Antimicrobial Therapy in Veterinary Medicine E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1939

Veröffentlichungsjahr: 2024

Beschreibung

Provides a comprehensive, fully updated reference book to the general principles and clinical applications of antimicrobials in veterinary medicine

The sixth edition of Antimicrobial Therapy in Veterinary Medicine has been updated to reflect advances in the field, including new international contributors and a broader global outlook. It includes extensive knowledge of both general principles of mechanisms of antimicrobial drug action including specific classes of antimicrobial agents, as well as chapters dedicated to antimicrobial drug use in a wide range of animal species. As antimicrobial resistance increases as a major global issue in both human and animal health, this book’s renewed focus on antimicrobial stewardship in companion animals, in food animals, and on global aspects keeps it at the forefront of this vital field.

The Sixth Edition of this classic text offers:

• Updates to every chapter, reflecting new developments and research, with a complete examination of the issues associated with antimicrobial resistance
• A comprehensive reference for all aspects of antimicrobial use in veterinary medicine, encompassing theory and practice
• A global perspective on antimicrobial therapy, with more international content than previous editions
• A stronger emphasis on antimicrobial stewardship, with practical guidance for prescribing antimicrobial drugs
• A companion website with tables and figures from the book available for download

Antimicrobial Therapy in Veterinary Medicine is an essential and accessible resource for veterinarians, veterinary students, scientists, and professionals in veterinary medicine and antimicrobial research and stewardship.

Leseprobe

Table of Contents

Cover

Table of Contents

Title Page

Copyright Page

Contributors

Preface

Acknowledgments

Important Notice

List of Abbreviations

Section I: General Principles of Antimicrobial Therapy

1 Antimicrobial Drug Action and Interaction: An Introduction

Spectrum of Activity of Antimicrobial Drugs

Mechanisms of Action of Antimicrobial Drugs

Antimicrobial Drug Combinations: Synergism, Antagonism, and Indifference

References and Bibliography

2 Antimicrobial Susceptibility Testing Methods and Interpretation of Results

Antimicrobial Susceptibility Testing Methods

Interpretation of Susceptibility Testing Results

Adjunctive Susceptibility Testing Methods

Role of Whole‐genome Sequencing in Predicting Antimicrobial Resistance

Conclusion

References and Bibliography

3 Antimicrobial Resistance and Its Epidemiology

Basic Concepts of Antimicrobial Resistance Epidemiology

Examples of Antimicrobial Resistance in Veterinary Medicine of Public Health Significance

Conclusion

References

4 Pharmacokinetics of Antimicrobials

Pharmacokinetic Models, Compartments, Rates, and Orders of Reactions

Drug Distribution

Designing Dosage Regimens for Clinical Patients

References

5 Pharmacodynamics of Antimicrobials

Measurements and Models in Pharmacodynamics

Clinical Pharmacodynamics

Clinical Breakpoints

Scientific Methods in Pharmacodynamics

References

6 Principles of Antimicrobial Drug Selection and Use

Does the Diagnosis Warrant Antimicrobial Therapy?

What Organism(s) is/are Likely to be Involved?

What is the Antimicrobial Susceptibility of the Organism(s)?

Will the Antimicrobial Reach the Site of Infection? Will It Be Active in the Infection Environment?

What Dosage Regimen will Maintain the Appropriate Antimicrobial Concentration for the Proper Duration of Time?

What Risks are Associated with Antimicrobial Treatment?

Adjunctive Treatment

Failure of Antimicrobial Therapy

References

Section II: Classes of Antimicrobial Agents

7 Beta‐lactam Antibiotics: Penam Penicillins

Beta‐lactam Antibiotics

Penam Penicillins

Group 1: Penicillin G and Long‐acting Parenteral Forms

Group 2: Orally Absorbed Penicillins

Group 3: Antistaphylococcal Isoxazolyl Penicillins: Cloxacillin, Dicloxacillin, Flucloxacillin, Methicillin, Nafcillin, and Oxacillin

Group 4: Extended‐spectrum Penicillins: Aminobenzyl Penicillins: Ampicillin, Amoxicillin

Group 4: Extended‐spectrum Penicillins: Amidinopenicillins: Mecillinam, Pivmecillinam

Group 5: Antipseudomonal Penicillins: Carboxypenicillins: Carbenicillin, Ticarcillin, and Temocillin

Group 5: Antipseudomonal Penicillins: Ureidopenicillins: Azlocillin, Mezlocillin, and Piperacillin

References and Bibliography

8 Beta‐lactam Antibiotics: Cephalosporins

General Considerations

First‐generation Cephalosporins: Cefacetrile, Cephaloridine, Cefazolin, Cephapirin, Cephradine, Cephalothin, Cefadroxil, Cephradine, Cephalexin, and Cephaloglycin

Second‐generation Cephalosporins: Cefaclor, Cefoxitin, Cefmetazole, Cefotetan, and Cefuroxime

Third‐generation Cephalosporins: Cefmenoxime, Cefotaxime, Cefovecin, Ceftizoxime, Ceftriaxone, Ceftiofur, Latamoxef, Cefetamet, Cefixime, Cefpodoxime proxetil, Cefoperazone, Cefsulodin, and Ceftazidime

Fourth‐generation Cephalosporins: Cefepime, Cefpirome, Cefquinome

Fifth‐generation Cephalosporins: Ceftobiprole, Ceftraroline

References and Bibliography

9 Other Beta‐lactam Antibiotics: Beta‐lactamase Inhibitors, Carbapenems, and Monobactams

Beta‐lactamases and Beta‐lactamase Inhibitors: Clavulanic Acid, Sulbactam, and Tazobactam

Carbapenems: Imipenem–Cilastatin, Meropenem, and Biapenem

Monobactams: Aztreonam

Tribactams

References and Bibliography

10 Peptide Antibiotics: Polymyxins, Glycopeptides, Bacitracin, and Fosfomycin

Polymyxins

Glycopeptides: Vancomycin, Teicoplanin, and Avoparcin

Bacitracin

Fosfomycin

References and Bibliography

11 Lincosamides, Pleuromutilins, and Streptogramins

Lincosamides: Lincomycin, Clindamycin, and Pirlimycin

Pleuromutilins: Tiamulin and Valnemulin

Streptogramins

References and Bibliography

12 Macrolides, Azalides, and Ketolides

Mechanism of Action

Resistance

Drug Interactions

Antiinflammatory and Prokinetic Activities of Macrolides

Macrolides Approved for Veterinary Use: Erythromycin, Tylosin, Spiramycin, Tilmicosin, Tulathromycin, Gamithromycin, Tildipirosin, and Tylvalosin

