The fifth edition of Antimicrobial Therapy in Veterinary Medicine, the most comprehensive reference available on veterinary antimicrobial drug use, has been thoroughly revised and updated to reflect the rapid advancements in the field of antimicrobial therapy. Encompassing all aspects of antimicrobial drug use in animals, the book provides detailed coverage of virtually all types of antimicrobials relevant to animal health. Now with a new chapter on antimicrobial therapy in zoo animals, Antimicrobial Therapy in Veterinary Medicine offers a wealth of invaluable information for appropriately prescribing antimicrobial therapies and shaping public policy.

Divided into four sections covering general principles of antimicrobial therapy, classes of antimicrobial agents, special considerations, and antimicrobial drug use in multiple animal species, the text is enhanced by tables, diagrams, and photos. Antimicrobial Therapy in Veterinary Medicine is an essential resource for anyone concerned with the appropriate use of antimicrobial drugs, including veterinary practitioners, students, public health veterinarians, and industry and research scientists.

KEY FEATURES• Presents a comprehensive reference on veterinary applications for antimicrobial drugs, written by leaders in the field• Provides a fully up-to-date, current resource on antimicrobial therapy, with updates throughout the book• Features a new chapter on antimicrobial therapy in zoological species• Covers common infectious diseases and appropriate dosages for frequently used antimicrobial agents in many species• Offers tables, diagrams, and photos to supplement the text

THE EDITORS

RELATED TITLES

ANTIMICROBIAL THERAPY

IN VETERINARY MEDICINEEdited by Steeve Giguère, John F. Prescott and Patricia M. Dowling

FIFTH EDITIONFIFTH EDITION

ANTIMICROBIAL THERAPY I N V E T E R I N A R Y M E D I C I N E

Guide to Antimicrobial Use in AnimalsEdited by Luca Guardabassi, Lars Bogø Jensen, and Hilde Kruse9781405150798

Veterinary Pharmacology and Therapeutics, Ninth EditionEdited by Jim E. Riviere and Mark G. Papich9780813820613

Steeve Giguère, DVM, PhD, DACVIM, is Professor of Large Animal Internal Medicine and the Marguerite Hodgson Chair in Equine Studies at the College of Veterinary Medicine, University of Georgia, in Athens, Georgia.

John F. Prescott, MA, VetMB, PhD, is Professor in the Department of Pathobiology at the University of Guelph in Guelph, Ontario.

Patricia M. Dowling, DVM, MS, DACVIM, DACVCP, is Professor of Veterinary Clinical Pharmacology at the University of Saskatchewan in Saskatoon, Saskatchewan.

ANTIMICROBIAL THERAPY

IN VETERINARY MEDICINE

Giguère Prescott Dowling

FIFTH EDITION

PS0001File Attachment9780470963029.jpg

Antimicrobial Therapy in Veterinary MedicineFifth Edition

Antimicrobial Therapy in Veterinary MedicineFifth Edition

Editors

Steeve GiguèreDVM, PhD, DACVIMProfessor, Large Animal Internal MedicineMarguerite Hodgson Chair in Equine StudiesCollege of Veterinary MedicineUniversity of Georgia

John F. PrescottMA, VetMB, PhDProfessorDepartment of PathobiologyUniversity of Guelph

Patricia M. Dowling DVM, MS, DACVIM, DACVCPProfessor, Veterinary Clinical PharmacologyVeterinary Biomedical SciencesUniversity of Saskatchewan

This edition first published 2013 © 2013 by John Wiley & Sons, IncCopyright is not claimed for chapters 3, 5, and 39, which are in the public domain.

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Library of Congress Cataloging-in-Publication Data

Antimicrobial therapy in veterinary medicine / [edited by] Steeve Giguère, John F. Prescott, Patricia M. Dowling. – 5th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-96302-9 (hardback : alk. paper) – ISBN 978-1-118-67501-4 – ISBN 978-1-118-67507-6 (pub) – ISBN 978-1-118-67510-6 (pdf) – ISBN 978-1-118-67516-8 (mobi) I. Giguère, S. (Steeve) II. Prescott, John F. (John Francis), 1949- III. Dowling, Patricia M. [DNLM: 1. Drug Therapy–veterinary. 2. Anti-Infective Agents–therapeutic use. SF 918.A48] SF918.A48 636.089′5329–dc23

2013012731

A catalogue record for this book is available from the British Library.

