Classes of antimicrobial drugs used in food and companion animals

Not surprisingly, given the limited number of therapeutically useful antibiotics, the classes of antimicrobial drugs used in animals are largely those used in human medicine. One difference is that a limited number of antimicrobial drugs that are unimportant in human medicine because of toxicity problems (glycopeptides and streptogramins) were or are used as growth-promoting feed antimicrobials in food animals. The selection of VRE in chickens and swine by avoparcin, a growth-promoting glycopeptide related to vancomycin, has led to withdrawal of use of this drug from animal use in many jurisdictions. Streptogramins such as virginiamycin have also been withdrawn in some jurisdictions because of induction of resistance to pristinamycin, a streptogramin recently introduced into human medicine to treat VREs. Antimicrobial drugs such as chloramphenicol, the nitrofurans and the nitroimidazoles have been banned from use in food animals in most jurisdictions because of potential toxicity or carcinogenicity for human beings inadvertently exposed through food residues. The ionophores are a class of relatively toxic orally administered antibiotics used uniquely in food animals to control coccidiosis and improve efficiency of food use. Pleuromutilins are a unique class of antibiotics used exclusively in food animals, with activity similar to that of macrolides, with which they can induce cross-resistance.

Types of use of antimicrobial drugs in food and companion animals

In general, the types of use of antimicrobial drugs are similar in animals and humans, and in companion animals are essentially identical (Institute of Medicine, 1998) (Table 1). A practice that is far more common in food animal use than in human medicine is mass medication with therapeutic concentrations of drugs immediately before an anticipated outbreak of disease, or immediately following the onset of disease in a population (‘metaphylaxis’). The greatest differences in usage are in food animals where, in some jurisdictions, antimicrobials are used for growth promotion and for disease prophylaxis (Table 1). Not only are antimicrobial drugs being used for growth promotion in many countries, but some drugs are administered in feed for prolonged periods at somewhat higher concentrations, the ‘subtherapeutic levels’ (defined in the United States as less than 200 g ton⁻¹ of feed, lower than concentrations approved for therapeutic purposes). Drugs 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, is particularly widespread in the swine industry in those countries in which the drugs are allowed for this purpose and is not under veterinary prescription.

Table 1. Types of antimicrobial drug use in animals (adapted from Health Canada: Animal Uses of Antimicrobials and Impact on Resistance and Human Health, 2002)

¹ Metaphylaxis describes mass medication of groups of food animals when some animals are diseased and others are incubating disease or at high risk.

Regulation of antimicrobial drug use in animals

In most countries, approval by the appropriate regulatory authority must be obtained before an antimicrobial drug can be legally sold, and depends on extensive testing to assure 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 (OIE), membership of which includes the EU and USA. 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 (Tollefson et al., Reference Tollefson, Morris, Boland, Kay and Aarestrup2006; Valois et al., Reference Valois, Endoh, Grein, Tollefson, Guardabassi, Jensen and Kruse2008). 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 (WHO, 2005, 2007). This is a highly contentious issue, since most antimicrobial drugs can, under various criteria, be claimed as ‘critically important’. Antimicrobial drug resistance is an inevitably dynamic field. For example, for decades polymyxins were almost unused in human medicine because of their relative toxicity and would until recently be described as ‘unimportant’. The rise of multi-drug resistant Acinetobacter spp. and Pseudomonas aeruginosa infections in hospitalized people means that they may be the only drug to which these infections are susceptible, and therefore become ‘critically important’ life-saving drugs. The drawback inherent in categorizing antimicrobial drugs into levels of importance is that the majority of antimicrobial drugs will inevitably end up on the ‘critically important’ list, and by implication and likely extension be unavailable for animal use. This issue is becoming a major battleground between medical and veterinary users of antimicrobials. 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) (Prescott et al., Reference Prescott, Hanna, Reid-Smith and Drost2002; Weese, Reference Weese, Giguère, Prescott, Baggot, Walker and Dowling2006). This approach has the advantage of simplicity of approach (for example, labels on bottles could indicate the category) and would enhance the use of laboratory diagnosis. Such an approach would reduce concern about the widespread use of third-generation cephalosporins in food animals with minimal restriction (Collignon and Aarestrup, Reference Collignon and Aarestrup2007), and their more recent use in companion animals with minimal restriction. Research is needed into whether such a categorization 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. Surprisingly, there is little or no research documenting the factors that determine how veterinarians decide what antimicrobial drugs to administer, and how readily these factors could be changed.

