Part 1 book Antibiotic and chemotherapy expert consult presentation of content: Historical introduction, modes of action, hharmacodynamics of antiinfective agentstarget delineation and susceptibility breakpoint selection, the problem of resistance, antimicrobial agents and the kidneys, antibiotics and the immune system,... Mời các bạn cùng tham khảo.
Antibiotic and Chemotherapy Commissioning Editor: Sue Hodgson Development Editor: Nani Clansey Editorial Assistant: Poppy Garraway/Rachael Harrison Project Manager: Jess Thompson Design: Charles Gray Illustration Manager: Bruce Hogarth Illustrator: Merlyn Harvey Marketing Manager (USA): Helena Mutak Antibiotic and Chemotherapy Anti-infective agents and their use in therapy N I N T H E D I T I O N Roger G Finch MB BS FRCP FRCP(Ed) FRCPath FFPM Professor of Infectious Diseases, School of Molecular Medical Sciences, Division of Microbiology and Infectious Diseases, University of Nottingham and Nottingham University Hospitals, The City Hospital, Nottingham, UK David Greenwood PhD DSc FRCPath Emeritus Professor of Antimicrobial Science, University of Nottingham Medical School, Nottingham, UK S Ragnar Norrby MD PhD FRCP Professor, The Swedish Institute for Infectious Disease Control, Stockholm, Sweden Richard J Whitley MD Distinguished Professor Loeb Scholar in Pediatrics, Professor of Pediatrics, Microbiology, Medicine and Neurosurgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA Edinburgh London New York Philadelphia St Louis Sydney Toronto 2010 SAUNDERS an imprint of Elsevier Limited © 2010, Elsevier Limited All rights reserved First edition 1963 Second edition 1968 Third edition 1971 Fourth edition 1973 Fifth edition 1981 Sixth edition 1992 Seventh edition 1997 Eighth edition 2003 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: http://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) The chapter entitled ‘Antifungal Agents’ by David W Warnock is in the public domain 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: 978-0-7020-4064-1 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 Contents Preface vii List of Contributors ix Section 2: Agents Introduction to Section 2 144 Section 1: General aspects Historical introduction David Greenwood Modes of action 10 Ian Chopra The problem of resistance 24 Olivier Denis, Hector Rodriguez-Villalobos and Marc J Struelens Pharmacodynamics of anti-infective agents: target delineation and susceptibility breakpoint selection 49 Johan W Mouton 12 Aminoglycosides and aminocyclitols 145 Andrew M Lovering and David S Reeves 13 β-Lactam antibiotics: cephalosporins 170 David Greenwood 14 β-Lactam antibiotics: penicillins 200 Karen Bush 15 Other β-lactam antibiotics 226 Karen Bush 16 Chloramphenicol and thiamphenicol 245 Mark H Wilcox Antimicrobial agents and the kidney 60 S Ragnar Norrby 17 Diaminopyrimidines 250 Göte Swedberg and Lars Sundström Drug interactions involving anti-infective agents 68 Keith A Rodvold and Donna M Kraus 18 Fosfomycin and fosmidomycin 259 David Greenwood Antibiotics and the immune system 104 Arne Forsgren and Kristian Riesbeck General principles of antimicrobial chemotherapy 110 Roger G Finch Laboratory control of antimicrobial therapy 115 Gunnar Kahlmeter and Derek Brown 10 Principles of chemoprophylaxis 123 S Ragnar Norrby 11 Antibiotic policies 126 Peter G Davey, Dilip Nathwani and Ethan Rubinstein 19 Fusidanes 262 David Greenwood 20 Glycopeptides 265 Neil Woodford 21 Lincosamides 272 David Greenwood 22 Macrolides 276 André Bryskier 23 Mupirocin 290 Adam P Fraise 24 Nitroimidazoles 292 Peter J Jenks 25 Oxazolidinones 301 Una Ni Riain and Alasdair P MacGowan vi Contents 26 Quinolones 306 Peter C Appelbaum and André Bryskier 27 Rifamycins 326 Francesco Parenti and Giancarlo Lancini 28 Streptogramins 334 Francisco Soriano 29 Sulfonamides 337 David Greenwood 30 Tetracyclines 344 Ian Chopra 31 Miscellaneous antibacterial agents 356 David Greenwood 32 Antifungal agents 366 David W Warnock 33 Antimycobacterial agents 383 John M Grange 34 Anthelmintics 395 George A Conder 35 Antiprotozoal agents 406 Simon L Croft and Karin Seifert 36 Antiretroviral agents 427 Mark Boyd and David A Cooper 37 Other antiviral agents 452 Richard J Whitley Section 3: Treatment 38 Sepsis 472 Anna Norrby-Teglund and Carl Johan Treutiger 39 Abdominal and other surgical infections 483 Eimear Brannigan, Peng Wong and David Leaper 40 Infections associated with neutropenia and transplantation 502 Emmanuel Wey and Chris C Kibbler 45 Infections of the lower respiratory tract 574 Lionel A Mandell and Robert C Read 46 Endocarditis 589 Kate Gould 47 Infections of the gastrointestinal tract 593 Peter Moss 48 Hepatitis 608 Janice Main and Howard C Thomas 49 Skin and soft-tissue infections 617 Anita K Satyaprakash, Parisa Ravanfar and Stephen K Tyring 50 Bacterial infections of the central nervous system 633 Jeffrey Tessier and W Michael Scheld 51 Viral infections of the central nervous system 650 Kevin A Cassady 52 Bone and joint infections 659 Werner Zimmerli 53 Infections of the eye 667 David V Seal, Stephen P Barrett and Linda Ficker 54 Urinary tract infections 694 S Ragnar Norrby 55 Infections in pregnancy 702 Phillip Hay and Rüdiger Pittrof 56 Sexually transmitted diseases 718 Sheena Kakar and Adrian Mindel 57 Leprosy 743 Diana Lockwood, Sharon Marlowe and Saba Lambert 58 Tuberculosis and other mycobacterial infections 752 L Peter Ormerod 59 Superficial and mucocutaneous mycoses 771 Roderick J Hay 60 Systemic fungal infections 777 Paula S Seal and Peter G Pappas 41 Infections in intensive care patients 524 Mark G Thomas and Stephen J Streat 61 Zoonoses 797 Lucy Lamb and Robert Davidson 42 Infections associated with implanted medical devices 538 Michael Millar and David Wareham 62 Malaria 809 Nicholas J White 43 Antiretroviral therapy for HIV 556 Anton Pozniak 44 Infections of the upper respiratory tract 567 Nicholas A Francis and Christopher C Butler 63 Other protozoal infections 823 Peter L Chiodini and Carmel M Curtis 64 Helminthic infections 842 Tim O’Dempsey Index 861 Preface The first edition of this book was published almost half a century ago Subsequent editions have generally been published in response to the steady flow of novel antibacterial compounds or the marketing of derivatives of existing classes of agents exhibiting advantages, sometimes questionable, over their parent compound In producing the ninth edition of this book the rationale has been not so much in response to the availability of new antibacterial compounds, but to capture advances in antiviral and, to a lesser extent, antifungal chemotherapy and also to highlight a number of changing therapeutic approaches to selected infections For example, the recognition that combination therapy has an expanded role in preventing the emergence of drug resistance; traditionally applied to the treatment of tuberculosis, it is now being used in the management of HIV, hepatitis B and C virus infections and, most notably, malaria among the protozoal infections The impact of antibiotic resistance has reached critical levels Multidrug-resistant pathogens are now commonplace in hospitals and not only affect therapeutic choice, but also, in the seriously ill, can be life threatening While methicillin-resistant Staphylococcus aureus (MRSA) has been taxing healthcare systems and achieved prominence in the media, resistance among Gram-negative bacillary pathogens is probably of considerably greater importance More specifically, resistance based on extended spectrum β-lactamase production has reached epidemic