magnesium-containing antacids, with a marked reduction in GI absorption noted with many oral FQ, likely due to the formation of cation–FQ complexes that are poorly absorbed. 105, 173 The concurrent ingestion of calcium with ciprofloxacin within 15 minutes has been shown to reduce ciproxacin absorption by 40%, and ingestion of ciprofloxacin within 4 hours after an aluminum/magnesium-containing antacid results in a 75% reduction in ciprofloxacin absorption. 105, 197, 198 Similarly, decreased GI absorption of FQ has been noted with co-administration of sucralfate and iron- or zinc-containing products. A practical guideline useful in clinical practice is to instruct patients to take their FQ antibiotic at least 1–2 hours before, and not within 4 hours after, the ingestion of the above drugs/products. 105, 198
Table 8-9 Drug interactions – fluoroquinolones Interacting drug group Examples and comments Drugs that may ↓ fluoroquinolone levels (loss of efficacy) through chelation * Antacids Divalent (calcium, magnesium) and trivalent (aluminum) cations; will ↓ GI absorption of fluoroquinolones through chelation Miscellaneous drugs Didanosine (is buffered), sucralfate (an aluminum salt of sulfated sucrose) Nutritional supplements Iron and zinc salts; chelation of fluoroquinolones by these products Fluoroquinolones ↑ serum levels (and potential toxicity) of these drugs – CYP1A2 inhibition Antiarrhythmic agents † Mexiletine; risk for arrhythmias, QT prolongation (torsades de pointes) Anticoagulants † Warfarin; CYP1A2 is one of three metabolic pathways for the R-enantiomer of warfarin (also 2C19, 3A4), risk of hemorrhage, check INR frequently Bronchodilators – xanthines † Aminophylline, theophylline; ↑ levels (levels may triple), risk CNS toxicity Chemotherapeutic agents † Erlotinib; also a CYP3A4 substrate Foods and beverages Caffeine; this ‘drug’ used in preclinical studies to assess 1A2 metabolism Lipoxygenase (5-LO) inhibitor † Zileuton; risk for hepatotoxicity Certain fluoroquinolones may ↑ risk of QT interval prolongation in combination with these drugs ‡ Antiarrhythmic agents † Amiodarone, bepridil, disopyramide, dofetilide, ibutilide, procainamide, quinidine Antibacterial – macrolides/related Clarithromycin, erythromycin Antidepressants Amitriptyline, clomipramine, desipramine, possibly others Antipsychotic agents † Haloperidol, olanzapine, phenothiazines (various), pimozide, ziprasidone Beta blockers † Sotalol (especially) Chemotherapeutic agents † Arsenic trioxide Miscellaneous drugs Domperidone, pentamidine Other drug interactions of importance involving fluoroquinolones Cardiac drugs – inotropic agents Digoxin; may ↑ serum levels, mechanism unknown Diabetic drugs Metformin, pioglitazone, repaglinide, sulfonylureas; risk ↑↑ or ↓↓ glucose Immunosuppressive agents Cyclosporine; ↑creatinine levels in transplant patients, monitor carefully
Note : Ciprofloxacin and other fluoroquinolones are CYP1A2 inhibitors.
* Allow at least 2 hours between administration of the fluoroquinolones and these chelating drugs.
† Drugs with ‘narrow’ therapeutic index, having significant potential risk upon coadministration with fluoroquinolones.
‡ Fluoroquinolones with the greatest risk of QT prolongation including (currently available) gatifloxacin, levofloxacin, moxifloxacin, sparfloxacin; and (drug withdrawn from US market – grepafloxacin).
Adapted from Facts & Comparisons, The Medical Letter Drug Interactions Program, E-pocrates, Hansten and Horn – references on pg. xxii.
Some important FQ drug interactions resulting in increased drug levels and toxicity include:

1. Theophylline metabolism is reduced by ciprofloxacin and norfloxacin, resulting in potential toxicity. 199
2. The metabolism of caffeine is similarly inhibited, and patients are best warned to consider reducing caffeine intake while taking an FQ, in order to avoid a ‘double espresso-like’ effect.
3. A decrease in warfarin and cyclosporine metabolism has also been documented, although cyclosporine is primarily metabolized by CYP3A4. 200, 201
4. Grepafloxacin (no longer available in the US), gatifloxacin, and moxifloxacin may increase the risk of torsades de pointes when given along with some antiarrhythmic drugs, and are contraindicated with drugs known to prolong QTc interval.

Dosage
Certain FQ (ciprofloxacin, levofloxacin, and moxifloxacin) are available for parenteral therapy. However, for most cutaneous infections parenteral therapy has no definitive advantage over the oral route, given the excellent oral bioavailability of most FQ. Exceptions include patients with CSSTI or more serious systemic infections, those who are unable to tolerate oral FQ due to GI adverse effects, and patients with more serious infections needing to frequently ingest agents that impair oral FQ absorption (see above). Some FQ can be given once daily. The preferred dosages for commonly used oral fluoroquinolones are listed in Table 8-10 .
Table 8-10 Commonly used oral fluoroquinolones * – dosage guidelines Generic name Tablet/capsule sizes (mg) Adult dosage Ciprofloxacin 100, 250, 500, 750, 1000 250–750 mg bid Levofloxacin 250, 500, 750 250–500 mg qd Moxifloxacin 400 400 mg qd
* These fluoroquinolones have FDA indication for skin and soft tissue infections.

Tetracyclines

Tetracycline, doxycycline, and minocycline
The first tetracycline (TCN) moiety was introduced in 1948, with the classic TCN nucleus derived from Streptomyces spp. When discussing the tetracyclines (TCNs), the designation TCNs refers to these agents as a drug class, with the individual drug tetracycline designated as TCN, unless otherwise specified. Q8-9 TCNs share 4 fused 6-membered rings, are bacteriostatic, and inhibit bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome. 202 Q8-10 In addition to their dose-dependent antibiotic effect, TCNs exhibit a wide variety of direct and indirect anti-inflammatory properties that are unrelated to their antibiotic activity. 1, 2, 203 – 208 Many of these anti-inflammatory properties may be operative when TCNs are used to treat dermatologic disorders that are inflammatory or immunologic in their etiology, such as acne vulgaris, rosacea, immunobullous diseases, and sarcoidosis. 2, 207, 208 These anti-inflammatory properties include:

1. Inhibition of the production of neutrophil chemoattractants by P. acnes (i.e., peptide chemotactic factor, lipase);
2. Inhibition of neutrophil migration in vitro and in skin window studies in vivo;
3. Inhibitory activity against granuloma formation in vitro, likely due to protein kinase C inhibition;
4. Inhibition of multiple matrix metalloproteinases (MMP), which are involved in dermal matrix degradation of both collagen and elastic tissue;
5. Downregulation of cytokines involved in the innate immune response; and
6. A possible scavenger effect against reactive oxygen species (ROS). 1, 2, 203 – 208
Q8-10 Directed modifications of the chemical structure of TCN can markedly alter the innate characteristics of the TCN compound to increase or reduce the antibiotic activities and/or anti-inflammatory properties and pharmacokinetic profile. 2, 206 – 208 Although not yet commercially available, there are chemically modified tetracyclines (CMT), including incyclinide and others, that exhibit only anti-inflammatory properties in the absence of antibacterial properties. 1, 2 Additionally, alterations of the TCN structure may alter its phototoxic potential, which is a dose-related phenomenon more commonly associated with doxycycline > TCN, and minimally from minocycline. 128, 152, 209 – 211 Demeclocycline has no dermatologic indications yet is the greatest photosensitizer of the TCN family; this drug has the unique ability to induce nephrogenic diabetes insipidus. 209, 212 This latter adverse effect of demeclocycline results in its beneficial use in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). 212 Incyclinide, a CMT discussed above, was discontinued because of multiple cases of photosensitivity in clinical trials for acne vulgaris.
Although dermatologists have been reported to account for approximately 0.03% of the total number of oral antibiotic prescriptions written by all US physicians, approximately 20% of all prescriptions for oral TCNs are written by dermatologists. 1, 5 Approximately 60–65% of the 8–9 million oral antibiotic prescription written by dermatologists annually between 2001 and 2005 were for a TCN agent, with 51.4%, 30.6%, and 18% of the total TCN prescriptions in 2003 written for minocycline, doxycycline, and TCN, respectively. 1, 5 Although the vast majority of prescriptions for the TCN family are for inflammatory skin conditions, doxycycline has a central role in the treatment of CA-MRSA. 1, 4, 7, 8
The TCNs are divided into (1) the short-acting tetracycline (half-life 6–12 hours); (2) intermediate-acting demeclocycline (half-life 16 hours); and (3) the long-acting drugs doxycycline (half-life 18–22 hours) and minocycline IR (half-life 11–22 hours), and minocycline ER formulations (reduced C max and AUC) ( Table 8-11 ).

Table 8-11 Currently available FDA-approved tetracyclines
Antibiotic resistance has become a global concern, with many countries establishing initiatives to promote rational antibiotic use. 1, 4, 5, 217 Studies throughout the world have confirmed that a reduction in community antibiotic exposure over time correlates with a reduction in the antibiotic resistance patterns with specific antibiotics. 1, 5, 217 In the 1990s, antibiotic resistance concerns prompted initiatives in the United Kingdom to reduce antibiotic prescriptions for acne vulgaris. 1, 128, 217 From 1995 to 2000, antibiotic prescriptions for acne vulgaris declined by 33%, with oral agents comprising the majority of the overall decrease. Nevertheless, TCNs remain central to the management of acne vulgaris and rosacea, with published recommendations available concerning more judicious use. 1, 4, 128, 152, 218 – 221

Pharmacology

Antibacterial activity

General antibacterial properties
The TCNs exhibit activity against many Gram-positive and Gram-negative bacteria, as well as Mycoplasma spp , Chlamydia spp , Rickettsia spp , spirochetes, and some parasites. 202 Overall, they possess greater Gram-positive than Gram-negative activity. Minocycline and doxycycline are more active against S. aureus than is TCN, with doxycycline and minocycline often used for treatment of USSTI caused by CA-MRSA. 7, 8, 178 Many strains of staphylococci, propionibacteria, and group A streptococci are now resistant to TCN, with increasing resistance of P. acnes to TCNs. 1, 4, 5, 202, 213 – 216 P. acnes antibiotic resistance patterns correlate with the extent of oral antibiotic use in various countries. 1, 4, 5, 128, 213 – 217 The greatest prevalence of P. acnes resistance is with TCN, reported in 20–26.4% of patients. 1, 4, 5, 213 – 216 Overall, antibiotic-resistant propionibacteria detected from the skin of untreated contacts of study subjects with acne ranges from 41% (Hungary) to 86% (Spain). 216

Mechanisms of resistance
Q8-7 Two major TCN resistance mechanisms acquired by bacteria are (1) ribosomal protection, and (2) drug efflux. The latter usually occurs via mobile genetic elements or ‘jumping genes’ (i.e., plasmids, transposons) transferred between strains of species more than between species. 1, 5, 12 In P. acnes , the TCN resistance is mediated exclusively through point mutation in genes encoding the 16S ribosomal RNA. 1, 222
Multiple in vitro and in vivo microbiologic and PK studies, and drug activity assays, have demonstrated a separation between the antibiotic and biologic/anti-inflammatory properties of doxycycline based on dose. 1, 2, 4, 206 – 208 ,223 ,224 Serial antibiograms from cultures from various anatomic sites confirm that subantimicrobial dosing of doxycycline does not induce antibiotic-resistant bacterial strains. 1, 2, 4, 206 – 208 ,223 ,224 Subantimicrobial doses of doxycycline without loss of anti-inflammatory activity are doxycycline 20 mg twice daily and doxycycline modified-release (MR) 40 mg once daily. 1, 4, 206 – 208 , 223 – 226 Doxycycline-MR is formulated as a bead-containing capsule with immediate release of 30 mg of the drug and delayed release of 10 mg. Doses of doxycycline ≥50 mg daily achieve serum levels that exceed the MIC of some bacteria and thus are no longer subantimicrobial. 1, 4, 206 – 208 , 223 , 224 – 226

Pharmacokinetics
Oral TCN, doxycycline, and minocycline are all available as immediate-release (IR) formulations for both cutaneous infections and non-infectious dermatologic uses. 227 – 229 Doxycycline modified release (MR), administered as 40 mg once daily, is not to be used for treatment of infection, given the subantimicrobial serum levels. 224, 226 Extended-release (ER) minocycline, administered at 1 mg/kg/day, produces subantimicrobial drug levels and so is used just for inflammatory lesions of moderate to severe acne vulgaris. 227, 229, 230
TCNs are lipophilic, reaching high concentrations in skin and nails. Their lipophilic properties allow significant drug levels in the pilosebaceous unit, and can cross the blood–brain barrier. 227 The order of lipophilicity among TCNs is minocycline > doxycycline > tetracycline. Tissue concentrations of doxycycline IR are approximately 5-fold greater in soft tissues than in serum, with minocycline IR achieving 47% higher concentrations in skin than in serum. 227, 228 Q8-2 With the exception of minocycline, ER is well absorbed even after eating, whereas other TCNs (especially TCN) are better absorbed overall in the fasting state. 227, 229 However, doxycycline (IR and MR) and minocycline IR are well absorbed regardless of food intake; a meal reduces GI absorption of doxycycline (IR and MR) by approximately 20% and of minocycline IR by 12%. 226, 227 – 231
Q8-2 Several metallic ions, many contained in high quantities in dairy products (i.e., milk, yogurt), vitamin/mineral supplements, antacids, and anti-diarrheal products, can markedly reduce the GI absorption of TCNs through chelation of TCNs in the stomach. 105, 231 – 233 In some cases, reduction in GI absorption of TCN was reduced by approximately 50%. 231 Examples of metallic ions that can reduce TCN absorption include calcium, aluminium, magnesium, iron, zinc, and bismuth. Additionally, a higher gastric pH may reduce GI absorption of TCN, although one study of TCN and cimetidine (H 2 antihistamine) demonstrated a negligible effect on TCN serum levels. 231 Administration of orange juice (200 mL) and coffee did not significantly affect the bioavailability of TCN in a single oral dose study. 231 Bismuth subsalicylate and kaolin–pectin, found in anti-diarrheal agents, have been shown independently to reduce GI absorption of TCN by approximately 50%. 231 It is important to question patients about OTC products for ‘indigestion’, ‘diarrhea’ or ‘stomach upset’ which may reduce serum levels of various TCNs. 105 With regard to minocycline, co-administration of iron (ferrous sulphate) with minocycline IR reduced minocycline absorption by 77%. 233
Many GI adverse effects, such as nausea, abdominal discomfort, and ‘pill esophagitis,’ are notably more common with doxycycline than with other TCNs and β-lactam agents. 234 – 237 Enteric coating of doxycycline, which delays release of doxycycline beyond the stomach and into the small intestine, has been shown to reduce GI adverse effects compared to IR formulations of doxycycline. 238, 239
Differences in the release rate of active drug in the GI tract among various minocycline IR formulations have been shown to reduce drug levels and reduce the incidence of vestibular adverse effects. 240 Minocycline ER, designed for subantimicrobial doses, reduces vestibular adverse effects. 227, 229, 230
Renal failure prolongs the half-life of most TCNs, except doxycycline, which is excreted primarily by the GI tract in bile and thus is acceptable for use in patients with renal failure. Caution is warranted when prescribing doxycycline for patients with severe liver disease. 241

Clinical use

Dermatologic indications
General dosage guidelines for commonly used oral TCN are given in Table 8-10 ; however, suggested daily dose and usual duration of therapy vary based on a variety of clinical factors.

Acne vulgaris
The main use of TCNs in dermatologic practice has been for chronic inflammatory facial dermatoses, primarily acne vulgaris, but also for rosacea and perioral dermatitis. 1, 2, 4, 5, 128, 152, 218, 221 The IR formulations of doxycycline and minocycline are not FDA approved in the US for treatment of acne vulgaris or rosacea; however, both were ‘grandparented’ for the adjunctive treatment of severe acne vulgaris. TCN has been available since the mid-1950s, doxycycline IR since 1967, and minocycline IR since 1972. 128 From 1969 through 2001 literature reviews have noted 12 studies evaluating TCN, doxycycline IR, and minocycline IR for acne vulgaris encompassing 953 patients, and a systematic review of clinical trials from 1962 to 1996 noting equal efficacy of all TCNs and no clear relationship between dose and efficacy. 128, 242
With doxycycline and minocycline IR formulations the typical reduction of inflammatory lesions is >50% at 12 weeks, with improvement observed in 70% of 90% of patients treated. 243 Doxycycline and minocycline formulations have two main advantages over TCN: (1) less frequent dosing, and (2) a lower prevalence of less sensitive P. acnes strains. 1, 4, 5, 128, 152, 215, 218, 227, 243 With TCN, doxycycline, and minocycline IR, adequate dose–response studies in acne vulgaris treatment have not been completed. 243 Oral antibiotic therapy with various TCNs usually requires at least 3 weeks before initial visible improvement, with maximum benefit between 3 and 6 months (with notable exceptions to these ranges). 128, 152, 243 Typically, about 50% of patients relapse within 8 weeks of oral antibiotic cessation, often requiring additional courses. 128, 152, 218, 243 Combined use of an oral TCN with topical therapy, especially a benzoyl peroxide-containing regimen, can (1) reduce the emergence of antibiotic-resistant P. acnes strains, and (2) augment efficacy. 1, 4, 5, 128 ,152 ,218 ,243 A subantimicrobial dose of doxycycline IR, 20 mg twice daily, was superior to placebo in reducing acne lesions in one small double-blind, randomized study (n=51) completed over a duration of 6 months. 223
In July 2006, minocycline tablets were released in the US, approved by the FDA for the treatment of inflammatory lesions of non-nodular, moderate to severe acne vulgaris in patients aged 12 years and older. 230 In a Phase II dose-ranging study (n=233), patients aged 12–30 years with acne vulgaris were randomized to receive minocycline ER tablets 1, 2, 3 mg/kg or placebo once daily for 12 weeks. 244 Efficacy was essentially equivalent across all dosage ranges and markedly superior to placebo. A pooled analysis of patients treated with minocycline ER (not approved for ‘infections’) 1 mg/kg/day (n=364) or placebo (n=364) as monotherapy in the Phase II dose-ranging trial and in 2 Phase III trials noted minocycline ER 1 mg/kg/day to be statistically superior to placebo in reducing inflammatory acne lesions (p<0.001). 245

Rosacea
Treatment of papulopustular rosacea with oral TCNs reduces inflammatory lesions, perilesional erythema (and to some extent background erythema), and symptoms (i.e., stinging, burning, pruritus), but does not improve erythematotelangiectatic (vascular) rosacea. With the exception of doxycycline MR 40 mg once daily, there is an overall lack of randomized, controlled studies evaluating TCNs treatment of rosacea, including the papulopustular subtype. 1, 4, 220, 221, 225, 246 Despite this, TCN and doxycycline are well established agents for the treatment of papulopustular rosacea and ocular rosacea (see below), based on available clinical trials and widespread clinical experience over 4–5 decades. 1, 4, 220, 221, 246, 247 Despite its availability since 1972, there is a conspicuous absence of published studies on minocycline IR in the treatment of papulopustular rosacea. 247
The only FDA-approved oral agent for papulopustular rosacea is doxycycline MR 40 mg once daily, which produces anti-inflammatory activity, yet being a subantimicrobial dose is devoid of antibiotic effects (see above). 1, 2, 4, 207, 208, 223 – 225 ,226 Given that rosacea is not definitively related to a bacterium, it is logical to use an anti-inflammatory approach to reduce the emergence of antibiotic resistance, especially as rosacea warrants prolonged therapy. 1, 4, 207, 208, 220 In two pivotal Phase III 16-week trials, doxycycline MR 40 mg once daily (n=269) was compared to placebo (n=268) and demonstrated superior reduction in inflammatory lesions compared to placebo, with no evidence of a plateau effect over the duration of the trials. 225 Several other studies have confirmed the efficacy of doxycycline MR 40 mg once daily for papulopustular rosacea, including use in combination with (1) metronidazole gel 1% (n=64), (2) or metronidazole 1% gel or azelaic acid gel 15% (n=194). In addition, a community-based trial evaluated its use as monotherapy with an existing topical regimen (n=224), and a comparative study versus doxycycline 100 mg daily (n=67). 248 – 252 Collectively, doxycycline MR 40 mg once daily was actively used to treat 1573 subjects in the aforementioned trials, including both Phase III pivotal trials. 225, 248 – 252 In one trial evaluating combination use with topical metronidazole, doxycycline MR once daily was equivalent in efficacy over several parameters compared to doxycycline IR 100 mg once daily, but with markedly fewer GI adverse effects. 252 One 12-week study evaluating subantimicrobial dose doxycycline IR 20 mg twice daily (n=20) versus placebo (n=20), both in combination with metronidazole lotion 0.75% twice daily, demonstrated better efficacy in the group actively treated with doxycycline. 253

Rosacea variants – ocular rosacea and perioral dermatitis
TCNs have also been used to treat ocular rosacea, based largely on the anti-inflammatory properties of TCNs agents. 1, 4, 247, 254 TCN and IR formulations of doxycycline and minocycline demonstrated efficacy in clinical trials and in case reports, typically with improvement within 6 weeks. 247, 254 Doxycycline 100 mg daily for 12 weeks markedly improved ocular symptoms of dryness, pruritus, blurred vision, and photosensitivity in patients with cutaneous rosacea and signs and symptoms of ocular rosacea (n=33). 247 Ocular findings of rosacea, including scales, erythema, telangiectasia, ciliary base injection, bulbar injection, papillary hypertrophy, and punctate epithelial erosions, all improved. 247
TCNs have been successfully used in case reports and small studies for perioral dermatitis, primarily with TCN and doxycycline (excluding MR). 255 – 257 The duration of therapy of the TCNs agent is generally over a range of 1–3 months. The authors’ clinical experience has found that a 4–8 week course of doxycycline MR 40 mg once daily is efficacious for perioral dermatitis, both as monotherapy and in combination with sulfacetamide lotion 10% twice daily. Pertinent to women with history of antibiotic-induced vaginal candidiasis, doxycycline MR 40 mg once daily is devoid of antibiotic selection pressure and was not associated with vaginal candidiasis in actively treated women (n=185) in the Phase III pivotal trials for rosacea. 225

Immunobullous dermatoses
Q8-1 Owing to their varied spectrum of multiple biologic and anti-inflammatory properties, TCNs have been used to treat a variety of inflammatory, immunobullous, and granulomatous disorders. 2, 3, 203 – 208 TCNs have been used, most often in combination with nicotinamide, for the treatment of immunobullous diseases such as bullous pemphigoid, linear IgA bullous dermatosis, pemphigus vulgaris, pemphigus foliaceus, benign familial pemphigus (Hailey–Hailey disease), and cicatricial pemphigoid. 1, 3, 258 – 265 Evidence supporting TCN or minocycline, with or without nicotinamide, in treating pemphigus vulgaris or pemphigus foliaceus is inconsistent, with some reports of high response rates and a possible ‘steroid-sparing’ effect, in cases of mild to moderate severity. 264 The addition of high-dose nicotinamide to oral minocycline provided subjective or clinical improvement in 5 of 8 patients with cicatricial pemphigoid. 265

Granulomatous dermatoses
Q8-1 Several potential mechanisms have been elucidated to explain the benefits of antibiotic therapy for cutaneous sarcoidosis. 1, 2, 3, 266 – 269 There is laboratory evidence for TCNs inhibiting T-cell proliferation and granuloma formation. 2, 3, 267 – 269 Minocycline IR 200 mg daily used over a median of 12 months in 12 patients with cutaneous sarcoidosis (3 patients with extracutaneous disease) produced complete response in 8 patients and a partial response in 1, with a median follow-up of 26 months. 268 In 3 patients who relapsed after discontinuation of minocycline IR, complete remission was achieved with use of doxycycline 200 mg/day. Doxycycline improved cutaneous sarcoidosis in 2 of 6 black male patients who did not respond to prednisone alone. 269 Interestingly, TCNs are also effective for other granulomatous dermatoses, including silicone granuloma (minocycline IR) and Melkersson–Rosenthal syndrome (prednisone + minocycline IR). 3

Miscellaneous inflammatory dermatoses
Q8-1 Some additional inflammatory dermatoses responding to various TCNs:

1. Minocycline IR 50–100 mg twice daily has been used to effectively treat confluent and reticulated papillomatosis (CRP), and is considered to be a first-line treatment; 3, 270 – 272
2. Prurigo pigmentosa presents with recurrent pruritic erythematous papules and reticulate hyperpigmentation and has been successfully treated with TCN or doxycycline; 273 – 276
3. Cetuximab-related acneiform cutaneous eruption (minocycline + topical tazarotene);
4. Oral lichen planus (doxycycline, TCN);
5. Acne keloidalis nuchae, erythema elevatum diutinum (TCN + niacinamide);
6. Follicular mucinosis (minocycline, TCN + benzoyl peroxide);
7. Palmoplantar pustulosis (TCN);
8. Panniculitis [Weber–Christian disease] (TCN);
9. Pityriasis lichenoides et varioliformis acuta (TCN) and pityriasis lichenoides chronica (TCN);
10. Pyoderma gangrenosum (minocycline); and
11. AIDS-related Kaposi sarcoma. (references for (3) through (11) 3, 202, 277 – 284 )
12. TCN oral suspension can improve acute symptoms of recurrent aphthous stomatitis if used 4 times daily as ‘swish and swallow’ (held in the mouth for 2 minutes followed by swallowing), but does not prevent recurrences. 28

CA-MRSA infections
Q8-13 Both doxycycline (except for subantimicrobial dosing) and minocycline IR (not ER) are effective for the treatment of USSTI caused by CA-MRSA. 7, 8, 178, 286 The duration of therapy may range from 2 to 4 weeks, depending on clinical response and extent of infection. A review of several studies suggests the IR formulations of doxycycline and minocycline be used as ‘first-line’ agents for USSTI caused by CA-MRSA, including abscesses and furuncles (ideally combined with incision and drainage), and purulent foci with surrounding localized cellulitis, unless TCNs antibiotic resistance patterns in the community dictate otherwise. 286

Rickettsial diseases
Importantly, only the IR formulations of doxycycline or minocycline are used to treat cutaneous infections. 1, 4, 223 – 227 , 229 ,230 Doxycycline is the treatment of choice for ‘the spotted fevers’ caused by Rickettsia spp, including Rocky Mountain spotted fever ( R. rickettsiae ), African tick bite fever ( R. africae ) and a wide variety of others (mostly due to R. conorii ). 287 Doxycycline 100 mg twice daily is recommended until patients are afebrile for at least 2 days, with a total duration of no less than 7 days. A variety of adjustments to this regimen varies by the type of rickettsial infection. 287 Owing to the potential morbidity and mortality of Rocky Mountain spotted fever, the prompt institution of TCNs therapy in children <9 years of age is highly recommended; minimal tooth discoloration was noted in children <5 years of age treated with fever than 6 courses (6 days of therapy per course) of TCN. 288, 289

Spirochete infections – syphilis
TCNs, primarily doxycycline (IR formulations), are often used to treat a variety of infections caused by spirochetes, including syphilis ( Treponema pallidum ), Lyme disease ( Borrelia spp), and the ‘non-venereal’ endemic spirochete infections yaws ( Treponema carateum ), and pinta ( Treponema pallidum subsp pertenue ). 290 – 298 In patients who are allergic to penicillin, doxycycline 100 mg twice daily for 14 days or TCN 500 mg 4 times daily for 14 days are recommended for the treatment of primary, secondary, or early latent syphilis. 290 – 292 The same daily dosage for either agent is recommended for uncomplicated late latent syphilis or syphilis of unknown duration in immunocompetent patients, with extension of the treatment course to 28 days; however, some authorities suggest a daily dose of doxycycline IR 200 mg twice daily in such cases. 290 – 292 Suboptimal responses have occurred in some HIV patients, warranting careful follow-up after completion of therapy. 290 – 292 In general, the major advantage of doxycycline over TCN in the treatment of infections, including syphilis, is less frequent daily dosing, which should correlate overall with better patient compliance.