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Cover design by Jennifer Miller

Set in 10/12pt Minion by SPi Publisher Services, Pondicherry, India

1 2013

v

ContentsContributors ix

Preface xiii

Important Notice xv

Abbreviations xvii

SECTion i GEnErAl PrinCiPlES oF AnTiMiCrobiAl ThErAPy 1

1 Antimicrobial Drug Action and Interaction: An Introduction 3Steeve Giguère

2 Antimicrobial Susceptibility Testing Methods and Interpretation of Results 11Joseph E. Rubin

3 Antimicrobial Resistance and Its Epidemiology 21Patrick Boerlin and David G. White

4 Principles of Antimicrobial Drug Bioavailability and Disposition 41J. Desmond Baggot and Steeve Giguère

5 The Pharmacodynamics of Antimicrobial Agents 79Marilyn N. Martinez, Pierre-Louis Toutain, and John Turnidge

6 Principles of Antimicrobial Drug Selection and Use 105Steeve Giguère

7 Antimicrobial Stewardship in Animals 117J. Scott Weese, Stephen W. Page, and John F. Prescott

SECTion ii ClASSES oF AnTiMiCrobiAl AGEnTS 133

8 Beta-lactam Antibiotics: Penam Penicillins 135John F. Prescott

9 Beta-lactam Antibiotics: Cephalosporins 153John F. Prescott

10 Other Beta-lactam Antibiotics: Beta-lactamase Inhibitors, Carbapenems, and Monobactams 175John F. Prescott

11 Peptide Antibiotics: Polymyxins, Glycopeptides, Bacitracin, and Fosfomycin 189Patricia M. Dowling

12 Lincosamides, Pleuromutilins, and Streptogramins 199Steeve Giguère

13 Macrolides, Azalides, and Ketolides 211Steeve Giguère

14 Aminoglycosides and Aminocyclitols 233Patricia M. Dowling

vi Contents

15 Tetracyclines 257Jérôme R.E. del Castillo

16 Chloramphenicol, Thiamphenicol, and Florfenicol 269Patricia M. Dowling

17 Sulfonamides, Diaminopyrimidines, and Their Combinations 279John F. Prescott

18 Fluoroquinolones 295Steeve Giguère and Patricia M. Dowling

19 Miscellaneous Antimicrobials: Ionophores, Nitrofurans, Nitroimidazoles, Rifamycins, and Others 315Patricia M. Dowling

20 Antifungal Chemotherapy 333Steeve Giguère

SECTion iii SPECiAl ConSidErATionS 357

21 Prophylactic Use of Antimicrobial Agents, and Antimicrobial Chemotherapy for the Neutropenic Patient 359Steeve Giguère, Anthony C.G. Abrams-Ogg, and Stephen A. Kruth

22 Performance Uses of Antimicrobial Agents and Non-antimicrobial Alternatives 379Thomas R. Shryock and Stephen W. Page

23 Antimicrobial Therapy of Selected Organ Systems 395Patricia M. Dowling

24 Antimicrobial Therapy of Selected Bacterial Infections 421Steeve Giguère

25 Antimicrobial Drug Residues in Foods of Animal Origin 431Patricia M. Dowling

26 Regulation of Antimicrobial Use in Animals 443Karolina Törneke and Christopher Boland

SECTion iV AnTiMiCrobiAl druG uSE in SElECTEd AniMAl SPECiES 455

27 Antimicrobial Drug Use in Horses 457Steeve Giguère and Tiago Afonso

28 Antimicrobial Drug Use in Dogs and Cats 473Jane E. Sykes

29 Antimicrobial Drug Use in Cattle 495Michael D. Apley and Johann F. Coetzee

30 Antimicrobial Drug Use in Mastitis 519Sarah Wagner and Ron Erskine

31 Antimicrobial Drug Use in Sheep and Goats 529Chris R. Clark

32 Antimicrobial Drug Use in New World Camelids 541Christopher K. Cebra and Margaret L. Cebra

Contents vii

33 Antimicrobial Drug Use in Swine 553David G.S. Burch

34 Antimicrobial Drug Use in Poultry 569Charles L. Hofacre, Jenny A. Fricke, and Tom Inglis

35 Antimicrobial Drug Use in Companion Birds 589Keven Flammer

36 Antimicrobial Drug Use in Rabbits, Rodents, and Ferrets 601Colette L. Wheler

37 Antimicrobial Drug Use in Reptiles 623Ramiro Isaza and Elliott R. Jacobson

38 Antimicrobial Drug Use in Zoological Animals 637Ellen Wiedner and Robert P. Hunter

39 Antimicrobial Drug Use in Aquaculture 645Renate Reimschuessel, Ron A. Miller, and Charles M. Gieseker

Index 663

ix

Contributors

Chapter numbers are in parentheses.

