History and Current Use of Antimicrobial Drugs in Veterinary Medicine

ABSTRACT

This chapter briefly reviews the history and current use of antimicrobials in animals, with a focus on food animals in the more economically developed countries. It identifies some of the differences between human medical and food animal use, particularly in growth promotional and “subtherapeutic” use of medically-important antibiotics in animals. The public health impact of the extensive use of antibiotics in food animals for these purposes, differences internationally in such usage, and the major changes in current practices now underway in agricultural use are summarized. The emerging framing of the dimensions of antimicrobial resistance within a “One Health” framework is focusing global efforts to address the antimicrobial resistance crisis in a collaborative manner. The rapidly evolving development and application of practices of antimicrobial stewardship in animal is a critical part of the huge global effort to address antimicrobial resistance. The outcome is still uncertain.

INTRODUCTION

The introduction of antimicrobial drugs into agriculture and veterinary medicine shortly after the Second World War caused a revolution in the treatment of many diseases of animals. In the “wonder drug era” of the late 1940s and early 1950s, the effective treatment of many infections that were previously considered incurable astonished veterinarians, such that some even feared for their livelihoods. Not all use of antimicrobial drugs in food animals is yet under veterinary prescription globally, despite repeated recommendations by the World Health Organization and other responsible organizations, so that the term “veterinary medicine” is used here rather generically to suggest use in animals rather than just use by veterinarians.

A broad overview of key features of the history of antimicrobial drug use in animals is given in Table 1, which traces developments from the preantibiotic era to the present day, where there are arguable fears that we are moving into the “postantibiotic” era but which may better be described as the antimicrobial stewardship era. Much of this overview will focus on antimicrobial use in food animals, the subject of an earlier review that partly focused on the public health aspects of the use of antimicrobials in food animals (1), but will include important aspects of use in companion animals.

TABLE 1.

Historical time line of important events and trends in the use of antimicrobial drugs in animals, with emphasis on food animals