Spirochete infections – Lyme disease
TCNs (only IR formulations) have been used effectively to treat Lyme disease, a multisystem disorder caused Borrelia spp spirochetes. 293 – 297 In the US the causative organism is B. burgdorferi and in Europe it is B. afzelii or B. garnii . 297 A retrospective analysis comparing tetracycline 500 mg 4 times daily for 14 days (n=27) and doxycycline 100 mg 2 or 3 times daily for 14 days (n=21) for Lyme disease associated with erythema migrans demonstrated no difference in efficacy or safety. 294 A prospective evaluation in this same category of Lyme disease compared doxycycline 100 mg 2 or 3 times a day for 14 days (n=21) versus doxycycline 100 mg 3 times a day for 20 days (n=38), demonstrating no advantage to the longer duration of therapy. 294 In patients with previously untreated Lyme borreliosis coupled with symptoms suggestive of but without definitive CNS involvement, treatment with oral doxycycline is as effective as with parenteral ceftriaxone. 295 Oral therapy for 20 days with either doxycycline 100 mg 3 times a day (n=113) or cefuroxime axetil 500 mg twice daily (n=119) was equally effective in the treatment of early Lyme disease associated with erythema migrans. 296 An extensive literature review recommended doxycycline 100 mg twice daily for 10–21 days as first-line treatment for early localized disease (erythema migrans, borrelial lymphocyctoma) except in children <8 years of age or pregnant women. Doxycycline 100 mg twice daily for 28 days for Lyme arthritis without neurologic involvement, with a second 28-day course suggested if there is persistence or recurrence of joint swelling. 297 A rare cutaneous finding of late Lyme disease, primarily in Europe, acrodermatitis chronica atrophicans, is a potential sequela of B. afzelii infection and may respond to doxycycline 100 mg twice daily for 14–21 days. 297 Neurologic involvement or advanced cardiac conduction block require alternative first-line therapy. 297

Uncommon spirochete infection
Penicillin remains the preferred therapy for the ‘non-venereal’ endemic spirochetal infections, pinta and yaws. TCN, doxycycline, and minocycline are recommended as second-line alternatives in adults and children >9 years of age, and can be used first-line in penicillin-allergic patients. 298

Less common sexually transmitted diseases
Doxycycline IR 100 mg twice daily for 21 days is the preferred approach for treatment of lymphogranuloma venereum (LGV), which is caused by C. trachomatis serovars L1, L2, and L3. 290, 299 Minocycline IR can be used for patients with doxycycline-induced GI upset or photosensitivity. 290, 299 Based on a recent review of the literature on LGV between 1998 and 2004, doxycycline 100 mg twice daily for 21 days remained the preferred treatment for LGV, including LGV proctitis and in HIV-infected patients (who may require more prolonged therapy). 290, 291, 299 Among other STDs, doxycycline was previously the preferred treatment for granuloma inguinale. A rising rate of therapeutic failure worldwide suggests that trimethoprim-sulfamethoxazole, azithromycin, or ciprofloxacin are more efficacious first-line agents. 290

Atypical mycobacterial infections
Treatment of atypical mycobacterial infections of the skin varies depending on the extent of involvement, the causative organism, and the immune status of the patient. In some cases, depending on the causative organism, and whether superficial and localized, antibiotic monotherapy may be successful. In other cases, with certain Mycobacteria spp, disease severity, and/or patient immune status, combination therapy with other antimycobacterial agents is used to circumvent the emergence of resistance. As cutaneous infections are caused by many atypical mycobacterial organisms, no specific treatment guidelines are available, so clinical experience, available literature, and susceptibility testing guide the regimens. 300 The following outlines general suggestions for the use of TCNs (infectious disease consultant involvement is frequently used for the following infections): 300 – 301

1. TCNs have been effective (both as monotherapy and at times as combination therapy) for the treatment of cutaneous infections caused by several atypical (non-tuberculosis) Mycobacterium spp; 300,301+
2. Minocycline IR 100–200 mg daily for 6–12 weeks (ideally 12 weeks) or doxycycline (IR formulation) 100 mg twice daily for 12–16 weeks as monotherapy may be used for M. marinum ;
3. Combination therapy with other antibiotics (e.g., clarithromycin, rifampin) may sometimes be needed for deeper soft tissue involvement and/or in immunocompromised patients; 300, 301
4. Minocycline IR 100–200 mg daily for 16 weeks has been effective with cutaneous M. kansasii infection in immunocompetent patients; however, ‘triple therapy’ with other antimycobacterial agents may be added for immunocompromised patients or severe cutaneous involvement; 301
5. M. fortuitum complex therapy (three ‘rapid grower’ organisms, M. fortuitum, M. chelonae , and M. abscessus), with infections due to percutaneous inoculation (including footbaths at spas) must be guided by susceptibility testing, with duration of therapy (often multidrug regimens) ranging from 6 weeks to 7 months. 300, 301
6. TCNs have been successfully used (often in ‘triple therapy’) for M. scrofulaceum and M. szulgai . 300
7. Because of activity against Vibrio vulnificus (not a mycobacterium) and M. marinum , TCNs have been successfully used to treat infected aquatic injuries. 302, 303
8. TCNs have not been suggested for treating cutaneous infections due to M. ulcerans (Buruli ulcer), M. simiae complex and M. haemophilum . 300, 301

Other uncommon infections
Among other infections where TCNs may be therapeutically beneficial, ciprofloxacin or doxycycline are recommended for antimicrobial prophylaxis against anthrax ( B. anthracis ), and also for treatment of adults and children. 304 Doxycycline is recommended as a second-line therapy for tularemia ( Francisella tularensis ) and plague ( Yersinia pestis ). 202, 304 With regard to additional infections related to bites and/or stings, doxycycline is preferred therapy for human monocytic ehrlichiosis and human anaplasmosis, both arthropod-borne disorders, and is used in malaria prophylaxis. 290 – 305 TCN may be second-line therapy (including for penicillin-allergic patients) for cutaneous actinomycosis ( Actinomyces spp). 366

Adverse effects

GI adverse effects
TCNs can cause GI adverse effects including nausea, vomiting, and abdominal discomfort, most commonly with doxycycline IR formulations compared to pelletized enteric-coated tablets or MR capsules. 226, 230, 235, 252, 307, 308 Administration with food may reduce the GI adverse effects associated with TCNs, although food impact on pharmacokinetics was previously discussed. Comparing doxycycline MR 40 mg once daily versus doxycycline IR 100 mg once daily (not enteric coated), a 5-fold greater incidence of GI adverse effects was found among patients treated with doxycycline IR; doxycycline MR patients experience rare GI adverse effects. Diarrhea is occasionally reported, but antibiotics-associated colitis due to C. difficile infection is rare with oral TCNs use.
‘Pill esophagitis’ is much more common with doxycycline than with other TCNs, especially with non-enteric-coated IR formulations. 236 – 238 , 308 – 318 Symptoms develop typically in the first few days, presenting most often as odynophagia, dysphagia, and retrosternal pain, and are usually avoidable with proper patient education to ingest with a large volume of water and not to take before reclining. 236, 237, 311, 314, 315, 317 Some cases of doxycycline-induced esophagitis can be very severe, and ulcerations may occur. 310 – 312 , 314 – 316 ,318 The presence of hiatal hernia may be a risk factor for ‘pill esophagitis;’ however, pre-existing gastroesophageal reflux disease was determined not to be a definitive risk factor. 313

Monitoring guidelines general pros and cons
Overall, drug-induced hepatitis and pancreatitis are very uncommonly observed with various TCNs. 1, 4, 128, 152, 319 The FDA-approved full prescribing information (package inserts) for TCNs, including all formulations of doxycycline and minocycline, include the following general ‘class labeling’ statement: ‘In long-term therapy, periodic laboratory evaluations of organ systems, including hematopoietic, renal, and hepatic studies should be performed’. 226, 230, 320 – 323 However, there is no mention of need for baseline testing and no specific suggestions as to the type, frequency, or timing of ‘periodic laboratory evaluations’. 226, 230, 320 – 323 Importantly, comprehensive reviews on long-term treatment of acne vulgaris and rosacea do not specify specific laboratory monitoring guidelines. Some package inserts of TCN also state: ‘Appropriate tests for autoimmune syndromes should be performed as indicated,’ thereby leaving this monitoring on a case-by-case basis. Autoimmune hepatitis and drug hypersensitivity syndrome are discussed in detail below. 324

Acute vestibular side effects
Acute vestibular side effects (AVSE), presenting mainly as dizziness or vertigo (possibly with nausea and vomiting), are most common by far with minocycline IR formulations. 240, 325, 326 Minocycline IR-associated AVSE may occur after the first dose or within a few days, and are more common in women, especially those of low body weight. 325 If AVSE vestibular adverse effects do not occur in the first few weeks of treatment they are not likely to occur later. Additionally, a comparison of several minocycline IR generic and trade name formulations, result in a rapid spike in serum level and greater C max , resulted in up to a 5-fold higher incidence of vertigo with several generic formulations versus a specific brand formulation (which was formulated for slower release of the active drug). 240 Minocycline ER, at 1 mg/kg once daily, produced a rate of AVSE that was comparable to placebo, with the 2–3 mg/kg/day dose demonstrating a much greater incidence of AVSE.

Benign intracranial hypertension
Benign intracranial hypertension (BIH), also referred to as pseudotumor cerebri, is an uncommon idiopathic reaction to the TCNs. 327 A high index of suspicion with headache and visual disturbances, accompanied by nausea and/or vomiting, is vital to allow early detection of BIH, as persistence of this disorder can lead to severe loss of vision which may be permanent 327 (see Drug Interactions section regarding BIH due to isotretinoin/TCNs interactions).

Photosensitivity
Q8-14 Cutaneous phototoxicity has been reported in association with some TCNs, especially demeclocycline and doxycycline. 202, 209 – 211 , 328 - 333 Although most cases present clinically with the appearance of an exaggerated sunburn, a popular variant has been reported which may simulate polymorphous light eruption. 330 TCNs have also induced photo-onycholysis, with most reports due to doxycycline (IR formulations). 27, 328, 334 – 336 Several studies have documented that of commercially available TCN, doxycycline exhibits the highest potential for photoxicity at doses of at least 100 mg/day, and rare with doxycycline MR 40 mg once daily. 210, 211, 225, 232, 333 Minocycline has been shown to exhibit negligible or absent phototoxicity potential. 211, 332, 337 Long-wave ultraviolet light (UVA) provokes phototoxicity with doxycycline; UVB may have a synergistic role. 331 It is prudent to educate patients on optimal photoprotection and avoidance of intentional natural and/or artificial UVA or UVB tanning when prescribing TCNs, especially doxycycline.

Dyspigmentation
Among TCNs, hyperpigmentation of skin, nailbeds, teeth, bone, and mucous membranes, including oral mucosa and sclera, has been reported mainly with minocycline IR, particularly with long-term acne therapy. 325, 326, 346 One study of acne patients treated with minocycline IR 100–200 mg daily (n=700) showed that all cases of hyperpigmentation developed after a cumulative dose of >70 g. 326 One study found that 41% of patients with rheumatoid arthritis (RA) treated with minocycline IR developed hyperpigmentation after use for at least 3 months, with a median onset at 12 months. 350 The formation of pigmentation was at sites of prior inflammation, trauma, areas of scar formation from multiple varied clinical scenarios with minocycline IR formulations. 338, 340, 344, 347 – 349 ,353
Hyperpigmentation, varying from blue to grey to brown, secondary to minocycline IR has presented with either a focal or a diffuse distribution at any of the affected anatomic sites, with some patients exhibiting more than one pigmentation pattern over time. 325, 326, 338 – 352 Long-term administration of minocycline IR has been reported to occasionally cause staining of adult teeth, which has presented as ‘black bones’, ‘black or green roots’ of teeth, and blue-gray to gray darkening of the crowns of permanent teeth. 355
Subtypes of cutaneous hyperpigmentation observed in association with minocycline IR have been classified and published: 347, 349, 356 – 362

1. Type I describes blue-black/gray pigmentation confined to facial sites of scarring or inflammation associated with acne (typically resolves slowly) that stains for iron and melanin.
2. Type II describes blue-gray pigmentation of normal skin on the lower legs (especially anterior) and forearms (typically resolves slowly) that stains for iron and melanin.
3. Type III describes diffuse, muddy brown pigmentation of normal skin, predominantly in sun-exposed skin (tends to persist); stains for melanin only.
4. Type IV, a rarely reported type, describes circumscribed blue-grey pigmentation in acne scars on the back (long-term course unknown) with calcium-containing melanin-like substance without iron.
Whether minocycline ER will eventually be associated with dyspigmentation is not fully known at present; weight-based dosing may minimize the risk. Additional information can be found in these references. 227, 229, 244, 371, 372 The use of various laser modalities to treat minocycline-induced hyperpigmentation is beyond the scope of this chapter. 324, 363 – 368 Tetracycline has been associated with discoloration of adult teeth. 355 Doxycycline has been associated with nail discoloration in pediatric patients 369 and with features clinically, histologically, and ultrastructurally resembling those of minocycline (with long-term, high-dose use). 370

Secondary infections
Antimicrobial selection pressure with alteration of normal flora associated with use of TCN can precipitate vaginal candidiasis, and with long-term therapy, Gram-negative acne or folliculitis. 202, 373, 374 Although the true incidence is unknown, vaginal candidiasis has been estimated to occur in 3.7% of women treated with TCNs using doses known to have antibiotic activity, with a negligible or absent risk in patients treated with subantimicrobial doses of doxycycline. 225, 373 In two pivotal Phase III 16-week trials evaluating doxycycline MR 40 mg once daily for papulopustular rosacea, none of the actively treated women (n=185) developed vaginal candidiasis.

Hypersensitivity reactions – general points
Some relatively uncommon hypersensitivity reactions include urticaria, fixed drug eruption, and drug-induced Sweet’s syndrome. 202, 375 – 377 Several additional categories of hypersensitivity include the following:

1. Q8-6 Serum sickness-like reactions (SSLR), albeit uncommon, have been reported most extensively with minocycline IR, and much less often with TCN and doxycycline, 9, 324 – 326 , 337 , 379 – 388 and typically occur during the first 1–2 months of therapy. Risk factors include HIV infection and black African ethnicity. 9, 324, 379, 382, 384, 388
2. Rare sporadic reports of Stevens–Johnson syndrome have been observed with doxycycline or minocycline use. 389 – 391
3. Autoimmune adverse reactions (autoimmune hepatitis, systemic lupus-like reactions, and ANCA vasculitis), occur almost exclusively with minocycline IR, tending to be delayed for months to years. 9, 324 – 326 , 337 , 386 , 392 – 410 The minocycline structure includes a para- N-N -dimethylaminophenol ring, with oxidation to reactive quinone metabolites by myeloperoxidase enzymes and microsomes, and is also likely related to genetic predisposition (i.e., HLA subtypes) 395 – 399 (see additional discussion on these autoimmune reactions below).

Drug hypersensitivity syndrome
Q8-15 Hypersensitivity, most commonly with minocycline, can present with single-organ dysfunction or involve multiple organ systems, with hepatitis being the most common component of multisystem involvement. 324, 383, 385 – 388 With multiple organ involvement, the clinical findings are known as drug hypersensitivity syndrome (DHS) or drug reaction with eosinophilia and systemic symptoms (DRESS). Patients present with high fever, often a morbilliform reaction (at times with target lesions), facial edema, malaise, hepatosplenomegaly, elevated transaminases and atypical lymphocytosis (along with eosinophilia), simulating a viral syndrome, such as Epstein–Barr virus (EBV) infection. 9, 324, 379 – 381 ,387 ,388 In addition to hepatotoxicity (which affects >50% of patients with minocycline-induced DHS), other organ systems can be involved, including pneumonitis, nephritis, myocarditis, cerebritis, and/or thyroiditis. 379, 383 ,385 Possible sequelae following resolution of DHS after 2 or more months include hypothyroidism, autoimmune hyperthyroidism, autoimmune type 1 diabetes, and myocarditis. 9, 324, 383, 384 In one case of minocycline-induced DHS with persistent myocarditis, significant improvement was noted with plasmapheresis and rituximab therapy. 383

Lupus-like syndrome
Q8-15 A lupus-like syndrome (LLS) and other autoimmune adverse reactions appear to be unique to minocycline, with multiple case reports, case series and reviews published in association with minocycline IR over the past 10–20 years. 324, 381, 392 – 410 Based on a nested case–control study of a cohort of 27 688 young acne patients, current single use of minocycline (IR formulations) was associated with an 8.5-fold higher risk of developing LLS than in non-users and past users of TCN combined, with 29 cases of LLS identified. 400 A retrospective cohort study of 94 694 young patients with acne, in which 24.8% were exposed to minocycline IR, 49% to doxycycline, 42.3% to TCN, and 17% not exposed to any TCN, indicated a hazard ratio of 3.11 for minocycline and lupus erythematosus (LE). 392 In order of frequency, based on a review of 82 affected patients, minocycline-induced LLS presented with arthralgias (73/82), arthritis (45/82), fever (38/82), and skin eruption (29/82). 386 In another review of 57 cases, polyarthralgias or polyarthritis was present in all, with cutaneous manifestations including ‘rash’, livedo reticularis, oral ulcerations, subcutaneous nodules, and alopecia. 396
Importantly, the emergence of a positive anti-nuclear antibody (ANA) test during drug therapy does not equate with autoimmune disease. Additionally, most patients with newly formed autoantibodies do not develop clinical disease. 411 It is also important to realize that drug-associated autoimmune reactions, including systemic LLS, do not often meet the established American Rheumatology Association (ARA) criteria required for diagnosis of idiopathic disease. 398 In addition to rheumatologic involvement, minocycline-induced LLS has been associated with autoimmune hepatitis, hyperthyroidism, progressive respiratory distress, and cutaneous vasculitis. 324, 393, 396, 398, 403, 407 – 409 A cross-sectional study of 252 acne patients, 69% treated with minocycline IR, showed no statistical differences in ANA positivity for minocycline-exposed (13%) and non-exposed (11%) patients, with higher titers in the minocycline-exposed (45%) than in the non-exposed group (12%). In 7% of the minocycline-exposed group ANCA positivity was noted, compared to 0% in the non-exposed group, with 58% of ANCA-positive tests demonstrating a perinuclear ANCA pattern (pANCA) with myeloperoxidase specificity. 394, 395 In minocycline-induced LLS ANA positivity is usually present, found in 19 of 23 patients and in 63 of 68 patients, in 2 separate studies, and in 57 of 57 patients in a third analysis. 384, 386, 394, 396, 406 – 408 Anti-double-stranded DNA (anti-dsDNA) antibodies may be positive, typically considered to be a relatively specific marker for idiopathic systemic LE. 386, 393 – 395 ,407 ,408 ,410 Minocycline-induced LLS has a low rate of absence of positivity for antihistone antibodies. 386, 407, 408 As with drug-induced DHS and SSLR, discontinuation of the causative agent as soon as possible is vital, although the resolution for minocycline-LLS upon dechallenge varies greatly.

Vasculitis
Minocycline-induced cutaneous polyarteritis nodosa (PAN) and vasculitis, presenting as reticulated (livedoid) erythema and/or subcutaneous nodules usually on the extremities (which is reversible), presents in some cases after 2 or 3 or more years of minocycline use. 412 – 414 Serologic testing has shown pANCA positivity in several cases, suggesting the term ‘drug-induced ANCA-positive vasculitis’. 413, 414

Hepatotoxicity (autoimmune)
Q8-15 As hepatotoxicity is a common feature of both DHS and as autoimmune hepatitis associated with minocycline therapy, differentiation of potential clinical presentations is important for the clinician. A report published in 2000 indicated that hepatic reactions accounted for 6% of all minocycline adverse events (493/8025) reported to the World Health Organization (WHO). Minocycline-induced hepatotoxicity can occur early, with a median exposure time of 35 days (DHS), with an average exposure time of 365 days (autoimmune hepatitis or as part of LLS). 408, 415 – 417 High-dose (>2 gm/day) IV TCN was associated with maternal hepatotoxicity in the 1960s. 418

Other potentially serious adverse effects
Immune thrombocytopenia presenting as Schamberg’s disease, and neutropenia as a component of LLS, have been reported with minocycline use. 404, 405 Demeclocycline has been associated with diabetes insipidus, and as a result is used to treat SIADH (see above). 212 TCNs may augment neuromuscular blockade. 202 An older report notes that TCN may cause Fanconi’s syndrome and progression of uremia in patients with renal disease. 419

Use in pregnancy and lactation
Q8-16 TCNs are pregnancy category D, and are reported to be contraindicated in the second and third trimesters of pregnancy. 11, 418 A thorough review of fetal risk with TCN exposure during pregnancy appears elsewhere, including discussion of first trimester exposure to TCN. 418 Potential concerns include adverse effects on fetal teeth and bones, congenital defects, maternal hepatotoxicity, and miscellaneous effects. Rarely is TCN justified in early pregnancy (very rare exceptions include early treatment of Rocky Mountain spotted fever). 289 TCNs use at any time during pregnancy for inflammatory disorders (i.e., acne vulgaris, rosacea) is not recommended. 152
TCNs are excreted in breast milk, albeit in low concentrations. 11, 418 Black breast milk was reported in one patient within 4 weeks of starting minocycline therapy, with positive staining for iron (similar to cutaneous pigmentation with minocycline). 420 Although the American Academy of Pediatrics classifies TCNs as compatible with breastfeeding, the authors suggest that TCNs be avoided during lactation, unless the benefits clearly outweigh the risks. 421 TCN should be avoided (apart from life-threatening infections) in children <9 years of age owing to yellow staining of teeth, and possibly other adverse effects on the development of bones and teeth. 11, 288, 289

Drug interactions
TCNs may potentiate the pharmacologic effects of warfarin, lithium, theophylline, digoxin, methotrexate, and insulin, potentially augmenting toxicity with these drugs 55, 56, 105, 422 ( Table 8-12 ).
Table 8-12 Drug interactions – tetracyclines Interacting drug group Examples and comments Drugs which may ↓ the gastrointestinal absorption of tetracyclines ACE inhibitors Quinapril; this ACE inhibitor has high magnesium content Antacids Chelation of tetracyclines to divalent (calcium, magnesium) and trivalent (aluminum) cations; caution including multivitamins with these minerals Antihistamines – H 2 antagonists Cimetidine, others; may induce a pH-dependent inhibition of drug dissolution Bile acid sequestrants Cholestyramine, colestipol Diabetes drugs – other Exetinide Miscellaneous drugs Didanosine (is buffered, with a similar mechanism to cimetidine), molindone (contain calcium salts as an excipient), sodium bicarbonate (a buffer) Other chelating drugs Bismuth salts, iron, zinc; chelation with these drugs may ↓ absorption of tetracyclines The following drugs may ↓ the levels of doxycycline by CYP3A4 induction Antibacterial – rifamycins Rifampin; similar to anticonvulsants below (effect primarily with doxycycline) Anticonvulsants Phenytoin, phenobarbital, carbamazepine; may induce doxycycline metabolism and thus ↓ drug levels (effect primarily with doxycycline) Tetracyclines may ↑ serum levels (and potential toxicity) of these drugs Anticoagulants – oral Warfarin; mechanism probably due to tetracycline-induced changes in gut flora affecting enterohepatic recirculation of warfarin Bronchodilators – xanthines Theophylline; ↑ levels and adverse effects, including CNS adverse effects Cardiac drugs – inotropic agents Digoxin; tetracyclines may ↑ digoxin levels in a small portion (10%) of patients, may persist for months Miscellaneous Lithium; uncertain mechanism (may also ↓ levels of lithium); monitor carefully Tetracyclines may ↓ serum levels of these drugs Hormonal contraceptives Highly controversial – theoretically inhibit enterohepatic recirculation of estrogens Miscellaneous drugs Atovaquone; a drug used to backup TMP-SMX for pneumocystis prophylaxis Tetracyclines may potentially ↑ the photosensitivity of the following drugs * ‘Alternative’ medical therapies St. John’s wort Porphyrins Amino levulinic acid, verteporfin Psoralens Methoxsalen, others; particular caution with tetracyclines and PUVA therapy Retinoids – oral and topical Both routes of administration may ↓ stratum corneum thickness Other potentially important interactions involving tetracyclines ‘Alternative’ medical therapies Black cohosh, kava; concomitant use may ↑ risk of hepatotoxicity Antibacterial – penicillins Tetracyclines (bacteriostatic) may interfere with bactericidal activity of penicillins, which depend on bacterial cell wall synthesis for efficacy Diabetes drugs – insulin Tetracyclines may ↓ insulin requirements Folate antagonists Methotrexate; ↑ levels with high methotrexate doses, unknown mechanism Retinoids – oral Acitretin, isotretinoin; concomitant use may ↑ risk of pseudotumor cerebri Urinary alkalinizers Sodium lactate, potassium citrate; may ↑ renal excretion of tetracyclines
* Order of likelihood for photosensitivity for the tetracyclines: doxycycline > tetracycline > minocycline (rarely).
Adapted from Facts & Comparisons, The Medical Letter Drug Interactions ProGram, E-pocrates, Hansten and Horn – references on pg. xxii.

Hormonal contraceptive efficacy
Q8-17 Tetracyclines and other oral antibiotics have been reported to reduce the effectiveness of oral contraceptives (OC), although the scientific basis of this alleged interaction is controversial (except for rifamycins such as rifampin), and has not been definitively supported by several reviews. 423 – 426 Owing to (1) an inherent failure rate of OC unrelated to drug interactions, (2) the wide range of interindividual differences in ethinyl estradiol (EE) serum levels, and (3) the potential that a subset of women may show decreases in EE serum levels with concurrent use of TCNs, a cautious approach has been suggested. 424 FDA-approved package inserts for TCNs do state that ‘concurrent use of tetracyclines may render oral contraceptives less effective,’ and some contain the statement ‘To avoid OC failure, female patients are advised to use a second form of contraception during treatment…’, including package inserts for minocycline ER and doxycycline MR. 226, 230, 320 – 323 .

Pseudotumor cerebri
The augmented risk of BIH caused by concurrent use of TCNs and oral retinoids (i.e., isotretinoin, acitretin) is controversial, and is based on the product monograph from the original manufacturer of the brand oral isotretinoin. 427 As TCNs and oral retinoids have both been independently associated with BIH, concern regarding an additive or synergistic effect has been noted, although not scientifically evaluated. Published clinical data are needed to more definitively assess the true risk of this interaction. Some cases of BIH associated with oral isotretinoin occurred in patients also using TCNs for acne treatment based on data on file with the manufacturer. 428 At present it is prudent to avoid co-administration of TCNs and oral retinoids whenever possible. 427

Loss of efficacy interactions
The interactions between TCNs and metallic ions found in many ingestants, such as vitamin/mineral supplements, antacids, and other OTC products, are discussed above in the Pharmacokinetics section.

Dosing
Table 8-13 contains general dosage guidelines for commonly used TCNs.
Table 8-13 Commonly used oral tetracyclines – dosage guidelines Generic name Tablet/capsule sizes (mg) Adult dosage Tetracycline * + 250, 500 250–1500 mg/day (qd or bid) Doxycycline * + 20 # , 50, 75 X , 100, 150 X 50–200 mg/day (qd or bid for total daily dose) Doxycycline MR M,#AD 40 mg M 40 mg once daily #,AD Minocycline IR +V 50, 75, 100 50–200 mg/day V (qd or bid for total daily dose) Minocycline ER ++#,1,F,L 45, 55, 65, 80, 90, 105, 115, 135 1 mg/kg/day #,1,F,L (given once daily) (all are ER ++ )
* Liquid or suspension formulations available. X Enteric-coated formulation available and shown to reduce incidence of GI adverse effects ( not extended release). + Immediate-release formulation = IR. ++ Extended-release formulation (tablet) = ER. M Modified-release formulation (capsule) = MR. AD Anti-inflammatory dose doxycline (30 mg IR + 10 mg MR capsule once daily) produces anti-inflammatory effects without antibiotic effect with FDA-approval for treatment of inflammatory lesions of rosacea. # Not to be used for treatment of infections V Incidence of vestibular adverse effects affected by release rate of individual IR formulation and dose administered. 1 1 mg/kg once daily dose with FDA-approval for treatment of inflammatory lesions in moderate to severe acne vulgaris (non-nodular type) in patients ≥12 years of age. F GI absorption not affected by administration with or without food. L 1 mg/kg once daily dose dose with same efficacy but lower incidence of acute vestibular adverse effects in pivotal trials as compared to 2 mg/kg/day and 3 mg/kg/day.
Rifamycins

Rifampin and others
Rifamycins are a family of antibiotics, with the first agent, rifamycin V, derived in 1957 in Milan, Italy, from the soil mold Amycolaptis rifamycinica (formerly Streptomyces mediterranei ). In 1959, a more stable semisynthetic rifamycin, ‘rifampicin’ was discovered. The names rifampicin and rifampin are interchangeable: rifampin is most widely used in the literature. 429 Other synonyms for rifampin include rifaldizine, R/AMP, and rofact (Canada). Rifampin, rifabutin rifapentine, and rifaximin are rifamycins that are currently available. Rifampin was released in 1967 and is the most commonly used ‘rifamycin’ in dermatology. Of the members of this family:

1. Rifampin, rifabutin, and rifapentine are well absorbed and used for systemic therapy.
2. Rifaximin is only used for selected GI tract infections due to lack of significant absorption.
3. Rifampin is also available for IV administration ( Table 8-14 ).

Table 8-14 Other antibacterial agents
Q8-12 Rifampin acts by binding to the β-subunit of bacterial DNA-dependent RNA polymerase, preventing RNA transcription and subsequent translation to proteins. 429 – 431 Thus rifampin is acting directly on messenger RNA (mRNA) synthesis. However, once binding to the template strand of DNA has begun, rifampin cannot terminate elongation of mRNA. Activity against M. tuberculosis may relate to mycolic acid complexation within the cell membrane of this bacterium which allows easy penetration of the drug into the cell.
Rifampin is FDA approved for the treatment of tuberculosis (TB) and is best used in combination therapy and for the meningococcal carrier state (but not for active disease, owing to the rapid development of resistance). 429 Off-label uses for rifampin include leprosy, atypical mycobacterial infections, anthrax, brucellosis, Legionella pneumophila infections, Listeria spp infections, and some infections caused by staphylococci, streptococci and Rhodococcus spp. 420, 431 Many of these and other uses in dermatology are discussed further below.