Anthony C.G. Abrams-Ogg (21)Associate ProfessorDepartment of Clinical StudiesOntario Veterinary CollegeUniversity of GuelphOntario, Canada

Tiago Afonso (27)Graduate Research AssistantCollege of Veterinary MedicineUniversity of GeorgiaAthens, Georgia

Michael D. Apley (29)Professor and Section HeadDepartment of Clinical SciencesKansas State UniversityCollege of Veterinary MedicineManhattan, Kansas

J. Desmond Baggot (4)75 Morehampton SquareDublin 4, Ireland

Patrick Boerlin (3)Associate ProfessorDepartment of PathobiologyOntario Veterinary CollegeUniversity of GuelphOntario, Canada

Christopher Boland (26)Director, Capstone ConsultantsAdvisor to Agricultural Compounds and Veterinary Medicines GroupNew Zealand Ministry for Primary IndustriesWellington, New Zealand

David G.S. Burch (33)DirectorOctagon Services Ltd.The Round House, The Friary, Old WindsorBerkshire, United Kingdom

Christopher K. Cebra (32)ProfessorDepartment of Clinical SciencesCollege of Veterinary MedicineOregon State UniversityCorvallis, Oregon

Margaret L. Cebra (32)Private Consultant33766 SE Terra CircleCorvallis, Oregon

Chris R. Clark (31)Assistant Professor, Large Animal MedicineDepartment of Large Animal Clinical SciencesWestern College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

x Contributors

Johann F. Coetzee (29)Associate Professor, CYCADS Section LeaderVeterinary Diagnostic & Production Animal MedicineCollege of Veterinary MedicineIowa State UniversityAmes, Iowa

Jérôme R.E. del Castillo (15)Associate Professor of Veterinary Pharmacology and ToxicologyDépartement de Biomédecine Vétérinaire, Université de MontréalSt-Hyacinthe, Québec, Canada

Patricia M. Dowling (11, 14, 16, 18, 19, 23, 25)Professor, Veterinary Clinical PharmacologyVeterinary Biomedical SciencesUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Ron Erskine (30)ProfessorLarge Animal Clinical SciencesCollege of Veterinary MedicineEast Lansing, Michigan

Keven Flammer (35)Professor of Avian MedicineClinical SciencesCollege of Veterinary MedicineNorth Carolina State UniversityRaleigh, North Carolina

Jenny A. Fricke (34)Associate VeterinarianPoultry Health Services Ltd.Airdrie, Alberta, Canada

Charles M. Gieseker (39)Office of ResearchCenter for Veterinary MedicineU.S. Food and Drug AdministrationLaurel, Maryland

Steeve Giguère (1, 4, 6, 12, 13, 18, 20, 21, 24, 27)Professor, Large Animal Internal MedicineMarguerite Hodgson Chair in Equine StudiesCollege of Veterinary MedicineUniversity of GeorgiaAthens, Georgia

Charles L. Hofacre (34)ProfessorPopulation HealthCollege of Veterinary MedicineUniversity of GeorgiaAthens, Georgia

Robert P. Hunter (38)Principal ConsultantEmerging Markets RegulatoryElanco Animal HealthGreenfield, Indiana

Tom Inglis (34)Poultry Health Services Ltd.Airdrie, Alberta, Canada

Ramiro Isaza (37)Associate ProfessorDepartment of Small Animal Clinical SciencesCollege of Veterinary MedicineUniversity of FloridaGainesville, Florida

Contributors xi

Elliott R. Jacobson (37)Emeritus ProfessorDepartment of Small Animal Clinical SciencesCollege of Veterinary MedicineUniversity of FloridaGainesville, Florida

Stephen A. Kruth (21)Professor EmeritusDepartment of Clinical StudiesOntario Veterinary CollegeUniversity of GuelphOntario, Canada

Marilyn N. Martinez (5)Senior Research ScientistOffice of New Animal Drug EvaluationCenter for Veterinary MedicineU.S. Food and Drug AdministrationRockville, Maryland

Ron A. Miller (39)Regulatory Review MicrobiologistOffice of New Animal Drug EvaluationCenter for Veterinary MedicineU.S. Food and Drug AdministrationRockville, Maryland

Stephen W. Page (7, 22)DirectorAdvanced Veterinary TherapeuticsNewtown NSW, Australia

John F. Prescott (7, 8, 9, 10, 17)ProfessorDepartment of PathobiologyUniversity of GuelphOntario, Canada

Renate Reimschuessel (39)DirectorVeterinary Laboratory Response NetworkCenter for Veterinary MedicineU.S. Food and Drug AdministrationLaurel, Maryland

Joseph E. Rubin (2)Assistant ProfessorDepartment of Veterinary MicrobiologyUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Thomas R. Shryock (22)Senior Research Advisor—MicrobiologyGlobal Regulatory AffairsElanco Animal HealthGreenfield, Indiana

Jane E. Sykes (28)ProfessorDepartment of Medicine & EpidemiologyUniversity of California, DavisDavis, California

Karolina Törneke (26)Senior ExpertMedical Products AgencyUppsala, Sweden

Pierre-Louis Toutain (5)Professor, EmeritusEcole Nationale Veterinaire de ToulouseFrance