Timeline	Feature of period	Antimicrobial drug development	Important events
1925–1935	Antiseptic era	Discovery of sulfonamides	Discovery of penicillin, first beta-lactam, by Alexander Fleming
1936–1940	Antiseptic, sulfonamide period	Penicillin efficacy shown in humans	Sulfonamides introduced into food animal use
1941–1945	Dawn of “wonder drug” era	Streptomycin, first aminoglycoside, discovered	Second World War is impetus for antimicrobial drug discovery for treatment of war wounds
1946–1950	“Wonder drug” era	Discovery bacitracin, chloramphenicol, neomycin, polymyxin, streptogramins, tetracycline antibiotics, all natural products of microorganisms, usually fungi	Penicillin, streptomycin released from military use for civilian population and animal use; widespread use in animals by 1950, largely empirical; far more wonder than science
1951–1955	“Wonder drug” era	Discovery of erythromycin, first macrolide; introduction of neomycin, aminoglycoside, for topical or intestinal infections in animalsIntroductions of nitrofurans into clinical use, especially for intestinal infections	Tetracyclines, chloramphenicol used therapeutically in animals; widespread, largely empirical, useIntramammary use of antibiotics for mastitis treatment widespreadDiscovery of and extensive use of antibiotics for growth promotion in food animals, pioneered in the USA
1956–1960	“Wonder drug” era	Discovery of vancomycin, first glycopeptideTylosin, novel macrolideVirginiamycin, streptogramin, used as growth promoters	More science and less wonder, but drug dosage still largely empiricalEarly studies of drug excretion in Denmark
1961–1965	Emerging resistance period	Methicillin and other penicillinase-resistant penicillinsIntroduction of spiramycin, a macrolide, into animal useGentamicin, antipseudomonal aminoglycoside	Discovery of transmissible, plasmid- or “R” factor-based, multiple drug resistance in EnterobacteriaceaeStudies of drug residues and withdrawal periods in animals
1966–1970	New drug analog period	Cephalothin, first-generation cephalosporinAmpicillin, first broad-spectrum penicillin, used in food and companion animals, example of a successful synthetic alteration of side chains of basic beta-lactam ring to expand activityAmikacin, for gentamicin-resistant infectionsFlavomycin introduced as growth promoter	New drug analogs successfully address resistance problemTransmissible, multiple-drug resistant, serious Salmonella infections, transmission from calves to human in UKBecause of transmissible resistance, Swann Report in UK removes drugs important in human medicine as feed antibiotics, allows their veterinary prescription-only use therapeutically in food animals
1971–1975	New drug analog period	Carbenicillin, antipseudomonal penicillinOther first-generation cephalosporins introducedTrimethoprim-sulfonamide combination	New drug analogs successfully address resistance problemFDA report (1972) suggests stopping feed use of subtherapeutic penicillin, tetracyclines; not implemented
1976–1980	Tissue drug residue problems in food animals; early pharmacokinetic period	Cexotin, first extended-spectrum (second-generation) cephalosporinMoxalactam, unusual beta-lactamIntroduction in Europe of avoparcin, glycopeptide, for growth promotion in food animals	Chloramphenicol use in food animals banned in USA and Denmark because of potential human toxicity through residues, followed by other countriesTransmissible, multiple-drug resistant, Salmonella typhimurium phage type 204 spreads from calves to humansJournal of Veterinary Pharmacology and Therapeutics started, to improve drug use in animalsFocus on pharmacokinetics and drug metabolism in food animals by J.D. Baggot (Ireland, USA), L.E. Davis (USA), P. Nielsen and F. Rasmussen (Denmark)
1981–1985	Pharmacokinetic, drug dosage prediction period	Cefotaxime, antipseudomonal cephalosporin, and other third-generation cephalosporinsBroad-beta-lactamase inhibitors combined with aminopenicillins, e.g., sulbactam-ampicillin used in food animalsImipenem-cilastatin, unusual broad-spectrum beta-lactam	Antimicrobial drug dosage prediction based on pioneering pharmacokinetic approach in food animals developed by Ziv in Israel, Hjerpe in USA, and othersChanges in sulfamethazine use in swine to address residue issueBan on nitrofuran and nitroimidazole drugs for food animals in USA because of mutagenicity
1986–1990	Increasing resistance problems in humans: MRSA emerges	Quinolones, fluoroquinolones introduced into human medicineCeftiofur, a second- to third-generation cephalosporin, introduced for food animals	Development of Food Animal Residue Avoidance Database (FARAD) in USAMoratorium on sulfamethazine use in dairy cows in USAMoratorium on most use of aminoglycosides in food animals in USA because of kidney residues
1991–1995	Increasing resistance problems in humans: VREs emerge	Azithromycin and other improved macrolides introduced into human medicineTilmicosin (macrolide), tiamulin (pleuromutilin), florfenicol (nontoxic introduced for food animal selected useFluoroquinolones introduced for selected use in food animals in Europe	First fluoroquinolone, enrofloxacin, introduced into food animal (poultry) use in USA, with severe restrictions; includes resistance monitoring through National Antimicrobial Resistance Monitoring System that integrates food animal and medical dataNational Council on Clinical Laboratory Standards (NCCLS) in USA establishes veterinary subcommittee to develop susceptibility testing methods and interpretationsAnimal Medicines Use Clarification Act in USA allows veterinary prescription extra-label use of certain approved drugs
1996–2000	Resistance crisis in medicine; now includes penicillin-resistant Streptococcus pneumoniae	Oral, third-generation cephalosporins in human medicine may partially drive resistance crisisEffective antivirals introduced into human medicineFluoroquinolone introduced for treatment of acute pneumonia in cattle in USA	VRE emergence linked to avoparcin use in food animals in Europe; ban of avoparcin and four other growth promoters in EuropeWHO (1998) recommends withdrawal of growth-promoting antimicrobials if significant for human medicineGlobal emergence of multidrug-resistant S. typhimurium DT104Japanese Veterinary Antimicrobial Resistance Monitoring Program startedNCCLS guidelines for veterinary bacterial susceptibility testing publishedCenter for Veterinary Medicine of FDA proposes “an approach for establishing thresholds in association with the use of antimicrobial drugs in food-producing animals” (Framework document)FDA Center for Veterinary Medicine proposes withdrawal of fluoroquinolones in poultry because of resistance in Campylobacter
2001–2005	Resistance crisis in medicine continues, expands	No new antimicrobial drugs introduced for food animals	WHO Global Strategy for Containment of Antimicrobial Resistance calls for prescription-only use of antimicrobials in food animals, national usage and resistance monitoring, phasing out of growth promoters if drugs important for humansWithdrawal of fluoroquinolones for use in poultry in USA because of emerging resistance in C. jejuniSpread of multidrug resistance including cephalosporinase (CMY2) genes among certain Salmonella serovars.Development of prudent use guidelines by practitioner specialty groups at national levels
2005–2010	Resistance crisis in medicine continues; MRSA and MRSP emerge in animals, spread partly by people	No new antimicrobial drugs introduced for food animalsVoluntary ban on use of ceftiofur in pigs in Denmark, and on use of ceftiofur in chickens in Canada	Resistance crisis in medicine focuses intense effort on improved infection and antimicrobial drug use control by physicians; some benefits observedVeterinary “prudent” or “judicious” use approaches increasingly replaced by emerging concept of stewardshipGlobal spread of food animal-associated MRSA, driven by zinc oxide use in food animalsVoluntary ban on ceftiofur use in Danish pigs followed by marked reduction in extended-spectrum cephalosporinase E. coli excretionMRSA emerges in Dutch animal workers; Holland proposes 50% reduction in antibiotic use in food animals within 5 yearsMRSP emerges in dogs, clonal spread in Europe and North America
2011–2016	Resistance crisis in medicine reaches highest political levelsUnited Nations affirms global collective action	Avilamycin introduced as first-in-class, animal-use-only, orthosomycin antibiotic to prevent mortality due to necrotic enteritis of broilers under veterinary prescription; first “new” antimicrobial drug for food animals in 10 years	Transatlantic Task Force on Antimicrobial Resistance to cooperate between USA and European Union on resistanceInnumerable calls for global solutions to antibiotic resistanceWHO Options for Action promotes development of national action plans incorporating human and animal health sectorsHuman medicine antibiotic resistance threats identified by microorganism level in USA, most unrelated to animal useConsumer demands for “antibiotic-free” animal production; McDonald’s Corporation adopts antimicrobial stewardship requirements for sourcing meatG7 agrees to address the resistance crisisO’Neill Report in UK’s final recommendations includes reducing unnecessary use in agriculture as one of 10 planks to fight resistancePlasmid-mediated colistin resistance gene mcr1 related to agricultural use in animals and humans identified in China, shown to be globally widespreadUnited Nations High-Level Meeting on the antimicrobial resistance threat unprecedented meeting
2017–	Stewardship era	Intense activity to find alternatives to antibiotics or “animal only” antibiotics for food animals	Political will to address the resistance crisis continues in placeAnticipated enhancement of surveillance, stewardship, and innovation as global response to antimicrobial resistance crisisInnovation in numerous fields relating to use of antibiotics anticipatedIncreasing adoption of a “One Health” approach to resistance may remove some of the conflict between agriculture and human medicineThe story continues