Pharmacology

Antimicrobial activity
Rifampin exhibits a broad spectrum of antibiotic activity that includes Mycobacterium spp, including M. tuberculosis and M. leprae , staphylococci (both coagulase-negative and coagulase-positive), N. meningitides , N. gonorrhoeae , H. influenzae , and several Chlamydia spp. 430 – 434 However, Gram-negative coverage is poor overall. When used for atypical mycobacterial infections or leprosy, rifampin is administered in combination with other anti-TB drugs and can be used over several months. 429 – 431 A high level of activity against atypical mycobacteria, especially M. kansasii and M. marinum , has been noted.
Q8-13 Although S. aureus strains may be sensitive to rifampin in vitro, resistance often develops rapidly when monotherapy is used. 7, 178, 432, 433 Rifampin has been used in combination with either clindamycin or trimethoprim-sufamexazole when treating CA-MRSA. 432 An important additional finding is that in vitro testing with rifampin in combination with other antibiotics may not always correlate with clinical results for treatment of S. aureus infections. 432
Rifabutin and rifapentine have a similar overall spectrum of activity as rifampin. 431, 435, 436 Q8-7 Rifampin-resistant strains can appear to be susceptible to rifabutin in vitro, but a clinical response is not likely, as resistance is controlled by rpoB mutation in both drugs. 430 Rifaximin is mainly used for GI disease and is active against non-invasive strains of E. coli . 437

Pharmacokinetics
Rifampin is available for oral or intravenous use, and is readily absorbed from the GI tract; however, peak serum concentrations may show wide variation between individuals. 429 Q8-2 GI absorption of rifampin may be reduced by approximately one-third when ingested with food. 429, 438 Administration of a 10 mg/kg dose to children 6–58 months of age demonstrated a half-life of 2.9 hours, which is comparable to that in adults. 429 The unbound (non-protein bound) drug fraction (20%) is able to diffuse freely into tissues. After a 600 mg dose of rifampin the average serum half-life is 3.35 hours, shortening to 2–3 hours with repeated dosing as the drug induces its own hepatic metabolism. 429, 439 Owing to extensive hepatic metabolism, dosage adjustment of rifampin is not necessary in patients with mild renal failure at doses of ≤600 mg daily; however, dosage adjustments are necessary in patients with a creatinine clearance <50 mL/h. 429, 439 After GI absorption, rifampin is quickly hydrolyzed in bile and undergoes enterohepatic circulation. 429 Urinary excretion accounts for approximately 30% of total rifampin elimination, with about 7% of the drug excreted unchanged in the urine. 429
Although rifampin crosses the placenta, several reviews of TB treatment during pregnancy have concluded that rifampin is not a teratogen for TB 440 although rifampin used in the last few weeks of pregnancy can cause hemorrhagic disease of the newborn and mother, with prophylactic vitamin K 1 required. 440, 441 There are very limited data on pregnancy exposure with other rifamycins. 440
Rifampin is a potent inducer of multiple CYP isoforms, which results in increased hepatic metabolism and more rapid clearance of wide variety of drugs. 55, 56, 105, 442 Rifabutin is a less potent inducer of CYP enzymes with relevance to HIV/AIDS patients discussed in the Drug Interactions section. 430, 435, 436 Rifapentine is an oral, long-acting analog of rifampin that may be given once weekly for TB treatment. Rifaximin is orally administered and is not used for systemic infections as <0.4% of an oral dose is absorbed systemically. 443, 444

Clinical use

Dermatologic indications

Mycobacterial infections
Antibiotic resistance to rifamycins develops rapidly, therefore this drug family is frequently used in combination with other antimicrobial agents. 445 Cutaneous tuberculosis is a major indication for rifampin therapy, where it is used along with other anti-TB drugs, including isoniazid, pyrazinamide, and ethambutol. 439, 445 Rifabutin is more effective than rifampin in the treatment of atypical mycobacteria infections, and is used often in combination with clarithromycin and ethambutol. 436 Rifampin is the only bactericidal drug against M. leprae , but it loses effectiveness after approximately 6 months. 446 The WHO recommends rifampin-based multiple-drug regimens for treatment of all forms of leprosy. 447 For treatment of M. marinum infections, rifampin has been used in conjunction with other antimycobacterials (i.e., ethambutol with or without clarithromycin). 300, 448, 449 Multidrug regimen with rifampin are also used for severe cutaneous infections in immunocompromised individuals. 450 Rifabutin is effective in prevention and treatment of disseminated atypical mycobacterial infection (including MAC) in HIV/AIDS patients with CD4 counts <50/µL. 450 Rifabutin has been granted ‘orphan drug’ status by the FDA for the above indication. 435, 436

Bartonella infections
Rifampin has also been used effectively for infections caused by Bartonella henselae (i.e., cat-scratch disease, bacillary angiomatosis, peliosis hepatis). 451–53 Although cat-scratch disease is usually self-limiting in immunocompetent individuals, there may be complications in some cases, particularly acutely ill patients with hepatosplenomegaly or painful lymphadenopathy, and in immunocompromised patients. 451, 453 Furthermore, antibiotic therapy is indicated in patients with B. henselae infections who develop bacillary angiomatosis, neuroretinitis, or Parinaud’s oculoglandular syndrome. 451–53

MSSA and MRSA infections
Q8-13 As noted earlier, rifampin is effective against USSTI caused by S. aureus , including CA-MRSA; however, rapid emergence of resistance limits its efficacy, especially as monotherapy. 7, 178, 286, 432, 439, 454, 455 When treating CA-MRSA rifampin should be prescribed concomitantly with either clindamycin or trimethoprim-sulfamethoxazole. 454 Additionally, the use of rifampin in combination with other systemic antibiotics to eradicate nasal carriage of MRSA has been inconsistent, with successful results ranging from 54% to 67%. 456

Other infections and related diseases
Cutaneous leishmaniasis and rhinoscleroma also respond to rifampin therapy, likely owing to its ability to penetrate the cell membranes and attack intracellular pathogens. 457 Rifampin has also demonstrated synergistic activity when combined with other antibacterial agents for the treatment of cat-scratch disease, aspergillosis, brucellosis, tularemia, chlamydial infections, and gonorrhea. 431 Some authors, albeit controversially, have suggested that rifampin may be useful as adjunctive therapy for psoriasis, possibly by reducing staphylococcal carriage and subsequent superantigen production. 15, 458 - 461 Rifampin has also been used to treat pruritus associated with primary biliary cirrhosis by increasing the degradation of pruritogenic bile salt metabolites via induction of hepatic metabolic enzymes. 462, 463

Adverse effects

Common adverse effects
With regard to adverse effects, rifampin is usually well tolerated. Rifampin (and other rifamycins) is intensely red in color and highly lipophilic, with widespread body distribution. Therefore, a frightening yet harmless orange-red discoloration of liquid body excretions (i.e., urine, sweat, tears, breast milk) may be noted by many patients for at least a few hours after ingestion of a dose, with light staining of fabric and permanent staining of soft contact lenses sometimes observed. 429 CNS symptoms of headache, drowsiness, ataxia, dizziness, inability to concentrate, and fatigue have also been described. 429 Q8-5 GI adverse effects of rifampin include epigastric distress, nausea, vomiting, and diarrhea, with antibiotic-associated colitis due to C. difficile rarely reported in association with rifampin use. 429

Immunologic effects
When used intermittently and in high doses rifampin has immunogenic properties leading to the formation of rifampin-dependent antibodies, with rare reports of Ig-E mediated anaphylaxis. 430, 464, 465 The adverse effects mediated by rifampin-dependent antibodies can be minor (cutaneous, gastrointestinal, and influenza-like syndromes) or more severe (thrombocytopenia, hemolytic anemia, respiratory insufficiency, and acute renal failure). 464 Isolated cases of SSLR, disseminated intravascular coagulopathy, conjunctival congestion, linear IgA bullous dermatosis, pemphigus foliaceous, and pemphigus vulgaris have also been reported. 464, 465

Liver toxicity
Asymptomatic changes in liver function tests (LFT), especially transaminases, may be associated with rifampin use; however, symptomatic hepatotoxicity is more likely when rifampin is used in combination with isoniazid. 429 In some patients hyperbilirubinemia is seen in the early days after initiation of rifampin, and is believed to be due to competition between rifampin and bilirubin for access to hepatic excretory pathways. 429 Serious hepatoxicity has also been noted with rifapentine. 466 Dosage reduction may be needed in patients with severe hepatic impairment. 466, 467 Use of rifampin, rifabutin, and rifapentine in patients with impaired liver function warrants careful clinical assessments and laboratory monitoring of LFT, at baseline then every 2–4 weeks during therapy. 429, 466

Other important adverse effects
Patients on rifampin therapy are at increased risk of developing deep venous thrombosis, with anecdotal reports of pulmonary fibrosis and ocular toxicity also noted. 439, 464 There have also been reports of exacerbation of porphyria by rifampin due to enzyme induction of δ aminolevulinic acid synthetase; the drug should be avoided in this patient population. 429, 464

Use in pregnancy and lactation
Rifampin and rifapentine are both pregnancy category C, and rifabutin is pregnancy category B. 440 Rifampin crosses the placenta, but this information is not known for rifabutin and rifapentine. Additionally, information on rifamycin pregnancy outcomes is often confounded by the frequent use of these agents in combination with other drugs, including anti-TB agents. 440 In addition, rifampin has been implicated as a cause of hemorrhagic disease of the newborn and mother when used within a few weeks of delivery, and it is recommended that prophylactic vitamin K 1 be administered. 440, 441 There are far fewer pregnancy exposure data for rifabutin and rifapentine; animal data suggest a low risk with rifabutin and a potential risk with rifapentine. 440 In particular for severe systemic mycobacterial infections, selected use in pregnancy may be justified.
With regard to use during lactation, rifampin is excreted in human breast milk in apparently low concentrations (0.05% of daily dose). 440 No reports of adverse effects in infants have been observed, and the American Academy of Pediatrics (AAP) classifies rifampin as compatible with breastfeeding. 421, 440, 468 Data on the use of rifapentine during breastfeeding are lacking, and the effect on the nursing infant is unknown. 440

Drug interactions
Rifampin is a potent inducer of multiple CYP isoforms, including CYP1A2, 2C9, 2C19, 2D6, and 3A4, with a resultant increased drug clearance and loss of efficacy of various drug substrates. 442, 463 Enzyme induction secondary to rifampin may take a few days to take effect, reaching its maximum effect 3 weeks after treatment initiation, and may persist up to 4 weeks after its discontinuation (‘offset’). Rifabutin is a weaker enzyme inducer than rifampin; rifabutin also inhibits CYP isoenzymes (i.e., CYP 3A4). Rifapentine is a CYP inducer, but is also an inhibitor for CYP3A4 and 2C8/9.
Therapeutic failure has been documented with concomitant rifampin use in a wide variety of drugs 55, 56, 105, 442, 463 ( Table 8-15 ). Some important loss-of-efficacy interactions include:

1. Q8-17 Increased clearance of oral contraceptive hormones leading to decreased efficacy and unintended pregnancy;
2. Decreased anticoagulant effects of warfarin leading to reduced ability to achieve therapeutic INR levels;
3. Reduced antifungal activity of azole antifungal agents leading to persistence of infection;
4. Decreased serum levels of calcium channel blockers (i.e., nifedipine, verapamil) leading to reduced antihypertensive, anti-anginal, and/or antiarrhythmic effects;
5. Reduced hypnotic effects of some benzodiazepines (i.e., triazolam, midazolam);
6. Decreased serum levels of several HMG CoA-reductase inhibitors (i.e., CYP3A4 substrates simvastatin, lovastatin, atorvastatin) leading to loss of cholesterol control;
7. Reduction in cyclosporine or tacrolimus serum levels leading to decreased immunosuppressive effects and therapeutic failure (i.e., rejection of transplanted organ, flare of psoriasis, etc.);
8. Reduced serum levels of theophylline with decreased efficacy;
9. Increased clearance of exogenous corticosteroids (i.e., methylprednisolone, dexamethasone) leading to loss of disease control (i.e., immunobullous disease) and/or addisonian crisis,
10. Decreased serum levels of phenytoin and lamotrigine leading to reduced anti-seizure effects;
11. Decreased serum levels of some antiarrhythmic agents (i.e., digoxin, digitoxin, quinidine, disopyramide, tocainide); and
12. Reduced serum levels of oral sulfonylurea hypoglycemic agents (i.e., tolbutamide, glipizide, glyburide) leading to modifications in blood glucose. 55, 56, 105, 429, 442, 463, 469 – 471
Table 8-15 Drug interactions – rifampin and related rifamycins Interacting drug group Examples and comments Drug levels ↓ due to enzyme induction various CYP isoforms – risk loss of efficacy Alzheimer’s disease drugs Donepezil Antiarrhythmic agents * Digoxin, disopyramide, mexiletine, propafenone, quinidine, tocainide Antibacterial – macrolides/related Clarithromycin (an azalide), erythromycin, telithromycin (a ketolide) Anticholinergic agents (Rx hyperactive bladder) Darifenacin, solifenacin Anticoagulants * Warfarin (R- and S-warfarin); risk of thrombosis, emboli; monitor INR Anticonvulsants * Carbamazepine, ethosuximide, felbamate, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, valproic acid; monitor serum levels of these drugs Antidepressants – non-selective, tricyclics * Buspirone, trazodone, various tricyclics, including amitriptyline, imipramine Antifungal agents – azoles/other Ketoconazole, itraconazole, voriconazole; also ↓ allylamine terbinafine Antipsychotic agents Aripiprazole, olanzapine, pimozide, quetiapine, risperidone, thiothixene Beta-blockers Carvedilol Bronchodilators – xanthine * Theophylline; monitor for ↑ bronchospasm due to ↓ levels Calcium channel blockers All calcium channel blockers are substrates of CYP3A4 Chemotherapeutic agents * Bortezomib, docetaxel, erlotinib, geftinib, imatinib, paclitaxel, vinca alkaloids (vincristine, vinblastine) Corticosteroids * Budesonide (inhaled), methylprednisolone Diabetes drugs – sulfonylureas/other * Sulfonylureas (first, second generation), exenatide, nateglinide, repaglinide Erectile dysfunction drugs Sildenafil, tadalafil, vardenafil HIV drugs – other * Delavirdine, efavirenz, nevirapine, zidovudine HIV drugs – protease inhibitors * Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir Hormonal contraceptives * Oral, transdermal, injectable contraceptives; potential for unintended pregnancy, irregular menses (↓ both estrogen and progestin components) Immunosuppressive agents * Cyclosporine; loss of efficacy of tremendous importance in transplantation Leukotriene D 4 receptor antagonists Montelukast, zafirlukast Miscellaneous drugs Aprepitant, caffeine, cinacalcet, colchicine, doxercalciferol, mifepristone Narcotics Alfentanil, meperidine, methadone, fentanyl, sufentanil, tramadol Sedatives – benzodiazepines/other Alprazolam, midazolam, triazolam; also bupropion Statins * All statins except pravastatin may have ↓ levels; monitor cholesterol levels Sulfones Dapsone Thyroid hormones Various synthetic forms of thyroid hormone Other potentially important interactions involving rifampin ‘Alternative’ medical therapies Kava; concomitant use ↑ risk of hepatotoxicity Analgesics – non-narcotic Acetaminophen; rifampin may ↑ formation of reactive/toxic metabolites Antacids H 2 antagonists, proton pump inhibitors, etc; ↑ absorption of rifampin Antituberculosis agents Isoniazid; concomitant use ↑ the risk of hepatotoxicity from rifampin Miscellaneous Leflunomide; rifampin may ↑ formation of active metabolite
Note : Rifamycins include rifampin, rifabutin, rifapentine.
Rifampin induces multiple CYP isoforms, especially 1A2, 2C9, 2C19, 3A4, and to a lesser extent 2D6; rifabutin induces only CYP3A4.
* ‘Narrow’ therapeutic drugs for which loss of efficacy due to rifampin CYP enzyme induction leads to a significant risk.
Adapted from Facts & Comparisons, The Medical Letter Drug Interactions Program, E-pocrates, Hansten and Horn – references on pg. xxii.
Rifabutin is less effective than rifampin in reducing serum levels of several protease inhibitors (i.e., saquinavir, ritonavir, indinavir), with less diminution of antiviral effects in HIV treatment. 472 The interaction of rifampin with digoxin may relate to enzyme induction of P-glycoprotein transport system, or both. 442 Q8-2 Lastly, concomitant antacid administration may reduce GI absorption of rifampin, and so rifampin should be given at least 1 hour before antacid intake. 429
Dermatologists should co-manage the above potential loss of efficacy along with the prescribing clinician for the above drugs, and monitor these reduced drug effects closely. An escalation in dosage of the metabolized drugs may be needed to assure therapeutic benefit. After discontinuation of rifampin use, reduced dosing of the metabolized drugs may be needed to assure therapeutic benefit. For example, the addition of rifampin to a stabilized cyclosporine regimen may require a 2–4-fold increase in cyclosporine dosage to maintain consistent therapeutic serum levels. Unless the cyclosporine dose is reduced to the baseline dose upon rifampin cessation, toxic serum levels can occur within 5–10 days after cyclosporine is discontinued. 473

Dosage
The recommended dosage of rifampin for treatment of cutaneous infections is usually 600 mg daily for adults, in a single or divided dose, and 10 mg/kg/day (600 mg maximum) for children ( Table 8-16 ). 429 Rifampin is optimally ingested with a full glass of water 1 hour before or 2 hours after a meal, and at least 1 hour before ingestion of antacids. 429 In patients unable to tolerate daily dosing of rifampin 600 mg/daily, doses >600 mg daily given once or twice a week to patients with TB produced a higher incidence of adverse effects, including flu-like symptoms, hematologic reactions (i.e., leukopenia, thrombocytopenia, acute hemolytic anemia), GI adverse effects, hepatotoxicity, dyspnea, anaphylaxis, and renal failure. 429
Table 8-16 Other commonly used oral antibacterial agents – dosage guidelines Generic name Tablet/capsule sizes (mg) Adult dosage Clindamycin 75, 150, 300 150–300 mg bid * Linezolid 400, 600 400 mg bid Rifampin 150, 300 300–600 mg/day TMP-SMX (DS) † 160/800 DS capsule bid
* An adult dosage range of 300–450 mg qid for 10 days has been commonly used for community-acquired MRSA.
† Fixed combination in this dosage ratio also known generically as co-trimoxazole.

Folate synthesis inhibitors

Trimethoprim-sulfamethoxazole
Q8-12 Trimethoprim-sulfamethoxazole (TMP-SMX), also referred to as co-trimoxazole, combines a dihydrofolate reductase inhibitor (trimethoprim, TMP) and a dihydropteroate synthetase inhibitor (sulfamethoxazole, SMX), thus synergistically inhibiting production of tetrahydrofolic acid. 474, 475 The resultant folate depletion interferes with bacterial nucleic acid and protein production. The mechanistic effect of TMP-SMX is believed to be more selective against bacterial than human cells, as trimethoprim binds bacterial dihydrofolate reductase 50 000–100 000 times more avidly than the corresponding mammalian enzyme. 474 In the US, the only available combination of this class is TMP-SMX, available both orally and for IV use ( Table 8-16 ). This popular antimicrobial agent contains a fixed dose ratio of 1 part TMP to 5 parts SMX.

Pharmacology

Antimicrobial activity
Both TMP and SMX are bacteriostatic, exhibiting synergistic activity when combined. 474 – 476 Many Gram-positive aerobic cocci, including S. aureus , CA-MRSA, S. pyogenes , Enterococcus faecalis , Streptococcus viridans, are inhibited by TMP-SMX, though resistance to sulfonamides is not uncommon. 474 – 476 H. influenzae and some Pseudomonas spp other than P. aeruginosa are also sensitive to TMP-SMX. 476 A wide variety of other organisms, including bacteria and protozoa, are sensitive to TMP-SMX, including Pneumocystis jirovecii (formerly P. carinii ). 474 – 478 TMP-SMX exhibits poor activity against anaerobic organisms such as Bacteroides spp. and Clostridium spp. 476, 479

Pharmacokinetics
Both TMP and SMX are both well absorbed orally (70–100%), with half-lives of 8–10 hours and 10–12 hours, respectively, in patients with normal renal function. 474, 479 In the presence of marked renal insufficiency the half-lives of TMP and SMX may be prolonged to 24 hours and 18–50 hours, respectively. Both are also distributed into breast milk and cross the placenta. 11, 480 Biotransformation of both TMP and MX is partially via hepatic metabolism, with the inactive acetylation metabolites of SMX retaining some of the toxicity of the parent compound. 474 Approximately 30–60% of TMP and 20–40% of SMX is excreted unchanged in the urine; renal clearance is delayed by impaired renal function. 474, 479

Clinical use

Dermatologic indications
There is a plethora of FDA-approved and unapproved uses for TMP-SMX for a wide variety of infections that are beyond the scope of this chapter. 474 – 476 ,479 ,482 Q8-13 The more common major dermatologic uses for oral TMP-SMX include as an alternative agent for acne vulgaris (not first-line), and for USSTI due to CA-MRSA. 7, 178, 128, 129, 152, 218, 286, 481, 482 Less common dermatologic uses for oral TMP-SMX include hidradenitis suppurativa, granuloma inguinale, some atypical mycobacterial infections, actinomycetoma, cat-scratch disease, Aeromonas spp infections, and chronic melioidosis ( Burkholderia pseudomallei ). 290, 300, 483 – 488

Adverse effects
As with most medications, GI and CNS adverse effects can occur with TMP-SMX, 474 – 476 includeing nausea, vomiting, loss of appetite, diarrhea, cephalgia, dizziness, and tinnitus. Q8-5 Antibiotic-associated colitis due to C. difficile has been reported with TMP-SMX, including when given as prophylaxis for P. jirovecii ( P. carinii ) pneumonia. 495, 496

Hypersensitivity reactions
TMP-SMX-induced cutaneous eruptions may be seen in 4–5% of healthy patients and approximately 15% of HIV-infected patients, usually manifesting within the first 1–2 weeks after starting therapy. These reactions include morbilliform and urticarial eruptions and/or pruritus, and less commonly fixed drug eruption. 376, 497
The adverse effects of greatest concern with TMP-SMX include sulfonamide-related DHS, Stevens–Johnson syndrome (SJS), TEN, and severe hematologic reactions such as agranulocytosis. 382, 481, 498, 499 Sulfonamides, including TMP-SMX, account for up to 30% of all cases of SJS/TEN, with the risk of TEN due to TMP-SMX use in adults estimated to be 2.6/100 000 exposures in the overall population, and 8.4/100 000 exposures in HIV-infected patients. 382, 498 In most cases, DHS or SJS/TEN manifest within the first 2–6 weeks after starting the drug. Patients receiving TMP-SMX should be told to discontinue treatment if they develop flu-like symptoms (fever, malaise, ‘swollen glands’, muscle aches), arthralgias, ‘hives’, ‘skin rash’, ‘sore throat’, ‘mouth or lip sores (erosions, ulcers)’, or painful skin. TMP-SMX should be avoided in patients with first-degree relatives who have experienced DHS or SJS/TEN associated with sulfonamide use, and in those that have a prior sulfonamide allergy. 500

Hematologic toxicity
In addition to agranulocytosis mentioned above, other uncommon hematologic reactions with TMP-SMX use are thrombocytopenia, neutropenia, hypoprothrombinemia, aplastic anemia (very rare), and pure red cell aplasia (very rare). 481, 499 Hemolytic anemia may occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. 475 TMP-SMX should be used very cautiously in patients with a possible folate deficiency, or in those with pre-existing megaloblastosis (increased mean corpuscular volume). 481, 499 It has been suggested that megaloblastosis may predispose patients to some hematopoietic adverse effects with exposure to TMP-SMX. 481, 499 A complete blood cell count (CBC) at baseline and monthly at least early in treatment has been suggested in patients on long-term dermatologic therapy with TMP-SMX. 474, 481

Other adverse effects
Other adverse reactions reported with TMP-SMX include hypersensitivity reactions presenting with pulmonary infiltrates, and upper respiratory symptoms, pustular skin eruptions, drug induced-Sweet’s syndrome, drug fever, cholestatic hepatitis, nephrolithiasis, interstitial nephritis and hyperkalemia. 474, 501 – 503 Nail changes following treatment with sulfonamides (including TMP-SMX) include Beau’s lines, paronychia, partial leukonychia, and photo-onycholysis. 27

Use in pregnancy and lactation
Both TMP and sulfonamides (such as SMX) are rated as pregnancy category C, and both are secreted into breast milk in low concentrations 11, 480 Although use in early pregnancy is not contraindicated, this recommendation likely applies to the use of short (3–5 days) courses of TMP-SMX or infections, such as urinary tract infections. 11, 504 A possible increased risk of congenital anomalies has been documented in pregnant women exposed to TMP-SMX. 11, 480 For dermatologic uses with prolonged treatment, alternatives that are safer in pregnancy are usually available. 11 Jaundice, hemolytic anemia and kernicterus have been related to maternal sulfonamide ingestion near term. 480 Although the AAP classifies both TMP and sulfonamides as compatible with breastfeeding, premature infants and those with hyperbilirubinemia should not be exposed to TMP-SMX via breast milk, as SMX competes with bilirubin binding to plasma albumin. 480 It is the overall opinion of the authors that breastfeeding be avoided in patients taking TMP-SMX.

Drug interactions
TMP-SMX has been associated with several clinically significant drug interactions: 55, 56, 105, 505

1. Increase dapsone serum levels warranting closer monitoring for dapsone toxicity (including methemoglobinemia);
2. Precipitate severe hyperkalemia when used concomitantly with an angiotensin-converting enzyme (ACE) inhibitor (i.e., enalapril);
3. Increase the risk of blood dyscrasias in patients on methotrexate;
4. Increase phenytoin serum levels predisposing patients to phenytoin serum levels predisposing patients to phenytoin toxicity;
5. Inhibit the metabolism of warfarin leading to increased anticoagulant effect and risk of bleeding. 505
6. Toxic delirium has been reported in individuals who have received amantadine and TMP. 474
7. Reversible nephrotoxicity has also been reported in renal transplantation recipients receiving cyclosporine and TMP-SMX; avoidance of co-administration if clinically feasible is suggested, as TMP-SMX (especially IV) can reduce cyclosporine serum levels, increase serum creatinine levels, and possibly predispose transplantation patients to organ rejection. 474, 506
8. A risk factor for many of the drug interactions involving TMP-SMX is renal insufficiency. 505, 507
9. Among elderly patients treated with ACE inhibitors and angiotensin receptor blockers, TMP-SMX is associated with a markedly increased risk of hospitalization due to hyperkalemia. 507

Dosage
A single-strength TMP-SMX tablet contains 80 mg TMP and 400 mg SMX. A double-strength TMP-SMX tablet contains 160 mg TMP and 800 mg SMX ( Table 8-16 ). For most disorders, TMP-SMX double strength is administered twice daily, with the duration of therapy dependent on the individual disease state and clinical response. Dosage adjustment of TMP-SMX is warranted for patients with renal insufficiency as noted above. See Table 8-16 for dosage guidelines for other commonly used oral antibacterial agents.

Lincosamides

Clindamycin
Clindamycin is a lincosamide antibiotic derived from Streptomyces lincolnensis . The drug is a derivative of lincomycin that has increased antibacterial activity and is better absorbed than its parent drug. 508 Q8-9 Through binding to the 50S subunit of bacterial ribosomal RNA (rRNA), clindamycin inhibits ribosomal translocation, resulting in reduced protein synthesis. 509

Pharmacology

Antimicrobial activity
Clindamycin is bacteriostatic against several aerobic Gram-positive cocci, including some staphylococci and streptococci (not enterococci), and a wide variety of anaerobes, including Bacteroides spp and Clostridium perfringens , although resistant B. fragilis strains are increasing. 508 – 510
Q8-13 Some strains of CA-MRSA are sensitive to clindamycin; however, inducible lincosamide resistance has led to reduced clindamycin activity against many CA-MRSA strains. 7 Where cases of CA-MRSA test in vitro as erythromycin-resistant and clindamycin-sensitive, if inducible resistance is present treatment failure to clindamycin can occur despite the indication of susceptibility on the antibiotic sensitivity report. In this case, the microbiology laboratory can perform a ‘D zone’ test, which, if positive, tells the clinician to avoid use of clindamycin for CA-MRSA as inducible resistance is present. 7
Although most aerobic Gram-negative bacteria, such as Pseudomonas spp and H. influenzae, are inherently resistant to clindamycin, an exception is Capnocytophaga canimorsus , which is highly susceptible to clindamycin. Among facultative anaerobes, Propionibacterium spp, such as P. acnes , are susceptible to clindamycin. Interestingly the protozoon T. gondii is inhibited by clindamycin. 508 – 510 Q8-7 Resistance to clindamycin generally can confer resistance to macrolides if the erm -encoded enzymes are constitutively produced. 1, 4, 5, 7

Pharmacokinetics
Clindamycin can be administered orally or parenterally (IV or IM) ( Table 8-16 ). The drug is well absorbed orally, independent of food, with wide tissue distribution. 509 When administered in an inactive salt form (i.e., clindamycin phosphate), hydrolysis to active clindamycin occurs rapidly in vivo. Clindamycin is metabolized predominantly in the liver, with a plasma half-life of 2.4–3.0 hours in adults and 2.5–3.4 hours in infants and children, both with normal renal function. The plasma half-life is raised slightly to 3–5 hours in adults with severe renal or hepatic failure. Clindamycin is highly protein-bound (92–94%), with over 85% excreted in urine as inactive metabolites, the remainder in urine (10%) or feces (3.6%) as clindamycin. Dosage adjustment of clindamycin is necessary for patients with liver failure; no dosage adjustment is needed in renal failure patients.