proportions in some hospitals and has also been recognized, somewhat belatedly, as a cause of much community infection There are also emerging links with overseas travel and possibly with the food chain The dearth of novel compounds to treat resistant Gram-negative bacillary infections is particularly worrying What is clear is that the appropriate use of antimicrobial drugs in the management of human and animal disease has never been more important As in the past, the aim of this book is to provide an international repository of information on the properties of antimicrobial drugs and authoritative advice on their clinical application The structure of the book remains unchanged, being divided into three parts Section addresses the general aspects of antimicrobial chemotherapy while Section provides a detailed description of the agents, either by group and their respective compounds, or by target microorganisms as in the case of non-antibacterial agents Section deals with the treatment of all major infections by site, disease or target pathogens as appropriate Some new chapters have been introduced and others deleted The recommended International Non-proprietary Names (rINN) with minor exceptions has once again been adopted to reflect the international relevance of the guidance provided viii Preface Our thanks go to our international panel of authors who have been selected for their expertise and who have shown patience with our deadlines and accommodated our revisions We also thank those who have contributed to earlier editions and whose legacy lives on in some areas of the text Here we wish to specifically thank both Francis O’Grady and Harold Lambert who edited this book for many years and did much to establish its international reputation Their continued support and encouragement is gratefully acknowledged We also welcome and thank Tim Hill for his pharmacy expertise in ensuring the accuracy of the information contained in the Preparation and Dosages boxes and elsewhere in the text Finally, we thank the Editorial Team at Elsevier Science for their efficiency and professionalism in the production of this new edition Roger Finch, David Greenwood, Ragnar Norrby, Richard Whitley Nottingham, UK; Stockholm, Sweden; Birmingham, USA February 2010 List of Contributors Peter C Appelbaum, MD PhD Professor of Pathology and Director of Clinical Microbiology Penn State Hershey Medical Center Hershey, PA, USA Stephen P Barrett, BA MSc MD PhD FRCPath DipHIC Consultant Medical Microbiologist Microbiology Department Southend Hospital Westcliff-on-Sea Essex, UK Mark Boyd, MD FRACP Clinical Project Leader, Therapeutic and Vaccine Research Program National Centre in HIV Epidemiology and Clinical Research and Senior Lecturer, University of New South Wales; Clinical Academic in Infectious Diseases and HIV Medicine St Vincent’s Hospital Darlinghurst Sydney, Australia Eimear Brannigan, MB MRCPI Consultant in Infectious Diseases Infection Prevention and Control Charing Cross Hospital London, UK Derek Brown, BSc PhD FRCPath Consultant Microbiologist Peterborough, UK André Bryskier, MD Consultant in Anti-Infective Therapies Le Mesnil le Roi, France Karen Bush, PhD Adjunct Professor Biology Department Indiana University Bloomington Bloomington, Indiana, USA Christopher C Butler, BA MBChB DCH FRCGP MD CCH HonFFPHM Professor of Primary Care Medicine, Cardiff University Head of Department of Primary Care and Public Health and Vice Dean (Research) Cardiff University Clinical Epidemiology Interdisciplinary Research Group School of Medicine, Cardiff University Cardiff, UK Kevin A Cassady, MD Assistant Professor of Pediatrics Division of Infectious Diseases Department of Pediatrics University of Alabama at Birmingham Children’s Harbor Research Center Birmingham, Alabama, USA Peter L Chiodini, BSc MBBS PhD MRCS FRCP FRCPath FFTMRCPS(Glas) Honorary Professor, Infectious and Tropical Diseases The London School of Hygiene and Tropical Medicine; Consultant Parasitologist, Department of Clinical Parasitology Hospital for Tropical Diseases London, UK Ian Chopra, BA MA PhD DSc MD(Honorary) Professor of Microbiology and Director of the Antimicrobial Research Centre Division of Microbiology, Institute of Molecular and Cellular Biology University of Leeds Leeds, UK George A Conder, PhD Director and Therapeutic Area Head Antiparasitics Discovery Research Veterinary Medicine Research and Development Pfizer Animal Health Pfizer Inc Kalamazoo, MI, USA David A Cooper, MD DSc Professor of Medicine Consultant Immunologist Faculty of Medicine University of New South Wales St Vincent’s Hospital National Centre in HIV Epidemiology and Clinical Research Darlinghurst Sydney, Australia Simon L Croft, PhD Professor of Parasitology Head of Department of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London, UK Carmel M Curtis, PhD MRCP Microbiology Specialist Registrar Department of Parasitology The Hospital for Tropical Diseases London, UK 380 CHAPTER 32 Antifungal agents Preparations and dosages Mepartricin Pharmacokinetics Preparations: Tablets, vaginal preparations, topical cream, oral suspension Oral absorption Complete Cmax 25 mg/kg 6-hourly oral 70–80 mg/L after 1–2 h Available in continental Europe; not available in the UK Plasma half-life 3–6 h Natamycin Volume of distribution 0.7–1 L/kg Preparations: Oral suspension, ophthalmic suspension, cream, vaginal preparations, lozenges Plasma protein binding c 12% Dosage: Adults, oral, tablets: oral candidiasis 10 mg every 4–6 h; intestinal candidiasis 100 mg every 4–6 h Available in continental Europe; not available in the UK Nystatin Proprietary names: Mycostatin, Nystan Preparations: Tablets, pastilles, oral suspension, vaginal and topical preparations Dosage: Adults, oral: oral candidiasis 100 000 units every h; intestinal candidiasis 500 000 units every h Prophylaxis: adults, million units per day; children, 100 000 units every h h; neonates, 100 000 units per day as a single dose Vaginal pessaries, 1–2 at night for at least 14 nights Widely available Absorption is slower in persons with impaired renal function, but peak concentrations are higher Levels in the CSF are around 75% of the simultaneous serum concentration More than 90% of a dose of flucytosine is excreted in the urine in unchanged form The serum half-life is much longer in renal failure, necessitating modification of the dosage regimen: for patients with a creatinine clearance below 40 mL/ the dosage interval should be doubled to 12 h; in severe renal failure the dosage interval should be further increased to once daily or less, based on frequent serum drug concentration measurements Interactions OTHER SYSTEMIC AGENTS FLUCYTOSINE 5-Fluorocytosine Molecular weight: 129.1 Cytosine arabinoside has been reported to inactivate flucytosine Drugs that are known to be myelosuppressive, such as zidovudine and ganciclovir, should be used with caution in individuals receiving flucytosine NH2 F N O N H A synthetic fluorinated pyrimidine available for intravenous infusion or oral administration Antifungal activity The spectrum of activity is restricted to Candida spp., Crypto coccus spp and some fungi causing chromoblastomycosis Acquired resistance About 2–3 of Candida spp isolates (more in some centers) are resistant before treatment starts, and resistance may develop during treatment The most common cause of resistance appears to be loss of the enzyme uridine monophosphate pyrophosphorylase Toxicity and side effects Nausea, vomiting, abdominal pain and diarrhea are common Serious side effects