The table illustrates many important features in the history of the use of antimicrobials in animals: (i) The development of resistance to antimicrobial drugs followed soon after their introduction. (ii) Resistance was usually dealt with by the development of new classes of antimicrobials by the isolation from nature of novel antibiotics within a particular class or by development of synthetic analogs of an existing class. (iii) The antimicrobial drugs used in animals were the same as those in human medicine, although a number of them that were rejected by human medicine because of toxicity problems (e.g., bacitracin) became growth-promoting feed antimicrobials in food animals. At least one of these drugs (colistin) is now being reclaimed for systemic use in humans. (iv) Antimicrobials were used in agriculture in feed as growth promoters, or for subtherapeutic purposes, almost as soon as they were discovered. (v) The majority of antimicrobial drugs used in animals (and shared with human medicine) belong to a small number of major classes, and only one major new class of antimicrobial drugs (fluoroquinolones; pleuromutilins are an exception, but have very restricted use) has been introduced for food animal use in the past 30 years. (vi) Significant antimicrobial contamination in carcasses or selected tissues was detected in the 1970s and 1980s, leading either to the banning of potentially toxic (e.g., carcinogenic or idiosyncratic effects) drugs or to rigorous, ongoing programs of detection in carcasses after slaughter. This was the major focus of regulations of use in food animals in those decades, and there is still confusion in some quarters about the difference between residues and resistance. (vii) The public health impacts resulting from the development of resistance, and especially because of transmissible resistance, have been a major battleground between agriculture and medicine for nearly 50 years. (viii) The resistance crisis in human medicine has led to unprecedented concern at the highest political levels globally about the threat of resistance to humanity, to an unprecedented focus on stewardship, and to major ongoing reduction and ongoing changes in agricultural use of antibiotics, at least in the developed world. (ix) The science and practices supporting optimal antimicrobial drug use in animals and in humans has developed relatively slowly and is not complete.

DISCOVERY OF ANTIBIOTICS AND EARLY USAGE

Antimicrobial drugs were introduced for animal (and human) use with a minimum of controlled experimental studies, so that from the start of their use there were frequent calls to move from the wonder to the science. As in human medicine, much of the early dosage used was empirical and based on inadequately controlled small-scale trials (2, 3), so that there was a “confusing hodge-podge of widely divergent optimum dose-ranges for the many livestock diseases allegedly amenable to the activity of penicillin” (4). In the United States such empiricism led to a licensed dosage of penicillin G in cattle that was clearly inadequate. It took four or five decades before the licensed drug dosage was more scientifically determined, based on quantitative understanding of the interaction of drug with the target microorganism (dosage, pharmacokinetic and pharmacodynamic parameters, in vitro susceptibility) as well as clinical data (Table 1). Clinical evaluation is still an important component used in the licensing of antimicrobial drugs, in part because the predictive science is imperfect.

In retrospect, for drugs whose use “has advanced the practice of medicine farther than any other single factor of any of the previous centuries” (5), the time taken to establish the science of the clinical use of antimicrobial drugs seems astonishing. As human medicine’s poor cousin, veterinary medicine lagged in the development of the science of optimal antimicrobial drug use, but the lag was only relative since the same delay was clearly visible in human medicine. In general, the science and practice of antimicrobial usage in animals has largely paralleled that in human medicine, in the same way that most antimicrobial drugs used were the same or were in the same drug class. There have been, however, a number of features unique to animal agriculture, as discussed below.

In most countries, approval by the appropriate regulatory authority must be obtained before an antimicrobial drug can be legally sold, and this depends on extensive testing to ensure safety and efficacy, as well as, in the case of food animals, studies of safety for people consuming their products. Registration requirements for veterinary medical products have been largely harmonized internationally under the International Cooperation on Harmonization of Technical Requirements of Veterinary Medicinal products (VICH) of the World Organization for Animal Health, membership of which includes the European Union and the United States. A harmonized VICH guideline, GL 27, defines the data requirements for risk of transfer of resistant bacteria or resistance determinants from foods of animal origin to humans. These data are assessed in terms of exposure of food-borne pathogens and commensal bacteria, and the “qualitative probability” that human exposure to resistant bacteria results in adverse human consequences. As part of this assessment, many countries are attempting to stratify the stringency of regulatory requirements by how important a drug is to public health, also discussed below. This is a highly contentious issue, since most antimicrobial drugs can, under various criteria, be claimed as “critically important.” A more useful and a more rational approach, which could be adopted in both human and veterinary medicine, is categorization into “lines” based in part on culture and susceptibility results (Table 2) (6). This approach has the advantage of simplicity (for example, labels on bottles could indicate the category) and would enhance the use of laboratory diagnosis. Research is needed into whether such a categorization scheme would be accepted in the animal (and human) health world, including the barriers to acceptance and what it would take to implement such a system so that it would be widely accepted.

TABLE 2.

Suggested categorization of antimicrobial drugs for veterinary use (6)

Class	Definition	Examples
First-line (primary)	Initial treatment of known or suspected bacterial infection in absence of culture and susceptibility results	Penicillin, most cephalosporins, trimethoprim-sulfonamides, tetracyclines
	These drugs may commonly be used in human medicine but are usually considered less important for treating serious human (and animal) infections or raise less concern about development of resistance
Second-line (secondary)	Used when culture and susceptibility testing, plus patient or infection factors, indicate that no first-line drugs are reasonable choices	Fluoroquinolones, third and later generation cephalosporins
	Drugs in this class may be more important for treatment of serious human (and animal) infections, or there may be particular concern about development of infection
Third-line (tertiary)	Used in serious, life-threatening infections, with the support of culture and susceptibility results, when no first-line or second-line drugs are indicated	Carbapenems
	Not for use in food animals
Restricted, voluntarily prohibited	Used only in life-threatening infections when culture and susceptibility testing indicate no other options	Vancomycin
	Not for use in food animals
	Additional requirements may be indicated, or use may be voluntarily prohibited

The regulation of antimicrobial drug use in animals is a complex process that has jurisdictional differences. Regulation is more stringent for use of these drugs in food animals, although “off- or extra-label” use (use of the product in any manner not specified on the label) is often approved under specific circumstances and constraints. Use of antimicrobial drugs in companion animals is subject to less stringent regulation, and there is likely more off-label use in companion animals (as there is in human medicine).

Although the situation is changing, there has been historically no formal interest by regulatory authorities in postapproval use (or periodic relicencing) of antimicrobial drugs in animals. Some of the label claims for some antimicrobial drugs list approval for use in bacteria that have had their names changed several times since approval or for diseases that have subsequently been shown to be caused by other agents, so that reading the labels can be like reading a outdated veterinary microbiology textbook from the 1960s. The postapproval monitoring of resistance in Campylobacter jejuni following the introduction of fluoroquinolones for use in broiler chickens in the United States, and the subsequent withdrawal of fluoroquinolones from use in poultry in the United States is, however, a well-known example of postapproval monitoring of the approved use of a drug.