Advanced‐generation Macrolide Antibiotics: Roxithromycin, Clarithromycin, and Azithromycin

Ketolides

References and Bibliography

13 Aminoglycosides and Aminocyclitols

General Considerations

Streptomycin/Dihydrostreptomycin

Dihydrosteptamine Aminoglycosides: Neomycin Group

Kanamycin Group

References and Bibliography

14 Tetracyclines

General Considerations

Chlortetracycline, Tetracycline, and Oxytetracycline

Doxycycline and Minocycline

Glycylcyclines

References

15 Chloramphenicol, Thiamphenicol, and Florfenicol

General Considerations

Chloramphenicol

Thiamphenicol

Florfenicol

References

16 Sulfonamides, Diaminopyrimidines, and Their Combinations

Sulfonamides

Antibacterial Diaminopyrimidines: Aditoprim, Baquiloprim, Ormetoprim, and Trimethoprim

Antibacterial Diaminopyrimidine–Sulfonamide Combinations (Potentiated Sulfonamides)

Antiprotozoal Diaminopyrimidines

References

17 Fluoroquinolones

Introduction

Chemistry

Mechanism of Action

Antimicrobial Activity

Pharmacokinetic Properties

Pharmacodynamic Properties

Drug Interactions

Toxicity and Adverse Effects

Dosage Considerations

Clinical Use

References

18 Miscellaneous Antimicrobials: Ionophores, Nitrofurans, Nitroimidazoles, Rifamycins, and Others

Ionophore Antibiotics

Nitrofurans

Nitroimidazoles

Rifamycins

Oxazolidinones

Carbadox

Fusidic Acid

Isoniazid

Mupirocin

Methenamine

Novobiocin

References

19 Antifungal Chemotherapy

General Considerations

Antifungal Drugs for Systemic Administration

Other Antifungal Agents for Systemic Use

Antifungal Drugs for Topical Application

References

Section III: Antimicrobial Stewardship

20 General Concepts in Antimicrobial Stewardship

Introduction

Antimicrobial Resistance is a Wicked, One Health Problem

What is Antimicrobial Stewardship?

Measuring Antimicrobial Use: Benchmarking

Antimicrobial Use Guidelines: Veterinary Medicine

Antimicrobial Use Categories

Laboratory Diagnostic Testing

Internal versus External Regulation in Promoting Stewardship

Addressing Potential Conflicts of Interest in Prescribing Practices

Regulatory Monitoring for Evaluation of AMS Measures

Use of Nonantimicrobial Treatment Options

Conclusion

References

21 Global Aspects of One Health Antimicrobial Stewardship

The Need for Global Antimicrobial Stewardship

The Global Burden of Antimicrobial Resistance

Global Hotspots of Antimicrobial Resistance

Global Coordination and Response to the Resistance Crisis

Promoting Antimicrobial Stewardship on the International Scale

Gaps and Way Forward

References

22 Antimicrobial Stewardship in Companion Animals

Introduction

Important Aspects of Antimicrobial Stewardship in Companion Animals

Clinical Antimicrobial Stewardship Approaches

Diagnostic Microbiology and Antimicrobial Stewardship

Future Directions

References

23 Antimicrobial Stewardship in Food‐producing Animals

Introduction

General Principles of Antimicrobial Stewardship in Food‐producing Animals

Case Study: The Dutch Experience and Its Lessons

Elements of National Veterinary Antimicrobial Stewardship Programs in Food‐producing Animals

Benchmarking and Setting Targets for AMU

Measuring Success

International Commitments

Issues for Resolution in Antimicrobial Stewardship in Food‐producing Animals

References

24 Antimicrobial Prophylaxis, Metaphylaxis, and the Treatment of Immunocompromised Patients

Introduction

Prophylactic and Metaphylactic Use of Antibiotics in Livestock

Antimicrobial Prophylaxis for Surgery

Antimicrobial Prophylaxis and Treatment of Immunocompromised Patients

References and Bibliography

25 Regulation of Antimicrobial Use in Animals

Regulations Surrounding Premarketing Authorization of Antimicrobials

Developments in Premarketing Evaluation of Veterinary Drugs

Regulations Surrounding Postauthorization Usage of Antimicrobials

References and Bibliography

26 Antimicrobial Drug Residues in Foods of Animal Origin

Regulation of Veterinary Drug Residues

Effect of Antimicrobial Residues in Food on Human Health

Causes of Violative Residues

Residue Detection

Residue Detection Programs

Preventing Residues: The Role of the FARADs

Conclusion

References and Bibliography

Section IV: Antimicrobial Therapy in Selected Animal Species

27 Antimicrobial Drug Use in Horses

Introduction

Responsibility, Reduction, Replacement, Refinement, Review

References and Bibliography

28 Antimicrobial Therapy in Dogs and Cats

Antimicrobial Drug Chemotherapy

Antimicrobial Drug Classes and Treatment of Resistant Bacterial Infections

Drug Formulations

Route of Administration

Dosing Rate and Duration of Therapy

Therapeutic Compliance

Factors Affecting Treatment Outcome

Antimicrobial Prophylaxis

References and Bibliography

29 Antimicrobial Therapy in Beef Cattle

General Considerations of Antimicrobial Use in Beef Cattle

Antimicrobial Use in Cattle

References and Bibliography

30 Antimicrobial Therapy in Dairy Cattle

Dairy Animal Use Considerations

Intramammary Infection

Metritis

Bovine Respiratory Disease in Dairy Cattle

Diarrhea

References and Bibliography

31 Antimicrobial Therapy in Sheep and Goats

General Recommendations

Interpreting Culture and Susceptibility Results for Sheep and Goats

Specific Conditions

Extra‐label Drug Use and Residue Avoidance

References and Bibliography

32 Antimicrobial Therapy in New World Camelids

Introduction

Pharmacokinetics and Pharmacodynamics in NWCs

Culture and Susceptibility Interpretation

Route of Administration

Antimicrobials Used in New World Camelids

Antifungals

References and Bibliography

33 Antimicrobial Therapy in Swine

Global Perspective on Antimicrobial Use in Swine

Patterns of Antimicrobial Use in Swine

Diagnostic Aspects of Antimicrobial Use in Swine

Administration of Antimicrobials in Swine

Antimicrobial Growth Promoters in Swine

Types of Antimicrobials Used in Swine

Antimicrobial Susceptibility of Pathogenic Bacteria in Swine

Empirical Treatment of Common Bacterial and

Mycoplasma

Infections in Swine

References and Bibliography

34 Antimicrobial Therapy in Poultry

Categories of Antimicrobial Drug Use in the Poultry Industry

Antimicrobial Drug Use in the Poultry Industries of Canada, United States, and UK