John Turnidge (5)Clinical ProfessorPathology and Paediatrics, Faculty of Health SciencesUniversity of AdelaideAustralia

xii Contributors

Sarah Wagner (30)Associate ProfessorDepartment of Animal SciencesNorth Dakota State UniversityFargo, North Dakota

J. Scott Weese (7)ProfessorPathobiologyOntario Veterinary CollegeUniversity of GuelphOntario, Canada

Colette L. Wheler (36)Saskatchewan Poultry Extension VeterinarianDepartment of Veterinary Pathology, Western College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

David G. White (3)Director, Office of ResearchCenter for Veterinary MedicineU.S. Food and Drug AdministrationLaurel, Maryland

Ellen Wiedner (38)Clinical Lecturer in Zoo and Wildlife MedicineCollege of Veterinary MedicineUniversity of FloridaGainesville, Florida

xiii

Preface

The field of anti-infective therapy has expanded considerably since the first edition of Antimicrobial Therapy in Veterinary Medicine was published in 1988. The fifth edition is a completely updated and considera-bly expanded version of the previous edition, with the same aim of providing a comprehensive source for this crucial topic in veterinary medicine. Everyone working with antimicrobial drugs is aware of the continuing threat of resistance and of the important role that each of us plays in trying to preserve the efficacy of these drugs.

The book is divided into four sections. The first pro-vides general principles of antimicrobial therapy and includes a new chapter on antimicrobial stewardship. The second section describes each class of antimicrobial agents, revised to include not only the most up-to-date information on antimicrobial agents specific to veteri-nary species but also newly developed drugs not yet used in veterinary medicine. The third section deals with special considerations. It includes chapters on pro-phylactic and metaphylactic use of antimicrobial agents, antimicrobial chemotherapy for the neutropenic patient, and approach to therapy of selected bacterial pathogens and organ systems. Chapters on regulations of antibiotic use in animals, performance uses of antimicrobial

agents, and antimicrobial drug residues in foods of animal origin have been revised extensively against the  background of new regulations and the extensive re-examination in many countries of the use of antimi-crobial agents as growth promoters or in the prevention of disease in animals. The final section addresses the specific principles of antimicrobial therapy in multiple veterinary species. A chapter on antimicrobial therapy in zoological animals has been added to this edition to reflect the increase in popularity of these species.

Two members of the previous editorial team (J.D. Baggot and R.D. Walker) have retired. We thank them for their outstanding contributions over the years and we wish them the best in their new endeavors. The fifth edition welcomes 13 new contributors. We are grateful to all the contributors for the care and effort they have put into their chapters. We thank the staff of Wiley Blackwell Publishing, particularly Susan Engelken and Erica Judisch, for their help, patience, and support of this book. We encourage readers to send us comments or suggestions for improvements so that future editions can be improved.

Steeve Giguère, John Prescott, and Patricia Dowling

xv

important notice

The indications and dosages of all drugs in this book are the recommendations of the authors and do not always agree with those given on package inserts prepared by pharmaceutical manufacturers in different countries. The medications described do not necessarily have the specific approval of national regulatory authorities, including the U.S. Food and Drug Administration, for

use in the diseases and dosages recommended. In addition, while every effort has been made to check the contents of this book, errors may have been missed. The package insert for each drug product should therefore be consulted for use, route of administration, dosage, and (for food animals) withdrawal period, as approved by the reader’s national regulatory authorities.

xvii

Abbreviations

Abbreviations used in this book include:

MIC minimum inhibitory concentrationMBC minimum bactericidal concentrationPO per os, oral administrationIM intramuscular administrationIV intravenous administrationSC subcutaneous administrationSID single daily administrationBID twice-daily administration (every 12 hours)TID 3 times daily administration (every 8 hours)QID 4 times daily administration (every 6 hours)q 6 h, q 8 h, q 12 h, etc. Every 6, 8, 12 hours, etc.

For example, a dosage of “10 mg/kg TID IM” means 10 milligrams of the drug per kilogram of body weight, administered every 8 hours intramuscularly.

Section IGeneral Principles of Antimicrobial Therapy

3

Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. Edited by Steeve Giguère, John F. Prescott and Patricia M. Dowling. © 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

Antimicrobial drug Action and interaction: An introductionSteeve Giguère

Antimicrobial drugs exploit differences in structure or biochemical function between host and parasite. Modern chemotherapy is traced to Paul Ehrlich, a pupil of Robert Koch, who devoted his career to discovering agents that possessed selective toxicity so that they might act as so-called “magic bullets” in the fight against infectious dis-eases. The remarkable efficacy of modern antimicrobial drugs still retains a sense of the miraculous. Sulfonamides, the first clinically successful broad-spectrum antibacte-rial agents, were produced in Germany in 1935.