PRACTICES IN ANTIMICROBIAL DRUG USAGE UNIQUE TO ANIMAL HUSBANDRY

The greatest differences in usage of antimicrobial drugs between animal husbandry and human medicine were, and in many countries still are, in the use in agriculture of antimicrobials for growth promotion and for long-term disease prophylaxis, although the situation is changing relatively rapidly. This has occurred particularly in countries where livestock, notably chickens and pigs, are reared intensively.

The growth-promotional benefits of adding low concentrations of many antibacterial drugs to feed was recognized almost as soon as antibiotics were introduced. The enhancement of growth rates and improved efficiency of use of feed were noted when pigs and poultry were fed the fungal waste derived from antibiotic production, originally intended as a source of vitamins and protein, but mostly as an efficient way to use the waste. The effect was originally attributed to the presence of vitamin B₁₂ (“animal protein factor”) in the mycelial mass, but with time it was recognized to be a direct effect of residual antibiotic. Interestingly, how antimicrobial drugs improve growth rate and efficiency of utilization is still unknown, although it is thought to be through an inhibitory or metabolic effect of some kind on the Gram-positive intestinal microflora. Curiously, until about the mid-1950s, low prolonged oral dosage of tetracycline was even used to improve the growth of underweight human infants and children, but this practice was dropped because of both resistance and discoloration of teeth. In animals, the growth-promotional and disease-prophylactic benefits appear to have remained constant over the years (7), supporting the idea that these effects result from metabolic rather than antibacterial activities. As the use of antibiotics as growth promoters in intensively reared livestock becomes illegal in much of the world, alternative approaches to manipulation of the microbiome may replace their growth-promoting effects.

Not only have antimicrobial drugs been used for growth promotion, but some drugs were and in some countries still are administered in feed for prolonged periods at somewhat higher concentrations, the “subtherapeutic levels” (defined in the United States as less than 200 g per ton of feed), which are lower concentrations than those approved for therapeutic purposes. The historical origin of subtherapeutic usage and indeed the meaning of this term are obscure, but it seems to have both beneficial growth-promotional and disease-prophylactic effects, particularly against pathogens that do not readily develop or acquire resistance. Drugs such as tetracyclines are administered “subtherapeutically” for many defined, licensed purposes at a range of concentrations varying with the drug, the food-animal species, and the purpose. Such usage, which can often be prolonged and thus inconsistent with important general principles of antimicrobial drug dosage (6), has been particularly widespread in the swine industry in countries in which the drugs are still allowed for this purpose (8). The practice is coming under increased scrutiny and will likely also be banned and replaced by short-term antimicrobial prophylaxis or short-term treatment targeted to specific pathogens. As noted earlier, a number of antimicrobial drugs (such as the streptogramins) that were too toxic for parenteral use in humans were relegated to growth-promotional and disease-prophylactic use in food animals.

Another practice that has historically been far more common in food animal use than in human medicine has been short-term mass medication with therapeutic concentrations of drugs immediately before an outbreak of disease can be anticipated, or immediately at the onset of disease in a population (9). This type of prophylaxis has been commonly practiced in beef feedlot and swine medicine and is most akin to the prophylactic use of antimicrobial drugs to prevent Haemophilus or Neisseria meningitis in humans. Prophylactic use of intramammary antimicrobial drugs to prevent development of new infections and to treat existing infections has become a standard practice in dairy cows in the two months before calving and re-entering the milking herd (“dry cow treatment”), with no apparent adverse effect on resistance development, perhaps in part because the very high concentrations of drugs achieved in the udder result in rapid killing of the target bacteria. Blanket use of dry cow treatment is also coming under scrutiny and is being replaced by use only when udders are known to be infected and likely to carry an infection over to the next lactation.

USE OF ANTIMICROBIAL DRUGS IN ANIMALS

Food Animals

Data on the quantities and types of antimicrobial used in food animals are increasingly available in highly developed countries, with countries such as Denmark and Sweden leading the way. A global assessment of trends in antimicrobial use in food animals recognized the relative lack of reliable quantitative data globally but forecasted a marked increase as livestock production practices intensified in middle- and low-income countries (10). In Europe, the Danish Integrated Antimicrobial Monitoring and Research Program (DANMAP), started in 1995, is a ground-breaking and very high-quality program that monitors both resistance in selected food-animal indicator organisms and pathogens and usage of antimicrobials in human and animal medicine. DANMAP can accurately record national antimicrobial use in animals to the kilogram level. In Sweden, the Swedish Veterinary Antibiotic Resistance Monitoring organization has had a similar program since 2000 and has integrated this with Swedish Antibiotic Utilization and Resistance in Human Medicine since 2011. In the United States, the National Antimicrobial Resistance Monitoring System has monitored resistance in food-animal indicator organisms and select human and animal pathogens nationally, but has not monitored use, since 1996. In Canada, the Canadian Integrated Program for Antimicrobial Resistance Surveillance has a similar program but has struggled for national jurisdictional reasons to obtain accurate food animal use data. In Europe, the European Medicines Agency collects data on antimicrobial use in animals from member countries (European Surveillance on Veterinary Antimicrobial Consumption).

These data have great value in “benchmarking” comparisons between antimicrobial use in food animals between different countries, which can vary widely, but there is uncertainty about the best way to compare antimicrobial use between different species (e.g., milligram/population corrected unit, animal daily dose) and about the validity of some of the comparisons based on sales data, differences in dosages, and differences in animal demographics including weight estimates (11, 12). This is discussed further in chapter 28. The importance of benchmarking cannot be underestimated as a driver for reducing antimicrobial use in food animals at the farm and the veterinarian level, as illustrated by the use of the “yellow” card system in Denmark and the experience of the value of benchmarking in Holland in its 50% reduction of use in food animals between 2007 and 2012 (13, 14). Reduction in use in food animals is associated with reduction of resistance in indicator bacteria (15), and a correlation between antimicrobial use in animals and resistance in indicator bacteria is well established (16). A robust approach to benchmarking has been developed (17).