Consequences of Antimicrobial Bans

Factors Influencing Antimicrobial Administration in the Poultry Industry

Practical Antimicrobial Drug Application under Commercial Poultry Conditions

Pharmacological Characteristics of Poultry Antimicrobials

Responsible Use of Antimicrobials in Poultry

References and Bibliography

35 Antimicrobial Therapy in Companion Birds

Establishing the Cause and Site of Infection

Choosing an AntimicrobialRegimen

Anatomical and Physiological Considerations

Routes of Administration

Compounding Considerations

References and Bibliography

36 Antimicrobial Therapy in Rabbits, Rodents, and Ferrets

Introduction

Antimicrobial Use and Resistance

Antimicrobial Toxicity

Extra‐label Use, Compounding, and Importation

Drug Dosages

Drug Administration

Animal Numbers and Use

Enhancing Therapeutic Success

References and Bibliography

37 Antimicrobial Therapy in Reptiles

Infectious Agents

Diagnostic Testing

Husbandry and Immunological Considerations

Anatomical and Physiological Considerations

Behavioral and Safety Considerations

Routes of Antimicrobial Administration

Antimicrobial Drug Selection

Allometric Scaling to Estimate Drug Dosages

Antimicrobial Stewardship

Conclusion

Acknowledgment

References and Bibliography

38 Antimicrobial Therapy in Zoo and Wildlife Species

Introduction

Clinical Breakpoint Interpretation in Zoological Medicine

Intra‐ and Interspecies Dose Extrapolation

A Practical Example of Allometry and Breakpoints

Administration Techniques

Treating Groups of Animals

Specific Examples of Antimicrobial Use in Zoo and Wildlife Species

Environmental Issues and Nontarget Wildlife Species

References and Bibliography

39 Antimicrobial Therapy in Aquaculture

Introduction

Aquaculture Definition

Antimicrobial Use in Aquaculture

Antimicrobial Stewardship and Prudent Use

Feed Rate, Antimicrobial Dose, and Antimicrobial Concentration in Feed

Conclusion

References and Bibliography

40 Antimicrobial Therapy in Honey Bees

Introduction

Honey Bee Biology

Transmission of Honey Bee Disease

Honey Bee Pathogens and Diagnosis

Therapy and Prevention of Honey Bee Disease

Therapy and Prevention of Specific Honey Bee Diseases

Conclusion

References and Bibliography

Index

End User License Agreement

List of Tables

Chapter 1

Table 1.1 Spectrum of activity of common antibacterial drugs.

Table 1.2 Antibacterial activity of selected antibiotics.

Chapter 2

Table 2.1 Drugs with veterinary‐specific CLSI resistance breakpoints accord...

Table 2.2 Intrinsic resistance phenotypes of importance to veterinary medic...

Table 2.3 Indicator drugs

a

.

Table 2.4 Examples of other susceptibility testing methods.

Chapter 3

Table 3.1 Examples of resistance mechanisms (note that this is not a compre...

Chapter 4

Table 4.1 Relationship of volume of distribution to body water.

Table 4.2 Influence of acid/base status on volume of distribution.

Table 4.3 High, medium, and low clearance values estimated according to spe...

Chapter 6

Table 6.1 Examples of adverse

in vivo

effects of drug interactions between ...

Chapter 7

Table 7.1 Classification of the six groups of penam penicillins (6‐aminopen...

Table 7.2 Usual dosages of penam penicillins in animals. Note that these us...

Table 7.3 Applications of penicillin G in clinical infections in animals.

Chapter 8

Table 8.1 Classification of cephalosporins into groups (and generations) ba...

Table 8.2 Dosage of first‐generation cephalosporins.

Table 8.3 Dosage of second‐, third‐, and fourth‐generation cephalosporins i...

Chapter 9

Table 9.1 Functional and molecular characteristics of the major groups of b...

Table 9.2 Suggested dosage of clavulanic acid‐, sulbactam‐ or tazobactam‐po...

Chapter 12

Table 12.1 Usual dosages of selected macrolides in animals.

Chapter 13

Table 13.1 Relative risks of toxicity of different aminoglycosides at usual...

Chapter 16

Table 16.1 Examples of usual dosages of sulfonamides in animals.

Table 16.2 Usual dosages of potentiated sulfonamide combinations in animals...

Chapter 17

Table 17.1 Fluoroquinolones used in veterinary medicine.

a

Table 17.2 Comparative pharmacokinetic parameters of selected fluoroquinolo...

Chapter 18

Table 18.1 Ionophore toxicity by drug and species.

Chapter 19

Table 19.1 Systemic and topical antifungal agents in use.

Chapter 20

Table 20.1 General principles of appropriate antimicrobial use.

Table 20.2 Summary of the different elements of antimicrobial stewardship d...

Table 20.3 An example of antimicrobial classification in a small animal vet...

Chapter 22

Table 22.1 Areas where current antimicrobial use and stewardship practices ...

Table 22.2 Different approaches to antimicrobial stewardship of value or po...

Table 22.3 Important points for sampling of common infections of the skin a...

Chapter 23

Table 23.1 General 5R principles of appropriate antimicrobial use specific ...

Table 23.2 Selected antimicrobial drug categorization, with examples from d...

Table 23.3 Major lessons from the Dutch experience in making substantial re...

Table 23.4 Good Stewardship Practice: measuring current status, objectives,...

Table 23.5 Examples of practical AMS interventions in production animals.

Chapter 24

Table 24.1 Definitions of antimicrobial prophylaxis (prevention) and metaph...

Table 24.2 Surgical wound classification.

Table 24.3 Recommendations for prophylactic antimicrobial therapy in humans...

Chapter 25

Table 25.1 Recent guidance documents for generating antimicrobial‐related d...

Chapter 26

Table 26.1 Joint FAO/WHO Expert Committee on Food Additives (JECFA) “food b...

Table 26.2 Sensitivities of on‐farm milk residue screening tests compared t...

Chapter 27

Table 27.1 Antimicrobial drug selection in infection of horses.

Chapter 28

Table 28.1 Antimicrobial drug selection for selected infections in dogs.

a

Table 28.2 Antimicrobial drug selection for selected infections in cats.

Table 28.3 Antimicrobial drugs that are potentially hazardous in renal fail...

Table 28.4 Suggested oral administration of selected antimicrobial drugs in...

Table 28.5 Conventional dosage regimens for systemically administered antim...