However, it was the discovery of the antibiotic peni-cillin, a fungal metabolite, by Fleming in 1929, and its subsequent development by Chain and Florey during World War II, that led to the antibiotic revolution. Within a few years of the introduction of penicillin, many other antibiotics were described. This was followed by the development of semisynthetic and synthetic (e.g., sulfonamides and fluoroquinolones) antimicrobial agents, which has resulted in an increas-ingly powerful and effective array of compounds used to treat infectious diseases. In relation to this, the term antibiotic has been defined as a low molecular weight substance produced by a microorganism that at low concentrations inhibits or kills other microorganisms. In contrast, the word antimicrobial has a broader defini-tion than antibiotic and includes any substance of natu-ral, semisynthetic, or synthetic origin that kills or inhibits the growth of a microorganism but causes little or no damage to the host. In many instances, antimicro-bial agent is used synonymously with antibiotic.

The marked structural and biochemical differences between prokaryotic and eukaryotic cells give antimi-crobial agents greater opportunities for selective toxicity against bacteria than against other microorganisms such as fungi, which are nucleated like mammalian cells, or viruses, which require their host’s genetic material for replication. Nevertheless, in recent years increasingly effective antifungal and antiviral drugs have been intro-duced into clinical practice.

Important milestones in the development of antibacterial drugs are shown in Figure 1.1. The therapeutic use of these agents in veterinary medicine has usually followed their use in human medicine because of the enormous costs of devel-opment. However, some antibacterial drugs have been developed specifically for animal health and production (e.g., tylosin, tiamulin, tilmicosin, ceftiofur, tulathromycin, gamithromycin, tildipirosin). Figure 1.1 highlights the rela-tionship between antibiotic use and the development of resistance in many target microorganisms.

Spectrum of Activity of Antimicrobial drugs

Antimicrobial drugs may be classified in a variety of ways, based on four basic features.

Class of MicroorganismAntiviral and antifungal drugs generally are active only against viruses and fungi, respectively. However, some imi-dazole antifungal agents have activity against staphylococci

1

Penicillin discovered 8

1930

2

4

6

8

'40

2

4

6

8

'50

2

4

6

8

'60

2

4

6

8

'70

2

4

6

8

'80

2

4

6

8

'90

2

4

6

8

2000

2

4

6

8

10

First sulfonamide released

Streptomycin, first aminoglycoside

Chloramphenicol

Chlortetracycline, first tetracycline

Erythromycin, first macrolide

Vancomycin

Methicillin, penicillinase-resistant penicillin

Gentamicin, antipseudomonal penicillin

Ampicillin Cephalothin, first cephalosporin

Amikacin, aminoglycoside for gentamicin-resistant strains

Carbenicillin, first antipseudomonal beta-lactam

Cefoxitin, expanded-spectrum cephalosporin

Cefaclor, oral cephalosporin with improved activity

Cefotaxime, antipseudomonal cephalosporin

Clavulanic-acid-amoxicillin, broad beta-lactamase inhibitor

Imipenem-cilastatinNorfloxacin, newer quinolone for urinary tract infections Aztreonam, first monobactam

Newer fluoroquinolone for systemic use

Improved macrolides

Oral extended-spectrum cephalosporins

Effective antiviral drugs for HIV Quinupristin-dalfopristin Linezolid, first approved oxazolidinone Broader-spectrum fluoroquinolones Telithromycin, first ketolide

Tigecycline, first glycylcycline Retapamulin, first pleuromutilin (topical)

Doripenem Telavancin, semi-synthetic derivative of vancomycin Ceftaroline

Antibacterial agents Human infectious diseases

Serious infections respond to sulfonamide

Florey demonstrates penicillin's effectiveness

Penicillin-resistant infections become clinically significant

Gentamicin-resistant Pseudomonas andmethicillin-resistant staphylococcal infections

become clinically significant

Beginning in early 1970s, increasing trend of nosocomial infections due to

opportunistic pathogens

Ampicillin-resistant infections become frequent

AIDS-related bacterial infections

Expansion of methicillin-resistant staphylococcalinfections

Vancomycin-resistant enterococci

Multidrug-resistant Mycobacterium tuberculosis

Penicillin-resistant Streptococcus pneumoniae

Spread of extended-spectrumbeta-lactamases among Gram-negatives

Multidrug-resistant Pseudomonas,Acinetobacter baumanii, and S. pneumoniae

Figure 1.1. Milestones in human infectious disease and their relationship to development of antibacterial drugs. Modified and reproduced with permission from Kammer, 1982.