Table 2. Suggested categorization of antimicrobial drugs for veterinary use (after Weese, Reference Weese, Giguère, Prescott, Baggot, Walker and Dowling2006)

The regulation of antimicrobial drug use in animals is a complex process that has jurisdictional differences (Valois et al., Reference Valois, Endoh, Grein, Tollefson, Guardabassi, Jensen and Kruse2008). 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 post-approval use (or periodic re-licensing) 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 labels can be like reading an outdated 1960s veterinary microbiology textbook. The post-approval monitoring of resistance in Campylobacter jejuni following the introduction of fluoroquinolones for use of broiler chickens in the USA (Food and Drug Administration, 2001), and the subsequent withdrawal of fluoroquinolones from use in poultry in the USA is, however, a well-known example of post-approval monitoring of approved use of a drug.

Monitoring antimicrobial drug usage in animals

Data on antimicrobial drug usage in animals, together with data on resistance in bacteria derived from animals, are crucially important in the development of policies to control resistance at the national and international levels (WHO, 2001, 2003, 2004; Grave et al., Reference Grave, Frøkjær, McEwen, Kruse and Aarestrup2006). The WHO (2001, 2003) has recommended that all countries develop national monitoring programs to assess the use of antimicrobial drugs in animals. The value of development of accurate usage data is considerable, particularly when also linked to data on resistance in animal pathogens and ‘indicator’ bacteria. Usage data allows comparison within and between countries, interpretation of trends in development of resistance in targeted bacteria, triggering of introduction of control measures, assessment of the impact of control measures, identification of needs for further targeted research on use and resistance, and development of policies for resistance containment (WHO, 2003; Grave et al., Reference Grave, Frøkjær, McEwen, Kruse and Aarestrup2006). There is considerable attention being paid internationally to the critical components and standardization required for useful monitoring systems (for example, the sources and reliability of the data, the antimicrobial classification systems to be used, the best units of measurement, and the purposes of monitoring), all complex issues excellently discussed by Grave et al. (Reference Grave, Frøkjær, McEwen, Kruse and Aarestrup2006).

The quality of the data on antimicrobial use in animals varies considerably between countries, because of variations in the regulations and infrastructure (Grave et al., Reference Grave, Frøkjær, McEwen, Kruse and Aarestrup2006). Data may be accumulated from sources such as voluntary disclosure by pharmaceutical companies, importers and customs forms, pharmacies, feed mills, veterinarians or farmers. Accurate data collection is most available where all antimicrobials are obtained only by prescription and dispensed by pharmacies. In these few countries (Denmark, Norway and Sweden) the quantities used in animals are known to the kg level. Other countries such as Canada are assessing use of voluntary reporting by ‘sentinel’ veterinarians or farmers who are regarded as typifying usage (Canadian Integrated Program for Antimicrobial Resistance Surveillance, 2005), but such an approach is expensive and inefficient (Grave et al., Reference Grave, Frøkjær, McEwen, Kruse and Aarestrup2006). One powerful argument for making dispensing of all antimicrobials ‘prescription only’ is that it would potentially allow accurate collection of data on usage. Whether drug usage is reported as total annual weight of active ingredients, doses, courses, animal daily doses (ADD) or prescribed daily doses (PDD), the amounts are useful as measures of ‘selection pressure’ for emergence of resistance only if they are related to total numbers of animals, and proportion of animal populations being treated. The detail available for total antimicrobial drug use in various species, age groups and types of animal, as well as resistance in bacteria obtained from these animals, in Denmark, Norway and Sweden is quite remarkable (for example, Danish Antimicrobial Resistance Monitoring and Research Program (2006); Swedish Veterinary Antimicrobial Resistance Monitoring (SVARM) (2007). The critical value of such high quality usage monitoring data has become apparent in the interpretation of AMR prevalence and changes, particularly in evaluating the usefulness of campaigns to promote prudent use and the impact of the removal of antimicrobial growth promoters on subsequent usage of antimicrobial drugs for therapy (WHO, 2002; Grave et al., Reference Grave, Frøkjær, McEwen, Kruse and Aarestrup2006). Precise usage data may identify surprising findings that can focus future research. For example, Heuer et al. (Reference Heuer, Jensen and Hammerum2005) reported that a comparatively small number of companion animals in Denmark annually consumed the same amount of fluoroquinolones and cephalosporins as a far larger population of food animals. In contrast to studies of use in food animals, the impact of AMR acquired by humans from companion animals as a result of use of antimicrobial drugs in these species has not been the subject of investigation, but may be seriously underestimated (Prescott et al., Reference Prescott, Hanna, Reid-Smith and Drost2002). The recent global emergence of methicillin-resistant Staphylococcus aureus in companion animals (Leonard and Markey, Reference Leonard and Markey2008) is one event focusing interest in the use of antimicrobial drugs and AMR in companion animals, including their role as reservoirs of AMR for humans.