include myelosuppression and hepatic toxicity; they occur more frequently when serum concentrations exceed 100 mg/L The nephrotoxic effects of amphotericin B can result in elevated blood concentrations of flucytosine, and levels of the latter drug should be monitored when these compounds are administered together Clinical use Candidosis (in combination with amphotericin B or fluconazole) Cryptococcosis (in combination with amphotericin B or fluconazole) Monitoring of flucytosine concentrations is desirable in all patients, and mandatory in those with renal impairment other topical agents Interactions Preparations and dosage Proprietary names: Alcobon, Ancobon, Ancotil Preparations: Tablets, capsules, i.v infusion Dosage: Adults, oral, i.v., 200 mg/kg per day in four divided doses For extremely sensitive organisms, 50–150 mg/kg per day in four divided doses may be sufficient Widely available Griseofulvin can diminish the anticoagulant effect of warfarin Its absorption is reduced in persons receiving concomitant treatment with phenobarbital Toxicity and side effects Adverse reactions occur in about 15% of patients and include headache, nausea, vomiting, rashes and photosensitivity Further information Francis P, Walsh TJ Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy Clin Infect Dis 1992;15:1003–1018 Vermes A, Guchelaar HJ, Dankert J Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions J Antimicrob Chemother 2000;46:171–179 Clinical use Dermatophyte infections of hair, skin and nail Preparations and dosage GRISEOFULVIN Proprietary names: Fulcin, Fulvicin, Grifulvin V, Grisactin, Grisovin, Grisol Molecular weight: 352.8 Preparations: Tablets, capsules, oral suspension CH3O O Dosage: Adults, oral, 500 mg per day as a single or divided dose In severe infections the dose may be doubled, reducing when response occurs Children, 10 mg/kg per day in divided doses, or as a single dose OCH3 O Widely available CH3O CI CH3 A fermentation product of various species of Penicillium, including Pen griseofulvum Available as fine-particle or ultrafine-particle formulations for oral use Antifungal activity The spectrum of useful activity is restricted to dermatophytes causing skin, nail and hair infections (Epidermophyton, Microsporum and Trichophyton spp.) Resistance has seldom been reported Pharmacokinetics Absorption from the gastrointestinal tract is dependent on drug formulation Administration with a high-fat meal will increase the rate and extent of absorption, but individuals tend to achieve consistently high or low blood concentrations It appears in the stratum corneum within 4–8 h as a result of secretion in perspiration However, levels begin to fall soon after the drug is discontinued, and within 48–72 h it can no longer be detected It is metabolized in the liver, the metabolites being excreted in the urine The elimination half-life is 9–21 h Further information Bennett ML, Fleischer AB, Loveless JW, et al Oral griseofulvin remains the treatment of choice for tinea capitis in children Pediatr Dermatol 2000;17:304–309 OTHER TOPICAL AGENTS There is a large and miscellaneous group of topical antifungal agents, all of which are effective treatments for superficial mycoses They include the following: • Amorolfine hydrochloride A synthetic morpholine derivative that inhibits ergosterol biosynthesis It is used for the treatment of tinea corporis, tinea cruris, tinea pedis and onychomycosis • Butenafine hydrochloride A synthetic benzylamine derivative which acts as an ergosterol biosynthesis inhibitor It is used for the treatment of tinea corporis, tinea cruris and tinea pedis • Ciclopirox A synthetic pyridinone used in onychomycosis and as the olamine salt in tinea corporis, tinea cruris, tinea pedis, cutaneous candidosis and pityriasis versicolor • Haloprogin A halogenated phenolic which is effective in tinea corporis, tinea cruris, tinea pedis and pityriasis versicolor • Tolnaftate A thiocarbamate used in tinea cruris and tinea pedis 381 382 CHAPTER 32 Antifungal agents Preparations and dosages Amorolfine hydrochloride Proprietary name: Loceryl Preparations: Nail solution, cream Dosage: For fungal skin infections, apply once daily for at least 2–3 weeks (up to weeks for tinea pedis) For nail infections, apply solution 1–2 times weekly; treat fingernails for months, toenails for 9–12 months Widely available Butenafine hydrochloride Proprietary name: Mentax Preparation: Topical Dosage: For fungal skin infections dosage and duration of treatment varies according to condition Widely available Ciclopirox Proprietary names: Loprox, Penlac Preparations: Nail solution, cream, powder Dosage: For fungal skin infections, apply twice daily for at least 2–4 weeks For nail infections, apply solution once daily for at least months Widely available Haloprogin Proprietary name: Halotex Preparation: Topical Dosage: For fungal skin infections dosage and duration of treatment varies according to condition Widely available Tolnaftate Proprietary names: Aftate, Mycil, Tinactin Preparation: Topical Dosage: For fungal skin infections dosage and duration of treatment varies according to condition Widely available Further information Haria M, Bryson HM Amorolfine, a review of its pharmacological properties and therapeutic potential in the treatment of onychomycosis and other superficial fungal infections Drugs 1995;49:103–120 McNeely W, Spencer CM Butenafine Drugs 1998;55:405–412 The use of product names in this chapter does not imply their endorsement by the U.S Department of Health and Human Services The findings and conclusions in this chapter are those of the author and not necessarily represent the views of the Centers for Disease Control and Prevention Chapter 33 Antimycobacterial agents John M Grange The mycobacteria causing human disease, and therefore requiring treatment by antibacterial agents, are divisible into three groups: the tuberculosis complex (principally Mycobacterium tuberculosis, M bovis and M africanum in humans); the leprosy bacillus (M leprae); and various environmental saprophytes that occasionally cause human disease Patients with AIDS are particularly likely to develop disease due to the latter species, notably the Mycobacterium avium complex (MAC), although the incidence of such infection has declined in regions where antiretroviral therapy is widely available Antimycobacterial agents include natural and semisynthetic antibiotics and synthetic agents Some, such as rifampicin (rifampin; Ch 27) and streptomycin (Ch 12), are active against a wide range of bacteria, although their use is mostly restricted to the treatment of mycobacterial disease, and some are synthetic agents, mostly with activity only against mycobacteria The four first-line drugs used in modern short-course antituberculosis regimens (Ch 58) are rifampicin, isoniazid, pyrazinamide and ethambutol, with the latter three being synthetic agents Resistance to one or more of these agents requires the use of second-line drugs of which there are six classes – aminoglycosides (streptomycin, kanamycin, amikacin), cyclic peptides (capreomycin and, rarely, viomycin), thioamines (ethionamide, prothionamide), fluoroquinolones (Ch 26), cycloserine and p-aminosalicylic acid As a result of the increasing prevalence of tuberculosis resistant to many or most of the currently available antituberculosis agents, there is a pressing need for new drugs but there was little financial incentive for the pharmaceutical industry to meet this need This serious deficit has been addressed by the establishment of