4

Chapter 1. Antimicrobial drug Action and interaction 5

and nocardioform bacteria. Antibacterial agents are described as narrow-spectrum if they inhibit only bacteria or broad-spectrum if they also inhibit mycoplasma, rickett-sia, and chlamydia. The spectrum of activity of common antibacterial agents is shown in Table 1.1.

Antibacterial ActivitySome antibacterial drugs are also considered narrow-spectrum in that they inhibit only Gram-positive or Gram-negative bacteria, whereas broad-spectrum drugs inhibit both Gram-positive and Gram-negative bacteria. However, this distinction is not always absolute, as some agents may be primarily active against Gram-positive bac-teria but will also inhibit some Gram-negatives (Table 1.2).

bacteriostatic or bactericidal ActivityThe minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial agent required to prevent the growth of the pathogen. In contrast, the minimum bactericidal concentration (MBC) is the low-est concentration of an antimicrobial agent required to kill the pathogen. Antimicrobials are usually regarded as bactericidal if the MBC is no more than 4 times the MIC. Under certain clinical conditions this distinction is important, but it is not absolute. In other words, some  drugs are often bactericidal (e.g., beta-lactams,

aminoglycosides) and others are usually bacteriostatic (e.g., chloramphenicol, tetracyclines), but this distinction is an approximation, depending on both the drug con-centration at the site of infection and the microorganism involved. For example, benzyl penicillin is bactericidal at usual therapeutic concentrations and bacteriostatic at low concentrations.

Time- or Concentration-dependent ActivityAntimicrobial agents are often classified as exerting either time-dependent or concentration-dependent activity depending on their pharmacodynamic prop-erties. The pharmacodynamic properties of a drug address the relationship between drug concentration and antimicrobial activity (chapter 5). Drug pharma-cokinetic features, such as serum concentrations over time and area under the serum concentration-time curve (AUC), when integrated with MIC values, can predict the probability of bacterial eradication and clinical success. These pharmacokinetic and pharma-codynamic relationships are also important in pre-venting the selection and spread of resistant strains. The most significant factor determining the efficacy of beta-lactams, some macrolides, tetracyclines, tri-methoprim-sulfonamide combinations, and chloram-phenicol is the length of time that serum concentrations

Table 1.1. Spectrum of activity of common antibacterial drugs.

Drug

Class of Microorganism

Bacteria Fungi Mycoplasma Rickettsia Chlamydia Protozoa

Aminoglycosides + - + - - -Beta-lactams + - - - - -Chloramphenicol + - + + + -Fluoroquinolones + - + + + -Glycylcyclines + + + + +/-Lincosamides + - + - - +/-Macrolides + - + - + +/-Oxazolidinones + - + - - -Pleuromutilins + - + - + -Tetracyclines + - + + + +/-Streptogramins + - + - + +/-Sulfonamides + - + - + +Trimethoprim + - - - - +

+/–: Activity against some protozoa.

6 Section i. General Principles of Antimicrobial Therapy

exceed the MIC of a given pathogen. Increasing the concentration of the drug several-fold above the MIC does not significantly increase the rate of microbial killing. Rather, it is the length of time that bacteria are exposed to concentrations of these drugs above the MIC that dictates their rate of killing. Optimal dosing of such antimicrobial agents involves frequent admin-istration. Other antimicrobial agents such as the ami-noglycosides, fluoroquinolones, and metronidazole exert concentration-dependent killing characteristics. Their rate of killing increases as the drug concentra-tion increases above the MIC for the pathogen and it is not necessary or even beneficial to maintain drug lev-els above the MIC between doses. Thus, optimal dos-ing of aminoglycosides and fluoroquinolones involves administration of high doses at long dosing intervals. Some drugs exert characteristics of both time- and concentration-dependent activity. The best predictor

of efficacy for these drugs is the 24-hour area under the serum concentration versus time curve (AUC)/MIC ratio. Glycopeptides, rifampin, and, to some extent, fluoroquinolones fall within this category (chapter 5).

Mechanisms of Action of Antimicrobial drugs

Antibacterial drugsFigure 1.2 summarizes the diverse sites of action of the antibacterial drugs. Their mechanisms of action fall into four categories: inhibition of cell wall synthesis, damage to cell membrane function, inhibition of nucleic acid syn-thesis or function, and inhibition of protein synthesis.

Antibacterial drugs that affect cell wall synthesis (beta-lactam antibiotics, bacitracin, glycopeptides) or

Table 1.2. Antibacterial activity of selected antibiotics.