The documentation of antimicrobial drug use in food animals nationally and internationally is a rapidly growing, fast moving, and evolving field that can only be briefly touched on here but is reviewed in detail in chapter 28. As promoted by the World Health Organization and others, surveillance and documentation of use, and of the impacts of reduction in use in animals, is an essential element in addressing the resistance crisis and improving how antimicrobials are used in animals.

There are now numerous studies of the antimicrobial-prescribing habits of veterinarians and factors influencing those habits (18, 19) which can be expected to continue as veterinary medicine embraces antimicrobial stewardship.

Companion Animals

The use of antimicrobials in companion animals essentially mirrors their use in human medicine, a discussion of which is far beyond the scope of this chapter. Only in recent years have antimicrobial use practices in companion animals come under scrutiny, both as sources of important emerging resistance issues (such as methicillin-resistant Staphylococcus aureus [MRSA] and Staphylococcus pseudintermedius [MRSP]) (20) and as potential sources for multidrug-resistant pathogens for humans. The rapid emergence and clonal spread of methicillin-resistant S. pseudintermedius has been a “wake-up call” for companion animal practice (20–22). Untreatable multidrug-resistant hospital-associated infections are now being encountered in companion animals. Studies of the use of antimicrobials in primary care companion animal veterinary practice have been characterized by their small sample size and labor-intensive nature. However, studies are now being reported that involve analysis of mega-data on usage obtained from shared practice software to obtain that involving large numbers of animals (e.g., one million dogs) (23). However, documentation of usage alone is not particularly useful since it may not be appropriate to the infections being treated. For example, in Canada, one study found that there was overuse of cefovecin and of fluoroquinolones for the treatment of cat and dog diseases for which antibiotics were either not indicated or for which first-line antimicrobials were appropriate (24). The potential value of companion animal usage data obtained electronically is that, as has been shown for food animals, it can be used for benchmarking purposes as part of a broader approach to improved antimicrobial stewardship.

PUBLIC HEALTH ASPECTS OF ANTIMICROBIAL DRUG USE IN ANIMALS

Food Animals

The effect of antimicrobial drug use in food animals on the development of resistance in bacteria that can cause disease in humans has been the subject of prolonged, acrimonious, and ongoing debate. The major and most accessible reviews of this issue are summarized in Table 3, which shows that the intensity of the criticism of agricultural usage of antimicrobial drugs intensified from the mid-1990s and has now reached a crescendo, paralleling the antimicrobial resistance crisis in human medicine (Table 1).

TABLE 3.

Historical time line of major reports and their conclusions or recommendations relating to the public health aspects of antimicrobial drug use in food animals