the Global Alliance for TB Drug Development by various agencies, especially the World Health Organization (WHO), and private foundations This Alliance has facilitated the development and clinical evaluation of several new agents, the progress of which is shown on the Alliance website, http://www.tballiance.org As at April 2010 PA-824, a nitroimidazole (Ch 24), moxifloxacin, a fluoroquinolone (Ch 26), and TMC 207, a diarylquinolone, were in clinical trial, and several other agents were undergoing preclinical evaluation In addition, the sequencing of the entire genome of M tuberculosis and innovations in computer modeling have paved the way to the development of ‘designer’ agents based on unique mycobacterial structures and metabolic pathways There is also growing interest in the use of adjunct immunotherapy to improve the treatment outcome in tuberculosis, particularly in drug-resistant cases The principal drugs for the treatment of leprosy (Ch 57) are dapsone, rifampicin and clofazimine, with prothionamide for patients who will not take clofazimine An alternative and increasingly used regimen is based on rifampicin, ofloxacin and minocycline Treatment of opportunist disease due to environmental mycobacteria poses serious problems as many patients have underlying complicating conditions, notably various causes of immunosuppression Drugs and regimens (see below) that are active in vitro are often ineffective clinically against these mycobacteria and novel approaches to treatment are required ANTIMICROBIAL ACTIVITY The action of antimycobacterial agents in vivo depends on the population dynamics of the mycobacteria within the lesions In the case of tuberculosis, some bacilli replicate freely in the walls of well-oxygenated cavities, some replicate more slowly in acidic and anoxic tissue and within macrophages and a few are in a near-dormant ‘persister’ state Isoniazid exerts a powerful and rapid bactericidal activity against the freely replicating bacilli and kills the great majority of such bacilli, with a substantial reduction of infectiousness, within a few days of commencing treatment It has little or no effect against the near-dormant bacilli, which are killed by rifampicin The slowly replicating bacilli in acidic, often anoxic, environments are killed by pyrazinamide, which is active only at low pH Thus a distinction may be drawn between agents that are bactericidal in vitro and those that actually ‘sterilize’ lesions in vivo Accordingly, the most widely used short-course antituberculosis regimen is based on a 2-month intensive phase of treatment with isoniazid, rifampicin, pyrazinamide and ethambutol, during which all except a few persisters are killed, and a 4-month continuation phase of rifampicin (which kills persisters during shorter bursts of metabolic activity) and 384 CHAPTER 33 Antimycobacterial agents isoniazid to kill any rifampicin-resistant mutants that might commence replication (Ch 58) In both tuberculosis and leprosy, the great majority of bacilli are killed during the first few weeks of therapy; prolonged therapy, with its associated problems of cost, compliance and the need for supervision, is required to kill a few remaining metabolically inactive persisters and thus prevent relapse In the absence of acquired drug resistance, strains of M. tuberculosis and related members of the tuberculosis complex are very similar in their susceptibility to the antituberculosis drugs, although strains of M bovis and some strains of M africanum are naturally resistant to pyrazinamide Environmental mycobacteria show very variable resistance to antituberculosis drugs and other antimicrobial agents, and in vitro susceptibility tests not accurately reflect clinical responses DRUG RESISTANCE Mutation to drug resistance occurs at a low but constant rate in all mycobacterial populations and such mutants (Table 33.1) are readily selected if the patient is treated with a single drug Successful therapy thus requires the use of at least two drugs to which the strain is susceptible An exception is the use of a single drug, usually isoniazid, to prevent the emergence of active tuberculosis in infected but healthy persons who are assumed to have very small numbers of bacilli in their tissues Emergence of drug resistance is uncommon in patients receiving a fully supervised course of modern shortcourse chemotherapy based on drugs of known quality Unfortunately, poor prescribing habits, unavailability of drugs, inadvertent use of time-expired or even counterfeit drugs, poor supervision of therapy and unregulated ‘overthe-counter’ sales of drugs have led to the emergence of drug-resistant tubercle bacilli in many countries Even fixed dose combination formulations occasionally lead to the development of single- or multiple-drug resistance if taken irregularly Tuberculosis resistant to rifampicin and isoniazid, with or without additional resistances, is termed multidrug-resistant (MDR) tuberculosis Extensive drug resistance (XDR) has arisen in many countries and is variously defined as MDR with additional resistance to three or more of the six classes of second-line drugs, or to fluoroquinolones and at least one injectable drug (aminoglycosides and cyclic peptides) The exact definition is an academic one as, despite the establishment of regional and supraregional reference laboratories, few countries have adequate facilities for conducting drug susceptibility tests Drug resistance may develop in an inadequately treated patient (acquired or secondary resistance) or a person may become infected with a resistant strain (initial or primary resistance) Likewise, primary and acquired drug resistance is encountered in leprosy and the WHO has advised that all cases of leprosy should be treated by combination therapy The WHO recommends that periodic surveys of primary drug resistance should be undertaken as these give a good measure of the efficiency of control programs The extent to which such surveys are carried out varies considerably from country to country: whereas in developed nations drug susceptibility tests are carried out on most or all clinical isolates of M tuberculosis, such testing is often carried out only sporadically, and perhaps on unrepresentative isolates, in many developing countries Table 33.1 Targets of antimycobacterial agents and genes determining resistancea Agent Target Gene(s) encoding target(s) or in which mutations conferring resistance occur p-Aminosalicylic acid Folic acid metabolism Unknown Clofazimine Uncertain Unknown Cyclic peptides (capreomycin and viomycin) 50S or 30S ribosomal subunit vicA (50S) or vicB (30S) Cycloserine Peptidoglycan synthesis alrA Dapsone Folic acid synthesis folP1 Ethambutol Cell wall arabinogalactan synthesis embA, embB and embC Isoniazid Mycolic acid synthesis katG, inhA gene or its promoter region, intergenic region of the oxyR–ahpC locus Pyrazinamide ? Bacterial membrane energetics and transport pncA Thioacetazone (amithiozone) Synthesis of cyclopropane rings in mycolic acid Genes coding for cyclopropane mycolic acid synthetase enzymes Thioamines (ethionamide and prothionamide) Mycolic acid synthesis inhA For details on aminoglycosides and rifampicin, see Chapters 12 and 27, respectively a TOXICITY AND SIDE EFFECTS Established market economy Central Europe Eastern Europe Latin America Eastern Mediterranean region Africa low HIV incidence Africa high HIV incidence South East Asia Western Pacific All regions 10 20 30 40 50 Percent Fig 33.1 Estimates, as a percentage, of multidrug-resistant tuberculosis among new (upper bar) and previously treated (lower bar) cases by World Health Organization epidemiological regions Black bars show the 95% confidence ranges In four global surveys of resistance undertaken between 1994 and 2007, the global prevalence of various patterns of drug resistance varied enormously from region to region, with particularly high levels in certain regions In 2008 the reported prevalence of MDR TB was over 5% in 14 regions: Armenia, Azerbaijan, the Baltic States (Estonia, Latvia, Lithuania), two provinces of China, Georgia, Moldova, three districts (Oblasts) of Russia, Ukraine and Uzbekistan The incidence of MDR TB in new and previously treated cases in the WHO epidemiological regions is shown in Figure 33.1 The precise incidence of XDR tuberculosis is unknown as resistance to the full range of antituberculosis agents is determined in a minority of laboratories worldwide, but in June 2008 cases had been reported in 49 countries In 2008, there were an estimated 490 000 cases of MDR TB and 40 000 cases of XDR TB PHARMACOKINETICS With the exception of streptomycin, other aminoglycosides and the cyclic peptides, all the antimycobacterial agents currently in use are absorbed adequately when given orally They are distributed to all tissues and organs and adequate amounts of the first-line antituberculosis agents cross the blood–brain barrier Thus, in principle, standard regimens and doses are suitable for treatment of all forms of tuberculosis, although many clinicians prescribe more prolonged courses of therapy for extrapulmonary tuberculosis, particularly tuberculous meningitis, and for cases of HIV-related tuberculosis Rifampicin, isoniazid, pyrazinamide, ethionamide and protionamide are either eliminated in the bile or metabolized, and may therefore be given in standard doses to patients with impaired renal function Ethambutol and aminoglycosides, which are eliminated predominantly or entirely by the kidney, should be avoided, if possible, in patients with impaired renal function Only small amounts of isoniazid and even smaller amounts of the other antituberculosis drugs enter the milk, so breast feeding is not contraindicated TOXICITY AND SIDE EFFECTS Unwanted side effects occur with all antituberculosis agents, but those caused by the first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) are less frequent and severe than those due to the older agents (streptomycin, p-aminosalicylic acid, thioacetazone) Side effects are particularly likely to occur in HIV-positive patients, who should never be given thioacetazone as fatal exfoliative dermatitis may occur (specific toxicities are discussed under the individual drugs) A transient and clinically insignificant rise in serum hepatic enzyme levels commonly occurs during the first few weeks of therapy and, unless the patient is known to have liver disease, routine assay of these enzymes is generally regarded as unnecessary Clinically evident hepatitis occurs in about 1% of patients and the incidence increases with age, although it usually resolves rapidly when therapy ends; usually therapy with the same drugs can be continued More generalized reactions, with rashes, influenzalike symptoms and sometimes lymphadenopathy and hepatic 385 386 CHAPTER 33 Antimycobacterial agents enlargement, with or without jaundice, may occur in the first months of therapy Therapy must be stopped, the responsible drug identified by giving small challenge doses sequentially, and treatment resumed without that drug Interactions between the antimycobacterial drugs themselves have been described: pyrazinamide and ethionamide may increase serum concentrations of isoniazid while pyrazinamide may decrease that of rifampicin, but these effects are of no known clinical significance More significant interactions occur between the antimycobacterial agents and drugs used for other purposes, particularly antiretroviral drugs (Chs 36 and 43) Most recorded drug interactions involve rifampicin and quinolones but some interactions with isoniazid have been described, especially in slow acetylators (p 390) CLINICAL USE Definite recommendations for the treatment of tuberculosis and leprosy have been made by the WHO (Chs 57 and 58) These regimens are also used for treating human tuberculosis due to M bovis and for the rare cases of disseminated disease due to the vaccine strain bacille Calmette-Guérin (BCG), although both are naturally resistant to pyrazinamide Isoniazid preventive therapy has a controversial history, but the HIV pandemic, leading to a greatly enhanced risk of tuberculosis, has led to re-evaluation of its protective role It can be safely used in HIV-infected persons as long as they not have active tuberculosis and it prevents the risk of the latter by 33–67% for up to years It is recommended for HIV-infected persons living in regions with a prevalence of latent tuberculosis of over 30% and for all those with known latent disease or exposure to a case of infectious tuberculosis Where available, a combination of isoniazid and antiretroviral therapy provides even greater protection Treatment of opportunist mycobacterial disease continues to pose problems, with a high failure rate, often due to coexistent HIV infection or other forms of immunosuppression Disease caused by slowly growing mycobacteria, principally the Mycobacterium avium complex, M kansasii, M xenopi and M. malmoense, is usually treated with rifampicin (or rifabutin) and ethambutol, together with clarithromycin or a fluoroquinolone In the absence of clinical trials, therapy of disease due to the rapidly growing mycobacteria, principally M abscessus, M. chelonae and M fortuitum, is empirical Limited infections such as post-injection abscesses respond to co-trimoxazole together with erythromycin More serious infections have responded to cefoxitin with amikacin The outcome of therapy is, however, unpredictable In-vitro drug susceptibility tests not give an accurate indication of clinical response lister-packs Several preparations containing rifampicin + b isoniazid, rifampicin + isoniazid + pyrazinamide or all four of the first-line drugs are commercially available but only those approved by the WHO should be used as in some combinations the bioavailability of the component drugs, especially rifampicin, is inadequate Further information Blomberg B, Spinaci S, Fourie B, Laing R The rationale for recommending fixeddose combination tablets for treatment of tuberculosis Bull World Health Org 2001;79:61–68 Colombo RE, Olivier KN Diagnosis and treatment of infections caused by rapidly growing mycobacteria Semin Respir Crit Care Med 2008;29:577–588 Crofton J, Chaulet P, Maher D Guidelines for the management of drug-resistant tuberculosis Geneva: WHO; 1997 Dorman SE, Chaisson RE From magic bullets back to the magic mountain: the rise of extensively drug-resistant tuberculosis Nat Med 2007;13:295–298 Gillespie SH Evolution of drug resistance in Mycobacterium tuberculosis: clinical and molecular perspective Antimicrob Agents Chemother 2002;46:267–274 Ginsberg AM Emerging drugs for active tuberculosis Semin Respir Crit Care Med 2008;29:552–559 Grange JM, Winstanley PA, Davies PDO Clinically significant drug interactions with antituberculosis agents Drug Safety 1994;11:242–251 Jenkins PA, Campbell IA, Banks J, Gelder CM, Prescott RJ, Smith AP Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunist mycobacterial lung diseases and an assessment of Mycobacterium vaccae immunotherapy Thorax 2008;63:627–634 Mitchison DA How drug resistance emerges as a result of poor