Spectrum

Aerobic Bacteria Anaerobic Bacteria

ExamplesGram + Gram – Gram + Gram –

Very broad + + + + Carbapenems; chloramphenicol; third-generation fluoroquinolones; glycylcyclines

Intermediately broad + + + (+) Third- and fourth-generation cephalosporins

+ (+) + (+) Second-generation cephalosporins

(+) (+) (+) (+) TetracyclinesNarrow + +/- + (+) Ampicillin; amoxicillin;

first-generation cephalosporins+ - + (+) Penicillin; lincosamides;

glycopeptides; streptogramins; oxazolidinones

+ +/– + (+) Macrolides+/- + - - Monobactams; aminoglycosides(+) + - - Second-generation

fluoroquinolones(+) (+) - - Trimethoprim-sulfa- - + + Nitroimidazoles+ - (+) (+) Rifamycin

+: Excellent activity.(+): Moderate activity.+/-: Limited activity.-: No or negligible activity.

Chapter 1. Antimicrobial drug Action and interaction 7

inhibit protein synthesis (aminoglycosides, chloram-phenicol, lincosamides, glycylcyclines, macrolides, oxazolidinones, streptogramins, pleuromutilins, tetra-cyclines) are more numerous than those that affect

cell  membrane function (polymyxins) or nucleic acid function (fluoroquinolones, nitroimidazoles, nitro-furans, rifampin), although the development of fluoro-quinolones has been a major advance in antimicrobial

Chloramphenicol

Nitroimidazoles,nitrofurans

Sulfonamides,trimethoprim

Purinesynthesis

Cell wall

Cell membrane

DNA FluoroquinolonesNovobiocin

Beta-lactamantibiotics,glycopeptides,bacitracin

Polyenes

RibosomeRifampin

MessengerRNA

Newprotein

TransferRNA

Amino acids

Tetracyclines,aminoglycosides

Oxazolidinones

Lincosamides,macrolides,streptogramins

30S

50S

Figure 1.2. Sites of action of commonly used antibacterial drugs that affect virtually all important processes in a bacterial cell. Modified and reproduced with permission after Aharonowitz and Cohen, 1981.

8 Section i. General Principles of Antimicrobial Therapy

therapy. Agents that affect intermediate metabolism (sulfonamides, trimethoprim) have greater selective toxicity than those that affect nucleic acid synthesis.

Searching for new Antibacterial drugsInfection caused by antibiotic-resistant bacteria has been an increasingly growing concern in the last decade. The speed with which some bacteria develop resistance considerably outpaces the slow development of new antimicrobial drugs. Since 1980, the number of antimi-crobial agents approved for use in people in the United States has fallen steadily (Figure  1.3). Several factors such as complex regulatory requirements, challenges in drug discovery, and the high cost of drug development coupled with the low rate of return on investment anti-biotics provide compared with drugs for the treatment of chronic conditions all contribute to driving pharma-ceutical companies out of the antimicrobial drug mar-ket. This has left limited treatment options for infections caused by methicillin-resistant staphylococci and van-comycin-resistant enterococci. The picture is even bleaker for infections cause by some Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumanii, and extended-spectrum beta-lactamase (ESBL)-resistant E. coli, Klebsiella spp., and Enterobacter spp., which are occasionally resistant to all the antimi-crobial agents on the market. Judicious use of the antibi-otics currently available and better infection control practices might help prolong the effectiveness of the

drugs that are currently available. However, even if we improve these practices, resistant bacteria will continue to develop and new drugs will be needed.

The approaches in the search for novel antibiotics include further development of analogs of existing agents; identifying novel targets based on a biotech-nological approach, including use of information obtained from bacterial genome sequencing and gene cloning; screening of natural products from plants and microorganisms from unusual ecological niches other than soil; development of antibacterial peptide mole-cules derived from phagocytic cells of many species; screening for novel antimicrobials using combinato-rial chemical libraries; development of synthetic antibacterial drugs with novel activities, such as oxa-zolidinones; development of new antibiotic classes that were abandoned early in the antibiotic revolution because there were existing drug classes with similar activities; development of “chimeramycins” by labora-tory recombination of genes encoding antibiotics of different classes; and combination of antibacterial drugs with iron-binding chemicals targeting bacterial iron uptake mechanisms.

Antifungal drugsMost currently used systemic antifungal drugs dam-age cell membrane function by binding ergosterols that are unique to the fungal cell membrane (polyenes, azoles; chapter 20). The increase in the number of

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Figure 1.3. New antimicrobial agents approved for use in people in the United States since 1980.

Chapter 1. Antimicrobial drug Action and interaction 9

HIV-infected individuals and of people undergoing organ or bone marrow transplants has resulted in increased numbers of immunosuppressed individuals in many societies. The susceptibility of these people to fungal infections has renewed interest in the discovery and development of new antifungal agents. The focus of antifungal drug development has shifted to cell wall structures unique to fungi (1,3-β-D-glucan synthase inhibitors, chitin synthase inhibitors, mannoprotein binders; Figure 20.1).