Date	Report/country	Major conclusions or recommendations
1962	Netherthorpe CommitteeUK, Joint Committee, Agricultural and Medical Research Councils	Recognized economic benefit of antimicrobials as growth promoters, saw no reason to discontinueHowever, continue to examine situation and substitute penicillin and tetracycline use if alternative nontherapeutic growth promoters become available
1969	Committee on Antibiotic Uses in Animal Husbandry and Veterinary Medicine; The Swann ReportUK, Report to Parliament	Restriction of use of antimicrobials into prescription-only therapeutic use and nonprescription feed additivesGrowth-promotional and subtherapeutic use of drugs important in human medicine were banned
1972	The Use of Antibiotics in Animal FeedsUSA, FDA Task Force	Use of antimicrobial drugs in food animals may promote resistance in Salmonella; manufacturers to show this is not a problemSufficient evidence to stop use of penicillin and chlortetracycline as growth promoters
1979	Drugs in Livestock FeedUSA, Office of Technology Assessment	Stop use of penicillin and tetracyclines as growth promoters, even though this would have short-term economic cost
1980	The Effects on Human Health of Subtherapeutic Use of Antimicrobials in AnimalsUSA, National Research Council	Could not conclude from data available that there was a direct relationship between subtherapeutic drug use in animal feed and human healthInsufficient data from UK that implementation of Swann report had reduce postulated hazards to human health
1981	Antibiotics in Animal FeedsUSA, Council for Agricultural Sciences and Technology	Irrational to ban subtherapeutic dosage without also banning therapeutic useCost of a ban on feed antimicrobials: about $3.5 billion
1989	Human Health Risks with the Subtherapeutic Use of Penicillin or Tetracyclines in Animal FeedUSA, Institute of Medicine	Unable to find substantial direct evidence of definite human health hazard in the use of subtherapeutic concentrations of penicillins and tetracyclines in animal feeds
1995	Impacts of Antibiotic-Resistant BacteriaUSA, Office of Technology Assessment	Need to collect more data to resolve the issue of the effect of feed antimicrobials in animals on human healthA further report will not resolve the issue
1997	Antimicrobial Feed AdditivesSweden, Ministry of Agriculture, Commission on Antimicrobial Feed Additives	As part of negotiations leading to European Union membership, Sweden, which had banned use of antimicrobial growth promoters in 1985, re-reviewed benefits of antibacterial feed additives and again concluded that benefits did not outweigh the risks
	The Medical Impact of the Use of Antimicrobials in Food AnimalsWHO	Stop using antimicrobials for growth promotion or subtherapeutic purposes in animals if used in human therapeutics or if they select for cross-resistance to antimicrobials used in human medicine
1998	A Review of Antimicrobial Resistance in the Food ChainUK, Ministry of Agriculture, Fisheries, and Food	Resistance in animal pathogens and commensal bacteria is selected for by antimicrobial drug use, can reach people through food chain, may cause disease or colonize people, can transfer resistance to human pathogens, Campylobacter and Salmonella, and certain antimicrobials are especially problematic
1999	The Use of Drugs in Food Animals: Benefits and RisksUSA, Committee on Drug Use in Food Animals: Panel on Animal Health, Food Safety and Public Health, National Research Council and Institute of Medicine	Use of drugs in food animals does not appear to constitute an immediate public health concern; additional data may alter conclusion, but data are lackingRecommended integrated national databases to support rational, visible, science-driven decision-making and policy development for regulatory approval and use of antimicrobials in food animalsEstimated cost of ban on nontherapeutic use in animals: between $5 and 10 per person per year in USA
2000	The Use of Antibiotics in Food-Producing Animals: Antibiotic-Resistant Bacteria in Animals and HumansAustralia: Joint Expert Advisory Committee on Antibiotic Resistance	Stop using growth promoters if same drugs important in human medicineAll antimicrobials for animals prescription onlyPredetermine “resistance thresholds” for animal antimicrobials that trigger investigation or mitigationDevelop a comprehensive and integrated resistance surveillance systemMonitor antimicrobial usageFind alternatives to antimicrobials for food animals
2001	Risk Assessment on the Human Health Impact of Fluoroquinolone Resistant Campylobacter Associated with the Consumption of ChickenUSA, Center for Veterinary Medicine	Risk assessment by highly detailed mathematical model with numerous explicit assumptions suggested that in 1998 mean estimate of 8,678 U.S. citizens had fluoroquinolone-resistant Campylobacter illnesses acquired from chicken and received fluoroquinolones for treatment
2002	The Need to Improve Antimicrobial Use in Agriculture: Ecological and Human Health ConsequencesUSA, Alliance for the Prudent Use of Antibiotics. Clinical Infectious Diseases 34; Supplement 3	Elimination of nontherapeutic use of antimicrobials in food animals will lower burden of antimicrobial resistance in the environment, with benefits to human and animal health
	Uses of Antimicrobials in Food Animals in Canada: Impact on Resistance and Human HealthCanada, Health Canada Advisory Committee on Animal Uses of Antimicrobials and Impact on Resistance and Human Health	Make all antimicrobials for disease control prescription onlyDevelop extra-label policyControl an importation of drugs “loop-hole”Stringently reassess growth-promotional use of drugsDevelop national surveillance of resistance and use
	Food Safety and Pig Production in Denmark. Controls on antibiotics, veterinary medicines and SalmonellaVerner Wheelock Associates Limited; Danish Bacon and Meat Council	Control of antimicrobial-resistant bacteria by banning antimicrobial growth promoters, and Salmonella control programs, has made Denmark a model and given the Danish pig industry competitive economic advantage
2003	Joint FAO/OIE/WHO Expert Workshop on Non-Human Antimicrobial Usage and Antimicrobial Resistance: Scientific AssessmentWHO	Clear evidence of adverse human health consequences due to resistant organisms resulting from nonhuman usageSurveillance of usage and resistance important to identify problems and choose interventionsMagnitude of impact accompanied by considerable uncertainty
	Impacts of Antimicrobial Growth Promotion Termination in DenmarkWHO	Review of the “Danish experiment” of terminating use of growth promoters on efficiency of food animal production, animal health, food safety, and consumer prices concluded that there have been no serious negative effectsVery beneficial in reducing total quantity of antimicrobials used and reducing antimicrobial resistance in important food animal reservoirs
2004	Second Joint FAO/OIE/WHO Expert Panel on Non-Human Antimicrobial Usage and Antimicrobial Resistance: Management OptionsWHOAntibiotic Resistance: Federal Agencies Need to better Focus Efforts to Reduce Risk to Humans from Antibiotic Use in AnimalsU.S. General Accounting Office	Establish national surveillance programs on use and resistance; follow WHO/OIE guidelines on responsible use; implement strategies to prevent transmission through food etc.Expedite risk assessments in animals of antibiotics critically important to humans; develop plan to assess and mitigate risk
2008	Antimicrobial Resistance from Food Animals.World Health OrganizationPutting Meat on the Table: Industrial Farm Animal Production in AmericaUSA, Pew Commission on Industrial Farm Animal Production	Continues to press for multiple approaches to improve antimicrobial use in food animals, prescription only, integrated use and resistance surveillance, identify barriers to implementation of international guidelines, etc.Phase out nontherapeutic antimicrobial use in food animals, restrict use to veterinary oversight and prescription, require reporting of annual sales, review previously approved antibiotics for animals etc.General approach very critical of modern intensive agriculture
2009	The American Veterinary Medical Association Response to the Final Report of the Pew Commission on Industrial Farm Animal ProductionAmerican Veterinary Medical Association (AVMA)	Described Pew Report as having some value but “dangerous and uninformed” and “shocking”The Pew Report and the AVMA response highlights the highly conflictive nature of the debate in the USA
2010–2014	No major reports during this period but numerous scientific papers investigating development and spread of livestock-associated MRSA, spread of extended-spectrum β-lactamase-producing E. coli or Salmonella in food animals treated with ceftiofur, and possible or definite spread to humansMany examples during this period of small groups of engaged academics reviewing the issue in different forums and making recommendations
2015	Antimicrobials in Agriculture and the Environment: Reducing Unnecessary Use and WasteUK, Review on Antimicrobial Resistance: O’Neill Report	Scale of antimicrobial use in global agriculture is massiveA review of the evidence supports a link between antimicrobial use in animals and resistance in human pathogensProposed global targets for antimicrobial use in animals, restrictions on use of certain antimicrobials, and improved surveillance
2016	Tackling Drug-Resistant Infections Globally: Final Report and Recommendations.UK, Review on Antimicrobial Resistance: O’Neill Report	Influential economist’s view of the present and future scale and costs, call for urgent global actionHighlights agricultural area as one of 10 major recommendations