compliance during short course chemotherapy of tuberculosis Int J Tuberc Lung Dis 1998;2:10–15 Mitchison DA Role of individual drugs in the chemotherapy of tuberculosis Int J Tuberc Lung Dis 2000;4:796–806 Mitnick CD, Shin SS, Seung KJ, et al Comprehensive treatment of extensively drug-resistant tuberculosis N Engl J Med 2008;359:563–574 Onyebujoh P, Zumla A, Ribiero I, et al Treatment of tuberculosis: present status and future prospects Bull World Health Org 2005;83:857–865 Peloquin CA Clinical pharmacology of antituberculosis drugs In: Davies PDO, Barnes PF, Gordon SB, eds Clinical tuberculosis 4th ed London: Hodder Arnold; 2008:205–224 Raviglione MC, Smith IM XDR tuberculosis – implications for global public health N Engl J Med 2007;356:656–659 World Health Organization/International Union Against Tuberculosis and Lung Disease Global project on anti-tuberculosis drug resistance surveillance 2008 Anti-tuberculosis drug resistance in the world Report no Geneva: WHO; 2008 World Health Organization 2003 (revision) Treatment of tuberculosis 3rd ed Guidelines for national programmes Geneva: WHO; 2005 World Health Organization Report of the expert consultation on immunotherapeutic interventions for tuberculosis Geneva: WHO; 2007 World Health Organization Guidelines for the programmatic management of drugresistant tuberculosis Emergency update Geneva: WHO; 2008 World Health Organization HIV/AIDS Department WHO Three I’s Meeting Intensified case finding (ICF), isoniazid preventive therapy (IPT) and TB infection control (IC) for people living with HIV WHO: Geneva; 2008 Zhang Y, Vilchèze C, Jacobs WR Mechanisms of drug resistance in Mycobacterium tuberculosis In: Cole ST, Eisenach K, McMurray D, Jacobs WR, eds Tuberculosis and the Tubercle Bacillus 2nd ed Washington, DC: American Society for Microbiology; 2005:115–140 FORMULATIONS CLOFAZIMINE Compliance with antituberculosis therapy is aided by use of fixed drug combination preparations and calendar Molecular weight: 473.4 CLINICAL USE a rare but serious complication of prolonged high-dose therapy for leprosy reactions Deposition of clofazimine in lymph nodes may interfere with lymphatic drainage, occasionally manifesting as edema of the feet Cl N N CH(CH3)2 N NH C1 One of a number of substituted iminophenazine dyes originally synthesized as potential antituberculosis agents It is almost insoluble in water It stimulates various phagocyte functions including release of free oxygen radicals, but it is not clear whether this contributes to its antimicrobial activity It also has anti-inflammatory properties, attributed to its ability to inhibit certain patterns of intracellular T-cell receptor-mediated signaling, making it a useful drug for treating leprosy reactions and possibly other autoimmune processes Antimicrobial activity The mode of action is not fully understood It has bacteristatic and weak bactericidal activity against several species of mycobacteria and some species of Actinomyces and Nocardia In-vitro minimum inhibitory concentrations (MICs) are: M. tuberculosis 0.5 mg/L and M leprae (assayed in a mouse model) 0.1–1 mg/L, but these MICs have limited clinical relevance as clofazimine shows marked differences in accumulation in various tissues Activity against M leprae is demonstrable in humans only after 50 days of therapy Clofazimine resistance, although reported, appears to be rare Pharmacokinetics Clofazimine is well absorbed by the intestine and is taken up by adipose tissue and cells of the macrophage/monocyte series, including those in the intestinal wall It has a very long half-life (variously estimated as 10–70 days) and is eliminated, mostly unchanged, in the urine and feces Toxicity and side effects Clofazimine is usually well tolerated, but some patients develop nausea, abdominal pain and diarrhea, relieved to some extent by taking the drug with a meal or glass of milk Dose-related, reversible, skin discoloration is very common and is unacceptable to some patients Discoloration of the hair, cornea, urine, sweat and tears also occurs Infants born to mothers receiving clofazimine are reversibly pigmented at birth Edema of the wall of the small intestine leading to subacute obstruction is Clinical use Multibacillary leprosy (in combination with other anti-leprosy drugs) Erythema nodosum leprosum (anti-inflammatory activity) Clofazimine has been suggested as a drug for treatment of MDR tuberculosis, although its efficacy is unproven It has been used to treat M ulcerans infection (Buruli ulcer) but with limited responses Use in disease caused by mycobacteria of the M avium complex is no longer recommended as more effective and less toxic alternative agents are available Preparations and dosage Proprietary name: Lamprene Preparation: Capsules Dosage: Multibacillary forms of leprosy: adults, oral, 300 mg once a month, supervised, and 50 mg per day or 100 mg on alternate days selfadministered Erythema nodosum leprosum: 300 mg once a day for no longer than months Further information Grange JM Detection of drug resistance in Mycobacterium leprae and the design of treatment regimens for leprosy In: Heifets L, ed Drug susceptibility in the chemotherapy of mycobacterial infections Boca Raton, FL: CRC Press; 1991:161–177 Jamet P, Traore I, Husser JA, Ji B Short-term trial of clofazimine in previously untreated lepromatous leprosy Int J Lepr 1992;60:542–548 Oommen ST, Natu MV, Mahajan MK, Kadyan RS Lymphangiographic evaluation of patients with clinical lepromatous leprosy on clofazimine Int J Lepr 1994;62:32–36 Reddy VM, O’Sullivan JF, Gangadharam PR Antimycobacterial activities of riminophenazines J Antimicrob Chemother 1999;43:615–623 Schaad-Lanyi Z, Dieterle W, Dubois JP, Theobold W, Vischer W Pharmacokinetics of clofazimine in healthy volunteers Int J Lepr 1987;55:9–15 Steel HC, Matlola NM, Anderson R Inhibition of potassium transport and growth of mycobacteria exposed to clofazimine and B669 is associated with a calciumindependent increase in microbial phospholipase A2 activity J Antimicrob Chemother 1999;44:209–216 DAPSONE Diaminodiphenyl sulphone (DDS) Molecular weight: 248.3 H2N SO2 NH2 The most effective of a number of sulfonamide derivatives to be tested against leprosy The dry powder is very stable It is only slightly soluble in water 387 388 CHAPTER 33 Antimycobacterial agents Antimicrobial activity Dapsone is active against many bacteria and some protozoa Fully susceptible strains of M leprae are inhibited by a little as 0.003 mg/L It is predominantly bacteristatic Resistance is associated with mutations in the folP1 gene involved in the synthesis of para-aminobenzoic acid Acquired resistance Resistance to high levels is acquired by several sequential mutations As a result of prolonged use of dapsone monotherapy, acquired resistance emerged in patients with multibacillary leprosy in many countries Initial resistance also occurs in patients with both paucibacillary and multibacillary leprosy Thus, leprosy should always be treated with multidrug regimens Resistance of M leprae to dapsone (and other anti-leprosy drugs) may now be determined by use of DNA microarrays Blood disorders include anemia, methemoglobinemia, sulfhemoglobinemia, hemolysis (notably in patients with glucose-6-phosphate dehydrogenase deficiency), mononucleosis, leukopenia and, rarely, agranulocytosis Severe anemia should be treated before patients receive dapsone The incidence of adverse reactions declined in the 1960s but reappeared around 1982 when multidrug therapy was introduced, and may represent an unexplained interaction