Table 28.6 Surgical procedures that may warrant antimicrobial prophylaxis....

Chapter 29

Table 29.1 Specific antimicrobial use suggestions. Individual product label...

Table 29.2

Mycoplasma bovis

susceptibility data.

Chapter 30

Table 30.1 Questions to ask about the cow before deciding to treat mastitis...

Table 30.2 Mastitis pathogens unlikely to respond to antimicrobial drug tre...

Chapter 31

Table 31.1 Antimicrobial drug selection for common conditions of sheep and ...

Chapter 32

Table 32.1 Pharmacokinetic data for selected antimicrobials in llamas and a...

Chapter 33

Table 33.1 Antimicrobials used in swine.

Table 33.2 Suggestion for prudent empirical selection of antimicrobial subs...

Chapter 34

Table 34.1 Medically Important Antimicrobials – WHO categories in relation ...

Chapter 35

Table 35.1 Conventional dosage regimens for antimicrobial drugs in companio...

Chapter 36

Table 36.1 Reported antimicrobial drug dosages in rabbits, guinea pigs, and...

Table 36.2 Reported antimicrobial dosages in hamsters, gerbils, rats...

Table 36.3 Reported antimicrobial dosages in ferrets, hedgehogs, and sugar ...

Table 36.4 Antimicrobial treatment in mice. Caution: most uses and dosages ...

Table 36.5 Antimicrobial treatment in hamsters. Caution: most uses and dosages...

Table 36.6 Antimicrobial treatment in gerbils. Caution: most uses and dosages are...

Table 36.7 Antimicrobial treatment in rats. Caution: most uses and dosages are...

Table 36.8 Antimicrobial treatment in guinea pigs. Caution: most uses and...

Table 36.9 Antimicrobial treatment in ferrets. Caution: most uses and...

Table 36.10 Antimicrobial treatment in chinchillas. Caution: most uses and...

Table 36.11 Antimicrobial treatment in rabbits. Caution: most uses and dosa...

Chapter 37

Table 37.1 Antimicrobial drug selection in chelonian infections.

Table 37.3 Antimicrobial drug selection for infections in snakes and lizard...

Table 37.4 Selected dosage regimens for antimicrobial drugs in reptiles.

Chapter 38

Table 38.1 Breakpoints for selected antituberculous drugs used in elephants...

Chapter 39

Table 39.1 Select florfenicol pharmacokinetic parameters in selected aquati...

Table 39.2 Select oxytetracycline pharmacokinetic parameters in selected aq...

Chapter 40

Table 40.1 Behaviors important in horizontal spread of pathogens of honey b...

Table 40.2 Comparison of prognosis and gross pathology of honey bee brood f...

Table 40.3 Antimicrobials licensed for use in honey bees in Canada and the ...

List of Illustrations

Chapter 1

Figure 1.1 Milestones in human infectious disease and their relationship to ...

Figure 1.2 Sites of action of commonly used antibacterial drugs that affect ...

Chapter 2

Figure 2.1 Disk diffusion: The results of the disk diffusion test can be inf...

Figure 2.2 Antimicrobial susceptibility testing methods.

Figure 2.3 In this MIC distribution graph, the observed gentamicin MICs for ...

Chapter 3

Figure 3.1 The four major mechanisms of antimicrobial resistance. Reduced pe...

Figure 3.2 The three mechanisms of horizontal transfer of genetic material b...

Figure 3.3 The ecology of the spread of antimicrobial resistance and of resi...

Chapter 4

Figure 4.1 For a drug with zero‐order elimination, a graph of drug concentra...

Figure 4.2 For a drug with first‐order elimination, a graph of drug concentr...

Figure 4.3 One‐compartment open model with IV injection and first‐order elim...

Figure 4.4 A one‐compartment open model with first‐order absorption and elim...

Figure 4.5 A two‐compartment open model with IV injection and first‐order el...

Figure 4.6 A three‐compartment model with IV injection and first‐order elimi...

Figure 4.7 Algorithm for determining clinically relevant protein‐binding int...

Figure 4.8 Plasma drug concentration profiles intravenous versus oral admini...

Figure 4.9 Most antimicrobial drugs are eliminated through the kidney by glo...

Figure 4.10 One drug may compete for secretion with another drug and decreas...

Figure 4.11 Decreasing the urine pH will increase the FR of an acidic drug a...

Figure 4.12 Metabolic fate of lipophilic antimicrobials to increase their wa...

Figure 4.13 Effect of antimicrobial drug dose on elimination kinetics. At lo...

Figure 4.14 With first‐order drug elimination, the t½ is constant along the ...

Figure 4.15 For a two‐compartment drug model, β is the terminal elimination ...

Figure 4.16 In horses, the plasma concentration versus time curve for the IM...

Figure 4.17 This is the plasma concentration versus time graph for an intrav...

Figure 4.18 When the dosage interval is less than the t½ (dosage interval 0....

Figure 4.19 When the dosage interval is greater than t½ (dosage interval 2 h...

Chapter 5

Figure 5.1 Histogram capturing an observed MIC distribution for a sample of ...

Figure 5.2 A simple drug–receptor interaction model, Langmuir’s isotherm as ...

Figure 5.3 A typical sigmoid dose–response model, as in Equation 6, describi...

Figure 5.4 A typical sigmoid dose–response model, as in

Equation 6

, describi...

Figure 5.5 A typical sigmoid dose–response model, as in Equation 6, describi...

Figure 5.6 A typical sigmoid dose–response model including Hill coefficient,...

Figure 5.7 The relationship between the

MIC

true

,

MIC

obs

, and a proposed unde...

Figure 5.8 Predicted average plasma concentrations of a hypothetical cephalo...

Chapter 6

Figure 6.1 Considerations for antimicrobial use to promote good antimicrobia...

Chapter 7

Figure 7.1 Structural formula of penicillin.

Figure 7.2 Core structures of naturally occurring beta‐lactams.

Figure 7.3 Summary of action and resistance to beta‐lactam drugs: Gram‐posit...

Figure 7.4 Summary of action and resistance to beta‐lactam drugs: Gram‐negat...

Figure 7.5 Structural formulae of some penicillins. (A) Basic structure of p...

Chapter 8

Figure 8.1 Structural formula of the cephalosporin nucleus.

Chapter 9

Figure 9.1 Structural formulas of clavulanic acid (A) and sulbactam (B).

Chapter 11

Figure 11.1 Chemical structure of lincomycin and clindamycin.

Chapter 12

Figure 12.1 Classification of macrolide antimicrobials according to the size...