The first major review of the effect of antimicrobial drug use on resistance in human and animal pathogens was carried out in the United Kingdom under the chairmanship of M.M. Swann. The impetus for the review was a combination of recognition of the increasing importance of (i) the phenomenon of “infectious,” transferable, drug resistance associated in part with the pioneering work of the distinguished British veterinary microbiologist H. Williams Smith, (ii) the emergence and dissemination in calves in Britain of multidrug-resistant Salmonella enterica serotype Typhimurium and its spread to humans, and (iii) experiences around this time of a difficult-to-control epidemic of chloramphenicol-resistant S. enterica serovar Typhi in Central America. Chloramphenicol was then the drug of last resort for typhoid fever in humans (25). The 1969 Swann Report to the British government gave a careful analysis of how different usage of antimicrobial drugs in animals might lead to selection of resistant bacteria and resistance plasmids and how such resistant bacteria, or their transmissible resistance traits, could lead to difficult to treat infections in humans. The major recommendations of the committee were as follows: (i) “Feed” antimicrobial drugs could only be used for growth promotion without prescription if they had little or no implication as therapeutic agents in humans, would not impair the value of prescribed drugs, and produced an economic benefit. Since penicillin and tetracyclines did not meet these criteria, they were withdrawn from growth-promotional use and could only be used therapeutically by veterinary prescription. (ii) The “therapeutic” antimicrobials (those other than growth-promotional antimicrobials) tylosin, sulfonamides, and nitrofurans should no longer be used without veterinary prescription. The spirit of the Swann report was to restrict the use of therapeutically effective antibiotics to only therapeutic use on a veterinary prescription basis. Withdrawal of penicillin and tetracyclines for growth-promotional and subtherapeutic purposes was, however, soon followed by their substitution by bacitracin, flavomycin, nitrovin, and virginiamycin for similar purposes.

It was perhaps unfortunate that little effort was made in Britain following the Swann report to improve the scientific base of understanding of the effect of antimicrobial drug use in animals on human health, or to document the effect of implementation of the report. Nevertheless, the sustained work of A.H. Linton (26) and that of his colleagues led to important conceptual understanding of the routes of movement of resistant bacteria between animals and humans, and the factors which enhanced the movement, although the scale of the movement still has considerable uncertainty (Fig. 1).

FIGURE 1.

Routes of exchange of Escherichia coli between animals and humans. Note the areas where antimicrobial drug selection for resistance is most likely. The size of the circles or boxes does not indicate the extent of the scale of the movement. After Linton (26), modified by R. Irwin; reproduced with permission.

In the United States, the response to the issues raised in the Swann report was largely unenthusiastic and critical (Table 3). Resistance to Swann’s recommendations was based on the estimates of the considerable economic contribution that growth-promoting and subtherapeutic (feed) antimicrobial drugs made to agriculture in comparison to what was criticized as the inadequate evidence, the dubious and slender risk, and the “special case pleading” on which the recommendations of the Swann report were regarded as based. The strong lobby of antimicrobial drug manufacturers and the absence in the United States of a national health system (i.e., the patient pays for illness, whereas in Europe it is the nation that bears the cost) may have helped to fuel the criticism. The data were regarded as inadequate to make clear judgements, but the scale of the problem was also thought to be minor. For example, the 1989 Institute of Medicine study (Table 3) suggested that use of subtherapeutic or growth-promoting drugs might contribute to perhaps 26 human deaths a year from antimicrobial-resistant Salmonella. For perspective, these numbers would have compared to about 40,000 automobile accident and 10,000 gunshot fatalities in the United States in the same year.

Despite the inconclusive nature of many of the reports in the United States in the period between 1972 and 1995, the issue refused to die. There were periodic highly publicized reports throughout this period of serious human illness caused by Salmonella carrying resistance genes thought to be acquired from subtherapeutic, or even therapeutic, use of antimicrobials in animals. One of several examples was that of Spika and others (27) of chloramphenicol-resistant S. enterica serotype Newport traced from hamburger meat to dairy farms. Such reports led to apparently carefully orchestrated media and even major science journal frenzies about the discovery of the “smoking gun,” with consequent fervent denials by the animal antimicrobial drug industry. Given the existing well-established understanding of the epidemiology of the movement of resistant intestinal bacteria (Fig. 1), these periodic frenzies seemed at the time both astonishing and somehow hysterical. The periodic surges in public interest, however, produced no political will in the United States to re-examine the problem.

The reason for the extensive re-examination of the issue from the mid-1990s was related to several factors. The most important of these was the antimicrobial resistance crisis in medicine, in which for the first time resistant bacteria moved “out of the hospital and into the community.” The very serious nature of the crisis led to a re-examination within the human medicine community of all aspects of antimicrobial use and even to the apparent rediscovery of the importance of basic infection control procedures such as hand-washing. The antimicrobial resistance crisis in medicine again focused the medical establishment on agricultural usage of antimicrobials, in some cases almost to the extent of using it as the scapegoat for the crisis in medicine.

Improvements in understanding of the microbiology of infectious diseases acquired from animals were less important, but also critical, forces in the re-examination of antimicrobial usage in agriculture. For example, at the time of the Swann report, C. jejuni was not recognized as a human pathogen, although it subsequently became identified as the most common cause of bacterial gastroenteritis in humans. The emergence of fluoroquinolone resistance in C. jejuni of poultry origin in the United States because of the use of fluoroquinolones to treat Escherichia coli infections in chickens (28) subsequently led to the ban of all use of this class of drug in chickens in the United States (Table 3). A subsequent risk analysis in the United States suggested that 8,678 citizens treated for this illness with fluoroquinolones had fluoroquinolone-resistant C. jejuni illness acquired from chickens (Table 3), a huge number compared to the “26 possible deaths because of resistant Salmonella” identified in the 1989 Institute of Medicine report.

Similarly, at the time of the Swann report, vancomycin-resistant enterococci (VREs) were also unknown, although subsequently, enterococcal infections emerged as major nosocomial, largely hospital-acquired, infections in humans, with vancomycin as the “drug of last resort” in such infections. Acquisition of transmissible vancomycin-resistance genes by these hospital-associated bacteria made them essentially untreatable, again raising the specter of the postantibiotic era (Table 1). Work by Aarestrup and his colleagues in Denmark was important in identifying avoparcin, a glycopeptide antimicrobial related to vancomycin, as selecting for the massive presence of VREs in the intestine of poultry and swine fed this drug as a growth promoter (29). For the first time, there was convincing large-scale evidence that eliminating the use of antimicrobial drugs in food animals could dramatically reverse the rise of resistant bacteria in these animals (30). Convincing molecular genetic typing evidence showed that VREs from animals colonized humans (31) and, most dramatically, the marked decline in human intestinal colonization by VREs in Europe following the withdrawal of avoparcin as a growth promoter (32) suggested that the scale of the movement of resistant intestinal bacteria from animals to humans, which had always been a matter of great uncertainty, was far larger than generally suspected previously. Molecular genetic typing and whole-genome sequencing of resistance genes and gene regions were unavailable at the time of the Swann Report but were subsequently used extensively to characterize the relatedness (and therefore sometimes the source) of both bacteria and their resistance genes obtained from animals and humans.