Antimicrobial drug stewardship

Antimicrobial stewardship (also called ‘prudent use’ or ‘judicious use’) describes the process of reduction of the development, maintenance and spread of resistance through the optimal selection of drug, dosage and duration of treatment, combined with reduction of inappropriate and excessive use (Weese, Reference Weese, Giguère, Prescott, Baggot, Walker and Dowling2006). Stewardship essentially means ‘management of’ and ‘assumption of responsibility for’ something of important value that one does not own, in the interests of its long-term sustainability (adapted from Allerberger and Mittermayer, Reference Allerberger and Mittermayer2008). The term stewardship resonates with a sense of religious obligation or of prudent preservation of wealth. The emergence and spread of resistance is a complex process that, if it is to be managed successfully, requires a multidisciplinary approach based on research, surveillance, regulation, education, clinical practice, and infection control, within the evolving conceptual framework encompassed ‘antimicrobial stewardship’ (Paskovaty et al., Reference Paskovaty, Pflomm, Myke and Seo2005; Barlam and DiVall, Reference Barlam and DiVall2006).

National veterinary professional organizations in many English-speaking countries have produced ‘prudent use’ guidelines within the last decade. These are readily available on the Web sites of these organizations (listed in Weese, Reference Weese, Giguère, Prescott, Baggot, Walker and Dowling2006). With a few significant differences, most read almost identically, and contain rather general ‘motherhood’ key advice (e.g. only use when an infection is present or likely present; use as narrow a spectrum antimicrobial as possible; use culture and susceptibility testing whenever possible; use for as short a time as possible; ensure compliance by clients; use only under veterinary prescription or endorsement, etc.). One of the most comprehensive guidelines for use of antimicrobial drugs in animals was developed by the American College of Veterinary Internal Medicine (Morley et al., Reference Morley, Apley, Besser, Burney, Fedorka-Cray, Papich, Traub-Dargatz and Weese2005). A number of national veterinary organizations are attempting to develop ‘practice- specific’ guidelines (e.g. what is the drug(s) of choice with the precise dosage to be used when a cow is presented for the first time with acute pneumonia), but developing these guidelines involves intense effort and are likely to end up unread on a shelf unless they are vigorously promoted. Even if they are vigorously promoted, they may not be supported by those for whom they are intended. Some veterinarians are quite cynical about attempting to promote ‘prudent use’ in those countries where many antimicrobial drugs can be readily obtained by farmers as ‘feed’ antimicrobials for growth promotion and disease prophylaxis without prescription.

Although textbooks are written about antimicrobial use in animals (Giguère et al., Reference Giguère, Prescott, Baggot, Walker and Dowling2006; Aarestrup, Reference Aarestrup2006; Guardabassi et al., Reference Guardabassi, Jensen and Kruse2008), there are numerous areas for improvement of how antimicrobial drugs are used and numerous ways in which their use can be avoided or reduced. Because ‘environmental stewardship’ is an area of intense current global interest, the term ‘antimicrobial stewardship’ may capture the imagination more than ‘prudent use’ or ‘judicious use’. One of the mantras of the environmental movement in relation to waste is ‘refuse, reduce, reuse, recycle’; in the case of antimicrobial drugs, ‘refuse’ (do not use) and ‘reduce’ will have the greatest impact on reducing resistance. However, many other approaches will reduce resistance. For example, optimal dosing is an area where resistance can be reduced. In pharmacodynamic terms, antimicrobial drug classes can be categorized into either ‘concentration-dependent’ or ‘time-dependent’ where their killing or inhibitory activity is dependent either on how much the concentration exceeds the minimum inhibitory concentration (MIC) (e.g. aminoglycosides and fluoroquinolones) or how long the drug exceeds the MIC (e.g. β-lactams). Ensuring that these features are optimal is crucial for reducing the emergence of resistance (Lees et al., Reference Lees, Svendsen, Wiuff, Guardabassi, Jensen and Kruse2008), and should be taken into account in drug dosage, including the regulatory approval of drug dosage regimens. It seems quite pointless for veterinary diagnostic laboratories to report MIC results without reporting how these could be used to ensure optimal dosing. For example, if MIC data particularly for concentration-dependent drugs could be entered by the recipient into a calculator on a Web site (with animal species and weight), then this could help to reduce the emergence of resistance. Even laboratories determining susceptibility by disk diffusion (Kirby Bauer) could report zone sizes so that they could be used in such calculations. This is an area where veterinary diagnostic laboratories could improve their value, in collaboration with pharmacologists, pharmaceutical companies and regulators. Other approaches to prudent use include categorization as 1st to 3rd line referred to earlier, use of restriction policies and of stop orders, development of practice-based guidelines, use of immunostimulants, and vaccination (Weese, Reference Weese, Giguère, Prescott, Baggot, Walker and Dowling2006). Poor infection control may be an important source of spread of multi-resistant animal pathogens (Anderson et al., Reference Anderson, Lefebvre and Weese2008) and there may be considerable scope to assess and if need be improve infection control procedures in veterinary practices.