Clinical use

Dermatology indications
As with TMP-SMX, clindamycin has been used for a variety of infections, both FDA approved and off-label. 508, 509, 511 Q8-13 With regard to common dermatologic uses, oral clindamycin is used for treatment of USSTI, primarily those caused by staphylococci, including susceptible strains of CA-MRSA, the latter highly dependent on geographic differences in true susceptibility patterns to clindamycin. 7, 178, 286, 512 Clindamycin is frequently used to treat cellulitis, folliculitis, furunculosis, carbuncles, impetigo, ecthyma, and hidradenitis suppurativa. 513 Deep soft tissue infections, including streptococcal myositis, necrotizing fasciitis, and C. perfringens infection, may also be treated with this agent. Clindamycin is also used as part of a combination regimen to treat infected diabetic foot ulcers. Q8-5 Concern regarding the risk of antibiotic-associated colitis has markedly limited clindamycin oral use in acne vulgaris patients. 514

Adverse effects

Antibiotic-associated colitis and other GI effects
Q8-5 Antibiotic-associated colitis (originally named ‘pseudomembraneous enterocolitis’), caused by toxins produced by C. difficile , has been reported in 0.1–10% of clindamycin-treated patients. 515 This syndrome may be lethal, although most ambulatory cases are relatively mild if clindamycin is discontinued within 24 hours of diarrhea onset. Rapid institution of therapeutic interventions based on severity include management of fluid/electrolyte balance, protein replacement, antibiotic therapy (i.e., metronidazole, oral vancomycin), and cholestryamine resin. Other GI adverse effects associated with clindamycin include nausea, vomiting, and elevated transaminases.

Other systemic adverse effects
Bone marrow suppression and renal impairment are rare.

Cutaneous adverse effects
These may include maculopapular or urticarial eruptions. Older reports have suggested anaphylaxis, erythema multiforme, and an SJS-type reaction with polyarthritis in association with clindamycin use. 511

Use in pregnancy and lactation
Clindamycin is category B in pregnancy, with no known teratogenicity. 11, 516 Although clindamycin is excreted in breast milk, it has been rated as compatible with breastfeeding; however, manufacturers of topical clindamycin products suggest discontinuation during lactation. 11, 516 In a single report of a lactating mother on clindamycin, her infant developed bloody stools while breastfeeding, although causation was not proven. 11

Drug interactions
Clindamycin has been shown to have neuromuscular blocking properties that may enhance other neuromuscular agents, such as tubocurare and pancuronium. 514

Dosage
The usual adult oral dose of clindamycin in dermatology is 150–300 mg twice daily ( Table 8-16 ). Conditions such as severe hidradenitis suppurativa may rarely require 300 mg three times daily. In children weighing ≤10 kg the minimum recommended dose is 37.5 mg every 8 hours.
Editor’s Note – The following five sections are concise summaries of five additional antibiotics or antibiotic groups. Some systemic antibacterial agents not covered in this chapter are listed in Table 8-17 .
Table 8-17 Antibacterial agents not emphasized in this chapter Aminoglycosides Sulfonamides Other categories Amikacin Sulfadiazine Chloramphenicol Gentamicin Sulfadoxin Metronidazole Kanamycin Sulfamethizole Nitrofurantoin Neomycin Sulfapyridine *   Netilmicin Sulfasalazine   Paramomycin Sulfisoxazole   Spectinomycin     Streptomycin     Tobramycin    
* Sulfapyridine has limited availability in the United States.

Glycyclines 517 – 524

1. Tigecycline, a parenteral (IV) agent, is the first in this new class of broad-spectrum antimicrobial agents known as glycyclines, and was approved by the FDA in June 2005. It is a synthetic analog of minocycline with structural changes that ‘bypass’ resistance to TCNs, β-lactams, macrolides, and fluoroquinolones. 517 – 519
2. Q8-9 Like tetracyclines, tigecycline is bacteriostatic and inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. 517, 518
3. Tigecycline is effective against antibiotic-resistant organisms, including S. aureus and MRSA; vancomycin-intermediate, vancomycin resistant, and penicillin-resistant S. pneumonia ; vancomycin-resistant Enterococcus faecalis ; and many other bacteria. 520
4. Tigecycline is structurally similar to tetracyclines and shares many of their adverse effects, with the potential for cross-reactions. The use of tigecycline during tooth development (last half of pregnancy, children <9 years of age) may cause permanent yellow-gray-brown discoloration of the teeth.
5. There have also been reports of acute pancreatitis and hypertriglyceridemia related to tigecycline. 524
6. Q8-16 Tigecycline is pregnancy category D, with known tetratogenicity and embryo lethality, and its safety during lactation is unknown. 523 The safety of tigecycline in pediatric patients younger than 18 years of age has not been established. 523
7. Co-administration with warfarin will reduce the clearance of warfarin, and closer monitoring of the INR is advised. 523 It may possibly reduce the effectiveness of oral contraceptives. 523

Oxazolidinones

Linezolid

1. Linezolid is the only member of this class currently approved for use in the US, and its tremendous cost limits widespread use in dermatology.
2. Q8-9 Oxazolidinones bind to the 23S portion of the 50S ribosomal subunit; owing to a unique binding site, there is no cross-resistance with other antimicrobial agents. 525
3. Q8-13 Linezolid has a wide s pectrum of activity against a variety of organisms, including multidrug-resistant strains such as MRSA, vancomycin-intermediate and -resistant strains of staphylococci, penicillin-resistant S. pneumoniae , and vancomycin-resistant enterococci (VRE). 526
4. Q8-7 Resistance in enterococci and staphylococci is due to a point mutation of the 23S ribosomal RNA. 527
5. Linezolid is 100% bioavailable, with serum half-life of 5–7 hours; its metabolism is unaffected by the CYP system. 528
6. No dosage adjustments are generally needed with renal or hepatic impairment.
7. Linezolid is effective against skin infections due to staphylococcus or streptococcus, including USSTI caused by S. aureus , including CA-MRSA, or susceptible S. pyogenes . 529, 530 Linezolid should be considered for treatment of CA-MRSA in patients who have failed oral doxycycline, minocycline, TMP-SMX, clindamycin/rifampin, or vancomycin. 530, 531
8. Elevations in serum transaminases and creatinine are rare; myelosuppression, including anemia, leukopenia, pancytopenia, and reversible thrombocytopenia (2% of patients), has been reported in patients receiving linezolid. 529 Platelets should be monitored when linezolid is used for more than 2 weeks or in those with pre-existing thrombocytopenia.
9. Serotonin syndrome characterized by cognitive dysfunction, hyperpyrexia, hyperreflexia, and incoordination has been reported in patients receiving linezolid and serotonergic drugs. 532, 533
10. Optic and peripheral neuropathy is reversible upon discontinuation of the drug, but may be progressive with prolonged use. 529, 534
11. Linezolid is pregnancy category C and should not be prescribed to lactating mothers. 535
12. Linezolid drug interactions include (a) MAO inhibitors, (b) SSRI, 529, 532, 533 (c) sympathomimetic agents (e.g., pseudoephedrine), (d) vasopressive agents (e.g., epinephrine, norepinephrine), or (e) dopaminergic agents (e.g., dopamine, dobutamine). 529
13. The adult dose for USSTI is 400 mg twice daily for 10–14 days. 529 For more serious infections, 600 mg twice daily is recommended.

Quinupristin and dalfopristin combination 525, 536 – 539

1. Quinupristin-dalfopristin, the first parenteral (IV) streptogramin formulation available in the US, combines two semisynthetic antibiotics in a 30 : 70 ratio, with a net synergistic effect against Gram-positive bacteria resulting in a greater antibacterial activity than when using either drug alone. 536
2. Q8-9 Quinupristin-dalfopristin enters bacteria by diffusion and binds to different sites on the 50S ribosomal subunit, resulting in an irreversible inhibition of bacterial protein synthesis. 525
3. Quinupristin-dalfopristin is effective against Gram-positive bacteria, including MRSA, VRE, and penicillin-resistant S. pneumonia , with its main use in the treatment of multidrug-resistant CSSTI due to Gram-positive organisms. 525, 530, 537
4. Quinupristin-dalfopristin is a potent inhibitor of the CYP3A4 isoform, with the typical interactions including simvastatin, atorvastatin, cyclosporine, and many others. 525, 539
5. Increased total bilirubin up to 5 times the upper limit has been reported. 539
6. Anaphylactic shock and angioedema have also been reported. 539

Daptomycin 525, 540 – 541

1. Daptomycin is a lipopeptide antibiotic available only in IV form which causes cell death by depolarization of the bacterial cell membrane leading to inhibition of protein, DNA and RNA synthesis, and cell death. 540, 541
2. Daptomycin has bactericidal activity limited to Gram-positive organisms, including MRSA, linezolid-resistant Gram-positive infections, and VRE. 525, 540 Daptomycin is approved for the treatment of CSSTI caused by Gram-positive bacteria, including MRSA, MSSA, Streptococcus spp, and E. faecalis .
3. Adverse effects include neuropathy, primarily paresthesias. 525, 540
4. Reversible skeletal muscle toxicity (myopathy), which is seen only at higher than approved doses, yet weekly creatinine phosphokinase (CPK) is recommended.
5. Eosinophilic pneumonia has been reported to develop during treatment with daptomycin, with potential for respiratory failure. 540
6. Daptomycin should be given cautiously in patients taking medications associated with myopathy, such as HMG CoA reductase inhibitors, but has no CYP-based drug interactions. 540

Lipoglycopeptides 542 – 549

1. Telavancin, dalbavancin, and oritavancin are novel second generation semisynthetic lipoglycopeptides (related to vancomycin) used for the treatment of multi-drug resistant Gram-positive pathogens. 542 Telavancin was approved by the FDA in 2009 for CSSTI, whereas the other two drugs are pending approval.
2. All the lipoglycopeptides that cover just Gram-positive bacteria show in vitro activity against S. aureus , S. epidermis , Streptococcus spp. vancomycin-resistant S. pneumonia , and vanA VRE. 542, 543
3. Dalbavancin, oritavancin, and telavancin are administered intravenously. Telavancin requires daily administration, with the long half-life of dalbavancin (once-weekly dosing) and oritavancin (one dose per course) having an advantage once approved. 542
4. These three agents are promising alternatives for the treatment of SSTI caused by organisms resistant to or less sensitive to vancomycin, or in patients with adverse reactions associated with vancomycin.
5. To date, there have been no clinically significant drug interactions identified with the lipoglycopeptides.

Summary
Systemic antimicrobial agents, especially oral antibiotics, are the most common category of systemic medications prescribed by dermatologists. This is explained by their frequent use to treat common inflammatory dermatoses in addition to a wide variety of cutaneous infections.
The inherent anti-inflammatory and other biologic properties of some antibiotics, unrelated to their antibiotic properties, has led to their use for a variety of cutaneous disorders that vary in clinical presentation and apparent pathogenesis. Among inflammatory dermatoses treated long-term with oral antibiotics are acne vulgaris, rosacea, perioral dermatitis, sarcoidosis, and immunobullous diseases.
Infections treated by dermatologists on a fairly regular basis include USSTI, atypical mycobacterial infections, a variety of STDs, and many other infections caused by myriad causative organisms. In some cases, regimens are well defined by clinical studies, large-scale analyses of outcomes with ‘expert consensus’ and government agencies. In other situations, especially for rare diseases, case reports and focused observational experience dictate treatment suggestions.
Collectively, there are factors that necessitate clinicians in dermatology to be aware of how to incorporate treatment, evaluate clinical response, and monitor for both common and uncommon adverse reactions, especially with agents commonly used by dermatologists, such as tetracyclines, macrolides, TMP-SMX, and cephalosporins.
Lastly, concerns related to antibiotic resistance are growing. It is important for dermatology as a discipline of medicine to remain consistently vigilant regarding the emergent patterns of antibiotic resistance, and to educate and update clinicians on the rational use of antibiotic therapy.

Abbreviations used in this chapter

Bibliography: important reviews and chapters *

Antibiotic use in dermatology: general issues
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Antibiotic resistance issues in dermatology
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Community-acquired MRSA
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Drug interactions
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β-lactam antibiotics
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Vancomycin
Finch RG, Eliopoulos GM. Safety and efficacy of glycopeptide antibiotics. J Antimicro Chemother . 2005;55(Suppl 2):5–13.

Macrolides
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472 Ibid, pp. 622–23.
473 Ibid, pp. 256–57.

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495 Gordin F, Gilbert C, Schmidt ME. Clostridium difficile colitis associated with trimethoprim- sulfamethoxazole given as prophylaxis for Pneumocystis carinii pneumonia. Am J Med . 1994;96:94–95.
496 Scott SA. Trimethoprim/sulfamethoxazole-associated pseudomembranous colitis. Drug Intell Clin Pharm . 1982;16:244–247.
497 Schopf E. Skin reactions to co-trimoxazole. Infection . 1987;15(suppl 5):S254–S258.
498 Gimnig J, MacArthur J, M’bang’ombe M, et al. Severe cutaneous reactions to sulfadoxine-pyramethamine and trimethoprim-sulfamethoxazole in Blantyre District, Malawi. Am J Trop Med Hyg . 2006;74:738–743.
499 Remlinger KA. Hematologic toxicity of drug therapy. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy . 2nd ed. Philadelphia, PA: WB Saunders; 2007:893–909.
500 Knowles SR, Shear NH. Drug hypersensitivity syndromes. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy . 1st ed. Philadelphia, PA: WB Saunders; 2001:872–884.
501 Bissonnette R, Tousignant J, Allaire G. Drug induced toxic pustuloderma. Int J Dermatol . 1992;31:172–174.
502 Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole associated acute febrile neutrophilic dermatosis. Case report and review of drug induced Sweet’s syndrome. J Am Acad Dermatol . 1996;34:918–923.
503 Munoz SJ, Martinez-Hernandez A, Maddrey WC. Intrahepatic cholestasis and phospholipidosis associated with the use of trimethoprim-sulfamethoxazole. Hepatology . 1990;12:342–347.
504 Bergus G. Urinary tract infections in pregnancy. In: Yankowitz J, Niebyl JR. Drug Therapy in Pregnancy . 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:68–69.
505 Hansten PD, Horn JR. Managing Clinically Important Drug Interactions . St. Louis: Wolters Kluwer Health; 2004. pp. 266, 334, 523, 594, 661
506 Tatro DS. Drug Interactions Facts . St. Louis: Wolters Kluwer Health; 2006. p. 489
507 Antoniou T, Gomes T, Juurlink DN, et al. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system. Arch Intern Med . 2010;170(12):1045–1049.

Clindamycin
508 McGehee RF, Jr., Smith CB, Wilcox C, et al. Comparative studies of antibacterial activity in vitro and absorption and excretion of lincomycin and clindamycin. Am J Med Sci . 1968;256:279–292.
509 Kalamazoo, MI. Cleocin(r) (clindamycin capsules), Full Prescribing Information, Upjohn Pharmaceuticals. 1991.
510 Sutter VL. In vitro susceptibility of anaerobes: comparison of clindamycin and other antimicrobial agents. J Infect Dis . 1977;135:7–12.
511 Dhawan VK, Thadepalli H. Clindamycin: a review of fifteen years of experience. Rev Infect Dis . 1982;4:1133–1153.
512 Klempner MS, Styrt B. Prevention of recurrent staphylococcal skin infections with low dose oral clindamycin therapy. JAMA . 1988;260:2682.
513 Falagas ME, Gorbach SL. Clindamycin and metronidazole. Med Clin North Am . 1995;79:845–867.
514 Anonymous. Clindamycin. American Hospital Formulary Service. Drug Information 1995. Am Soc Health Syst Pharm . 1995:357–361.
515 Bartlett JG. Antimicrobial agents implicated in Clostridium difficile toxin associated diarrhea or colitis. Johns Hopkins Med J . 1981;149:6–9.
516 Briggs GG, Freeman RK, Yaffe SJ. Clindamycin. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation . 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:343–344.

Glycyclines
517 Meagher AK, Ambrose PG, Grasela TH, et al. The pharmacokinetic and pharmacodynamic profile of Tigecycline. Clin Infect Dis . 2005;41:S333–S340.
518 Zhanel GG, Homenuik K, Nichol K, et al. The glycylcyclines: a comparative review with the tetracyclines. Drugs . 2004;64(1):63–88.
519 Meagher AK, Ambrose PG, Grasela TH, et al. Pharmacokinetic/pharmacodynamic profile for tigecycline—a new glycylcycline antimicrobial agent. Diagn Microbiol Infect Dis . 2005;52(3):165–171.
520 Kasbekar N. Tigecycline: A new glycylcycline antimicrobial agent. Am J Health Syst Pharm . 2006;63:1235–1243.
521 Fritsche TR, Sader HS, Stilwell MG, et al. Antimicrobial activity of tigecycline tests against organisms causing community-acquired respiratory tract infection and nosocomial pneumonia. Diagn Microbiol Infect Dis . 2005;52:187–193.
522 Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis . 2005;41(Suppl 5):S341–S353.
523 Tygacil (r) (tigecycline for injection), Full Prescribing Information. Philadelphia, PA: Wyeth Pharmaceuticals Inc, 2005.
524 Hung WY, Kogelman L, Volpe G, et al. Tigecycline-induced acute pancreatitis: case report and literature review. In J Antimicrob Agents . 2009;34(5):486–489.

Oxazolidinones
525 Lundstrom TS, Sobel JD. Antibiotics for Gram-positive bacterial infections: vancomycin, quinupristin-dalfopristin, linezolid, and daptomycin. Infect Dis Clin N Amer . 2004;18(3):651–658.
526 Wesson KM, Lerner DS, Silverberg NB, Weinberg JM. Linezolid, quinupristin/dalfopristin, and daptomycin in dermatology. Clin Dermatol . 2003;21(1):64–70.
527 Wilson P, Andrews JA, et al. Linezolid resistance in clinical isolates of Staphylococcus aureus. J Antimicrob Chemother . 2003;51:186–188.
528 Di Paolo A, Malacarne P, Guidotti E, et al. Pharmacological issues of linezolid: an updated critical review. Clin Pharmcokinet . 2010;49(7):439–447.
529 Zyvox(r) (linezolid injection, tablets, and oral suspension), Full Prescribing Information. New York, NY: Pfizer, Inc, 2008.
530 Schweiger ES, Scheinfeld NS, Tischler HR, et al. Linezolid and quinupristin/dalfopristin: novel antibiotics for Gram-positive infections of the skin. J Drugs Dermatol . 2003;2(4):378–383.
531 Howden BP, Ward PB, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis . 2004;38:521–528.
532 Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis . 2002;34:1651–1652.
533 Bernard L, Stern R, Lew D, et al. Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis . 2003;36:1197.
534 McKinley SH, Foroosan R. Optic neuropathy associated with linezolid treatment. J Neuroophthalmol . 2005;25:18–21.
535 Briggs GG, Freeman RK, Yaffe SJ. Linezolid. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation . 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:922–923.

Quinupristin and Dalfopristin Combination
536 Lorian VM, Fernandes F. Synergistic activity of vancomycin-quinupristin/dalfopristin combination against Enterococcus faecium. J Antimicrob Chemother . 1997;39(Suppl A):63–66.
537 Bryson HM, Spencer CM. Quinupristin-dalfopristin. Drugs . 1996;52:406–415.
538 Soltani M, Beighton D, Phipott-Howard J, et al. Mechanisms of resistance to quinupristin-dalfopristin among isolates of Enterococcus faecium from animals, raw meat and hospital patients in Western Europe. Antimicrob Agents Chemother . 2000;44:433–436.
539 Synercid(r) (quinupristin/dalfopristin for injection). Full Prescribing Information. Bridgewater, NJ: Aventis Pharmaceuticals Inc, 2000.

Daptomycin
540 Cubicin(r) (daptomycin for injection), Full Prescribing Information. Lexington, MA: Cubist Pharmaceuticals, 2003.
541 Silverman JA, Pelmutter NG, Shaprio HM. Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother . 2003;47:2538–2544.

Lipoglycopeptides
542 Zhanel G, Calic D, Schweizer F, et al. New lipopglycopeptides: A comparative review of dalbavancin, oritavancin and telavancin. Drugs . 2010;70(7):859–886.
543 Jones RN, Silwell MG, Sader HS, et al. Spectrum and potency of dalbavancin tested against 3322 Gram-positive cocci isolated in the United States Surveillance ProGram (2004), Diagnostic Microb. Infect Dis . 2006;54(2):149–153.
544 Zhanel GG, Trapp S, Gin AS, et al. Dalbavancin and telavancin: novel lipoglycopeptides for the treatment of Gram-positive infections. Expert Rev Anti Infect Ther . 2008;6(1):67–81.
545 Seltzer E, Dorr MB, Goldstein BP, et al. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for the treatment of skin and soft tissue infections. Clin Infect Dis . 2003;37(10):1298–1303.
546 Jauregui LE, Babzadeh S, Seltzer E, et al. Randomized double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis . 2005;41(10):1407–1415.
547 Stryjewski ME, Chambers HF. Skin and soft-tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Clin Infect Dis . 2008;46(Suppl 5):S368–S377.
548 Stryjewski ME, Graham DR, Wilson SE, et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms. Clin Infect Dis . 2008;46(11):1683–1693.
549 Greenblatt DJ, Zhao Y, Duan SX, et al. Effects of oritavancin on human cytochromes P450 in vitro [poster no.A1–1284] 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 12–5, 2009, San Francisco, CA.

* Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com .
9 Systemic antifungal agents

Aditya K. Gupta


 Questions

Q9-1 What are several of the drugs currently available for systemic fungal indications or in the drug development process that have a future role in dermatologic drug therapy? ( Pgs. 99, 108 )
Q9-2 Considering terbinafine, itraconazole, and fluconazole, (a) which drug has the greatest overall bioavailability, and (b) which drug’s bioavailability is most affected by gastric pH? ( Pg. 99 )
Q9-3 How do the pharmacokinetics of terbinafine, itraconazole, and fluconazole in (a) the sweat, sebum, and stratum corneum, (b) the nails, and (c) the hair influence the option of intermittent/pulse therapy? ( Pgs. 100, 101, 102 )
Q9-4 What is a possible explanation for the higher efficacy of terbinafine against endothrix compared to ectothrix infections in tinea capitis? ( Pg. 102 )
Q9-5 Considering the allylamine mechanism (terbinafine), (a) what enzyme is inhibited, (b) what conversion step is inhibited, and (c) is the net in vitro result fungicidal or fungistatic? ( Pg. 102 )
Q9-6 Considering the azole mechanism (itraconazole, fluconazole), (a) what enzyme is inhibited, (b) what conversion step is inhibited, and (c) is the net in vitro result fungicidal or fungistatic? ( Pg. 102 )
Q9-7 Considering all 5 main systemic antifungal agents in this chapter, which have the most optimal coverage against (a) Candida infections, (b) dermatophytes, (c) non-dermatophyte mold infections, and (d) Pityrosporum infections? ( Pgs. 102, 105, 107 )
Q9-8 Why did terbinafine and itraconazole largely replace griseofulvin as treatment for dermatophyte onychomycosis? ( Pg. 104 )
Q9-9 Considering terbinafine, itraconazole, fluconazole and griseofulvin treatment of tinea capitis in children, what pharmacokinetic properties might influence their efficacy? ( Pg. 106 )
Q9-10 In which clinical situations should oral antifungals (as opposed to topical antifungals) be used for tinea corporis, tinea cruris and tinea pedis? ( Pg. 106 )
Q9-11 Which antifungal agent has a significant risk of inducing (a) congestive heart failure, and (b) depression? ( Pgs. 109, 112, 119 )
Q9-12 What are the rare severe dermatologic adverse events reported for terbinafine, itraconazole, and fluconazole? ( Pgs. 109, 112, 113 )
Q9-13 Considering all 5 main systemic antifungals discussed, which is (a) the strongest CYP3A4 inhibitor, (b) a CYP2D6 inhibitor, (c) a CYP3A4 inducer, and (d) a CYP2C9 inhibitor (and the most important drug interactions with each)? ( Pgs. 113x2, 115 , Tables 9-9 and 9-10 )
Q9-14 Considering all 5 main systemic antifungal agents in this chapter, which has drug interactions with a risk of (a) torsades de pointes, and (b) inducing an increased INR? ( Pg. 113x2 )

Introduction
The availability of modern antifungal agents has greatly improved the treatment of a wide range of superficial and systemic dermatomycoses. Systemic antifungal agents have been particularly helpful in improving the efficacy of onychomycosis and tinea capitis treatment. Five main systemic agents for superficial dermatologic indications are available: (1) terbinafine, (2) itraconazole, (3) fluconazole, (4) griseofulvin, and (5) ketoconazole. This chapter focuses on terbinafine, itraconazole and fluconazole, as the traditional agents, griseofulvin and ketoconazole, now have limited use in the management of onychomycosis and other dermatomycoses ( Table 9-1 ). 1 – 9 A new generation of systemic antifungal agents has been developing, including voriconazole, posaconazole, and ravuconazole. 10 – 12 These agents are not currently approved for any superficial dermatomycoses, but voriconazole and posaconazole have approved systemic antifungal indications and in this chapter will be briefly compared and contrasted with their predecessors itraconazole and fluconazole.

Table 9-1 Systemic antifungal agents
Terbinafine is an allylamine that was developed in 1974. Oral terbinafine was first approved for use in the United Kingdom in February 1991, in Canada in May 1993, and in the United States in May 1996. Topical terbinafine was approved in the United States in December 1992. The first allylamine to be approved for use in humans was naftifine; however, it is only available as a topical treatment.
Itraconazole is a triazole that was synthesized in 1980. It first obtained international registration in 1987. Itraconazole was approved in the United States for the treatment of systemic mycoses in September 1992, and as continuous therapy for onychomycosis of the fingernails and toenails in October 1995. Itraconazole pulse therapy has been approved in the United States for the treatment of fingernail onychomycosis since January 1997.
Fluconazole is a triazole that was initially approved for use in humans in France and the United Kingdom in 1988 and in the United States in January 1990. In September 1993, Finland and China were the first countries to receive approval for fluconazole treatment of onychomycosis. In the United States, fluconazole is not approved for the treatment of onychomycosis or other dermatomycoses.
Griseofulvin was isolated from the mold Penicillium griseofulvum Dierckx by Oxford in 1939. In the late 1950s and early 1960s, griseofulvin was found to be effective in the treatment of superficial fungal infections in humans. It was the first significant oral antifungal agent available for the management of dermatomycoses. Although the use of griseofulvin has declined over the years, it is still widely used for the treatment of tinea capitis in children.
Ketoconazole was the first significant oral imidazole to become available for the treatment of mycotic infections. The drug was released in the United States in 1981. Previous therapies for systemic mycoses or severe dermatomycoses required intravenous administration (e.g., amphotericin B or miconazole), or had a limited spectrum of action (e.g., griseofulvin for dermatophytes or nystatin for Candida albicans ).
Voriconazole , posaconazole , and ravuconazole are members of a second generation of triazoles. Q9-1 Voriconazole and posaconazole have been respectively approved for the treatment and prophylaxis of invasive fungal infections, whereas ravuconazole is still under clinical investigation. Both posaconazole and ravuconazole have been used for onychomycosis clinical trials with favorable results, and these new antifungals might have future dermatologic indications.

General pharmacokinetic properties of the oral antifungals
The major properties of the most frequently used oral antifungals are summarized in Table 9-2 . 1 – 12 Antifungal agents typically fall into the structural families: (1) triazoles – itraconazole, fluconazole, voriconazole, posaconazole and ravuconazole, (2) imidazoles – ketoconazole, and (3) allylamines – terbinafine, naftifine ( Figure 9-1 ). Triazoles and imidazoles are subsets of the broader category of azole antifungals. Q9-2 Terbinafine and itraconazole have bioavailabilities of approximately 40% and 55%, respectively, and both drugs are extensively metabolized by the liver ( Table 9-2 ). 1, 5 In contrast, fluconazole has a bioavailability >90%, and undergoes little hepatic metabolism. Absorption of itraconazole in a fasting state, or in individuals with relative or absolute achlorhydria (e.g., those on H 2 inhibitors, antacids, or proton pump inhibitors), may be increased when the itraconazole is administered with at least 8 oz of a cola beverage. 1 When fluconazole 50–400 mg is given once daily, steady-state concentrations are achieved within 5–10 days, but may be attained more rapidly by doubling the dose on the first day. 4

Table 9-2 Key pharmacology concepts – systemic antifungal agents

Figure 9-1 Drug structures – terbinafine, itraconazole, fluconazole.
In patients with liver cirrhosis, terbinafine clearance was reduced by approximately 50% compared to normal volunteers, and itraconazole elimination half-life showed a 2-fold increase. 1, 5 Careful monitoring is suggested in these patients. In patients with renal insufficiency (serum creatinine >3.4 mg/dL, or creatinine clearance <50 mL/min), terbinafine clearance is decreased by about 50%. 5 Itraconazole bioavailability is slightly reduced for subjects with renal insufficiency. 1 Elderly subjects with age-related renal impairment may require dosing adjustments.
Metabolism of oral antifungals by the cytochrome P-450 (CYP) enzyme system provides the potential for interactions with concomitant medications. Drug interactions are discussed later in this chapter.