Figure 12.2 Structural formulas of macrolides.

Chapter 13

Figure 13.1 Aminoglycoside cations interact with phospholipid anions on the ...

Figure 13.2 Chemical structure of kanamycin.

Chapter 14

Figure 14.1 Classifications of the tetracyclines. The former names are in pa...

Figure 14.2 Functional groups and moieties that determine the solubility and...

Figure 14.3 (A) Photograph under ultraviolet light of bones from a pig fed c...

Chapter 15

Figure 15.1 Chemical structure of chloramphenicol, florfenicol, and thiamphe...

Chapter 16

Figure 16.1 Structural formulas of some sulfonamide antimicrobials.

Figure 16.2 Pathway for folic acid synthesis and inhibition by sulfonamide a...

Figure 16.3 Structural formulas of some diaminopyridines.

Chapter 17

Figure 17.1 Structures of fluoroquinolones used in veterinary medicine.

Figure 17.2 Concentration‐dependent killing effect of a fluoroquinolone test...

Figure 17.3 Relationship between AUC

0‐24

/MIC and the probability of se...

Figure 17.4 Time (days of therapy) to bacterial eradication (in humans) vers...

Chapter 18

Figure 18.1 Structural formulas of nitroimidazole drugs. (A) Metronidazole. ...

Figure 18.2 Structural formula of rifampin.

Figure 18.3 Structural formula of novobiocin.

Chapter 19

Figure 19.1 Action of antifungal agents on the fungal cell.

Figure 19.2 Structural formula of amphotericin B.

Figure 19.3 Structural formulas of representative azole compounds.

Chapter 20

Figure 20.1 Antimicrobial resistance is a wicked, One Health problem. This f...

Figure 20.2 Antimicrobial stewardship is the term used to describe the multi...

Chapter 21

Figure 21.1 Distribution pathways of galactooligosaccharide (GOS) and GOS‐co...

Figure 21.2 Plasmid from a multiresistant clinical isolate of

Corynebacteriu

...

Figure 21.3 A timeline of pivotal global initiatives to address the antimicr...

Figure 21.4 Objectives of the WHO’s Global Action Plan on Antimicrobial Resi...

Figure 21.5 Organizations represented in the Interagency Coordination Group ...

Figure 21.6 Progress in achieving AMS‐related goals in the veterinary sector...

Chapter 23

Figure 23.1 Description of the different elements of successful national app...

Chapter 24

Figure 24.1 Recommended approach for antimicrobial therapy of dogs with febr...

Chapter 26

Figure 26.1 Response curves of screening tests for antimicrobials in milk.

Chapter 30

Figure 30.1 Example herd mastitis treatment protocol incorporating on‐farm c...

Chapter 33

Figure 33.1 Bioavailability (%) of antimicrobials when given fasted or after...

Figure 33.2 Comparative antimicrobial pharmacokinetic curves following injec...

Chapter 34

Figure 34.1 Graphic representation of the percentage of broiler chickens rai...

Chapter 40

Figure 40.1 Brood frame with clinical signs of American foulbrood including ...

Figure 40.2 Brood frame with clinical signs of European foulbrood including ...

Figure 40.3 (A) Colony with evidence of dysentery at the hive entrance sugge...

Figure 40.4 (A) Removal of a top honey super from the bottom two brood chamb...

Guide

Cover Page

Table of Contents

Title Page

Copyright Page

Contributors

Preface

Acknowledgments

Important Notice

List of Abbreviations

Begin Reading

Index

WILEY END USER LICENSE AGREEMENT

Pages

iii

iv

ix

x

xi

xii

xiii

xv

xvii

xix

1

3

4

5

6

7

8

9

10

11

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

109

110

111

112

113

114

115

116

117

118

119

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

401

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

545

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

671

672

673

674

675

676

677

678

679

680

681

682

683

685

686

687

688

689

690

691

692

693

694

695

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

791

792

793

794

795

796

797

798

799

800

801

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

819

820

821

822

823

824

825

826

827

828

829

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

Antimicrobial Therapy in Veterinary Medicine

Sixth Edition

Edited by

Patricia M. Dowling, DVM, MSc, DACVIM, DACVCP

Western College of Veterinary Medicine

University of Saskatchewan

John F. Prescott, MA, VetMB, PhD, FCAHS

Ontario Veterinary College

University of Guelph

Keith E. Baptiste, BVMS, MSc, PhD, MRCVS, DACVIM, DECEIM

Danish Medicines Agency (Lægemiddelstyrelsen)

Copyright © 2025 by John Wiley & Sons, Inc. All rights reserved, including rights for text and data mining and training of artificial intelligence technologies or similar technologies.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750‐8400, fax (978) 750‐4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748‐6011, fax (201) 748‐6008, or online at http://www.wiley.com/go/permission.

Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United States and other countries and may not be used without written permission. All other trademarks are the property of their respective owners. John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762–2974, outside the United States at (317) 572–3993 or fax [phone].

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging‐in‐Publication Data Applied for:

Hardback ISBN: 9781119654599

Cover Design: WileyCover Images: World Map: © teekid/Getty Images; Farm Animals: © Vectorig/Getty Images; Livestock: © mollyw/Shutterstock; Fish: © RobinOlimb/Getty Images; Reptiles: © RobinOlimb/Getty Images; Insects: © Kristtaps/Getty Images; Zoo Animals: © JulieWeiss/Getty Images; Medicine pills: © Alexander Raths/Shutterstock

Contributors

Chapter numbers are in parentheses.

Michael D. Apley (29)Frick Professor of Clinical SciencesDepartment of Clinical SciencesKansas State UniversityCollege of Veterinary MedicineManhattan, Kansas, USA

Keith E. Baptiste (12, 18, 19, 25, 27)Specialist Veterinary ConsultantDepartment of Veterinary MedicineDanish Medicines Agency (Lægemiddelstyrelsen)Copenhagen South, Denmark

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

Mark E. Caudell (21)Food and Agricultural Organization of the United NationsGigiri, Nairobi, Kenya

Ronan J.J. Chapuis (14)Assistant ProfessorBiomedical SciencesRoss University School of Veterinary MedicineBasseterre, St Kitts, West Indies

Alan Chicoine (25)Assistant ProfessorVeterinary Biomedical SciencesWestern College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Peter Damborg (2, 22, 28)Associate ProfessorDepartment of Veterinary and Animal SciencesFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen, Denmark

Sarah Depenbrock (30)Assistant ProfessorMedicine & EpidemiologySchool of Veterinary MedicineDavis, California, USA