with rifampicin Clinical use Leprosy (multidrug regimens) Prophylaxis of malaria, treatment of chloroquine-resistant malaria (in combination with pyrimethamine) Prophylaxis of toxoplasmosis (in combination with pyrimethamine) Prophylaxis (monotherapy) and treatment (in combination with trimethoprim) of Pneumocystis jirovecii pneumonia Dermatitis herpetiformis and related skin disorders Pharmacokinetics Preparations and dosage Oral absorption >90% Preparation: Tablets Cmax 100 mg oral c mg/L after 3–6 h Plasma half-life 10–50 h Plasma protein binding c 50% Dosage: For all forms of leprosy (in combination with other anti-leprosy drugs): Adults, 100 mg per day, children 1–2 mg/kg (maximum dose, 100 mg per day) Duration of treatment depends on type of leprosy and the other agents used It is slowly but almost completely absorbed from the intestine and widely distributed in the tissues, but selectively retained in skin, muscle, kidneys and liver It is metabolized by N-oxidation and also by acetylation, which is subject to the same genetic polymorphism as isoniazid (p 390) The elimination half-life is consequently very variable, but on standard therapy the trough levels are always well in excess of inhibitory concentrations It is mostly excreted in the urine: in the unchanged form (20%), as N-oxidation products (30%) and as a range of other metabolites Toxicity and side effects Although usually well tolerated at standard doses, gastrointestinal upsets, anorexia, headaches, dizziness and insomnia may occur Less frequent reactions include skin rashes, exfoliative dermatitis, photosensitivity, peripheral neuropathy (usually in non-leprosy patients), tinnitus, blurred vision, psychoses, hepatitis, nephrotic syndrome, systemic lupus erythematosus and generalized lymphadenopathy The term ‘dapsone syndrome’ is applied to a skin rash and fever occurring 2–8 weeks after starting therapy and sometimes accompanied by lymphadenopathy, hepatomegaly, jaundice and/or mononucleosis Further information Ahrens EM, Meckler RJ, Callen JP Dapsone-induced peripheral neuropathy Int J Dermatol 1986;25:314–316 Byrd SR, Gelber RH Effect of dapsone on haemoglobin concentration in patients with leprosy Lepr Rev 1991;62:171–178 Matsuoka M, Aye KS, Kyaw K, et al A novel method for simple detection of mutations conferring drug resistance in Mycobacterium leprae, based on a DNA microarray, and its applicability in developing countries J Med Microbiol 2008;57:1213–1219 Rai PP, Aschhoff M, Lilly L, Balakrishnan S Influence of acetylator phenotype of the leprosy patient on the emergence of dapsone resistant leprosy Indian J Lepr 1988;60:400–406 Richardus JH, Smith TC Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy Lepr Rev 1989;60:267–273 Williams DL, Spring L, Harris E, Roche P, Gillis TP Dihydropteroate synthase of Mycobacterium leprae and dapsone resistance Antimicrob Agents Chemother 2000;44:1530–1537 Zuidema J, Hilbers-Modderman ES, Merkus FW Clinical pharmacokinetics of dapsone Clin Pharmacokinet 1986;11:299–315 ETHAMBUTOL Hydroxymethylpropylethylene diamine Molecular weight (dihydrochloride): 277.2 CLINICAL USE CH2OH HC NH C2H5 CH2 CH2 NH C2H5 CH CH2OH A synthetic ethylenediamine derivative formulated as the dihydrochloride for oral administration The dry powder is very soluble and stable Antimicrobial activity Ethambutol is active against several species of mycobacteria and nocardiae MICs on solid media are: M tuberculosis 0.5–2 mg/L; M kansasii 1–4 mg/L; other slowly growing mycobacteria 2–8 mg/L; rapidly growing pathogens 2–16 mg/L; Nocardia spp 8–32 mg/L Resistance is uncommon and is a multistep process due to mutations in the embA, embB and embC gene cluster A mutation in codon 306 of the embB gene predisposes to the development of resistance to a range of antituberculosis agents, possibly by affecting cell-wall permeability Pharmacokinetics Oral absorption c 80%, but some patients absorb it poorly Cmax 25 mg/kg oral 2–6 mg/L after 2–3 h Plasma half-life 10–15 h Volume of distribution >3 L/kg Plasma protein binding 20–30% Absorption is impeded by aluminum hydroxide and alcohol It is concentrated in the phagolysosomes of alveolar macrophages It does not enter the cerebrospinal fluid (CSF) in health but CSF levels of 25–40% of the plasma concentration, with considerable variation between patients, are achieved in cases of tuberculous meningitis Various metabolites are produced, including dialdehyde, dicarboxylic acid and glucuronide derivatives Around 50% is excreted unchanged in the urine, with an additional 10–15% as metabolites, and 20% is excreted unchanged in feces color perception, and the drug should not be given to young children and others unable to comply with this advice Other side effects include gastrointestinal upsets, peripheral neuritis, arthralgia, nephritis, myocarditis, hyperuricemia, dermal hypersensitivity and, rarely, thrombocytopenia and hepatotoxicity Clinical use Tuberculosis (initial intensive phase of short-course therapy) Other mycobacterioses (M kansasii, M xenopi, M malmoense and the M. avium complex) (with appropriate additional drugs) Preparations and dosage Proprietary name: Myambutol Preparations: Tablets (and syrup on special request) Dosage: Adults and children, oral, 15–25 mg/kg per day for months or 25–30 mg/kg three times a week or 45–50 mg/kg twice a week If more prolonged therapy is indicated, the daily dose should not exceed 15 mg/kg; retreatment 25 mg/kg per day for the first 60 days Widely available Further information Citron KM Ocular toxicity from ethambutol Thorax 1986;41:737–739 Donald PR, Maher D, Maritz JS, Qazi S Ethambutol dosage for the treatment of children: literature review and recommendations Int J Tuberc Lung Dis 2006;10:1318–1330 Safi H, Sayers B, Hazbón MH, Alland D Transfer of embB codon 306 mutations into clinical Mycobacterium tuberculosis strains alters susceptibility to ethambutol, isoniazid, and rifampin Antimicrob Agents Chemother 2008;52:2027–2034 McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients Antimicrob Agents Chemother 2006;50:1170–1177 ISONIAZID Isonicotinic acid hydrazide (INH) Molecular weight: 137.1 N Toxicity and side effects CONHNH2 The most important side effect is optic neuritis, which may be irreversible if treatment is not discontinued This complication is rare if the higher dose (25 mg/kg) is given for no more than months National codes of practice for prevention of ocular toxicity should be adhered to; in particular, patients should be advised to stop therapy and seek medical advice if they notice any change in visual acuity, peripheral vision or One of a number of nicotinamide analogs found to have antituberculosis activity, following the observation that nicotinamide inhibited the replication of M tuberculosis It is soluble in water The dry powder is stable if protected from light It is a prodrug requiring oxidative activation by KatG, a mycobacterial catalase–peroxidase enzyme 389 390 CHAPTER 33 Antimycobacterial agents Antimicrobial activity Susceptibility to isoniazid is virtually restricted to the M tuberculosis complex (MIC 0.01–0.2 mg/L) It is highly bactericidal against actively replicating M tuberculosis Other mycobacteria are resistant, except for some strains of M.xenopi (MIC 0.2 mg/L) and a few strains of M kansasii (MIC mg/L) Acquired resistance Mutations in the katG gene, the inhA gene or its promoter region, and in the intergenic region of the oxyR–ahpC locus confer resistance to isoniazid (Table 33.1, p 384) The relative proportions of such mutations vary