Pharmacokinetics in skin Q9-3


Terbinafine
Terbinafine is delivered to the stratum corneum by passive dermoepidermal diffusion, through sebum and through incorporation of drug from migrating basal keratinocytes. 13 High concentrations of drug (well above the minimum inhibitory concentration [MIC]) are reached in the stratum corneum within hours of starting therapy. 14 Within 2 days of administering terbinafine 250 mg daily, the drug achieves a high level in the sebum. 14 Terbinafine has not been detected in eccrine sweat. 15 The elimination half-life of terbinafine from the stratum corneum and sebum is 3–5 days. 14 After administration of terbinafine 250 mg daily for 12 days, drug concentrations above the MIC for most dermatophytes may be present for 2–3 weeks after oral therapy is discontinued. 14

Itraconazole
Itraconazole is delivered to the skin mainly as a result of passive diffusion from the plasma to the keratinocytes, with strong drug adherence to keratin. 16 Itraconazole becomes detectable in the sweat within 24 hours after the initial intake of drug. Despite the early detection in sweat, excretion of itraconazole by this route is minimal, in contrast to griseofulvin, ketoconazole, and fluconazole. 17, 18 There is extensive excretion of itraconazole into sebum. 16 A negligible amount of itraconazole redistributes back from the skin and appendages to the plasma; therefore, itraconazole is eliminated as the stratum corneum renews itself, and when the hair and nails grow out. 16, 18 Itraconazole may persist in the stratum corneum for 3–4 weeks after discontinuation of therapy. 16 In an ex vivo model, the therapeutic effect of itraconazole in the stratum corneum remained for 2–3 weeks after stopping therapy. 19

Fluconazole
When two doses of fluconazole (150 mg once weekly) are administered, the drug accumulates in the stratum corneum through sweat and by direct diffusion through the dermis and epidermis. 20 Excretion in the sebum may be more limited. After discontinuation of therapy there may be rediffusion of fluconazole from the skin into the systemic circulation, but at a rate lower than elimination from the plasma. 18 In healthy subjects given a single fluconazole dose of 200 mg, the concentration in the plasma and stratum corneum was 3 µg/mL and 98 µg/g, respectively, 7 hours after administration. 21 Over a 5-day fluconazole course (200 mg daily), the elimination of fluconazole from the stratum corneum occurred with a half-life of approximately 60–90 hours. 21 This was 2–3 times slower than the elimination from plasma. The pharmacokinetic data suggest that fluconazole 150 mg given once weekly should be effective in the treatment of cutaneous fungal infections.

Pharmacokinetics in nails Q9-3


Terbinafine
In patients given terbinafine 250 mg daily, the drug may be detected in the distal nail in the majority of patients within 1 week of starting therapy. 15, 22, 23 In peripheral nail clippings, levels of terbinafine were 0.43 µg/g after 7 days of therapy, or 10–100 times the MIC for most dermatophytes. The data indicate that terbinafine diffuses into the nail plate via both the nail matrix and the nail bed. When terbinafine 250 mg daily is administered for 6 or 12 weeks to treat onychomycosis, maximum nail levels of 0.52 and 1.01 µg/g respectively are detectable after 18 weeks of therapy. 22 After completion of 6 and 12 weeks of therapy, terbinafine is detected in the nail for 30 and 36 weeks, respectively. 22

Itraconazole
Itraconazole has been detected in the distal end of the fingernail and toenail within respectively 1 and 2 weeks of starting therapy. 24, 25 This is consistent with itraconazole reaching the free end of the nail plate via both the nail matrix and the nail bed. Furthermore, after receiving itraconazole 200 mg daily for 10 days, the concentration of itraconazole in the subungual nail material is more than double the corresponding level in the distal nail clippings. In patients treated with pulse therapy, 200 mg twice daily for 1 week, the drug levels achieved in the fingernails exceed the MIC. 18 After itraconazole intermittent therapy for 2 pulses (200 mg twice daily for 1 week and 3 weeks off drug), the drug becomes undetectable in fingernail by 9 months after the initiation of therapy. 18 When toenail onychomycosis is treated with 3 pulses of itraconazole, drug levels have been detected in the nail for 11 months. 18 The faster clearance of drug from fingernails than from toenails is probably due to the faster outgrowth of the former. 25, 26 In contrast, plasma levels decrease to very low or negligible levels within 7–14 days of stopping itraconazole therapy.

Fluconazole
Fluconazole demonstrates rapid uptake to the nail and may be detected at the distal end of the nail plate within 1 day of starting treatment with 50 mg. 27 This suggests that fluconazole diffusion from the nail bed to the nail plate is an important route of drug delivery. When 150 mg of fluconazole is given once weekly for 12 months, it can be detected in the nail plate for at least 6 months after the discontinuation of therapy in both healthy and diseased nails (n = 36 patients). 28 After 1 and 6 months of therapy, the mean concentration of fluconazole in healthy nails was 3.09 and 8.54 µg/g, respectively. Fluconazole concentrations in healthy and diseased toenails were 1.4 and 1.9 µg/g, respectively, 6 months after discontinuation of the drug (n = 3 patients). These data suggest that there is the potential for ongoing improvement in the onychomycosis well after discontinuation of active drug therapy.

Pharmacokinetics in hair Q9-3


Terbinafine
Terbinafine has been detected in hair within 1 week of starting therapy. 15 Early detection in hair may be due to delivery of drug to hair via the sebum. The drug may become incorporated into hair by hair matrix cells. When terbinafine 250 mg daily is administered for 14 days, the drug has been detected in hair for at least 50 days after the start of dosing. 22 Q9-4 It should be noted that terbinafine may be more effective against tinea capitis caused by endothrix organisms (e.g., Trichophyton tonsurans ) than against ectothrix infections (e.g., Microsporum canis ), as the drug accumulates preferentially in the hair shaft. 29, 30

Itraconazole
Itraconazole may be delivered to the hair primarily by two routes: via the sebum, and by incorporation into the hair follicle. 31 Preliminary testing of both continuous and pulse regimens of itraconazole found that itraconazole was detectable in hair after 1 week of therapy. 16, 32 When a pulse regimen was used for Majocchi’s granuloma, the concentration of itraconazole in hair was 2.6- and 3.4-fold higher after the second and third pulses, respectively, than at the end of the first pulse. After discontinuation of pulse therapy, drug was detectable in hair for up to 9 months, suggesting that the pulse regimen with itraconazole may be an option for the treatment of tinea capitis. 32

Fluconazole
Relatively little has been published about the pharmacokinetics of fluconazole in hair. When fluconazole 100 mg was administered daily to healthy volunteers for 5 days, fluconazole was detectable in scalp hair 4–5 months after completion of therapy. 21

Mechanism of action
The oral antifungals exert their effect by interfering with the enzymes involved in the manufacture of ergosterol, a crucial component of the fungal cell membrane. Deficiency of ergosterol interferes with membrane function, leading to an arrest in cell growth which may be fungicidal or fungistatic. It is not clear whether the in vitro fungicidal or the in vitro fungistatic properties of these drug categories translate into similar properties in vitro .


Allylamines – terbinafine
Q9-5 Terbinafine and other allylamines inhibit squalene epoxidase, leading to accumulation of squalene and a subsequent deficiency of ergosterol ( Figure 9-2 ). 33 This deficiency of ergosterol leads to the fungistatic action that is associated with terbinafine use. The accumulation of squalene may be associated with the fungicidal action of terbinafine noted in vitro , possibly by its deposition in lipid vesicles, which leads to cellular membrane disruption. 33

Figure 9-2 Systemic antifungal agents mechanism.

Triazoles – itraconazole, fluconazole, voriconazole, posaconazole
Q9-6 The triazole family inhibits the CYP-dependent enzyme lanosterol 14α demethlyase, with resultant inhibition of the conversion of lanosterol to ergosterol ( Figure 9-2 ). 10, 11, 34, 35 Because of this mechanism of inhibition these drugs are associated with a fungistatic action. Azole-resistant organisms have been detected in rare cases following prophylaxis or long-term therapy, and there may be some potential for cross-resistance between azole agents which has not been adequately characterized. 1, 10 – 12

Sensitivities of specific fungi
Q9-7 The main Trichophyton species, T. rubrum , T. mentagrophytes , and T. tonsurans , have similar low in vitro MIC values to terbinafine and itraconazole. 36 Similarly, low MIC values were found for terbinafine and itraconazole when tested in vitro with Microsporum species and Epidermophyton floccosum . Fluconazole was less effective than terbinafine or itraconazole against dermatophytes in vitro . However, in vitro testing has confirmed that fluconazole may be effectively used against the dermatophyte organisms. Itraconazole and fluconazole were more effective than terbinafine during in vitro MIC testing of C. albicans , and C. parapsilosis . 36 Terbinafine and itraconazole showed the lowest MIC values in vitro for non-dermatophyte organisms tested, including Fusarium proliferatum , Fusarium solani , Onychocola canadensis , Scopulariopsis brevicaulis , Aspergillus sydowii , and Aspergillus terreus . 36 As expected, the second-generation triazoles, voriconazole and posaconazole, had respectively lower MIC values than fluconazole and itraconazole for dermatophytes and Candida species. 36 – 38 In contrast, ravuconazole had similar MIC values to itraconazole for dermatophytes but similar or lower MIC values than posaconazole for Candida species tested. 36

Clinical use

FDA-approved indications
Tables 9-3 and 9-4 summarize the indications, both FDA approved and off label, for each of the main oral antifungal drugs.

Table 9-3 Systemic antifungal agents – FDA-approved indications and off-label uses (superficial mycoses)

Table 9-4 Systemic antifungal agents – FDA-approved indications and off-label uses (deep or systemic fungal infections)

Terbinafine
Terbinafine is indicated by the FDA for the treatment of dermatophyte onychomycosis of the toenails and/or fingernails in adults. 5 A granule formulation of terbinafine is also approved for tinea capitis in patients 4 years and older. 6

Itraconazole
Itraconazole is indicated by the FDA for the treatment of dermatophyte onychomycosis of the toenails and/or fingernails in non-immunocompromised adults. It is also approved in immunocompromised and non-immunocompromised patients for systemic mycoses such as blastomycosis, histoplasmosis, and aspergillosis in patients who are intolerant of or refractory to amphotericin B. 1 – 3

Fluconazole
Fluconazole is indicated for the treatment of vaginal candidiasis, oropharyngeal and esophageal candidiasis, and cryptococcal meningitis. 4 With regard to prophylaxis, fluconazole is also indicated for use in reducing the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy or radiation therapy.

Griseofulvin
Griseofulvin is indicated for the treatment of dermatophyte infections of the skin, scalp, and nails. 9 As with other oral antifungal agents, the use of griseofulvin is not justified for the treatment of tinea infections that would be expected to respond satisfactorily to topical antifungals. Griseofulvin is not effective in the treatment of pityriasis (tinea) versicolor, bacterial infections, candidiasis (moniliasis), or deep mycotic infections.

Voriconazole
Voriconazole is indicated for the following: invasive aspergillosis; esophageal candidiasis; candidemia in non-neutropenic patients, as well as disseminated Candida infections in skin and Candida infections in abdomen, kidney, bladder wall and wounds; serious fungal infections caused by Scedosporium apiospermum and Fusarium spp in patients intolerant of, or refractory to, other therapy. 10

Posaconazole
Posaconazole is FDA indicated for the following: prophylaxis of invasive Aspergillus and Candida infections in patients 13 years or older who are at high risk of developing such infections owing to being severely immunocompromised; treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. 11 In Canada, posaconazole (Posanol) is indicated for the above conditions, and also for treatment of invasive aspergillosis in patients 13 years or older who are refractory to amphotericin B or itraconazole (progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy), or are intolerant to these medicinal products. 12

Specific dermatologic indications (FDA approved and off label)

Dermatophyte onychomycosis
Resolution of dermatophyte onychomycosis ( Trichophyton sp., Microsporum sp., and Epidermophyton sp.) typically requires oral therapy. Limited success has been noted with topical monotherapies, but these treatments are beyond the scope of this chapter. 39 Successful therapy may also require implementation of preventative measures by the patient, which include proper nail care, use of proper footwear, and drying the feet completely after a bath or shower. 40
Use of combinations of antifungals (oral/oral or topical/oral) has had limited testing and will not be discussed further in this chapter. The combination of oral antifungals with differing mechanisms of action may provide synergistic effects upon nail fungal organisms. 41, 42 Similarly, adjunct use of a topical medication with an oral drug may reduce the amount of oral drug required, improving the safety and cost of treating severe cases if onychomycosis. 39 – 41 ,43 We refer the reader to Baran and colleagues, 2008 44 for review.

Griseofulvin
Q9-8 Although griseofulvin is approved for tinea infection of the nails, its affinity for keratin is low and long-term therapy (at least 9–12 months) is required. 45 Treatment efficacy is also low, and the newer azole and allylamine agents have largely replaced griseofulvin for this indication. 45

Terbinafine
For terbinafine, the recommended dosage is 250 mg daily for 6 and 12 weeks for fingernail and toenail onychomycosis, respectively. 40, 45 An analysis of studies where terbinafine 250 mg daily was administered for 12–16 weeks to treat dermatophyte onychomycosis of the toenails demonstrated a mycological cure rate meta-average ± 95% confidence interval (95% CI) of 76 ± 3% (18 trials, n = 993 patients). 46 The clinical response (nail visually clear of infection or showed marked improvement) meta-average rate was 66 ± 5% (15 trials, n = 1199 patients). Similar mycological cure rates are found for dermatophyte fingernail onychomycosis. 47, 48 Several intermittent terbinafine regimens aimed to reduce cost and increase safety are also reported in the literature. 49

Itraconazole
The FDA-approved regimen for dermatophyte toenail onychomycosis in immunocompetent patients with or without fingernail involvement is continuous itraconazole 200 mg daily for 12 weeks. 45 When only fingernails are infected, pulse itraconazole dosing is the approved regimen. Each pulse consists of 200 mg twice daily (400 mg daily) for 1 week per month, with 2 pulses being the accepted regimen. 45 In many countries, pulse therapy is the approved regimen for toenail onychomycosis using 3–4 pulses, and this regimen has become the standard in the US for many physicians despite FDA labeling. 3, 45, 46
Where itraconazole was used continuously for 12–16 weeks to treat dermatophyte toenail onychomycosis, a mycologic cure rate meta-average ± 95% CI of 59 ±5% (7 trials, n = 1131 patients) was found. 46 The clinical response (nail visually clear of infection or showed marked improvement) meta-average rate was 70 ± 5% (7 trials, n = 1135 patients). The mycologic cure rate meta-average ± 95% CI for itraconazole pulse therapy for toenails was 63 ± 7 (6 trials, n = 318 patients). 46 The clinical response (nail visually clear of infection or showed marked improvement) meta-average rate was 70 ± 11% (6 trials, n = 329 patients). 46 Itraconazole pulse therapy has also shown good efficacy in small trials for dermatophyte fingernail onychomycosis (2 trials, n = 38 patients). 50, 51

Fluconazole
In countries where fluconazole is approved for the treatment of onychomycosis, the most frequently used schedule is fluconazole 150–300 mg once weekly until the abnormal-appearing nail has grown out. This may occur in 3–6 months, and 9–12 months, for dermatophyte fingernail and toenail onychomycosis, respectively. 45 For toenail onychomycosis, the mycologic cure rate meta-average ± 95% CI was found to be 48 ± 5% (3 trials, n = 131 patients). 46 The clinical response (nail visually clear of infection or showed marked improvement) meta-average rate was 45 ± 21% (3 trials, n = 132 patients). For fingernail onychomycosis, fluconazole showed a mycologic cure rate of 89–100% and a clinical cure rate of 76–90%. 52

Onychomycosis caused by Candida species and non-dermatophyte molds
Q9-7 Non-dermatophyte molds and Candida species are rarely diagnosed as causative organisms in onychomycosis infections. Candida nail infections are associated with immunocompromised status (chronic mucocutaneous candidiasis, HIV infection, use of immunosuppressive drugs). 53 Most oral antifungals have a wide spectrum of action and show efficacy in treatment of non-dermatophyte mold onychomycosis, though treatment efficacy may be species specific. 39, 53

Terbinafine and itraconazole
Data regarding the use of terbinafine to treat non-dermatophyte molds are limited relative to dermatophytes. 54 Aspergillus sp. infections may be treated effectively with terbinafine or itraconazole. 54 Terbinafine and itraconazole monotherapies may have limited efficacy in many patients with S. brevicaulis and Fusarium sp. toenail infections, although one study reported a good cure rate with terbinafine for S. brevicaulis . 55 Combination of oral therapy with topical therapy may increase treatment efficacy. 53 Oral therapies are reported to be ineffective for Scytalidium sp. and O. canadensis infections. 53
Compared to its efficacy against dermatophytes, terbinafine is less effective when the causative agent of the onychomycosis is Candida species, in particular C. albicans . 56 – 58 Itraconazole continuous regimens of 200 mg daily or pulse regimens of 400 mg daily for 1 week each month have been effective against Candida onychomycosis. 53, 59 – 61

Fluconazole
Experience with fluconazole for the treatment of onychomycosis caused by non-dermatophyte molds is limited. Fluconazole 150 mg daily for 12 weeks has been effective against Scopulariopsis brevicaulis , 55 whereas 50 mg daily or pulse therapy of 300 mg/week has been effective against Candida onychomycosis, using a 6-week duration of therapy for fingernails and 3 months for toenails. 53, 54

Tinea capitis
Oral antifungals have been of great benefit in the effective treatment of tinea capitis, as they are able to penetrate the infected hair shaft where topical therapies cannot, thereby providing better cure rates. However, it should be noted that topical therapies such as ketoconazole shampoo, selenium sulfide, and povidone-iodine can also have an important role as adjunct therapy for tinea capitis infection. 62, 63 Control of infection transmission via fomites and symptom-free carriers may need to be addressed, using adjunct therapies and techniques such as counseling about not sharing items such as hats, combs, and toys, and identifying infected pets. 62, 63 Griseofulvin and terbinafine are the only antifungals approved for use in tinea capitis. However, terbinafine seems to be superior for the treatment of T. tonsurans infection, whereas griseofulvin remains the treatment of choice for M. canis infections. 64, 65 Q9-9 This observation may reflect the different infection patterns of the organisms: Trichophyton infections are endothrix (inside the hair shaft, where drug accumulation may help eradicate infection), while Microsporum are ectothrix (outside the hair shaft, requiring drug to be secreted to the hair surface via sweat or sebum). As children have little sebum secretion prior to puberty, terbinafine may not reach ectothrix infections adequately for treatment, whereas its incorporation into the hair shaft is effective in endothrix infections. 66 In contrast, griseofulvin and the azoles tend to be secreted in sweat and may reach the ectothrix infections more effectively than terbinafine. 66 The efficacies and safety profiles of terbinafine, itraconazole, and fluconazole are similar to those of griseofulvin, and may be used where griseofulvin therapy has failed.

Griseofulvin
Griseofulvin dosing for the treatment of tinea capitis ranges from 8 to 30 mg/kg daily, based on drug formulation (microsize or ultramicrosize oral suspension), with a treatment duration of 6–8 weeks being recommended for either formulation ( Table 9-5 ). 62, 63 One study has suggested that doses >20 mg/kg/day do not significantly increase the complete cure rate compared to <20 mg/kg/day. 65 Griseofulvin appears to provide superior efficacy to terbinafine when treating tinea capitis due to Microsporum sp. 64, 65 In some countries, including the United States, griseofulvin oral suspension, 125 mg/5 mL, is available ( Table 9-1 ). Alternatively, the tablets can be pulverized and administered with food.

Table 9-5 Dosing for tinea capitis in children

Terbinafine
Prior to 2007 tebinafine tablets were commonly prescribed off label for tinea capitis infections using a weight-based dosing regimen ( Table 9-5 ). 62, 63 In 2007, the FDA approved a terbinafine oral granule formulation for tinea capitis. The label-indicated weight-based dose for the granule formulation is: <25 kg, 125 mg daily; 25–35 kg, 187.5 mg daily; >35 kg, 250 mg daily, which is given for 6 weeks. 6 Although the label-indicated duration of therapy is 6 weeks, pulsed dosing regimens and shorter durations have also been reported to be effective. 63, 67, 68 A dose–response study using terbinafine found that doses >4.5 mg/kg daily were more likely than lower doses to produce a cure in both Trichophyton and Microsporum infections, with duration of therapy being less important. 69, 70 A recent meta-analysis has demonstrated that terbinafine has superior efficacy to griseofulvin for treating tinea capitis due to Trichophyton sp. 64

Itraconazole
Itraconazole continuous and pulse therapies have been used to treat tinea capitis effectively. The dosing regimens used are 5 mg/kg daily for 4–8 weeks, or, in the case of pulse therapy, 5 mg/kg daily for 1 week a month, given for 2–4 months ( Table 9-5 ). 63, 66 Where the oral solution is used, dosage is reduced to 3 mg/kg daily, whether used continuously or as pulse therapy. 63, 71

Fluconazole
A limited number of studies have shown that continuous fluconazole 6 mg/kg daily lasting 3 weeks can effectively treat tinea capitis ( Table 9-5 ). 62, 63 A comparative study of 5 mg/kg daily for 4 weeks showed similar efficacy to griseofulvin 15 mg/kg daily for 6 weeks. 72 Once weekly therapy with fluconazole for tinea capitis has also been found to be effective. 73, 74

Tinea corporis, tinea cruris, and tinea pedis
Q9-10 Typically, successful treatment is provided by topical antifungal medications; oral antifungals are not generally approved for these indications. Off-label use of oral antifungals may be practical where the tinea involvement is extensive and application of a topical is not feasible. 40

Griseofulvin
Griseofulvin is indicated in the United States for the treatment of tinea infections that would not be expected to respond satisfactorily to topical antifungals. Suggested dosage for tinea corporis/cruris is 250 mg twice daily until a cure is reached. 75 For tinea pedis, the suggested dosage is 660 or 750 mg daily for 4–8 weeks. 76

Terbinafine
Terbinafine has been used for tinea corporis/cruris at 250 mg daily for 2–4 weeks, and for tinea pedis at 250 mg daily for 2–6 weeks. 75, 76

Itraconazole
A continuous itraconazole regimen of 200 mg daily for 1 week is recommended for tinea corporis/cruris, though a regimen of 100 mg daily for 2 weeks has also been reported to be effective. 75, 77, 78 For tinea pedis, itraconazole regimens of 100 mg daily for 30 days or 4 weeks, 400 mg daily for 1 week, and 200 mg daily for 2–4 weeks have been reported. 40, 76, 79

Fluconazole
The suggested dose of fluconazole for tinea corporis/cruris is 150–300 mg once weekly, administered for 2–4 weeks. 75 The most frequently reported dosage for tinea pedis is 150 mg once weekly, administered for 2–6 weeks. 80 – 83

Ketoconazole
Ketoconazole tablets may be used for the treatment of severe recalcitrant cutaneous dermatophyte infections in patients who have not responded to topical therapy or oral griseofulvin, or who are unable to take griseofulvin. 84 It is strongly recommended to order liver transaminases at least every 2–4 weeks during the initial months of therapy should ketoconazole be used in these uncommon circumstances. The suggested dosage for all three indications is 200–400 mg daily for 4–8 weeks. 75, 76

Pityriasis (tinea) versicolor and seborrheic dermatitis
As with dermatophyte infection, the Malassezia yeasts associated with tinea versicolor and seborrheic dermatitis are most often successfully treated with topical therapy. However, oral medications are occasionally used off label, particularly when large areas of the body are affected. 40 It should be noted that even though symptoms of tinea versicolor infection may resolve within 2 weeks of therapy, pigmentation abnormalities may persist for many months before returning to normal. 85 Recurrence of tinea versicolor infection is common. 86 Topical corticosteroids are commonly used for seborrheic dermatitis, but alternative therapies are commonly used to avoid adverse events associated with prolonged topical corticosteroid use. 87
Q9-7 Griseofulvin and terbinafine have not been effective in tinea versicolor infection. 85, 86 Based on a meta-analysis, itraconazole therapy (200 mg daily given for 5–7 days or 100 mg daily for 2 weeks) was effective in pityriasis (tinea) versicolor. 88 Fluconazole doses of 300 mg weekly for 1–4 weeks have shown high rates of mycological cure. 40, 88 Ketoconazole tablets may be used for the treatment of severe recalcitrant cutaneous dermatophyte infections such as disfiguring or disabling pityriasis versicolor in patients who have not responded to topical therapy. Doses of 400 mg weekly for 2 weeks, 200 mg daily for 5 days and 200 mg daily for 2–5 weeks, have produced good rates of mycological cure. 40, 86, 88, 89 Other possible dosage regimens include 400 mg per month and three 400 mg doses spaced 12 h apart. 87, 90
For seborrheic dermatitis, dosages of oral antifungals used include ketoconazole 200 mg daily for 4 weeks, itraconazole 200 mg daily for 7 days, and terbinafine 250 mg daily for 4 weeks. 40, 87, 91, 92 Patients with facial lesions did not benefit from terbinafine treatment. 92

Prophylaxis of tinea versicolor
A single 400 mg dose of itraconazole once monthly for 6 months may be useful as prophylaxis for tinea versicolor patients who suffer recurrent outbreaks. 85

Oral antifungal use in children with superficial fungal infection
With the exception of tinea capitis, most superficial dermatophyte infections are infrequently diagnosed in children, and few published data exist on pediatric use of oral antifungals in these other conditions. As a result, oral antifungals are typically not formally approved for use in children; however, pediatric use has been documented widely in the medical literature and has typically demonstrated a safety profile similar to use in adults. 93 – 95 When using oral antifungals in children, dosing regimens are typically adjusted by weight, as in tinea capitis dosing. Where swallowing the tablets or capsules may be an issue, terbinafine tablets can be crushed or cut up and terbinafine ‘granules’ can be sprinkled on food; itraconazole capsules can be opened and mixed with fatty foods such as peanut butter. 96
Oral suspensions have been developed for many of the oral antifungal medications, which can provide easier dosing for children. These suspensions may have improved pharmacological qualities and different safety profiles compared to capsule or tablet formulations; therefore, suggested dosing regimens may differ and some formulations may not be used interchangeably.

Children with onychomycosis
As few children present with distal lateral subungual or proximal subungual onychomycosis (DLSO and PSO, respectively), no oral antifungal has been approved for use in children with dermatophyte onychomycosis. For superficial white onychomycosis or milder cases of DLSO, topical therapy may be preferred over the use of oral antifungals. The choice of therapy should take into account the causative organism, concomitant drug therapies, cost-effectiveness, patient preference, and physician familiarity with the antifungal agents. 96 Mycological confirmation of infection is suggested prior to initiation of any oral agent. 96, 97

Terbinafine
Both terbinafine and itraconazole have been reported as effective and safe when used off-label for onychomycosis in children. 39, 98 – 102 With terbinafine, the duration of therapy is similar to that in adults: fingernail and toenail onychomycosis for 6 and 12 weeks, respectively. 96 The suggested terbinafine dosage schedule is >40 kg, 250 mg daily; 20–40 kg, 125 mg daily; and <20 kg, 62.5 mg daily. 96

Itraconazole
For itraconazole capsules the suggested dosage is 2 and 3 pulses for fingernails and toenails, respectively. 96 Each pulse is 5 mg/kg daily lasting for 1 week, or >50 kg, 200 mg twice daily; 40–50 kg, 200 mg daily; 30–40 kg, 100 mg daily alternating with 200 mg daily; 20–30 kg, 100 mg daily; and 10–20 kg, 50 mg on alternating days or 3 times a week. Itraconazole oral solution given as pulse therapy may be another option, at dosages of 3–5 mg/kg daily. 96, 103

Fluconazole
Reported use of fluconazole for children with onychomycosis is limited. Use of fluconazole for dermatophyte onychomycosis in general requires relatively long-term therapy. Suggested dosage is an intermittent regimen of 3–6 mg/kg once weekly for 18–26 and 12–weeks, respectively, for toenail and fingernail onychomycosis. 96, 97

Deep fungal infections

Terbinafine
Successful use of terbinafine has been reported in subcutaneous and systemic mycoses such as chromoblastomycosis, sporotrichosis, fungal mycetoma, aspergillosis, and histoplasmosis. 104 Terbinafine regimens are not clearly established; however, effective dosing for systemic mycoses would appear to require 500–1000 mg daily. 104

Itraconazole
Itraconazole capsules are indicated for the treatment of the following fungal infections: blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary, pulmonary, and disseminated, non-meningeal disease), and aspergillosis (pulmonary and extrapulmonary in patients who are intolerant of or refractory to amphotericin B therapy). 1 Life-threatening histoplasmosis and blastomycosis may require intravenous itraconazole. 105

Fluconazole
Fluconazole is effective for systemic Candida infections, including candidemia and disseminated candidiasis, and is available as an intravenous formulation. 4, 105 High-dose oral fluconazole (400–600 mg daily) has been recommended for coccidioidal meningitis; however, fluconazole has relatively poor efficacy against endemic mycoses such as histoplasmosis, blastomycosis, and paracoccidioidomycosis. 105, 106 The high oral bioavailability of fluconazole is an asset, but the narrow spectrum of action limits its use as a prophylactic. 105

Ketoconazole
Ketoconazole is also indicated for the treatment of the following systemic fungal infections: vulvovaginal candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. 84

Voriconazole and posaconazole
Q9-1 Voriconazole is FDA approved for the treatment of invasive aspergillosis, disseminated Candida infections, candidemia in non-neutropenic patients, esophageal candidiasis, and serious fungal infections caused by Scedosporium and Fusarium spp in patients intolerant of or refractory to other therapy. 10 Posaconazole is FDA approved for prophylaxis of invasive aspergillosis and Candida infections in patients 13 years of age and older who are at risk of developing these infections, e.g., in allogenic stem cell transplant patients with graft-versus-host disease and chemotherapy-induced neutropenic patients. 11 Posaconazole is also indicated in the treatment of oropharyngeal candidiasis, including cases refractory to itraconazole and fluconazole treatment. Both voriconazole and posaconazole have been shown to be effective in salvage therapy for histoplasmosis and coccidioidomycosis, whereas only voriconazole has been used for central nervous system blastomycosis. 107

Other off-label uses for oral antifungals

Terbinafine
There have been isolated reports of terbinafine use in patients with Majocchi’s granuloma, 108 tinea imbricata, 109, 110 cutaneous sporotrichosis, 111 black piedra, 112 aspergillosis, 113 and chromoblastomycosis. 114

Itraconazole
Itraconazole may also be effective in the treatment of Majocchi’s granuloma, 32 HIV-associated eosinophilic folliculitis, 115 tinea imbricata, 109 vaginal candidiasis, chronic mucocutaneous candidiasis, 60, 116 cutaneous sporotrichosis 111 and other C. albicans infections. 59

Fluconazole
Fluconazole is effective in the treatment of cutaneous candidiasis, using 150 mg once weekly given for 2–4 weeks. 80, 117

Griseofulvin
Griseofluvin, 500 mg twice daily for 4–6 weeks, has been effective treatment for tinea imbricata, but may require concomitant topical therapy. 110

Contraindications
Contraindications and precautions are summarized in Table 9-6 1 – 6 , 10 – 12 , 118 – 120 for terbinafine, itraconazole, fluconazole and the new azoles. All of the oral antifungals are contraindicated for patients who are allergic to the drug or its excipients.