Patricia M. Dowling (4, 6, 10, 13, 15, 17, 18, 26, 36)ProfessorVeterinary Biomedical SciencesWestern College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Suzanne N. Eckford (21)Head, International OfficeVeterinary Medicines DirectorateAddlestone, Surrey, United Kingdom

David French (34)Clinical Associate ProfessorDepartment of Population HealthPoultry Diagnostic and Research CenterAthens, Georgia, USA

Diego E. Gomez (24)Assistant ProfessorDepartment of Clinical StudiesOntario Veterinary CollegeUniversity of GuelphGuelph, Ontario, Canada

Leticia Trevisan Gressler (11)Adjunct ProfessorLaboratory of Veterinary Microbiology and ImmunologyInstituto Federal FarroupilhaFrederico Westphalen, RS, Brazil

Marisa Haenni (3)Deputy Head, Antibioresistance et Virulence Bactériennes UnitAgence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du TravailMaisons‐Alfort, France

Laura Y. Hardefeldt (7, 8, 9, 20)National Centre for Antimicrobial StewardshipFaculty of Veterinary and Agricultural SciencesAsia‐Pacific Centre for Animal HealthUniversity of MelbourneMelbourne, Victoria, Australia

Robert P. Hunter (38)Veterinary PharmacologistOne Medicine ConsultingOlathe, Kansas, USA

Timothy S. Kniffen (39)Technical Services VeterinarianGlobal Aquaculture MarketingMerck Animal HealthDe Soto, Kansas, USA

Ivanna V. Kozii (40)Department of Veterinary PathologyWestern College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Amanda J. Kreuder (31)Assistant ProfessorVeterinary Microbiology and Preventive MedicineCollege of Veterinary MedicineIowa State UniversityAmes, Iowa, USA

Hélène Lardé (15)Assistant ProfessorVeterinary Biomedical SciencesFaculté de médecine VétérinaireUniversité de MontréalRimouski, Quebec, Canada

Jeffrey T. LeJeune (21)Food Safety and Quality OfficerFood and Agriculture Organization of the United NationsRome, Italy

Brian V. Lubbers (29)Associate ProfessorFood Animal TherapeuticsCollege of Veterinary MedicineKansas State UniversityManhattan, Kansas, USA

Grazieli Maboni (11)Assistant ProfessorDepartment of Infectious DiseasesCollege of Veterinary MedicineUniversity of GeorgiaAthens, Georgia

Jenny A. Nicholds (34)Clinical Associate Professor, Avian MedicineDepartment of Population HealthPoultry Diagnostic and Research CenterAthens, Georgia, USA

Peter O’Kane (34)Senior Associate VeterinarianSlate Hall Veterinary ServicesMetheringham, Lincolnshire, United Kingdom

Simon Otto (39)Associate ProfessorSchool of Public HealthUniversity of AlbertaEdmonton, Alberta, Canada

Stephen W. Page (20, 21, 23)DirectorAdvanced Veterinary TherapeuticsNewtown, New South Wales, Australia

Daniel Parker (34)Director EmeritusSlate Hall Veterinary ServicesMetheringham, Lincolnshire, United Kingdom

Ken Steen Pedersen (33)Professor of Herd Diagnostics and Antibiotic Use in PigsFaculty of Health and Medical SciencesUniversity of CopenhagenFrederiksberg C, Denmark

John F. Prescott (1, 7, 8, 9, 12, 16, 22, 23)University Professor EmeritusDepartment of PathobiologyOntario Veterinary CollegeUniversity of GuelphGuelph, Ontario, Canada

Jennifer M. Reinhart (16)Assistant ProfessorSmall Animal Internal MedicineDepartment of Veterinary Clinical MedicineCollege of Veterinary MedicineUniversity of IllinoisUrbana‐Champaign, Illinois, USA

Joseph E. Rubin (2)ProfessorDepartment of Veterinary MicrobiologyWestern College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Nora D. Schrag (29)Veterinary ConsultantLivestock Veterinary Resources, LLCOlsburg, Kansas, USA

Elemir Simko (40)ProfessorDepartment of Veterinary PathologyWestern College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Joe S. Smith (14, 26, 31, 32)Assistant ProfessorLarge Animal Clinical SciencesCollege of Veterinary MedicineUniversity of TennesseeKnoxville, Tennessee, USA

David C. Speksnijder (23)Assistant ProfessorFaculty of Veterinary Medicine,Department Biomolecular Health Sciences, Division of Infectious Diseases and ImmunologyUtrecht UniversityUtrecht, The Netherlands

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

Marike Visser (35)Veterinary Clinical Research ManagerZoetis Inc.Kalamazoo, Michigan, USA

Jaap A. Wagenaar (23)Department of Infectious Diseases and ImmunologyFaculty of Veterinary MedicineUniversity of UtrechtUtrecht, The Netherlands

Sarah Wagner (30)Professor of PharmacologyTexas Tech School of Veterinary MedicineAmarillo, Texas, USA

J. Scott Weese (6, 20, 22, 24, 37)ProfessorDepartment of PathobiologyOntario Veterinary CollegeUniversity of GuelphGuelph, Ontario, Canada

Colette L. Wheler (36)Clinical Research VeterinarianVaccine and Infectious Disease OrganizationUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Patrick Whittaker (39)Head VeterinarianGrieg Seafood BC Ltd.Campbell River, British Columbia, Canada

Ted Whittem (5)Professor and DeanCollege of Public Health, Medical and Veterinary SciencesTownsville, North Queensland, Australia

Ellen Wiedner (38)Hyrax Consulting, LLC.Durango, Colorado, USA

Sarah Wood (40)WCVM Research Chair in Pollinator Health/Associate ProfessorWestern College of Veterinary MedicineUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada

Andrew P. Woodward (5)Applied Biostatistics ResearcherFaculty of HealthUniversity of CanberraCanberra, Australian Capital Territory, Australia

Preface

The first edition of Antimicrobial Therapy in Veterinary Medicine was published in 1988 and was followed by four subsequent editions as the knowledge and practice of evidence‐based animal treatment evolved. The increasing impact of antimicrobial resistance on human and animal health prompted the need for a sixth edition with an increased global focus on all the earlier topics covered in this book but with the addition of three chapters focusing specifically on antimicrobial stewardship concepts in different types or spheres of veterinary practice at both national and international level. To achieve this global perspective, we’ve assembled a group of editors and chapter authors with strong international experience. This enhances the traditional goal of this textbook – that practicing veterinarians, veterinary specialists, drug regulators, educators, and students find it to be an indispensable reference on the general principles and clinical applications of all types of antimicrobials used in veterinary medicine.