Antibacterial drug interactions: Synergism, Antagonism, and indifference

Knowledge of the different mechanisms of action of antimicrobials provides some ability to predict their interaction when they are used in combination. It was clear from the early days of their use that combinations of antibacterials might give antagonistic rather than additive or synergistic effects. Concerns regarding combinations include the difficulty in defining syner-gism and antagonism, particularly their method of determination in vitro; the difficulty of predicting the effect of a combination against a particular organism; and the uncertainty of the clinical relevance of in vitro findings. The clinical use of antimicrobial drug combi-nations is described in chapter 6. Antimicrobial com-binations are used most frequently to provide broad-spectrum empiric coverage in the treatment of patients that are critically ill. With the availability of  broad-spectrum antibacterial drugs, combinations of  these drugs are less commonly used, except for specific purposes.

An antibacterial combination is additive or indifferent if the combined effects of the drugs equal the sum of their independent activities measured separately; syner-gistic if the combined effects are significantly greater than the independent effects; and antagonistic if the combined effects are significantly less than their inde-pendent effects. Synergism and antagonism are not absolute characteristics. Such interactions are often hard to predict, vary with bacterial species and strains, and may occur only over a narrow range of concentrations or ratios of drug components. Because antimicrobial drugs may interact with each other in many different ways, it is apparent that no single in vitro method will

detect all such interactions. Although the techniques to quantify and detect interactions are relatively crude, the observed interactions occur clinically.

The two methods commonly used, the checkerboard and the killing curve methods, measure two different effects (growth inhibition and killing, respectively) and have sometimes shown poor clinical and laboratory cor-relation. In the absence of simple methods for detecting synergism or antagonism, the following general guide-lines may be used.

Synergism of Antibacterial CombinationsAntimicrobial combinations are frequently synergistic if they involve (1) sequential inhibition of successive steps in metabolism (e.g., trimethoprim-sulfonamide); (2) sequential inhibition of cell wall synthesis (e.g., mecilli-nam-ampicillin); (3) facilitation of drug entry of one antibiotic by another (e.g., beta-lactam-aminoglycoside); (4) inhibition of inactivating enzymes (e.g., amoxicillin-clavulanic acid); and (5) prevention of emergence of resistant populations (e.g., macrolide-rifampin).

Antagonism of Antibacterial CombinationsTo some extent the definition of antagonism as it relates to antibacterial combinations reflects a labora-tory artifact. However, there have been only a few well-documented clinical situations where antagonism is clinically important. Antagonism may occur if anti-bacterial combinations involve (1) inhibition of bacte-ricidal activity such as treatment of meningitis in which a bacteriostatic drug prevents the bactericidal activity of another; (2) competition for drug-binding sites such as macrolide-chloramphenicol combinations (of uncertain clinical significance); (3) inhibition of cell permeability mechanisms such as chlorampheni-col-aminoglycoside combinations (of uncertain clini-cal significance); and (4) induction of beta-lactamases by beta-lactam drugs such as imipenem and cefoxitin combined with older beta-lactam drugs that are beta-lactamase unstable.

The impressive complexity of the interactions of antibiotics, the fact that such effects may vary depend-ing of the bacterial species, and the uncertainty of the applicability of in vitro findings to clinical settings make predicting the effects of some combinations hazardous. For example, the same combination may cause both antagonism and synergism in different strains of the

10 Section i. General Principles of Antimicrobial Therapy

same bacterial species. Laboratory determinations are really required but may give conflicting results depend-ing on the test used. Knowledge of the mechanism of action is probably the best approach to predicting the outcome of the interaction in the absence of other guidelines.

In general, the use of combinations should be avoided, because the toxicity of the antibiotics will be at least additive and may be synergistic, because the  ready availability of broad-spectrum bactericidal drugs  has made their use largely unnecessary, and because they may be more likely to lead to bacterial superinfection. There are, however, well-established circumstances, discussed in chapter 6, in which combinations of drugs are more effective and often less toxic than drugs administered alone.

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tion of pharmaceuticals. Sci Am 245:141.Boucher HW, et al. 2009. Bad bugs, no drugs: no ESKAPE!

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Bryskier A. 2005. In pursuit of new antibiotics. In: Bryskier A (ed). Antimicrobial Agents: Antibacterials and Antifungals. Washington, DC: ASM Press.

Cantón R, et al. 2011. Emergence and spread of antibiotic resistance following exposure to antibiotics. FEMS Microbiol Rev 35:977.

Kammer RB. 1982. Milestones in antimicrobial therapy. In: Morin RB, Gorman M (eds). Chemistry and Biology of Beta-Lactam Antibiotics, vol. 3. Orlando: Academic Press.

Pillai SK, et al. 2005. Antimicrobial combinations. In: Lorian V (ed). Antibiotics in Laboratory Medicine, 5th ed. Philadelphia: Lippincott Williams and Wilkins.