Table 9-6 Systemic antifungal contraindications and precautions


Terbinafine
Terbinafine (capsule or granule formulation) is not recommended for patients with chronic or active liver disease. 5, 6 Terbinafine clearance is reduced by approximately 50% in patients with renal impairment (creatinine clearance <50 mL/min) compared to normal volunteers, and terbinafine may not be a suitable choice for patients with renal impairment. 5 Terbinafine, as a CYP2D6 inhibitor, also shows potential drug interactions with a number of other drug classes sharing the CYP2D6 pathway ( Table 9-9 ). 5, 6
Table 9-9 Drug interactions—terbinafine * Q9-13 Interacting drug group Interactions with terbinafine   CYP2D6 inhibitor Contraindications No specific drug contraindications Known interactions Drugs predominantly metabolized by CYP2D6: Tricyclic antidepressants (e.g., desipramine,dextromethorphan) Selective serotonin reuptake inhibitors β-Blockers Antiarrhythmics class 1C (e.g., flecainide, propafenone) Monoamine oxidase inhibitors type B Careful monitoring when used with terbinafine; may require reduction in drug dose Anticoagulants Increased prothrombin time with warfarin; causal relation not established Ethoxycoumarin: no inhibition by terbinafine Antiarrhythmic Terbinafine does not affect clearance of digoxin Anticonvulsants No information Azoles Fluconazole increases terbinafine concentration; likely that other CYP2C9, CYP3A inhibitors will also substantially increase terbinafine Calcium channel blockers No information Gastric motility agents Cisapride – no inhibition by terbinafine HMG-CoA reductase inhibitor ‘statins’ Fluvastatin – no inhibition by terbinafine Immunosuppressants Cyclosporine – increases terbinafine; no inhibition by terbinafine, terbinafine increases cyclosporine clearance Nucleoside reverse transcriptase inhibitors Zidovudine – NCS Oral contraceptives No information – actions on terbinafine Ethinylestradiol – no inhibition by terbinafine Oral hypoglycemic agents No information – actions on terbinafine Tolbutamide – no inhibition by terbinafine Thiazide diurectic No information Others: Theophylline – NCS; Sulfamethozazole – NCS; Trimethoprim – NCS Antipyrine – terbinafine does not affect clearance Caffeine – terbinafine decreases clearance Rifampin – increases terbinafine clearance 100% Cimetidine – decreases terbinafine clearance 33%
NCS = no clinically significant interactions reported.
* This table covers only those interactions described in the current prescribing information. Interaction studies with medications other than those listed here may not have been conducted; other interactions may occur. Other sources may need to be consulted for information where interactions may be suspected.

Itraconazole, fluconazole and the new azoles
Q9-11 Itraconazole should not be administered for onychomycosis in patients with evidence of ventricular dysfunction, such as congestive heart failure or history of congestive heart failure, as temporarily decreased cardiac contractility has been noted in a healthy volunteer study. 1 – 3 Similarly, albeit not always strictly contraindicated, caution is advised when using any of the azoles in patients with potentially proarrhythmic conditions. 4, 10 – 12
For both itraconazole and fluconazole, serious cardiovascular events such as prolongation of the QT interval, torsades de pointes, ventricular tachycardia, cardiac arrest and sudden death have been noted. Co-administration of cisapride, pimozide, and quinidine, which are known to prolong the QT interval, is contraindicated with all the azoles. 1 – 4 , 10 – 12 Itraconazole is also contraindicated with dofetilide, levacetylmethadol (levomethadyl), the HMG CoA-reductase inhibitors such as lovastatin and simvastatin, the benzodiazepines midazolam and triazolam, the calcium channel blocker nisoldipine, and CYP3A4 ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine). 1 – 3 Fluconazole is contraindicated with erythromycin, cisapride, astemizole, pimozide, and quinidine, as well as terfenadine when dosing of fluconazole is 400 mg or greater. 4 Itraconazole and posaconazole inhibit the cytochrome P-450 3A4 enzyme; fluconazole and voriconazole inhibit CYP3A4 and CYP2C9, with voriconazole also involved with CYP2C19, giving these two drugs somewhat expanded interactions compared to itraconazole. 1 – 4 , 10 – 12 Fluconazole and the newer triazoles have not been studied in all medications contraindicated with itraconazole, but interaction may occur between these azoles and the itraconazole-contraindicated medications. 4, 10 – 12
Itraconazole use is strongly discouraged in patients with active liver disease, elevated or abnormal liver enzymes, or previous experience of liver toxicity with other drugs. 1 – 3 Caution is advised when any of the azoles are used in these patient populations, and monitoring of liver functions is suggested for all patients both before and during therapy. 4, 10 – 12
Caution should also be used when administering an azole agent to patients who have exhibited past sensitivity to another azole agent, as there may be some potential for cross-reaction between azole drugs. 1 – 4 , 10 – 12

Adverse effects


Terbinafine
Terbinafine is considered a safe medication for the general population, as well as children, the elderly, transplant patients, diabetics, and HIV patients. 121 The safety profile of the oral granule formulation is comparable to that of the tablet formulation ( Table 9-7 ). 5, 6 The more common adverse effects with terbinafine use are headache, gastrointestinal symptoms (diarrhea, dyspepsia, abdominal pain, nausea, and flatulence), dermatologic manifestations (rash, pruritus, urticaria), liver enzyme abnormalities greater than or equal to twice the upper limit of normal, taste disturbance and visual disturbance. 5 Events were noted in small proportions of subjects and were generally mild, and transient.

Table 9-7 Adverse events with terbinafine and itraconazole
Rare severe reactions have been noted with terbinafine. Q9-12 Severe skin reactions such as erythema multiforme, toxic epidermal necrolysis, and Stevens–Johnson syndrome were reported with oral terbinafine use in 38, 4, and 9 cases, respectively, out of 2313 adverse reactions reported in the World Health Organization worldwide database (data reported December 1996). 122 Severe skin reactions may present initially as a serum sickness-like reaction. 122, 123
Rare development of idiosyncratic hepatobiliary dysfunction has been reported (1 : 45 000 to 1 : 120 000). 124, 125 Hepatitis produced by terbinafine typically develops within 4–6 weeks of treatment initiation, and has the features of both hepatocellular necrosis and cholestatic injury. 125 In most cases liver functions return to normal several months after stopping the medication. 125
Terbinafine has been reported infrequently to precipitate or exacerbate cutaneous and systemic lupus erythematosus, and should be discontinued in patients showing signs of lupus erythematosus. 5 Q9-11 Post-marketing data also revealed several cases of subjects experiencing depressive symptoms during use of terbinafine. 5 Terbinafine is rated as pregnancy category B and is not recommended for use in pregnant or nursing women. No effects on testosterone levels were detected with terbinafine use in a healthy male population. 126

Itraconazole
With itraconazole the common adverse effects are headache, gastrointestinal disorders, and cutaneous disorders ( Table 9-7 ). 1 – 3 When itraconazole is given as a pulse regimen for the treatment of onychomycosis, it may be associated with an improved adverse effects profile compared to the continuous regimen using this triazole. 127
Q9-12 In the General Practice Research Database in the UK sampling nearly 27 000 patients, 2 cases of serious skin disorders were found with itraconazole use: angioedema (1 case) and erythema multiforme (1 case). 128 Stevens–Johnson syndrome has been rarely reported with itraconazole. 1
Abnormal liver function tests were found in 3% of 1845 patients treated with continuous itraconazole compared to 1.9% of 2867 patients treated with pulse itraconazole (200 mg twice daily, for 1 week out of each month). 127 Serious adverse liver events were recorded in 3.2 per 100 000 prescriptions. 125 The estimated incidence of itraconazole inducing clinically significant symptoms and signs of hepatobiliary dysfunction, for which no other cause was apparent, is 1 : 500 000. 124
Itraconazole is rated as pregnancy category C and is not to be used in women who are pregnant, planning a pregnancy, or nursing. In contrast to ketoconazole, use of itraconazole showed no effect on androgen levels and that alteration of male reproduction is unlikely. 129, 130
Safety profiles are similar for capsules as the oral suspension. 1, 2 Preclinical testing of the hydroxy-propyl-β-cyclodextrin vehicle used in the itraconazole oral suspension found some potential for pancreatic adenocarcinomas in rats, but no other tested animal species. 2 The potential for carcinoma development in humans has not been determined.

Fluconazole, voriconazole, posaconazole
Both at the doses used in dermatology and at higher doses, fluconazole has shown a favorable adverse effects profile. 4, 131 – 134 Adverse event profiles seen in pediatric fluconazole use are similar to those in adults. 4 Voriconazole and posaconazole’s target populations vary from those of the other azoles, but show a similar profile of adverse events. The most frequently reported adverse events in clinical trial patients receiving these azoles are headache, nausea, vomiting, abdominal pain, and diarrhea ( Table 9-8 ). 4, 10 – 12 , 125 , 128 , 131 – 134

Table 9-8 Adverse events with fluconazole, voriconazole and posaconazole
Q9-12 Rare cases of exfoliative skin disorders have been reported with voriconazole, and cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, angioedema, and erythema multiforme have been reported with fluconazole. 4, 10, 125, 128, 133 Rare cases of serious hepatic toxicity have been reported, with no obvious relationship to daily dose, therapy duration or other factors. 4 Self-limiting hepatic and biliary abnormalities were noted in 0.5% of patients using fluconazole, whereas elevated enzyme levels, particularly aspartate aminotransferase, occurred in 10% of subjects using chronic fluconazole therapy. 125
Voriconazole has shown some cases of skin photosensitivity, leading to cases of melanoma and squamous cell carcinoma. 10 A variety of vision disturbances have also been reported in clinical trials and post-marketing for voriconazole ( Table 9-8 ). 10
Fluconazole is rated as pregnancy category D, with birth defects being noted by a few case reports in subjects using a high dose (400–800 mg/day). Fluconazole, voriconazole and posaconazole should not be used in women who are pregnant, planning a pregnancy, or nursing. In contrast to ketoconazole, fluconazole at 25–50 mg/day showed no significant effect on testosterone levels in healthy male volunteers. 120

Drug interactions
In general, before prescribing a new drug, it is important to obtain a complete history of all drugs the patient is currently taking, both prescription and non-prescription. The inquiry should extend to herbal and recreational agents.
Q9-13 The potential drug interactions associated with terbinafine are listed in Table 9-9 . 5, 6 Terbinafine has relatively few drug interactions compared with the azoles. Terbinafine has been reported to inhibit CYP2D6. 5, 6 Clinicians should be cautious regarding concomitant administration of terbinafine with CYP2D6 substrates such as the tricyclic antidepressants doxepin and amitriptyline.
The azole drugs share many important drug interactions ( Table 9-10 ). Co-administration of itraconazole (capsules, injection, or oral solution) with cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) is contraindicated ( Table 9-6 ). 1 Q9-14 Similarly, concomitant use of ketoconazole, fluconazole, voriconazole or posaconazole with cisapride, or the antihistamines terfenadine (fluconazole doses 400 mg or greater) and astemizole is contraindicated. 4, 10 – 12 Levels of these drugs may become elevated and cause serious cardiovascular events such as QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death. 1 Although terfenadine, astemizole, and cisapride are no longer available in many countries, these contraindications may still be relevant in others.

Table 9-10 Drug interactions—itraconazole, fluconazole, voriconazole and posaconazole*
Q9-13 The azole drugs interfere to varying degrees with CYP3A4, with fluconazole also inhibiting CYP2C9, and voriconazole using CYP2C9 and CYP2C19 as well as CYP3A4. Drugs using these metabolic pathways may have drug concentrations altered when given concomitantly with an azole antifungal agent. Where significant interaction has been reported, concomitant drug levels or activities may need to be monitored and/or dose reduced, to minimize the interaction risk ( Table 9-10 ). Q9-14 The most notable CYP2C9 interactions with the azoles are through co-administration with warfarin, which can lead to significant increases in INR values and excessive anticoagulation. When itraconazole (and to a degree low-dose fluconazole) and cyclosporine are given concomitantly, careful monitoring of cyclosporine concentration and serum creatinine concentration is recommended. 4 Blood glucose levels may require careful monitoring when oral hypoglycemic agents are used concomitantly with azoles. Similarly, agents with narrow therapeutic windows, such as phenytoin and theophylline, may need to have careful monitoring of drug levels, as interactions secondary to azole use may more easily predispose the patient to significant adverse events.

Monitoring guidelines
For drug specific monitoring the readers are referred to Table 9-6 . Pre-existing liver disease should be assessed before prescribing terbinafine (serum transaminase tests: ALT, AST). 5 Patients should be instructed to report any symptoms of liver dysfunction, such as persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine, or pale stools. Patients reporting such symptoms, or otherwise suspected of having hepatic dysfunction, should discontinue terbinafine and have a complete liver profile performed. 5 The US package insert indicates that physicians should consider monitoring complete blood counts in patients with known or suspected immunodeficiency who are administered oral terbinafine for longer than 6 weeks. 5 Q9-11 Patients should also be instructed to report taste disturbance, depression symptoms and progressive rash. 5
When giving azoles, liver function monitoring should be considered for any subject. 1 Liver function tests should be done for any subject with pre-existing hepatic function abnormalities, or any subject with previous experience of liver toxicity with other medications. 1
During prolonged griseofulvin therapy, periodic assessment of renal, hepatic, and hematopoietic functions should be performed. 9
Clinicians dealing with common cutaneous conditions should ideally avoid use of ketoconazole for more than 7–10 days. For this treatment duration, monitoring is not needed. Given the multiple alternative drugs with markedly less hepatic risk, ketoconazole has a limited role in dermatologic therapy beyond this brief dosing duration.

Conclusion
Systemic oral antifungal agents have widespread use in dermatology. Dosing and efficacy vary with indication. Clinical use has demonstrated the general safety of oral antifungal use. However, possible risks exist for each agent, and careful monitoring of the patient should be undertaken regardless of agent used.

Abbreviations used in this chapter ALT Alanine aminotransferase AST Aspartate aminotransferase CYP Cytochrome P-450 DLSO Distal lateral subungual onychomycosis FDA Food and Drug Administration HIV Human immunodeficiency virus MIC Minimum inhibitory concentration PSO Proximal subungual onychomycosis

Bibliography: important reviews and chapters

Antifungal drug therapy overviews
Gupta AK, Cooper EA. Update in antifungal therapy of dermatophytoses. Mycopathologia . 2008;166:353–367.
Girmenia C. New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs . 2009;18(9):1279–1295.

Reviews of individual drugs and specific fungal infections
Van Duyn Graham L, Elewski BE. Recent updates in oral terbinafine: its use in onychomycosis and tinea capitis in the US. Mycoses . 2011;54:e679–e685.
Welsh O, Vera-Cabrera L, Welch E. Onychomycosis. Clin Dermatol . 2010;28:151–159.
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Adverse effects and drug interactions
Gubbins PO. Triazole antifungal agents drug-drug interactions involving hepatic cytochrome P450. Expert Opin Drug Metab Toxicol . 2001;7(11):1411–1429.

Electronic references:
Product inserts
Terbinafine (Lamisil tablets, oral granules)
Website location http://www.pharma.us.novartis.com/info/products/index.jsp
PDF-tablets http://www.pharma.us.novartis.com/product/pi/pdf/Lamisil_tablets.pdf
PDF – oral granules http://www.pharma.us.novartis.com/product/pi/pdf/Lamisil_Oral_Granules.pdf

Itraconazole (Sporanox)
Website location http://www.janssenpharmaceuticalsinc.com/our-products/product-list
PDF http://www.janssenpharmaceuticalsinc.com/assets/sporanox.pdf

Fluconazole (Diflucan)
Website location http://www.pfizer.com/products/#D
PDF http://labeling.pfizer.com/ShowLabeling.aspx?id=575

Griseofluvin (Gris-PEG)
Website http://www.pedinol.com/product_detail.php?id=33
PDF http://www.pedinol.com/productpdf/Gris-PEGPIRev12-10.pdf

Ketoconazole
PDF (from Drugs@FDA website) http://www.accessdata.fda.gov/drugsatfda_docs/anda/99/75-273_Ketoconazole_prntlbl.pdf

Voriconazole
Website location http://www.pfizer.com/products/#V
PDF http://labeling.pfizer.com/ShowLabeling.aspx?id=618

Posaconazole
Website location http://www.merck.com/product/prescription-products/home.html#H
PDF http://www.spfiles.com/pinoxafil.pdf

Web references

Pharmacology—general pharmacokinetic properties of the oral antifungals
1 Sporonox (itraconazole) Capsules prescribing information. Janssen Pharmaceuticals Inc, November 2009.
2 Sporonox (itraconazole) Oral Solution prescribing information. Centocor Ortho Biotech Products, L.P., April 2011.
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Pharmacokinetics in nails
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Tinea capitis
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Tinea corporis, cruris and pedis
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Pityriasis (tinea) versicolor and seborrheic dermatitis
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91 Gupta AK, Bluhm R, Cooper EA, et al. Seborrheic dermatitis. Dermatol Clin . 2003;21:401–412.
92 Stefanaki I, Katsambas A. Therapeutic update on seborrheic dermatitis. Skin Therapy Lett . 2010;15:1–4.

Oral antifungal use in children with superficial fungal infections
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95 Gupta AK, Cooper EA, Lynde CW. The efficacy and safety of terbinafine in children. Dermatol Clin . 2003;21:511–520.

Children with onychomycosis
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97 Tosti A, Piraccini BM, Iorizzo M. Management of onychomycosis in children. Dermatol Clin . 2003;21:507–509.
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Deep fungal infections
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Other off-label uses for oral antifungals
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112 Gip L. Black piedra: the first case treated with terbinafine (Lamisil). Br J Dermatol . 1994;130:26–28.
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115 Berger TG, Heon V, King C, et al. Itraconazole therapy for human immunodeficiency virus-associated eosinophilic folliculitis. Arch Dermatol . 1995;31:358–360.
116 Burke WA. Use of itraconazole in a patient with chronic mucocutaneous candidiasis. J Am Acad Dermatol . 1989;21:1309–1310.
117 Stengel F, Robbo-Soto N, Galinberti R, et al. Fluconazole versus ketoconazole in the treatment of dermatophytoses and cutaneous candidiasis. Int J Dermatol . 1994;33:726–729.

Contraindications: adverse events
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120 Hanger DP, Jevons S, Shaw JTB. Fluconazole and testosterone: In vivo and in vitro studies. Antimicrob Agents Chemother . 1988;32:646–648.
121 Gupta AK, Ryder JE, Lynch LE, et al. The use of terbinafine in the treatment of onychomycosis in adults and special populations: a review of the evidence. J Drugs Dermatol . 2005;4:302–308.
122 Gupta AK, Lynde CW, Lauzon GJ, et al. Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature. Br J Dermatol . 1998;138:529–532.
123 Wolf R, Orion E, Marcos B, et al. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol . 2005;23:171–181.
124 Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol . 1993;29:S50–S54.
125 Orion E, Matz H, Wolf R. The life-threatening complications of dermatologic therapies. Clin Dermatol . 2005;23:182–192.
126 Nashan D, Knuth UA, Weidinger G, et al. The antimycotic drug terbinafine in contrast to ketoconazole lacks acute effects on the pituitary-testicular function of healthy men: a placebo-controlled double-blind trial. Acta Endocrinol (Copenh) . 1989;120:677–681.
127 Gupta AK, Lambert J, Revuz J, et al. Update on the safety of itraconazole pulse therapy in onychomycosis and dermatomycoses. Eur J Dermatol . 2001;11:6–10.
128 Castellsague J, Garcia-Rodriguez L-A, Duque A, et al. Risk of serious skin disorders among users of oral antifungals: a population-based study. BMC Dermatol . 2002;2:14.
129 Van Cauteren H, Heykants J, De Coster R, et al. Itraconazole: pharmacologic studies in animals and humans. Rev Infect Dis . 1987;9(Suppl 1):S45–S46.
130 Anaissie EJ, Kontoyiannis DP, Huls C, et al. Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. J Infect Dis . 1995;172:599–602.
131 Stevens DA, Diaz M, Negroni R, et al. Safety evaluation of chronic fluconazole therapy. Chemotherapy . 1997;43:371–377.
132 Duswald KH, Penk A, Pittrow L. High-dose therapy with fluconazole greater than or equal to 800 mg per day. Mycoses . 1997;40:267–277.
133 Dalle S, Skowron F, Ronger-Savie S, et al. Erythema multiforme induced by fluconazole. Dermatology . 2005;211:169.

References *

40 Gupta AK, Cooper EA, Ryder JE, et al. Optimal management of fungal infections of the skin, hair, and nails. Am J Clin Dermatol . 2004;5:225–237.
44 Baran R, Hay RJ, Garduno JI. Review of antifungal therapy, part II: Treatment rationale, including specific patient populations. J Dermatolog Treat . 2008;19(3):168–175.
53 Tosti A, Piraccini BM, Lorenzi S, et al. Treatment of nondermatophyte mold and Candida onychomycosis. Dermatol Clin . 2003;21:491–497.
63 Roberts BJ, Friedlander SF. Tinea capitis: a treatment update. Pediatric Annals . 2005;34:191–200.
69 Friedlander SF, Aly R, Krafchik B, et al. Terbinafine in the treatment of Trichophyton tinea capitis: a randomized, double-blind, parallel-group, duration-finding study. Pediatrics . 2002;109:602–607.
70 Lipozencic J, Skerlev M, Orofino-Costa R, et al. A randomized, double-blind, parallel-group, duration-finding study of oral terbinafine and open-label, high-dose griseofulvin in children with tinea capitis due to Microsporum species. Br J Dermatol . 2002;146:816–823.
75 Gupta AK, Chaudhry M, Elewski B. Tinea corporis, tinea cruris, tinea nigra and piedra. Dermatol Clin . 2003;21:395–400.
76 Gupta AK, Chow M, Daniel CR. Treatments of tinea pedis. Dermatol Clin . 2003;21:431–462.
86 Gupta AK, Kogan N, Batra R. Pityriasis versicolor: a review of pharmacological treatment options. Expert Opin Pharmacother . 2005;6:165–178.
96 Gupta AK, Skinner AR. Onychomycosis in children: a brief overview with treatment strategies. Pediatr Dermatol . 2004;21:74–79.
106 Herbrecht R, Nivoix Y, Fohrer C, et al. Management of systemic fungal infections: alternatives to itraconazole. J Antimicrob Chemother . 2005;56(Suppl. S1):i39–i48.
107 Freifeld AG, Bariola JR, Andes D. The role of second-generation antifungal triazoles for treatment of the endemic mycoses. Curr Infect Dis Rep . 2010;12:471–478.
120 Wolf R, Orion E, Marcos B, et al. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol . 2005;23:171–181.
121 Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol . 1993;29:S50–S54.
122 Orion E, Matz H, Wolf R. The life-threatening complications of dermatologic therapies. Clin Dermatol . 2005;23:182–192.

* Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com .
10 Systemic antiviral agents

George D. Magel, Kassie A. Haitz, Whitney J. Lapolla, Catherine M. DiGiorgio, Natalia Mendoza, Stephen K. Tyring


 Questions

Q10-1 What is the spectrum of dermatologic conditions that human herpes virus (HHV) infections can cause? ( Pg. 121 , Table 10-1 )
Q10-2 What are the two primary steps (one step with two parts) by which acyclovir reaches the form that inhibits viral replication (similar steps for valacyclovir and famciclovir) ( Pg. 121 , Figure 10-2 )
Q10-3 How common is acyclovir resistance, and what are the clinical implications of this resistance? ( Pgs. 124, 129 )
Q10-4 What is the rationale for the use of acyclovir or valacyclovir in patients with recurrent erythema multiforme, and which regimens are most effective? ( Pgs. 125, 127 )
Q10-5 Of the three drugs for HHV infections discussed in this chapter, which two are defined as ‘prodrugs’ for another active drug? ( Pgs. 125, 127 )
Q10-6 How does the bioavailability differ between acyclovir, valacyclovir, and famciclovir? (How might this relate to treating varicella-zoster virus (VZV) infections, which are less sensitive to these drugs than are herpes simplex virus (HSV) infections?) ( Pgs. 125, 127 )
Q10-7 What are the most important clinical circumstances that may justify long-term antiviral suppressive therapy for recurrent HSV infections? ( Pg. 128 )
Q10-8 What are the key points concerning the development of the VZV vaccine and the priorities for clinical use of this vaccine? ( Pg. 129 )
Q10-9 Concerning antiretroviral medications discussed in this chapter, (a) which have been reported to induce Stevens–Johnson syndrome, and (b) which has induced a hypersensitivity reaction resembling the drug hypersensitivity syndrome? ( Tables 10-8 , 10-9 , 10-10 , 10-11 , Pg. 130x4 )
Q10-10 Which antiretroviral medications for HIV are inhibitors of the P-450 (CYP) system? ( Pg. 130 )
Q10-11 Concerning vaccine development for HIV prevention, (a) what are several of the methods of development used, and (b) what combination product offers the greatest hope? ( Pgs. 132, 134 )

Introduction
Viral diseases in dermatology can be very frustrating to treat. Prevention strategies such as vaccines, proper sanitation, vector control, blood testing, condom use/abstinence, and education remain essential to managing viral spread. Once viruses such as human herpes viruses (HHV) and human immunodeficiency virus (HIV) are acquired, antiviral agents are essentially the sole method of treatment. A large number of antiviral medications have been approved by the US Food and Drug Administration (FDA) during the past 2 decades. New antiviral agents and vaccines are continuously being researched for more effective control of these viral diseases.
To date, there are almost 30 FDA-approved systemic antiviral drugs for treatment of infections due to HHV and HIV, as well as for hepatitis viruses, influenza, etc. This chapter primarily addresses the current use of systemic antiviral agents (against HHV) in dermatology, as well as new agents currently under investigation. Also provided is a brief overview of antiviral therapy for HIV infections.

Drugs for human herpes virus infections
HHV are double-stranded, linear DNA viruses that cause a variety of illnesses. Q10-1 The HHV family includes herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), which most frequently produce herpes labialis (cold sores) and genital lesions, respectively; however, both types of lesion can be caused by either virus. HSV-1 and -2 have also been shown to cause gingivostomatitis, ocular disease, herpes gladiatorum, eczema herpeticum, herpetic whitlow, neonatal herpes, lumbosacral herpes, herpetic keratoconjunctivitis, herpes encephalitis, cervicitis, and erythema multiforme. 1 HHV type 3 is also known as varicella-zoster virus (VZV). It is more commonly called chickenpox in its primary form and herpes zoster (HZ) or shingles in its recurrent form. The remaining members of the HHV family and resulting conditions are listed in Table 10-1 . The three primary drugs that have efficacy against HSV-1, HSV-2, and VZV are acyclovir, valacyclovir, and famciclovir ( Table 10-2 ).
Table 10-1 Human herpes viruses HHV number Older nomenclature Resultant diseases HHV 1 Herpes simplex virus type 1 (HSV-1) Herpes labialis, etc. HHV 2 Herpes simplex virus type 2 (HSV-2) Genital herpes, etc. HHV 3 Varicella-zoster virus (VZV) Chicken pox, HZ HHV 4 Epstein–Barr virus (EBV) Mononucleosis, Burkitt’s lymphoma HHV 5 Cytomegalovirus (CMV) CMV retinitis HHV 6 No specific name Roseola infantum, etc. HHV 7 No specific name Pityriasis rosea, * etc. HHV 8 Kaposi’s sarcoma herpes virus Kaposi’s sarcoma (classic and epidemic)
* The causal role of HHV 7 in pityriasis rosea has not been fully established.

Table 10-2 Systemic antiviral agents used to treat HHV infections

Acyclovir

Pharmacology
Acyclovir (9-2-hydroxyethoxymethyl guanine or acycloguanosine) (ACV), a guanosine analog, is the most well-known and widely used antiviral drug in the world ( Figure 10-1 ). 2 Q10-2 Activation of ACV requires phosphorylation by herpes-specific thymidine kinase (TK) before bi- and triphosphorylation by host cellular enzymes. The active triphosphorylated ACV inhibits viral DNA polymerase by serving as an obligate chain terminator (i.e., complete and irreversible inhibition of further viral DNA synthesis) ( Figure 10-2 ). 3 Furman and co-authors suggested that activated triphosphate of ACV is substantially more effective in inactivating the viral polymerase than the cellular DNA polymerase. 4 Table 10-3 contains the key pharmacologic concepts for ACV.