The book is divided into four sections. The first provides general principles of antimicrobial therapy including susceptibility testing, antimicrobial resistance, and antimicrobial pharmacokinetics and pharmacodynamics. The second section describes each class of antimicrobial agents, revised to include the most up‐to‐date information on the drugs used in veterinary medicine. The third section deals with the increasingly critical topic of antimicrobial stewardship. As part of this section, the regulation of antimicrobials in animals and antimicrobial drug residues in foods of animal origin is reviewed from a global perspective. The final section addresses the specific principles of antimicrobial therapy in major veterinary species. A chapter on antimicrobial therapy in bees has been added to this edition to reflect the increase in veterinary involvement in the health of bees.

Before beginning this new edition, we were greatly saddened by the untimely death of Dr Steeve Giguère, the editor in chief of the fifth edition. It is our goal to maintain the high standard of scholarship set by Steeve so we have added Dr Keith E. Baptiste to the editorial team. We also mourn the death in 2016 of Dr J. Desmond Baggot, the distinguished veterinary pharmacologist and one of the founders of this book. 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 Merryl Le Roux, 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.

Patricia M. Dowling, John F. Prescott, and Keith E. Baptiste

Acknowledgments

Patricia M. Dowling: I thank my husband, Brian Zwaan, for his support of my work on this text. And I thank the contributors for their work through the global pandemic to support antimicrobial stewardship in veterinary medicine.

John F. Prescott: I thank my wife Cathy Prescott for her unwavering support during the production of the six editions since the inception of this book.

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, 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.

List of Abbreviations

ADI

acceptable daily intake

EDI

estimated daily intake

EFSA

European Food Safety Authority

EU

European Union

FAO

Food and Agriculture Organization of the United Nations

FDA

Food and Drug Administration

JECFA

Joint FAO/WHO Expert Committee on Food Additives

LOD

limit of detection

LOQ

limit of quantification

MBC

minimum bactericidal concentration

MDR

multidrug resistant

MIC

minimum inhibitory concentration

MPC

mutant prevention concentration

MRL

maximum residue limit

NOAEL

no‐observed‐adverse‐effect level

USA

United States of America

VDD

Veterinary Drugs Directorate

WHO

World Health Organization

For dosages:

PO

per os, oral administration

IM

intramuscular administration

IV

intravenous administration

SC

subcutaneous administration

SID

single daily administration

BID

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

1Antimicrobial Drug Action and Interaction: An Introduction

John F. Prescott

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 diseases. The remarkable efficacy of modern antimicrobial drugs still retains the sense of the miraculous. Sulfonamides, the first clinically successful broad‐spectrum antibacterial agents, were produced in Germany in 1935.

However, it was the discovery of the antimicrobial penicillin, 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 antimicrobials were described. This was followed by the development of semisynthetic and synthetic antimicrobial agents which has resulted in an increasingly powerful and effective array of compounds used to treat infectious diseases.

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 definition than antibiotic and includes any substance of natural, semisynthetic, or synthetic origin that kills or inhibits the growth of a microorganism but causes little or no damage to the host. Antimicrobial agent and antibiotic are commonly used synonymously. The term antimicrobial is preferentially used in this book as the more encompassing term.

The marked structural and biochemical differences between prokaryotic and eukaryotic cells give antimicrobial 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 introduced into clinical practice.

Important milestones in the development of antibacterial drugs are shown in Figure 1.1. Because of the enormous costs of development, the therapeutic use of these agents in veterinary medicine has usually followed their use in human medicine. However, some antimicrobials have been developed specifically for animal health and production (e.g., tylosin, tiamulin, tilmicosin, ceftiofur, tulathromycin, gamithromycin, tildipirosin), although all these are related to drug classes used in human medicine. A few classes not used because of toxicity for humans, such as the orthosomycins, have been relegated to oral use in animals for treatment of enteric infections. Figure 1.1 highlights the relationship between antimicrobial use and the development of resistance in many target microorganisms.

Figure 1.1 Milestones in human infectious disease and their relationship to development of antimicrobial drugs, 1930–2010, illustrating the relationship between the introduction of an antibacterial drug and the emergence of resistance.

Source: Modified and reproduced with permission from Kammer (1982).

Spectrum of Activity of Antimicrobial Drugs

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

Class of Microorganism

Antiviral and antifungal drugs generally are active only against viruses and fungi, respectively. However, some imidazole antifungal agents have activity against staphylococci and nocardioform bacteria. Antibacterial agents can be described as narrow spectrum if they inhibit only Gram‐positive and Gram‐negative bacteria or broad spectrum if they also inhibit a wider range of bacteria such as chlamydia, mycoplasma, and rickettsia (Table 1.1).

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.

Antibacterial Activity

Within the class description of antibacterial drug activity, antimicrobial drugs can further also be described as narrow spectrum if they inhibit only either Gram‐positive or Gram‐negative bacteria and as broad‐spectrum drugs if they inhibit both Gram‐positive and Gram‐negative bacteria. This distinction is often not absolute since, although some agents may be primarily active against Gram‐positive bacteria, they may also inhibit some Gram negatives (Table 1.2). It seems likely that some antimicrobial drugs developed in the future may be narrow spectrum and targeted to particular pathogens, avoiding the considerable “bystander” effect of broad‐spectrum antimicrobials on the nonpathogenic microflora.

Bacteriostatic or Bactericidal Activity

The 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 lowest concentration of an antimicrobial agent required to kill the pathogen. Antimicrobials are usually regarded as bactericidal if the MBC is no more than four times the MIC. This distinction is rarely important for treatment of clinical conditions. Some drugs are routinely bactericidal (e.g., beta‐lactams, aminoglycosides) whereas others are usually bacteriostatic (e.g., chloramphenicol, tetracyclines), but this distinction depends on both the drug concentration at the site of infection and the microorganism involved. For example, benzyl penicillin is bactericidal at usual therapeutic concentrations but bacteriostatic at lower concentrations.

Table 1.2 Antibacterial activity of selected antibiotics.

Spectrum

Aerobic Bacteria

Anaerobic Bacteria

Examples

Gram +

Gram –

Gram +

Gram –

Very broad

+

+

+

+

Carbapenems; chloramphenicol; third‐generation fluoroquinolones; glycylcyclines

Intermediately broad

+

+

+

(+)

Third‐ and fourth‐generation cephalosporins

+

(+)

+

(+)

Second‐generation cephalosporins

(+)

(+)

(+)

(+)

Tetracyclines

Narrow

+

+/–

+

(+)

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.