More recent application of whole-genome sequencing to antimicrobial-resistant extrapathogenic E. coli from human urinary tract infections and comparison to isolates from healthy chickens clearly indicates that some resistant human isolates derive from chickens (33). Recognition of the likelihood of such a previously unsuspected “insidious epidemic” suggests that the scale and importance of the movement of resistant bacteria and their genes into the human population may be far greater than suspected. One group suggested that cephalosporin use in poultry was responsible for about 1,500 human deaths annually in Europe (34). A voluntary ban on ceftiofur use in Danish swine production was shown to effectively reduce extended-spectrum cephalosporinase-producing E. coli in slaughter pigs (35). It seems likely that similar bans, voluntary or involuntary, may be adopted in different jurisdictions in agriculture. The World Health Organization ranking of antimicrobials according to their importance in human medicine (36) remains an important issue for animal use, since the World Health Organization classification of “critically important” includes drugs such as penicillin, and essentially all antibiotics are classified as important, highly important, or critically important. Further discussion, which will likely focus on “highest-priority critically-important antimicrobials” (36), is clearly required as one of the steps in addressing the global resistance crisis.

It is highly ironic that the recent emergence and global dissemination of MRSA in livestock, particularly of clonal complex 398 associated with swine, and the emergence and dissemination of livestock-associated MRSA infections in humans (37, 38) has been linked to the use of zinc oxide in the feed of intensively reared livestock (39). Following the European ban on antimicrobial growth promoters, zinc oxide was introduced as an alternative to to prevent enteric infections in young animals.

Companion Animals

There has been no systematic study of the effect of antimicrobial drug use in companion animals (meaning, particularly, dogs and cats) and transfer of resistant bacteria or their genes to humans. As a generalization, resistance to antimicrobials is growing among bacteria that cause infection in pets, such as S. aureus, S. pseudintermedius, and E. coli (40), and such bacteria can be transmitted between pets, owners, and veterinary staff both directly and indirectly. Practicing veterinarians are far more likely than controls to be nasally colonized by S. aureus (41). Companion animals have been documented to act as reservoirs of some of the high-risk multidrug-resistant clones of Enterobacteriaceae (42–44), some of which are likely to be acquired from their human owners. Infection with such resistant bacteria may be amplified by antimicrobial use in veterinary clinics or hospitals and subsequently spread back to animal owners in the dance of infection (Fig. 1).

THE EMERGING CONCEPT AND PRACTICE OF ANTIMICROBIAL STEWARDSHIP IN VETERINARY MEDICINE

As the science of antimicrobial resistance moves onto the political stage, the past 2 years have seen dramatic changes in the global response to the antimicrobial resistance crisis, culminating most recently in the September 2016 United Nations High-Level Meeting and the commitment of members to address the issue in a multifaceted way. This follows earlier similar commitment by members of the G7 and numerous important analyses of how to address the crisis (45, 46) (Table 1). In the United States, there has been game-changing commitment (Guidance 213, Guidance for Industry 233) to remove antibiotics from use as growth promoters and to bring all antibiotics used in feed or water of food animals under veterinary oversight. Canada has followed suit. Another major change has been adoption of a “One Health” approach to resistance (reviewed in chapter 26), an approach that involves multidisciplinary and multijurisdictional approaches to very complex problems involving people, animals, and the environment (47). An evolving concept and practice, a One Health approach may reduce some of the conflict between the use of antimicrobials in human and veterinary medicine by focusing efforts and energy on resolving resistance issues in a collaborative rather than blaming manner.

Antimicrobial resistance is a multifaceted problem with all the complexities of climate change, to which it is highly analogous. It has multiple causes, with no single actor or factor that can be blamed, has the well-established ability to be self-sustaining, and has the potential to be catastrophic. No single intervention will address the problem, but the combination of multiple interventions and approaches has the potential to have a cumulative impact that will help in its control. A stewardship approach which integrates so much of what we now know about effective antimicrobial use (6), and about infection generally, is the best approach for first-line veterinary practitioners to address the resistance crisis. “Antimicrobial stewardship,” reviewed in chapter 32, is the term increasingly used in medicine to describe the multifaceted approaches required to sustain the efficacy of antibiotics and minimize the emergence of resistance. The concept and practice of antimicrobial stewardship continues to evolve in human and veterinary medicine, but it is an approach that takes an active, dynamic process of continuous improvement encapsulated in the idea of good stewardship practice (GSP) (6, 48). Only a GSP mind-set will ensure the long-term sustainability of antimicrobial drugs. Antimicrobial stewardship and GSP involve coordinated approaches and interventions designed to promote, improve, monitor, and evaluate the judicious use of antimicrobials to preserve their future effectiveness and promote and protect human and animal health. This involves a “5R” approach of responsibility, reduction, refinement, replacement, and review (49). Critically, a GSP approach to stewardship also could be evaluated quantitatively as a standard of veterinary practice.

The question for the future is how to preserve existing and develop new drugs in the face of bacterial pathogens, some of which appear to have become particularly adept at developing or acquiring resistance over the past 60 years. Using some of the tools available as we enter the “golden age of microbiology” to improve the way we diagnose infections and develop new, likely targeted, antimicrobials is promising (50). However, as noted by one writer in respect to resistant bacterial infections in companion animal practice (40), resolving the issue of multidrug-resistant endemic bacterial infections will not be through development of new antibiotics if current hygiene practices remain and if we don’t undertake good stewardship practices to preserve our existing drugs.

With respect to the changing relationship to antimicrobial drugs in human and veterinary medicine that the resistance crisis has produced, there’s a sense that humanity is perhaps in the intermission after the first act of a three-act play, and we’re still trying to determine if the play is a comedy or a tragedy. It currently feels like both. There’s a huge amount to be done.