Figure 10-1 Acyclovir, valacyclovir, famciclovir.

Figure 10-2 Antiviral drug mechanism.

Table 10-3 Key pharmacologic concepts

Clinical use
Indications and contraindications for ACV are found in Box 10-1 . 1 , 3 , 5 – 19

Box 10-1
Acyclovir indications and contraindications 1, 3, 5 – 19

FDA approved indications
Herpes simplex infections 1 , 3 , 5 – 12
Primary episode
Recurrent episodes
Suppressive therapy
Varicella-zoster infections
Chicken pox 1, 13 – 15
HZ 1, 16
Herpes simplex or varicella-zoster infections
Immunocompromised patients (such as HIV infections)
Other dermatologic uses

Recurrent erythema multiforme (presumed/proven due to HSV) 17 – 19
Other subsets of herpes simplex infections (see text)
Contraindications

Hypersensitivity to acyclovir
Hypersensitivity to any component of the formulation
Pregnancy prescribing status – Category B

FDA-approved indications

Herpes simplex virus infections
ACV can be administered topically, orally, and intravenously. The oral form is the most widely used for HSV infections. In the therapy of genital HSV, oral ACV is indicated for treatment of the initial episode and recurrent disease as well as for suppressive therapy. For first-episode genital HSV, the original recommended dose was 200 mg five times daily for 10 days. Although ACV has greater efficacy when used for first-episode genital HSV, it also shows significant benefit in recurrent disease if therapy is initiated during the prodromal phase. For recurrent genital HSV, originally ACV was dosed as 200 mg 5 times daily for 5 days. 3 Far more commonly clinicians use ACV dosed as 400 mg three times daily for 10 days (first-episode HSV) or 5 days (HSV recurrences). The decreased frequency leads to greater convenience and increased patient compliance. Suppressive therapy is recommended for frequent recurrences. Continuous suppressive therapy with ACV 400 mg twice daily reduces recurrence of genital HSV by 80–90%, and reduces asymptomatic viral shedding of HSV-2 by 95%. 5 Preventing recurrences prior to childbirth is essential for avoiding perinatal transmission and/or the need for cesarean delivery. Prophylactic ACV beginning before 36 weeks’ gestation reduces recurrences, viral shedding, and the number of caesarean deliveries. 6
ACV is also beneficial in recurrent orofacial HSV (herpes labialis). ACV 200 mg 5 times daily for 5 days expedites crusting, but does not appear to reduce healing time significantly. Maximal therapeutic benefits are seen when therapy is initiated during the prodromal stages prior to vesicle formation. Suppressive therapy can also be employed for those with more than 2 outbreaks annually or a history of ocular HSV disease. Suppressive doses of ACV 400 mg twice daily reduces the frequency of HSV labialis and ocular HSV recurrence by 50–78%. 7, 8 Topical ACV is also promoted for the treatment of orofacial HSV. However, penetration of the stratum corneum is low and the resulting efficacy is low. 3
Intravenous ACV is reserved for severe illness and in the immunocompromised. Indications include disseminated HSV disease, complicated primary infection, neonatal infection, eczema herpeticum, herpes encephalitis, and HSV that fails oral therapy. Intravenous ACV is used in immunocompromised patients because of its greater bioavailability. 1 In a meta-analysis evaluating the clinical efficacy of high-dose ACV in patients with HIV infection, results showed that ACV offered a modest survival benefit. 9 Although the mechanism is unclear as ACV has no antiretroviral activity, suppression of bursts of HIV replication during active HSV infections may contribute to prolonged survival. 9 – 11
Q10-3 Although ACV resistance is low in immunocompetent patients, HSV-2-resistant isolates are more common in HIV-positive patients. 12 In ACV-resistant strains, antiviral susceptibilities should be determined and foscarnet or cidofovir used as primary therapy. See Tables 10-4 and 10-5 regarding the use of ACV for HHV infections in immunocompetent and immunocompromised patients.

Table 10-4 Clinical regimen for human herpes virus infections in immunocompetent patients

Table 10-5 Clinical regimen for human herpes virus infections in immunocompromised patients

Chickenpox
When used to treat first-episode VZV the recommended adult dose of oral ACV is 800 mg 5 times daily for 7 days and 20 mg/kg 4 times daily (up to a maximum of 800 mg per dose) for children. 13 For efficacious treatment, ACV must be initiated within the first 24–72 hours after appearance of the characteristic skin eruption. A meta-analysis revealed that ACV can shorten the duration of fever and reduce the number of lesions; however, its effects on pruritus and onset of new lesions were not consistent. 14 ACV treatment of chickenpox, even in otherwise healthy children, is considered cost-effective because it allows the child to return to school at least 2 days earlier, thus enabling the parent to return to work sooner. Intravenous ACV is recommended for pregnant women with any evidence of pneumonia because of the high fetal morbidity and mortality. No ACV-related fetal risk has been documented. 15

Herpes zoster (HZ)
ACV is used for recurrences of VZV known as HZ (or shingles). 1 Acute HZ requires 800 mg of ACV to be taken 5 times daily for 7–10 days. Placebo-controlled trials indicate accelerated healing time when therapy is initiated within 1–2 days of the initial symptoms and signs of infection. Although there is much controversy regarding the effects of ACV on HZ, this dose has been shown to reduce the mean duration of the postherpetic neuralgia (PHN) from 62 days for patients treated with placebo to 20 days for patients treated with ACV. 16 Intravenous ACV (10 mg/kg three times daily for 7–10 days) is used in the immunocompromised and those with severe trigeminal nerve distribution.

Off-label dermatologic uses

Recurrent erythema multiforme
Q10-4 Over the past 20 years there have been a variety of clinical studies and case series evaluating intermittent and suppressive ACV therapy for recurrent erythema multiforme proven or presumed to be due to HSV. 17 – 19 The majority of patients in these studies had oral mucosal involvement. In one study, 55% of children receiving doses ranging from 20 to 25 mg/kg daily had a favorable response. 17 For suppressive therapy, ACV 400 mg twice daily is given. ACV is a reasonable therapeutic option for frequent, painful recurrences of erythema multiforme that are likely due to preceding HSV infections.

Other herpes simplex infections
A variety of subsets of HSV can be treated with ACV in a fashion similar to the regimens outlined for oral and genital HSV infections that have FDA approval. These subsets include primary gingivostomatitis, recurrent herpes labialis, herpes gladiatorum, eczema herpeticum, herpetic whitlow, and herpetic keratoconjunctivitis. Empiric dosages can be identical to those used for primary infection, recurrences, and suppressive regimens outlined in the Therapeutic Guidelines – Drugs for HHV Infections section.

Adverse effects
ACV is generally well tolerated regardless of the route of administration. Infrequent adverse effects with oral and intravenous treatment include nausea, vomiting, diarrhea, and headache. Intravenous infusions can be associated with phlebitis and infusion-site inflammation, in addition to reversible renal impairment due to a crystalline nephropathy.

Drug interactions
Because ACV is not metabolized by hepatic microsomal (CYP) enzymes, there is a relative paucity of important drug interactions. A few minor interactions are detailed in Table 10-6 .
Table 10-6 Acyclovir, valacyclovir, and famciclovir drug interactions Precipitant drug Target drug Mechanism Drugs that increase antiviral drug levels Probenecid Acyclovir famciclovir ↑ bioavailability, ↓ renal clearance due to ↓ renal tubular secretion Zidovudine Acyclovir Uncertain mechanism – severe drowsiness and lethargy can occur Cimetidine Famciclovir Small ↑ penciclovir levels – no clinical importance Theophylline Famciclovir Small ↓ penciclovir renal clearance – no clinical importance Drug levels increased by antiviral agents Famciclovir Digoxin Uncertain mechanism – levels ↑ 19% Decreased rate of conversion valacyclovir to acyclovir Cimetidine Valacyclovir ↓ rate but not extent of conversion to acyclovir Probenecid Valacyclovir ↓ rate but not extent of conversion to acyclovir
Adapted from CliniSphere 2.0 CD ROM, St. Louis, June 2006, Facts and Comparisons.

Valacyclovir

Pharmacology
Q10-5 Valacyclovir (VACV) is an oral prodrug of acyclovir. (Note that the drug is also commonly spelled ‘valaciclovir’ in the literature.) Q10-6 This 1-valyl ester of ACV has a bioavailability 3–5 times greater than that of oral ACV. In the oral form it is nearly as potent as intravenous ACV (see Figure 10-1 ). 1 Apart from the differences in bioavailability, the mechanism, clinical spectrum, and adverse effects are similar (see Pharmacology section and Table 10-3 ).

Clinical use
Indications and contraindications for VACV are found in Box 10-2 . 1, 20 – 31

Box 10-2
Valacyclovir indications and contraindications 1, 20 – 31

FDA-approved indications
Herpes simplex infections 1 , 20 – 28
Primary episode
Recurrent episodes
Suppressive therapy
Varicella-zoster infections
HZ 29, 30
Herpes simplex or varicella-zoster infections
Immunocompromised patients (such as HIV infections)
Other dermatologic uses

Recurrent erythema multiforme (presumed/proven due to HSV) 31
Other subsets of herpes simplex infections (see text)
Contraindications

Hypersensitivity to valacyclovir or acyclovir
Hypersensitivity to any component of the formulation
Pregnancy prescribing status – Category B

FDA-approved indications

Herpes simplex infections
VACV is indicated for the treatment of both genital and orofacial HSV infections. For first-episode genital HSV, VACV 1000 mg twice daily for 10 days is recommended. 1 ACV 200 mg 5 times daily for a 10-day course and VACV twice daily are equally effective in accelerating the resolution of first-episode genital HSV. 20 The twice-daily regimen of VACV is also more convenient for patients, which leads to potentially greater patient compliance. For episodic treatment of recurrent genital HSV, VACV is dosed at 500 mg twice daily for 3 days. 21 Continuous therapy with 500 mg daily for suppression of recurrent genital HSV is approved for people with 9 or fewer episodes yearly. Alternatively, patients with 10 or more episodes yearly may require 1 g daily or 500 mg twice daily. A recent study demonstrated that daily use of VACV also reduces HSV transmission by reducing asymptomatic HSV shedding, prompting its approval by the FDA for this use. During the 8-month study, HSV-2 transmission was reduced by 50% among susceptible partners. 22 In another study, it was discovered that patients with newly diagnosed HSV-2 infection had a 78% reduction in viral shedding with VACV 1 g daily compared to placebo. 23
VACV is approved for use in HIV-seropositive patients with recurrent genital HSV. In a double-blind controlled trial, 1062 HIV-infected patients with a history of recurrent anogenital HSV were randomized to receive VACV 500 mg twice daily, VACV 1000 mg daily, or ACV 400 mg twice daily for 1 year. Whereas there was no significant difference between VACV 1000 mg daily and ACV 400 mg twice daily, patients treated with VACV 500 mg twice daily had significantly fewer recurrent episodes of genital HSV. 24, 25 In another randomized, double-blinded placebo-controlled study of 293 HIV-positive patients, VACV 500 mg twice daily was found to be effective at reducing the recurrence of genital HSV at 6 months. The time to first genital HSV recurrence was also significantly shorter in the placebo group (median 59 days) than in the treatment group (median 180 days). 24, 25 In immunocompromised patients subsequent upon solid organ or bone marrow transplantation, VACV 2000 mg four times daily is also an effective prophylactic strategy against CMV infection. 26
VACV is also approved for the treatment of recurrent orofacial HSV. When given during the prodromal stage, VACV 2000 mg twice daily for 1 day is beneficial. 27 VACV is also useful for suppression of HSV labialis. Two randomized, double-blind placebo-controlled studies found oral VACV 500 mg daily to be efficacious in the suppression of HSV labialis over 4 months among patients with a history of 4 or more recurrent lesions in the previous year. The recurrence rate was reduced from 68% to 40%. 28 VACV 500 mg twice daily was also demonstrated to be an effective prophylactic strategy against orofacial HSV when started 1 day prior to laser cutaneous resurfacing and continued for 10–14 days. 29

Herpes zoster (HZ)
VACV has an FDA indication for use in HZ. Treatment requires 1000 mg 3 times daily for 7 days. VACV has been shown to be as effective as ACV in its effect on the appearance of new lesions, time to crusting, and time to 50% healing. VACV is more efficacious than ACV in ameliorating PHN. VACV patients had a median duration of 40 days of pain after lesion resolution compared to 60 days of pain after lesion resolution for ACV recipients. In terms of zoster-related discomfort overall, it is estimated that VACV provides a 25% greater benefit over ACV. The more convenient dosing schedule, as well as quicker cessation of pain, makes VACV more efficacious than ACV in treating acute HZ. (See the Therapeutic Guidelines subsection under Drugs for HHV Infections.)

Off-label dermatologic uses

Recurrent erythema multiforme
Q10-4 There are few reports in the English-language literature on suppressive VACV therapy for recurrent erythema multiforme due to HSV infection. Given the reasonable level of success with ACV for this condition, and the significantly greater bioavailability of VACV, further evaluation of this potential indication for VACV is in order.

Other herpes simplex infections
A variety of subsets of HSV can be treated with VACV in a fashion similar to the regimens outlined for oral and genital HSV infections that have FDA approval. These subsets include primary gingivostomatitis, herpes gladiatorum, eczema herpeticum, herpetic whitlow, and herpetic keratoconjunctivitis. Empiric dosages can be identical to those used for primary infection, recurrences, and suppressive regimens outlined in the Therapeutic Guidelines – Drugs for HHV Infections section.

Adverse effects
The reported adverse effects of VACV include nausea and headaches (as in ACV), with incidences usually not significantly different from those of placebo. Like ACV, VACV is a strikingly safe drug with excellent patient tolerance.

Drug interactions
Given that VACV and its active form ACV are not metabolized by hepatic microsomal (CYP) enzymes, there is a relative paucity of important drug interactions. A few minor interactions are detailed in Table 10-6 .

Famciclovir

Pharmacology
Q10-5 FCV is the oral prodrug of penciclovir (PCV), an acyclic nucleoside (see Figure 10-1 ). Like ACV, PCV must be phosphorylated to PCV triphosphate to be pharmacologically active. PCV triphosphate has a much longer intracellular half-life (10–20 hours in HSV-infected cells and 7 hours in VZV-infected cells) than ACV triphosphate (<1 hour in HSV- and VZV-infected cells). 3
Q10-6 Oral FCV has a 77% bioavailability compared to the 15–30% bioavailability of oral ACV and 55% for oral VACV. 30, 31 Pharmacologic key concepts of FCV can be found in Table 10-3 .

Clinical use
Indications and contraindications for FCV are found in Box 10-3 . 1, 32 – 45

Box 10-3
Famciclovir indications and contraindications 1, 32 – 45

FDA-approved indications
Herpes simplex infections 1 , 32 – 37
Primary episode
Recurrent episodes
Suppressive therapy
Immunocompromised patients (such as HIV infections) 37 – 41
Varicella-zoster infections
HZ 42 – 44
Immunocompromised patients (such as HIV infections) 45
Other dermatologic uses

Other subsets of herpes simplex infections (see text)
Primary varicella
Contraindications

Hypersensitivity to famciclovir
Hypersensitivity to any component of the formulation
Pregnancy prescribing status – Category B

FDA-approved indications

Herpes simplex infections
FCV is used for treatment of both orofacial and genital HSV. In the treatment of genital HSV it is used for primary infection, episodic treatment of recurrent infections, and continuous suppressive therapy. For first-episode genital HSV, FCV is given as 250 mg 3 times daily for 10 days. Compared to ACV, there is no significant difference in terms of decreasing viral shedding, time to complete healing, and loss of all symptoms. 1, 46 For episodic treatment of recurrent genital HSV, FCV is FDA-approved at a dose of 125 mg twice daily for 5 days or 1000 mg twice daily for 1 day. FCV causes a significant reduction in pain, burning, tenderness, and tingling in patients with recurrent genital HSV. 1, 47 FCV is also approved for suppression of recurrent genital HSV. 32 A meta-analysis from several 2-year multicenter trials compared FCV 250 mg twice daily versus placebo. FCV-treated patients had approximately 80% fewer recurrences per year than placebo recipients. Long-term use of FCV is well tolerated, with a safety profile similar to that seen with placebo. 33, 34 Another recent study demonstrated that FCV 1000 mg administered twice daily for 1 day was similar in both safety and efficacy to VACV 500 mg given twice daily for 3 days, thus providing immunocompetent adults suffering from recurrent genital HSV with an alternative and more convenient treatment regimen. 35
FCV has also been evaluated for use in episodic treatment of orofacial HSV. The recommended dose for recurrent orofacial HSV is a single 1500 mg dose given at the earliest onset of symptoms. FCV 250 and 500 mg three times daily for 5 days are comparably efficacious for early treatment of UV-induced recurrences. 34 Both 250 mg and 500 mg taken twice daily have also demonstrated efficacy in preventing recurrences after laser resurfacing. The higher doses are recommended for patients with a history of frequent recurrences. 36
FCV has also proved effective for the treatment of HSV-1 and -2 in immunocompromised patients. It has been approved by the FDA at a dose of 500 mg twice daily for 7 days for the treatment of recurrent genital HSV in individuals who have HIV infection. In a blinded trial conducted on 293 patients who were HIV positive with recurrent genital HSV, 500 mg of FCV taken twice daily for 7 days was equivalent in efficacy to ACV 400 mg 5 times daily for 7 days. 37 A double-blind placebo-controlled trial found that daily FCV is efficacious in suppressing symptomatic and asymptomatic HSV reactivation in persons with HIV infection. In addition to delaying the time to the first HSV reactivation, FCV resulted in a marked decrease in total, symptomatic, and asymptomatic HSV shedding. FCV reduced total HSV-2 shedding by 87% and reduced the frequency of genital signs and symptoms by 65%. The percentage of days with genital lesions was reduced from 13.8% to 4.9%. 36 Likewise, another double-blind placebo-controlled study demonstrated that in patients seropositive for HIV and HSV, 500 mg FCV taken twice daily for 8 weeks suppressed HSV-2 reactivation by almost 50%, reduced days with lesions by 8%, and reduced asymptomatic shedding by 4%. 38
HSV is one of the most common viral infections complicating HIV infection. Up to 95% of patients who are HIV positive are seropositive for either HSV-1, HSV-2, or both. 39 In a study conducted on 12 men with HIV infection and a history of symptomatic HSV-2 infection, HIV-1 virions were consistently detected (via polymerase chain reaction) in genital ulcers caused by HSV-2. This suggests that genital HSV infection may increase the efficiency of the sexual transmission of HIV-1. 40

Herpes zoster (HZ)
FCV has been shown to be highly effective in the treatment of HZ. The FDA-recommended FCV dose for zoster in immunocompetent patients is 500 mg orally 3 times daily for 7 days. At this dose FCV has been shown to reduce the time to healing of the cutaneous manifestations of zoster, as well as reduce the duration of PHN. 41 PHN resolved twice as fast in patients who received FCV for acute HZ than in patients receiving placebo. Patients over 50 years old are at increased risk for developing PHN with a longer duration of pain. In these patients FCV was shown to cause resolution of pain 2.6 times faster, which resulted in a 3.5-month reduction in the median duration of PHN. 41 There are no differences in efficacy or safety compared to VACV. 42 FCV was also demonstrated to be equally safe and effective as ACV 800 mg 5 times daily for ophthalmic zoster, but FCV was more convenient (i.e., 3 times daily dosing). 43
In immunocompromised patients, such as bone marrow and organ transplant recipients, cancer patients receiving chemotherapy and irradiation, and patients who are HIV positive, VZV infection can be particularly severe, with significant morbidity and mortality. Intravenous ACV has been the mainstay of therapy for the immunocompromised patient with VZV requiring hospitalization or home intravenous care. Oral FCV compared favorably with oral ACV in the treatment of HZ in immunocompromised patients. 44 The recommended dose of FCV in immunocompromised patients is 500 mg 3 times daily for 10 days. This regimen provides more convenient and effective dosing for immunocompromised patients with HZ. There were also minimal adverse effects in the use of FCV for acute HZ, including nausea, headache, and vomiting, at a rate similar to that of oral ACV. FCV is an efficacious oral agent that can be used as an alternative to intravenous antiviral therapy in immunocompromised patients. However, patients must be monitored closely and started on intravenous antivirals if they develop any signs or symptoms of disseminated disease. See Tables 10-4 and 10-5 regarding the use of FCV for HSV and VZV infections.

Off-label dermatologic uses

Other herpes virus infections
A variety of subsets of HSV can be treated with FCV in a fashion similar to the regimens outlined for oral and genital HSV infections that have FDA approval. These subsets include primary gingivostomatitis, herpes gladiatorum, eczema herpeticum, herpetic whitlow, and herpetic keratoconjunctivitis. Empiric dosages can be identical to those used for primary infections, recurrences, and suppressive regimens outlined in the section on Therapeutic Guidelines – Drugs for HHV Infections . FCV may also be used for primary varicella infections, although this indication needs further clinical evaluation.

Adverse effects
Like ACV, FCV can rarely cause such adverse effects as headache, nausea, or diarrhea. FCV shares with ACV and VACV an excellent safety profile and patient tolerance.

Drug interactions
Given that FCV and its active form PCV are not metabolized by hepatic microsomal (CYP) enzymes, there is a relative paucity of important drug interactions. A few minor interactions are detailed in Table 10-6 .

Therapeutic guidelines – drugs for HHV infections
In general, ACV, VACV, and FCV are equivalent in their safety and efficacy. The primary exception to this rule is that VACV and FCV are somewhat more effective in reducing the duration of zoster-associated pain than ACV, owing to their superior bioavailability. Because of this, either VACV or FCV is generally preferred over ACV for VZV infections; ACV still has a significant role in HSV infections, which are more sensitive to all three drugs. VACV and FCV are considered overall equivalent for therapy of HSV and VZV infections (despite some pharmacologic differences). 42 Table 10-4 outlines clinical regimens for the immunocompetent patient with an HHV infection. Table 10-5 outlines the clinical regimens for the immunocompromised patient with an HHV infection. Both tables include various clinical scenarios of HSV, HZ, and primary varicella.
Any one of these drugs can be used to suppress recurrent genital HSV or HSV labialis. Q10-7 Reasons to offer suppression versus episodic therapy include:

1. Frequency of outbreaks (e.g., 6 or more per year);
2. Severity of outbreaks (physical and/or emotional);
3. Lack of a sufficient prodrome such that episodic therapy would have little benefit; and
4. Having a sexual partner who is seronegative via western blotting for HSV (particularly HSV-2), thereby reducing outbreaks, asymptomatic viral shedding and transmission.
Immunocompromised patients include those with HIV, patients with solid organ transplantation, persons taking systemic immunosuppressive drugs, and patients with internal malignancies. A spectrum in the degree of immunosuppression, from mild to severe, exists within each of these conditions. Oral preparations of these three drugs have been used to treat HSV and VZV infections, as well as to suppress HSV infections in immunocompromised persons. Little information is available comparing the relative safety and efficacy of these agents in immunocompromised patients.
Q10-3 Frequent use of ACV for the treatment and suppression of HSV infections has led to the emergence of ACV-resistant HSV strains. In immunocompetent individuals HSV infections are susceptible to treatment; however, in immunocompromised patients, especially in those with HIV or who have undergone bone marrow transplantation or are on immunosuppressive therapies, the prevalence of ACV-resistant infections may be as high as 7%. 45 ACV-resistant HSV strains are often cross-resistant to VACV and FCV as well. Patients who fail standard therapy with oral and intravenous ACV can be managed with intravenous foscarnet or cidofovir. The CDC also recommends the use of topical cidofovir for the treatment of ACV-resistant strains of HSV. Resistance to ACV most frequently results from mutations in the viral thymidine kinase gene, and less frequently with mutations in viral DNA polymerase. 45, 48 Foscarnet and cidofovir are more toxic than ACV and are therefore not recommended as first-line HSV treatment. Both work through inhibition of viral DNA polymerase and do not require phosphorylation by thymidine kinase.
In the first-line therapy of HSV there is little basis to recommend either ACV, VACV, or FCV over any of the others, except for the greater convenience regarding the dosing frequency of VACV and FCV (relative to ACV). Reasons for recommending intravenous ACV over the oral drugs include the following: (1) severe immunosuppression, (2) inability to swallow oral medication, (3) impaired memory and/or mental capacity, (4) long distance or lack of transportation to medical care in case of complications with oral therapy, and (5) disseminated disease.

Vaccines for HHV infections

Varicella-zoster virus vaccines
The first available vaccine for prevention of a HSV virus infection is a live attenuated vaccine given for the prophylaxis of primary varicella. Q10-8 Before FDA approval of the varicella vaccine in 1995, approximately 4 million Americans were infected annually with chickenpox, resulting in over 100 deaths and more than 9000 hospitalizations, which led to an annual cost of hundreds of million dollars in medical bills and lost productivity. 49 Varicella was the leading cause of vaccine-preventable death in children in the United States. Studies have shown that the varicella vaccine is 70–90% effective in completely preventing varicella and results in milder disease in the remainder. 3
This vaccine may be administered along with the measles/mumps/rubella (MMR) vaccine at approximately 1 year of age. Although in the past, children under the age of 12 received only a single dose of the VZV vaccine, recently the Advisory Committee on Immunization Practices (ACIP) to the CDC voted to recommend a second dose of varicella (chickenpox) vaccine for children 4–6 years old to improve the level of protection against the disease. The ACIP also recommends that children, adolescents and adults who previously received one dose only should receive a second dose as well. It is believed that the greatest risk factor for the development of HZ in patients with previous varicella infection is a positive family history of zoster. 50 Fortunately, HZ appears less commonly in persons given the vaccine to prevent primary VZV. Elderly patients with a history of primary varicella infection who receive a booster dose of the (14-fold concentrated version) live attenuated vaccine demonstrate enhanced immunity with a half-life of 54 months. Typically, 6 years after vaccination the T-cell responding frequency remains elevated above baseline. The incidence of HZ and the severity of PHN in vaccinated individuals appear to be reduced. This is a significant benefit and an indication for vaccination in the elderly, who are particularly susceptible to the development of PHN. 51, 52 In 2006 Zoster Vaccine Live became the first FDA-approved vaccine for the prevention of HZ in individuals 60 years of age and older. The vaccine is a lyophilized preparation of the Oka/Merck strain of live attenuated VZV. In a Phase III Shingles Prevention Study of 38 500 adults age 60 and over, the vaccine reduced the incidence of HZ by 51%. Patients who received the vaccine but still developed shingles experienced less pain and discomfort than placebo recipients and had a lower incidence of postherpetic neuralgia.

Herpes simplex virus vaccines
Prophylactic and therapeutic HSV vaccines have been in development for more than 90 years. Vaccination strategies have included the use of inactivated whole virus vaccines, recombinant subunits, viral vectors, attenuated viral strains, DNA preparations, and genetically engineered mutant HSV vaccines. To date, inactivated whole virus vaccines and live attenuated viral vaccines lack sufficient immunogenicity. 51 Recombinant viral subunit vaccines appear the most promising. The first was developed by Chiron and contained glycoproteins B and D along with the adjuvant MF59. This vaccine was found to be ineffective in both prophylactic and therapeutic applications. 53, 54 A second recombinant vaccine, developed by GlaxoSmithKline, contains glycoprotein D and the adjuvant monophosphoryl lipid A immunostimulant. Trials reveal that this vaccine prevents the acquisition of HSV-2 infection in 40% of women who are seronegative for HSV-1 and -2, and prevents symptomatic acquisition in 73% of these women. However, the vaccine gives no protection to men or women who are HSV-1 seropositive. 55
DNA vaccines are also in development. Inoculation of plasmid DNA encoding desired viral genes has demonstrated promising results for prevention in animal studies. Although plasmids can only encode a few viral antigens, they can induce cell-mediated immunity without adjuvants. Several of these agents are in preclinical development.
A genetically engineered growth-defective HSV mutant vaccine, by AuRx, was designed to induce Th1 immunity by deleting ICP10PK, Th2 polarizing gene, during vaccine construction. In clinical trials this vaccine prevented recurrent disease in 37.5% of treated subjects and reduced the frequency and severity of recurrence episodes. 56 Other genetically engineered vaccine strains are currently being studied. The potential impact of an effective HSV vaccine is immense. The reduction in disease acquisition, disease severity, and HSV-related morbidity and mortality will be significant, especially considering the impact on neonatal, perinatal, and orofacial disease.