Time‐ or Concentration‐dependent Activity

Antimicrobial agents are often classified as exerting either time‐dependent or concentration‐dependent activity, depending on their pharmacodynamic properties. These properties of a drug address the relationship between drug concentration and antimicrobial activity (Chapter 5). Drug pharmacokinetic 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 pharmacodynamic relationships are also important in preventing the selection and spread of resistant strains. The most significant factor determining the efficacy of beta‐lactams, some macrolides, tetracyclines, trimethoprim‐sulfonamide combinations, and chloramphenicol is the length of time that serum concentrations 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 administration.

Other antimicrobial agents such as the aminoglycosides, fluoroquinolones, and metronidazole exert concentration‐dependent killing characteristics. Their rate of killing increases as the drug concentration increases above the MIC for the pathogen and it is not necessary or even beneficial to maintain drug levels above the MIC between doses. Thus, optimal dosing 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‐time curve (AUC)/MIC ratio. Glycopeptides, rifampin, and, in some situations, fluoroquinolones fall within this category (Chapter 5).

Mechanisms of Action of Antimicrobial Drugs

Antibacterial Drugs

Figure 1.2 summarizes the diverse sites of action of commonly used antibacterial drugs. Their mechanisms of action fall into four categories: inhibition of cell wall synthesis, damage to cell membrane function, inhibition of nucleic acid synthesis or function, and inhibition of protein synthesis.

Antibacterial drugs that affect cell wall synthesis (beta‐lactam antimicrobials, bacitracin, glycopeptides) or inhibit protein synthesis (aminoglycosides, chloramphenicol, lincosamides, glycylcyclines, macrolides, oxazolidinones, streptogramins, pleuromutilins, tetracyclines) are more numerous than those that affect cell membrane function (polymyxins) or nucleic acid function (fluoroquinolones, nitroimidazoles, nitrofurans, rifampin). Agents that affect intermediate metabolism (sulfonamides, trimethoprim) have greater selective toxicity than those that affect nucleic acid synthesis.

Developing New Antibacterial Drugs

Infection caused by antimicrobial‐resistant bacteria has been an increasing and rapidly developing problem and has reached a crisis in medicine. The speed with which some bacteria develop resistance considerably outpaces the slow development of new antimicrobial drugs. Since 1980, the number of antimicrobial agents approved for use in people has fallen steadily. What has been approved are variations of existing drugs; no new classes of antimicrobials have been discovered since the 1980s.

Several factors contribute to driving large pharmaceutical companies out of the antimicrobial drug market. These include expensive regulatory requirements, the challenges of drug discovery and the high cost of drug development coupled with the low rate of return on investment compared with drugs for the treatment of chronic “life‐style” conditions. This has left limited treatment options for infections caused by methicillin‐resistant staphylococci and vancomycin‐resistant enterococci. The picture is even bleaker for infections caused by some Gram‐negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumanii, extended‐spectrum beta‐lactamase (ESBL)‐resistant E. coli, Klebsiella spp., and Enterobacter spp., which are occasionally resistant to all safe antimicrobial agents. Judicious use of the antimicrobials currently available and better infection control practices, discussed in Chapters 20–24, will prolong the effectiveness of the drugs that are currently available. However, even if we improve these practices, resistant bacteria will continue to emerge and to spread, and new drugs will be needed.

While improvements in some existing classes of antimicrobial drugs continue to be laboriously made, numerous technological advances and improved understanding of bacterial pathogens hold considerable promise for the development of novel antimicrobial drugs. However, such development is challenging and extremely expensive. Novel targets for antimicrobial drugs that have been identified include those involved in essential amino acid biosynthesis, in cell wall lipid biosynthesis, in metal chelator biosynthesis, in quorum sensing, in efflux pumps, and in regulation of gene expression, among others. The investigation of novel antimicrobial sources has undergone a revival, and many novel antimicrobials have been identified, including numerous peptides. Development of antimicrobial drugs targeting specific pathogens is more straightforward than developing broad‐spectrum compounds and, combined with increasing sensitivity of specific agent diagnosis, is likely to be an important part of the future of antimicrobial therapy in human medicine.

Figure 1.2 Sites of action of commonly used antibacterial drugs that affect virtually all the important processes in a bacterial cell.

Source: Modified and reproduced with permission after Aharonowitz and Cohen (1981).

Despite a degree of optimism about the future development of new antimicrobials, the costs are considerable and this and other reasons are likely to preclude veterinary application. Bringing a novel antimicrobial into human clinical use takes an estimated 10–15 years and costs an estimated US$1 billion, with the constant threat of development of resistance among important pathogens, which appear increasingly adept at spreading resistance. Many multinational companies have abandoned the search for new antimicrobials.

If candidate drugs found in preclinical development are identified, they are moved into three phases of human clinical trials, the last of which can consume 80% of the total research and development costs, which include the high costs of regulatory approval, all of which have to be recovered. Historically, only about 60% of drugs entering Phase 3 clinical trials are approved. Such expensive antimicrobials will therefore tend to have restricted use as “last resort” drugs, further limiting the return on investment.

A record of bankruptcy of companies that have brought novel drugs to market does not inspire private investment. Public–private philanthropic initiatives such as CARB‐X (Combating Antibiotic‐resistant Bacteria Biopharmaceutical Accelerator; www.carb‐x.org) have been developed to help support drug discovery. In 2022, there were 62 antibacterial compounds of various types under clinical development for human medicine, with three antibacterials introduced since 2020 (Butler et al., 2023). As a result of funding initiatives, an encouraging increasing number of compounds are entering early Phase 1 evaluation studies. However, the clinical pipelines and recently introduced drugs are insufficient to address the emergence and spread of antimicrobial resistance. Most are direct‐acting small molecules including peptides, but others include bacteriophage‐related or antivirulence products.

The development of new antimicrobial drugs is inevitably focused on human rather than veterinary medicine, but research continues into new antimicrobial drugs targeted to topic use in specific veterinary infections (Greco et al., 2019; Bellavita et al., 2020).

Antifungal Drugs

Most currently used systemic antifungal drugs damage cell membrane function by binding ergosterols that are unique to the fungal cell membrane (polyenes, azoles) (Chapter 19). The increase in the number of 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‐beta‐D‐glucan synthase inhibitors, chitin synthase inhibitors, mannoprotein binders).

Antimicrobial Drug Combinations: Synergism, Antagonism, and Indifference

In general, the use of combinations should be avoided because the toxicity of the antimicrobials will be at least additive and may be synergistic, because the ready availability of broad‐spectrum bactericidal drugs has made use of combinations 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.