geographically and are related to the distribution of the various lineages or superfamilies of M tuberculosis Isoniazid resistance is the commonest form of drug resistance worldwide and the great majority of strains resistant to another agent are also resistant to isoniazid (see pp 384–385) Pharmacokinetics Oral absorption >95% Cmax 300 mg oral 3–5 mg/L after 1–2 h Plasma half-life 0.5–1.5 h (rapid acetylators) 2–4 h (slow acetylators) Volume of distribution 0.6–0.8 L/kg Plasma protein binding Very low Absorption and distribution Isoniazid is almost completely absorbed from the gut and is well distributed Absorption is impaired by aluminum hydroxide Therapeutic concentrations are achieved in sputum and CSF It crosses the placenta and is found in breast milk Metabolism Isoniazid is extensively metabolized to a variety of pharmacologically inactive derivatives, predominantly by acetylation As a result of genetic polymorphism, patients are divisible into rapid and slow acetylators About 50% of Caucasians and Blacks, but 80–90% of Chinese and Japanese, are rapid acetylators Acetylation status does not affect the efficacy of daily administered therapy The rate of acetylation is reduced in chronic renal failure Toxicity and side effects Toxic effects are unusual on recommended doses and are more frequent in slow acetylators Many side effects are neurological, including restlessness, insomnia, muscle twitching and difficulty in starting micturition More serious but less common neurological side effects include peripheral neuropathy, optic neuritis, encephalopathy and a range of psychiatric disorders, including anxiety, depression and paranoia Neurotoxicity is usually preventable by giving pyridoxine (vitamin B6) 10 mg per day Pyridoxine should be given to patients with liver disease, pregnant women, alcoholics, renal dialysis patients, HIV-positive patients, the malnourished and the elderly Encephalopathy, which has been reported in patients on renal dialysis, may not be prevented by, or respond to, pyridoxine, but usually resolves on withdrawal of isoniazid Isoniazid-related hepatitis occurs in about 1% of patients receiving standard short-course chemotherapy The incidence is unaffected by acetylator status It is more common in those aged over 35 years and preventive isoniazid monotherapy should be used with care in older people Less common side effects include arthralgia, a ‘flu’-like syndrome, hypersensitivity reactions with fever, rashes and, rarely, eosinophilia, sideroblastic anemia, pellagra (which responds to treatment with nicotinic acid) and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency It exacerbates acute porphyria and induces antinuclear antibodies, but overt systemic lupus erythematosus is rare Drug interactions Isoniazid increases the plasma concentrations of phenytoin and carbamazepine, sometimes enough to cause toxicity; antiepileptic therapy requires monitoring and adjustment of dosage as necessary It enhances defluorination of the anesthetic enflurane Drug interactions may be more pronounced in slow acetylators Prednisolone reduces isoniazid levels in both slow and rapid acetylators, but the mechanism is unclear Clinical use Tuberculosis (intensive and continuation phases) Prevention of primary tuberculosis in close contacts and reactivation disease in infected but healthy persons (monotherapy) Preparations and dosage Preparations: Tablets, elixir and injectable form Excretion Dosage: Adults, oral, 300 mg per day; children, 5–10 mg/kg per day (maximum dose, 300 mg per day) Neonates, 3–5 mg/kg per day (maximum dose, 10 mg/kg per day) Nearly all the dose is excreted in the urine within 24 h, as unchanged drug and metabolic products Widely available CLINICAL USE Further information Baker LV, Brown TJ, Maxwell O, et al Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates from England and Wales reveals the phylogenetic significance of the ahpC–46A polymorphism Antimicrob Agents Chemother 2005;49:1455–1464 Banerjee A, Dubnau E, Quemard A, et al InhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis Science 1994;263:227–230 Cheung WC, Lo CY, Lo WK, Ip M, Cheng IKP Isoniazid induced encephalopathy in dialysis patients Tuber Lung Dis 1993;74:136–139 Ellard GA The potential clinical significance of the isoniazid acetylator phenotype in the treatment of pulmonary tuberculosis Tubercle 1984;65:211–217 Gagneux S, Burgos MV, DeRiemer K, et al Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis PLoS Pathog 2006;2:e61 Guo H, Seet Q, Denkin S, Parsons L, Zhang Y Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA J Med Microbiol 2006;55:1527–1531 International Union Against Tuberculosis and Lung Disease/World Health Organization Tuberculosis preventive therapy in HIV-infected individuals Tuber Lung Dis 1994;75:96–98 Israel HL, Gottleib JE, Maddrey WC Perspective: preventive isoniazid therapy and the liver Chest 1992;101:1298–1301 Lee H, Cho SN, Bang HE, et al Exclusive mutations related to isoniazid and ethionamide resistance among Mycobacterium tuberculosis isolates from Korea Int J Tuberc Lung Dis 2000;4:441–447 Snider DE, Tabas GJ Isoniazid associated hepatitis deaths: a review of available information Am Rev Respir Dis 1992;145:494–497 PYRAZINAMIDE Pyrazinoic acid amide Molecular weight: 123.1 N CONH2 N Like isoniazid, pyrazinamide is a synthetic nicotinamide analog, although its mode of action is quite distinct is technically demanding as it requires very careful control of the pH of the medium, but molecular methods for detection of resistance-conferring mutations are available Pharmacokinetics Oral absorption >90% Cmax 20–22 mg/kg oral 10–50 mg/L after h Plasma half-life c h Plasma protein binding c 50% It readily crosses the blood–brain barrier, achieving CSF concentrations similar to plasma levels It is metabolized to pyrazinoic acid in the liver and oxidized to inactive metabolites, which are excreted in the urine, although about 70% of an oral dose is excreted unchanged Toxicity and side effects It is usually well tolerated Moderate elevations of serum transaminases occur early in treatment Severe hepatotoxicity is uncommon with standard dosage, except in patients with pre-existing liver disease Its principal metabolite, pyrazinoic acid, inhibits renal excretion of uric acid, but gout is extremely rare An unrelated arthralgia, notably of the shoulders and responsive to analgesics, also occurs Other side effects include anorexia, nausea, mild flushing of the skin and photosensitization Clinical use Antimicrobial activity It is principally active against actively metabolizing intracellular bacilli and those in acidic, anoxic inflammatory lesions Activity against M tuberculosis is highly pH dependent: at pH 5.6 the MIC is 8–16 mg/L, but it is almost inactive at neutral pH Other mycobacterial species, including M bovis, are resistant Activity requires conversion to pyrazinoic acid by the mycobacterial enzyme pyrazinamidase, encoded for by the pncA gene, which is present in M tuberculosis but not M. bovis A few resistant strains lack mutations in pncA, indicating alternative mechanisms for resistance, including defects in transportation of the agent into the bacterial cell Acquired resistance Drug resistance is uncommon and cross-resistance to other antituberculosis agents does not occur Susceptibility testing Tuberculosis (a component of the early, intensive phase of short-course therapy) Preparations and dosage Proprietary names: Tebrazid, Zinamide Preparation: Tablets Dosage: Adult, oral, g per day (>50 kg), 1.5 g per day (