Drugs for human immunodeficiency virus infections
Cutaneous manifestations of HIV often lead to its diagnosis. Most commonly, the clinical manifestations of primary disease include a papulosquamous exanthem similar to a variety of other viral diseases. 57 The exanthem lasts approximately 2 weeks and then spontaneously regresses. However, as the disease progresses to AIDS, 90% of patients develop mucocutaneous manifestations secondary to infections, neoplasms, etc. 58, 59 Herpes viruses, pox viruses, and human papilloma viruses are the most common opportunistic viral infections that lead to cutaneous manifestations in individuals who are HIV positive. 57 Antiretroviral medications also may produce a host of cutaneous adverse effects.
The search for a cure has led to extensive studies of different treatment modalities. Currently, there are over 20 FDA-approved antiretroviral drugs falling into 7 categories:

1. Nucleoside reverse transcriptase inhibitors – zidovudine, lamivudine, didanosine, zalcitabine, stavudine, abacavir, emtricitabine;
2. Nucleotide reverse transcriptase inhibitor – tenofovir;
3. Non-nucleoside reverse transcriptase inhibitors – nevirapine, delavirdine, efavirenz, and etravirine;
4. Protease inhibitors – saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, atazanavir, lopinavir, tipranavir, and darunavir;
5. Fusion inhibitor – enfuvirtide;
6. Entry inhibitor/CCR5 co-receptor antagonist – maraviroc; and
7. Integrase inhibitor – raltegravir.
In an effort to increase medication compliance and reduce viral resistance, 6 combination antiretrovirals are also available:

1. Atripla (efavirenz, emtricitabine, tenofovir);
2. Combivir (zidovudine, lamivudine);
3. Trizivir (zidovudine, lamivudine, abacavir);
4. Truvada (tenofovir, emtricitabine);
5. Kaletra (lopinavir, ritonavir); and
6. Epzicom (lamivudine, abacavir) (see Table 10-7 ).

Table 10-7 FDA-approved antiretroviral agents for HIV infections
Initiation of antiretroviral therapy should preferably be managed by those with specific training, as provider experience correlates with patient outcome.

Nucleoside analogs
Nucleoside reverse transcriptase inhibitors (NRTI) are activated following intracellular phosphorylation ( Q10-9 Table 10-8 60 – 70 ). The triphosphorylated metabolites bind to viral reverse transcriptase and are incorporated into the growing DNA chain, where they cause DNA chain termination. In effect, these drugs inhibit RNA-dependent DNA synthesis. 71 Resistance to one NRTI can often lead to resistance across the entire line.

Table 10-8 Nucleoside analogs (NRTI) 60 – 70

Nucleotide analogs
The lone nucleotide reverse transcriptase inhibitor tenofovir functions much like NRTI by binding to viral reverse transcriptase and causing DNA chain termination. However, unlike all NRTI, tenofovir does not require phosphorylation by cellular kinases for activation and is not cross-resistant to other nucleoside analogs.

Non-nucleoside analogs
Non-nucleoside reverse transcriptase inhibitors (NNRTI) work at the same stage of replication as the nucleoside reverse transcriptase inhibitors; however, this family of drugs uses a different mechanism of action ( Q10-9 Table 10-9 69, 72 – 77 ). These drugs bind non-competitively to the viral RNA-dependent DNA polymerase, altering its structure and thereby inhibiting its function. Unlike nucleoside analogs, these drugs do not require activation. As with other antiretrovirals, monotherapy results in the emergence of resistance and cross-resistance exists between NNRTI. Non-nucleoside analogs are approved for use in combination therapy for HIV-1 infections, and are not active against HIV-2 infections.

Table 10-9 Non-nucleoside analogs (NNRTI) 69, 72 – 77

Protease inhibitors
HIV-1 protease inhibitors (PI) have offered a new dimension to the treatment of HIV since they became widely available in 1996 ( Q10-9 Table 10-10 69, 72, 76, 78 – 85 ). These drugs block the protease enzyme involved in the final processing of viral proteins, resulting in decreased assembly of new progeny viruses from newly infected or chronically infected cells. This offers a greater advantage over the various reverse transcriptase inhibitors, which only inhibit replication in newly infected cells. Currently approved PI are used in combination with NRTI or NNRTI. This combination can produce at least a 2-log decrease in viral load in most patients, whereas reverse transcriptase inhibitors used in monotherapy only produce a 0.5-log decrease. 78 Among antiretroviral medications, PI are associated with more adverse effects. Q10-10 Several of the PI are significant CYP3A4 inhibitors, including ritonavir and nelfinavir.

Table 10-10 Protease inhibitors (PI) 69, 72, 76, 78 – 85

Fusion inhibitors
Fusion inhibitors are a novel class of antiretroviral drug ( Q10-9 Table 10-11 69, 86 – 88 ). They bind to proteins on the viral envelope and inhibit the conformational change needed for fusion between the viral envelope and CD4 cells. Thus, the virus cannot infect healthy CD4 cells.

Table 10-11 Other antiretroviral drugs 69, 86 – 88

Entry inhibitors/CCR5 co-receptor antagonist
Entry inhibitors comprise a unique class of antiretroviral drug ( Table 10-11 69, 86 – 88 ) that work by inhibiting the binding of viral glycoprotein 120 to human CCR5 co-receptor, which the virus uses to enter the host cells.

Integrase inhibitors
Integrase inhibitors comprise a unique class of antiretroviral drug ( Table 10-11 69, 86 – 88 ). They work by blocking integrase, a critical HIV protein that is required for the integration of the viral genetic material into the host chromosome, thereby preventing the virus from infecting host cells.

Investigational drugs
Resistance mutations to antiretrovirals can already be found even in treatment-naïve patients. 89 New drugs are constantly being developed and studied for their role in fighting HIV infection. As more is known about viral replication, new targets for treatment are being investigated. Each step in the entry of HIV into cells is now being targeted for therapeutic design. Chemokine receptor antagonists target viral entry by antagonizing the CXCR4 co-receptor (as well as the CCR5 co-receptor discussed earlier). Viral assembly and disassembly are being targeted with NCp7 zinc finger-targeted agents. Additional fusion inhibitors will also become available. Unlike enfuvirtide, many of the investigational compounds are bioavailable in oral forms. Furthermore, new nucleoside analogs, NNRTI, and PI with increased activity against resistant strains are being investigated for their use in combination therapy. 90, 91

Therapeutic guidelines – drugs for HIV infections
Editor’s note – due to the fact that clinicians outside of dermatology almost exclusively prescribe the antiretroviral medications in this chapter, the interested reader is referred to ref. #57 and/or the second book edition version of this chapter for further details.

HIV vaccine development
Q10-11 The greatest hope for the future of HIV control is to minimize transmission by using a prophylactic vaccine. Different types of vaccine are currently being investigated, including subunit vaccines, recombinant vector vaccines, vaccine combinations (recombinant vector vaccine followed by subunit vaccine booster), peptide vaccines, virus-like particle vaccines, anti-idiotype vaccines, whole-inactivated virus vaccines, and a live-attenuated virus vaccine. 92 Only one, a recombinant gp120 vaccine known as AIDSVAX, has reached Phase III trials. Although initial studies indicated that 99% of vaccinated individuals developed neutralizing antibodies, Phase III trials demonstrated that vaccinated individuals contracted HIV as frequently as their non-vaccinated counterparts. 93, 94 Live virus vector vaccines with recombinant canary pox and vesicular stomatitis virus as well as cell-mediated immunity vaccines (e.g., adenovirus) have also been studied, but have not been effective in preventing HIV infection or reducing early viremia.
Q10-11 One area that has shown promise is the use of a prime–boost vaccination technique. The first trial to use this technique was the RV144 trial, which used a combination of ALVAC HIV (prime) and AIDSVAX B/E (boost) versus placebo in HIV-negative subjects in Thailand. Results from the study showed that this novel combination was effective in reducing the risk of HIV infection. However, future trials studying the vaccine’s success are needed. Another trial, known as the HVTN 505 Study, is also using the prime–boost technique and is currently under way in the United States. In this study, circumcised homosexual men are given a combination of a DNA vaccine (prime) and adenovirus serotype 5 (boost).

Summary
Although great progress has been made in the study and treatment of HHV and HIV, a great deal of work still remains to be done. Vaccine research continues to strive for preventive medicine for those who are at risk for the acquisition of disease. Focusing on a preventive approach could spare individuals from the social stigma, physical and emotional pain, and significant healthcare costs they may face. Education regarding the transmission of HSV-1 and -2 can also reduce transmission by promoting safer sexual practices. Equally important for both physicians and patients is education regarding the early signs and symptoms of HZ, which may prevent PHN in individuals, as well as education regarding the need for vaccinations in at-risk populations. For individuals already afflicted with disease, studies have shown that the existing therapies are effective for both treatment and reduction of outbreaks.
In the realm of HIV, new protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, fusion inhibitors, integrase inhibitors, and CCR5 receptor antagonists continue to be tested daily in multicenter trials. Agents with different mechanisms of action are also being developed for future use. For HIV, the most effective method of reducing transmission is through education on safe sex and abstinence, testing of blood products, the use of sterile needles, and proper handling of body fluids potentially containing HIV.

Acknowledgment
Thanks to Patricia C. Lee MD for her input to this chapter.

Abbreviations used in this chapter ACIP Advisory Committee on Immunization Practices ACV Acyclovir AIDS Acquired immunodeficiency syndrome AZT Azidothymidine ( same as zidovudine) CDC Center for Disease Control CYP Cytochrome P-450 GI Gastrointestinal FCV Famciclovir FDA Food and Drug Administration HAART Highly active antiretroviral therapy HHV Human herpes virus HIV Human immunodeficiency virus HSV Herpes simplex virus HZ HZ MMR Measles/mumps/rubella NRTI Nucleoside reverse transcriptase inhibitor NNRTI Non-nucleoside reverse transcriptase inhibitor PHN Postherpetic neuralgia PI Protease inhibitor PPC Pregnancy prescribing category rx Prescription or medication SJS Stevens–Johnson syndrome TEN Toxic epidermal necrolysis TK Thymidine kinase VACV Valacyclovir VZV Varicella-zoster virus

Bibliography: Important Reviews and Chapters *

Overviews for treatment of human herpes virus infections
Trizna Z, Tyring SK. Antiviral treatment of diseases in pediatric dermatology. Dermatol Clin . 1998;16:539–552.

Reviews of specific drugs for human herpes virus infections
Chakrabarty A, Tyring SK, Beutner K, et al. Recent clinical experience with famciclovir—a ‘third generation’ nucleoside prodrug. Antivil Chem Chemother . 2004;15:251–253.
Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis . 2002;186(Suppl 1):S40–S46.

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64 Shuurman R, Nijhuis M, van Leeuwen R, et al. Rapid changes in human immune deficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine. J Infect Disease . 1995;171:1431.
65 Staszewski S. Coming therapies: abacavir. Int J Clin Pract . 1999;103(Suppl):35–38.
66 Foster RH, Faulds D. Abacavir. Drugs . 1998;55:729–738.
67 Clay PG, Rathbun RC, Slater LN. Management protocol for abacavir-related hypersensitivity reaction. Ann Pharmacother . 2000;34:247–249.
68 Chang Y, Tyring SK. Therapy of HIV infection. Dermatol Ther . 2004;17:449–464.
69 Antiviral Briefs. AIDS Patient Care STDS . 2004;18(10):614.
70 Dando TM, Wagstaff AJ. Emtricitabine/tenofovir disoproxil fumarate. Drugs . 2004;64(18):2075–2082.
71 Goldschmidt RH, Moy A. Antiretroviral drug treatment for HIV/AIDS. Am Fam Phys . 1996;54:574–580.

Non-nucleoside analogs
72 Wynn P. Class of AIDS drugs boost combination therapy approach. Dermatol Times . 1996;17:33.
73 Bellman PC. Clinical experience with adding delavirdine to combination therapy in patients in whom multiple antiretroviral treatment including protease inhibitors has failed. AIDS . 1998;12(Suppl A):S165–S174.
74 Rotunda A, Hirsh RJ, Scheinfeld N, et al. Severe cutaneous reactions associated with the use of human immunodeficiency virus medications. Acta Derm Venereol . 2003;83:1–9.
75 Ruiz N. Clinical history of efavirenz. Int J Clin Pract . 1999;103(Suppl):3–7.
76 Watts DH. Management of human immunodeficiency virus infection in pregnancy. N Engl J Med . 2002;346:1879.
77 De Santis M, Carducci B, De Santis L, et al. Periconceptional exposure to efavirenz and neural tube defects. Arch Intern Med . 2002;162:355.

Protease inhibitors
78 McDonald CK, Kurtzkes DR. Human immunodeficiency virus type 1 protease inhibitors. Arch Intern Med . 1997;157:951–959.
79 Cameron W, Sun E, Markowitz M, et al. Combination use of ritonavir and saquinavir in HIV-infected patients: Preliminary safety and activity data. In: Program and Abstracts of the 11th International Conference on AIDS (abstract Th.B 934). Vancouver, British Columbia, July 1996.
80 Gathe J, Burkhardt B, Hawley P, et al. A randomized phase II study of Viracept, a novel HIV protease inhibitor, used in combination with stavudine vs stavudine alone (abstract MB 413). In: Program and Abstracts of the XI International Conference on AIDS. Vancouver, British Columbia, July 1996.
81 Moyle GJ, Youle M, Higgs C, et al. Extended follow-up and safety and activity of Agouron’s HIV protease inhibitor from the UK phase I/II dose finding study (abstract MB 173). In: Program and Abstracts of the 11th International Conference on AIDS. Vancouver, British Columbia, July 1996.
82 Adkins JC, Faulds D. Amprenavir. Drugs . 1998;55:837–844.
83 Tipranavir (Aptivus) for HIV. Med Lett Drugs Ther . 2005;47:83–84.
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85 Resino S, Bellon JM, Ramos JT, et al. Salvage lopinavir-ritonavir therapy in human immunodeficiency virus-infected children. Pediatr Infect Dis J . 2004;23:923–930.
86 Squires K, Pozniak AL, Pierone G, et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med . 2003;139:313–320.

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87 Raffi F. Enfuvirtide, first fusion inhibitor in the treatment of human immunodeficiency virus infection: mechanism of action and pharmacokinetics. Med Mal Infect . 2004;34:3–7.
88 Raffi F. Clinical efficacy and tolerance of enfuvirtide (Fuzeon), new antiretroviral inhibitors in intracellular penetration of human immunodeficiency virus (HIV) type 1. Med Mal Infect . 2004;34:8–17.
89 Weinstock HS, Zaidi I, Heneine W, et al. The epidemiology of antiretroviral drug resistance among drug-naïve HIV-1 infected persons in 10 US cities. J Infect Dis . 2004;189:2174–2180.
90 De Clercq E. New developments in anti-HIV chemotherapy. Curr Med Chem . 2001;8:1543–1572.
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92 Shelton DL. Vaccines now being tested around the world. Am Med News . January 20, 1997.
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94 McCarthy M. HIV vaccine fails in phase 3 trial. Lancet . 2003;361:755–756.

* All the references in the reference list are available online at www.expertconsult.com .
11 Systemic antiparasitic agents

Dirk Elston


 Questions

Q11-1 Concerning ivermectin therapy for scabies, (a) how does ivermectin compare with topical permethrin, and (b) is ivermectin alone effective treatment for crusted scabies? (Pgs. 135, 136)
Q11-2 What are several mechanisms of action for ivermectin in parasitic infestations? (Pg. 135)
Q11-3 What are the FDA-approved indications for (a) ivermectin, (b) albendazole, and (c) thiabendazole? (Pgs. 135, 137, 138)
Q11-4 Should ivermectin be utilized differently in immunocompromised patients, including HIV patients? (Pg. 136)
Q11-5 What are the 4 most common ivermectin adverse effects when used to treat helminth infestations? (Pg. 136)
Q11-6 What is the role of the efflux transporter, P-glycoprotein in the theoretical CNS risk from ivermectin therapy? (Pg. 136)
Q11-7 What are the clinical implications of increasing parasite resistance to ivermectin in treating (a) onchocerciasis, and (b) scabies? (Pg. 136)
Q11-8 Is it generally considered safe to use ivermectin in young children (size limit)? (Pg. 137)
Q11-9 What is the mechanism of action for albendazole? (Pg. 137)
Q11-10 What is the probable mechanism of action for thiabendazole? (Pg. 138)

Ivermectin
Ivermectin is a semisynthetic antihelminthic derived from the fermentation products of Streptomyces avermitilis. It is the 22,23-dihydro derivative of avermectin B 1, and is classified as a macrocyclic in the avermectin family. Its structure is similar to that of the macrolide antibacterial agents.
Q11-1 A recent Cochrane review of randomized controlled trials of drug treatments for scabies concluded that topical permethrin appears to be the most effective treatment for scabies, whereas ivermectin appears to be an effective oral agent. 1 Data considering both cost and efficacy suggest that benzyl benzoate and ivermectin are most cost-effective for the treatment of scabies. 2 Some data suggest that topical benzyl benzoate is the more effective of the two, although data are mixed. 3 In patients with crusted scabies the response to oral ivermectin is variable, and oral therapy in combination with topical scabicides and keratolytics has been advocated. 4 Clinical experience has shown that ivermectin alone often fails in crusted scabies. In other patients ivermectin appears comparable or slightly inferior to permethrin in efficacy, but has the convenience of oral dosing.

Pharmacology
After administration the time to peak serum levels is about 4 hours, and the half-life is about 18 hours. Metabolism is primarily hepatic, with excretion in feces over an estimated 12 days. Ivermectin is metabolized primarily by CYP3A4. Less than 1% of the administered dose is excreted in the urine, so dose adjustment is needed with biliary obstruction, but renal failure is not likely to affect metabolism. Bioavailability is increased when the drug is administered with a high-fat meal. Although product labeling does not recommend this, some authors have recommended dosing with food to increase absorption.

Mechanism of action
Q11-2 Ivermectin binds selectively to glutamate-gated chloride ion channels found in invertebrate nerve and muscle cells. Binding results in increased permeability of cell membranes to chloride ions, with hyperpolarization of the nerve or muscle cells resulting in death of the parasite. Ligand-gated ion channels represent the primary ivermectin targets in invertebrates. 5 Ivermectin positively modulates CNS ATP-gated purinergic P2X4 receptors and is believed to act in the same region as ethanol. 6
Following administration of a single dose of ivermectin, the cutaneous microfilarial burden is reduced by half after 24 h, by 85% after 72 h, and by 94% after 1 week. 7 After mass administration of ivermectin between 1995 and 2001 in three villages endemic for onchocerciasis, the prevalence of skin microfilariae was reduced from 69.3% to 39.3% and the microfilarial load from 7.11 to 2.31 microfilariae per skin snip. Unfortunately, these levels still present a risk of active transmission. 8

Clinical use

Approved indications
Q11-3 Labeled indications include the treatment of intestinal strongyloidiasis caused by Strongyloides stercoralis and onchocerciasis caused by Onchocerca volvulus . It should be noted that FDA-reviewed trials have only established that ivermectin is active against the microfilaria of Onchocerca volvulus and the intestinal forms of Strongyloides stercoralis .

Off-label indications
Ivermectin is most widely used in dermatology for the treatment of scabies, and to a lesser extent for the treatment of pediculosis and cutaneous larva migrans. A single dose of ivermectin has been used empirically to reduce the pruritus in homeless populations. 9 Worldwide, it has also been used to treat infestations caused by Ascaris lumbricoides , Enterobius vermicularis (pinworm), Mansonella ozzardi , Gnathostomia spingerum , Mansonella streptocera , and Trichuris trichiura (whipworm), as well as both bancroftian and brugian filariasis.

Therapeutic guidelines
Dosages range from 150 to 400 µg/kg. In the treatment of scabies, 200 µg/kg (which is roughly 1 mg/10 pound body weight) is commonly given as a single dose, and repeated in a week to 10 days. For lice, a single 400 µg/kg dose has been given on day 1 and day 8. Follow-up clinical evaluations with scrapings and stool examinations are recommended depending on the organism being treated. Q11-1 Q11-4 In the setting of crusted scabies (common in immunocompromised patients), ivermectin should generally be used in conjunction with keratolytics and topical therapy, but dosing is otherwise the same as in immunocompetent patients. Ivermectin has been used in the control of hospital and institutional outbreaks of scabies, and may be superior to topical treatment in the setting of mass infestations 10 – 12 ( Table 11-1 ).
Table 11-1 Weight-based guidelines for ivermectin dose close to 200 µg/kg Patient weight (kg) Dose (mg) 15–24 3 25–35 6 36–50 9 51–65 12 66–79 15

Adverse effects
More than 350 million people have been safely treated with ivermectin worldwide, and there are few significant adverse reactions. Rare deaths have most often been associated with high levels of Loa loa microfilaremia, and serious and potentially fatal encephalopathy has been reported in patients co-infected with loiasis. Encephalopathy following the administration of ivermectin in other patients has demonstrated vascular pathology in the brain similar to that in previously reported cases of Loa loa-associated death following diethylcarbamazine treatment. 13
Q11-5 Cutaneous and systemic reactions in patients with onchocerciasis are termed Mazzoti reactions and may include rash, systemic symptoms, and ophthalmological reactions. These may be due to allergic and inflammatory responses to the death of microfilariae or to microorganisms within the worms. Doxycycline can eliminate endosymbiotic bacteria within filarial worms, reducing the incidence of Mazotti reactions.
The following reactions to ivermectin have been reported in >10% of patients in the setting of helminthic infestations. They are less common in the setting of scabies infestation.

1. Mazzotti-type reaction: The overall incidence of rashes, including edema and urticaria, is 23% in the setting of helminthic infestation.
2. Pruritus (28% in the setting of helminthic infestation)
3. Fever (23% in the setting of helminthic infestation)
4. Lymphadenopathy or lymph node tenderness (1–14%)
Less frequent reactions include tachycardia, facial edema, orthostatic hypotension, diarrhea, and nausea. CNS symptoms and Stevens–Johnson syndrome are rare. Liver function test abnormalities have been reported.
A single Canadian report of increased deaths among nursing home patients using ivermectin has not been confirmed in other trials. Many of the reported patients were ill or suffered from dementia, and were housed in a single closed ward. Although an increase in patient deaths was reported in the one Canadian study, no causal association was established.
Q11-6 P-glycoprotein restricts the entry of ivermectin across the blood–brain barrier by an ATP-driven efflux mechanism, and deficiencies have been implicated as a risk factor for neurotoxicity. In dogs with a homozygous mutation, ivermectin accumulates in the brain, producing neurotoxicosis and even death. In this animal model, selamectin is safer than ivermectin. In knockout mice, both drugs have been shown to be substrates of P-glycoprotein, but selamectin accumulates to a much lesser degree than ivermectin in the absence of P-glycoprotein. 14 Mutations in the P-glycoprotein drug resistance gene ABCB1 (MDR1) are responsible for the severe neurotoxicity seen in collie dogs treated with ivermectin, but the same mutations do not appear to be responsible for the subchronic neurotoxicity seen in other breeds following macrocyclic lactone treatment for generalized demodicosis, suggesting that other genes or other mechanisms of toxicity may be important. 15
Ivermectin is routinely used to treat parasitic infestations in cattle. There have been ongoing concerns about residual drug present in milk products, and single nucleotide polymorphisms in transport proteins may result in higher residual amounts in milk from certain cows. 16 This has raised concerns about the potential for hypersensitivity reactions and the emergence of resistance.

Drug interactions
Ivermectin may enhance the anticoagulant effect of vitamin K antagonists such as warfarin. There is some potential for interaction with drugs that affect levels of CYP3A4, although metabolism by this enzyme system is relatively minor. Rifampicin and phenobarbital enhanced CYP3A activity, and alter ivermectin gastrointestinal disposition via enhanced P-glycoprotein-mediated intestinal transport. Of the two, phenobarbital had the greater effect in a rat model. 17

Resistance
Q11-7 Suboptimal responses to ivermectin in onchocerciasis control efforts in Ghana have raised concern about the development of resistance to ivermectin. 18 Although ivermectin remains a potent microfilaricide, resistant adult parasite populations are emerging which could eventually lead to recrudescence of the disease. 19 Increased expression of ABC transport proteins is associated with nematode resistance to ivermectin. Resistant strains can demonstrate a multidrug resistance phenotype with cross-resistance to moxidectin, levamisole, and pyrantel. 20 Ivermectin resistance in Onchocerca volvulus may be related to single nucleotide polymorphisms of P-glycoprotein-like protein. 21
Emerging evidence suggests that scabies mites are also becoming resistant to oral ivermectin, prompting the study of alternatives as well as synergists that could be used in conjunction with ivermectin. 22 Piperonyl butoxide, S,S,S -tributyl phosphorotrithioate, and diethyl maleate show promise as synergists for pyrethroids. There is mounting concern about the emergence of both permethrin and ivermectin resistance in scabies mites. 23 Ivermectin-resistant scabies mites have already been identified in heavily endemic areas and resistance is likely to be seen elsewhere as well. 24 An outbreak of scabies in and outside a nursing home in The Netherlands persisted despite treatment with lindane and ivermectin, suggesting clinically significant resistance to these drugs. 25 Sarcoptes scabiei var. hominis mites from scabies-endemic communities in northern Australia have shown increasing resistance to both 5% permethrin and oral ivermectin, based on increased drug metabolism and efflux mechanisms. 26, 27 Ivermectin-resistant ticks are also emerging, posing a problem for cattle farmers and making ivermectin a somewhat less attractive option for the treatment of humans with massive tick infestation. 28, 29

Pregnancy prescribing status: category C
Teratogenic effects have been observed in some animal studies. The manufacturer states that ivermectin should not be used during pregnancy, as safety in pregnancy has not been established. Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given repeatedly at doses of respectively 0.2, 8.1, and 4.5 times the maximum recommended human dose. In animals, developmental effects were found only at or near doses that were toxic to the pregnant female, suggesting that the drug is not selectively toxic to the developing fetus.

Lactation
Q11-8 The drug enters breast milk, and safety and efficacy for use in children <15 kg have not been established; therefore, ivermectin use is not recommended during lactation. It is not recommended for children under 15 kg.

Clinical comparisons
There have been few head-to-head trials. Although some studies have shown ivermectin to be inferior to permethrin and benzyl benzoate, in one study in a population where infestation was highly endemic it compared favorably to topical benzyl benzoate and monosulfiram. 30 Several authors have suggested that mass infestations are the best setting for the use of ivermectin.

Albendazole
The chemical name for albendazole is methyl 5-(propylthio)-2-benzimidazolecarbamate. It is classified as a benzimidazole carbamate with both antihelminthic and antiprotozoal activity.

Pharmacology
Albendazole has low aqueous solubility and is poorly absorbed from the gastrointestinal tract. Levels of the parent drug are negligible or undetectable in plasma as it is rapidly converted to a sulfoxide metabolite before reaching the systemic circulation. The systemic antihelminthic activity has been attributed to this primary metabolite, albendazole sulfoxide. Oral bioavailability is enhanced when albendazole is taken with a fatty meal. Its main metabolite, the sulfoxide, attains maximum concentration after approximately 2.5 hours. The half-life of the major metabolite in the plasma is 8 hours. Urinary excretion of the metabolite albendazole sulfoxide is minor, with less than 1% of the dose recovered in the urine. Biliary elimination is presumed to be the major route of excretion, so biliary obstruction will affect blood levels, but renal failure is unlikely to affect levels. Albendazole sulfoxide is 70% bound to plasma protein and achieves excellent distribution throughout the body. Therapeutic levels can be detected in urine, bile, liver, cyst fluid, and cerebral spinal fluid.

Mechanism of action
Q11-9 Albendazole acts by inhibiting tubulin polymerization, which immobilizes and then kills the susceptible organisms.

Clinical use

Approved indications
Q11-3 Albendazole is approved for the treatment of neurocystocercosis and hydatid disease.

Off-label indications
Its uses include infestations caused by Ascaris lumbricoides, Trichuris trichiura, Enterobius vermicularis, Ancylostoma duodenale and Necator americanus (hookworms), Taenia spp. (tapeworms) and Strongyloides stercoralis. It is also used for the treatment of Giardia infestations.
Crusted scabies has been treated with oral albendazole in combination with topical crotamiton and salicylic acid 5%. 31 As the latter two are not very effective in this setting, improvement may relate to the albendazole. In regard to reductions in Pediculus humanus capitis infestation, ivermectin-containing antihelminthic regimens are significantly more effective than those containing diethylcarbamazine (DEC) alone, or DEC plus albendazole (p < 0.05). 32
Cutaneous disease and granulomatous amebic encephalitis caused by Balamuthia mandrillaris has been reported to respond to a combination of miltefosine, fluconazole, and albendazole. 33 Ivermectin is often combined with albendazole in the treatment of bancroftian filariasis. 34 Water-soluble albendazole–cyclodextrin–polymer systems (albendazole-β-cyclodextrin-polyvinylpyrrolidone) have produced good pharmacokinetic profiles (based on C max and AUC (area under the curve)) and good cysticidal efficacy against Taenia crassiceps . 35
Albendazole has a potent anti-angiogenic effect, inhibiting endothelial cell migration, lumen formation, vasopermeability, VEGF receptor-2 expression and retinal neovascularization. 36 The anti-angiogenic effect suggests a potential role in treating cutaneous tumors.

Therapeutic guidelines ( Table 11-2)
For other indications in adults, the drug is typically given at a dose of 400 mg (2 × 200 mg tablets) as a single dose. The tablets may be chewed, swallowed, or crushed and mixed with food. Albendazole has not been adequately studied in children under 1 year of age.

Table 11-2 Albendazole dosing (from package insert)

Adverse effects
Albendazole can cause bone marrow suppression, aplastic anemia, and agranulocytosis. Bone toxicity may occur in patients with and those without underlying hepatic dysfunction. Blood counts should be monitored. The manufacturer recommends a CBC at the beginning of each 28-day cycle of therapy, and every 2 weeks while on therapy; periodic liver function tests would also be wise. Patients with liver disease, including those with hepatic echinococcosis, appear to be at increased risk for bone marrow suppression. Other adverse effects include hepatotoxicity, gastrointestinal discomfort, diarrhea, headache, and dizziness. Less frequent reactions include hypersensitivity reactions presenting with rash, pruritus, or urtic