Risks Due to Antimicrobial Residues in Animal‐derived Foodstuffs

Minute quantities of microbiologically active drug residues are evaluated for their potential impact on the human gastrointestinal flora. This impact may be through colonization barrier disruption (i.e., changes in normal human gut flora) or the emergence of antimicrobial resistance in enteric microorganisms. Quantitative assessment of minimum inhibitory concentration (MIC) data allows for the generation of a HBGV known as the microbiological Acceptable Daily Intake (mADI). This is typically calculated from the lower 90% confidence interval for the mean MIC₅₀ of the most susceptible genera typically present in the human colon. The mADI is based on chronic consumption of this antimicrobial residue and considers typical food consumption patterns over a lifetime.

However, when considering potential acute exposure to antimicrobial residues (such as after ingestion of an extremely large meal, or consumption of a tissue injection site containing high concentrations of residues), a different HBGV known as the microbiological Acute Reference Dose (ARfD) is considered. Because of its acute nature, the endpoint of concern for the microbiological ARfD will be disruption of colonization barrier (emergence of resistance is typically not considered, unless such concerns exist following a single exposure).

Once the microbiological ADI and ARfD are determined for the compound, Maximum Residue Limits (MRLs) are derived to ensure that human exposure to such antimicrobial residues, using standardized food consumption values, will not exceed either HBGV.

Other Risks of Antimicrobials Evaluated During Drug Approval Process

Human ingestion of microbiologically active residues of veterinary drugs administered to food animals is not the only concern when evaluating veterinary antimicrobial products. Antimicrobial resistance risks to the target animal itself and the potential for zoonotic transmission of antimicrobial resistance pathogens to humans (e.g., companion animal owners, farm workers, food or the environment) from treated animals are other considerations. For example, while the antimicrobial residue risk may focus on colonization barrier disruption (i.e., changes to the human gut flora), the antimicrobial risk assessment may also consider changes to the target animal’s enteric flora after antimicrobial administration. This is particularly relevant if treated animals demonstrate increased shedding of potentially pathogenic species such as Salmonella or Campylobacter, thus increasing the potential for zoonotic transmission to humans or contaminating the carcass during food processing.

For antimicrobials administered to companion animals such as dogs and cats, emergence of antimicrobial resistance in commensal bacteria in the oral cavity, mucosa, or skin of treated animals (such as methicillin‐resistant staphylococci) is an increasing concern. However, antimicrobial use in companion animals has, to date, received only a fraction of the regulatory attention as use in food‐producing animals. This is best exemplified by the US Center for Veterinary Medicine’s Timeline of FDA Action on Antimicrobial Resistance (2020) of which only one of 44 points relates specifically to companion animals, specifically to begin data collection on antimicrobial use in dogs and cats.

User safety (occupational exposure) and environmental risk assessment are also considered during the veterinary antimicrobial approval process. For example, the limited absorption of some oral antimicrobial agents (e.g., aminoglycosides, colistin, ionophores, tetracyclines, etc.) administered in feed results in large quantities of unchanged antimicrobials in manure. The environmental risk assessment of medications used in aquaculture operations is also rigorous. Any medicated feed not consumed by the fish, or drug ingested but subsequently excreted unchanged, results in active drug available to other organisms in the aquatic environment.

Antimicrobial Human Health Risk Assessment During the Drug Approval Process

The human health risk assessment estimates the likely increase in antimicrobial‐resistant pathogens in the treated animal, the probability of human exposure to the resistant bacteria from the treated animal, and finally, the likelihood that such exposure to the resistant strain will produce negative health consequences (i.e., the severity of outcome) in people. One determinant of the “severity” of any potential infection is the availability of human‐approved antimicrobial formulations likely to be effective in treating such a resistant zoonotic pathogen. As also discussed in Chapters 20 and 23, under critically important antimicrobials, the World Health Organization (WHO) has categorized antimicrobial drugs based on their relative importance in human health (i.e., for treating infections in people, not in animals) (WHO, 2024). The WHO’s sixth iteration lists two criteria and three prioritization factors of importance of antimicrobial drugs, with drugs in criterion 1 being in an antimicrobial class that is the sole therapy, or one of limited available therapies, to treat serious bacterial infections in people.

Many national regulatory organizations have comparable antimicrobial categorization schemes for veterinary drugs based on importance in human medicine (see Chapter 23, Table 23.2). Broadly speaking, the various categorization schemes have significantly more similarities than differences. However, differences between antimicrobial categories do result from differences in terminology, in antimicrobial availability, or in local usage patterns in veterinary and/or human medicine (see Table 23.2).

Producing a robust antimicrobial resistance risk assessment during the veterinary drug approval process is an exceptionally complex process, requiring multiple inputs which are often unknown or have high degrees of uncertainty. Despite these ongoing challenges, development of numerous new approaches in antimicrobial resistance modeling offers promise for improving the quantitative risk assessment (Chandrasekaran and Jiang, 2019).

Veterinary Oversight and Therapeutic Use Considerations

Although some jurisdictions (e.g., Scandinavia) have long had veterinary oversight of all antimicrobials sold for veterinary use, other jurisdictions have historically had some or all veterinary antimicrobials available for purchase without oversight. In North America, until recently, some older antimicrobials approved for use in food animals (e.g., procaine penicillin G, short‐acting oxytetracycline, sulfonamide or aminoglycoside boluses) could be purchased (over the counter, OTC) without a veterinary prescription. This practice was recently changed in the United States through the FDA’s Center for Veterinary Medicine adoption of Guidance for Industry (GFI) #209 (2012) and #213 (2013), which require veterinary oversight for all medically important veterinary antimicrobials used in feed/water. Likewise, in 2018, Health Canada placed all remaining OTC antimicrobials approved for veterinary use on the Prescription Drug List (PDL).

Such changes in veterinary oversight of antimicrobial use necessarily shift the responsibility of antimicrobial stewardship towards veterinary practitioners, specifically requiring a robust veterinary–client–patient relationship (VCPR). Increased veterinary oversight is generally considered to improve responsible use of antimicrobials. However, major concerns regarding veterinary antimicrobial oversight persist, including the potential for conflicts of interest inherent in the typical business distribution model of veterinary practice. Unlike human medicine, in most countries veterinarians are allowed to profit from pharmaceutical sales to clients, as part of their total income. The exception is Scandinavia where income only stems from veterinary services.

In complementary regulatory changes, many jurisdictions have also enacted label changes to limit the use of medically important antimicrobials in food‐producing animals to those considered necessary for assuring animal health (i.e., the treatment of diagnosed infectious conditions). The result of this change was to remove any nonhealth‐related label indications (such as growth promotion/increased feed efficiency) of such products. Since many veterinary antimicrobials with growth promotion claims also had therapeutic/preventive claims, clear regulatory guidance describing the specific conditions under which antimicrobial mass medication is justified for the prevention (prophylaxis) or control (metaphylaxis) of infectious disease minimizes the potential for such use as a cover for growth promotional effects (see Chapter 24).

Changes in antimicrobial drug use in food animals, especially in the higher income countries (see Chapter 23), in recent years have led to a remarkable reduction in antimicrobial drug use and antimicrobial resistance (AMR) in “indicator” surveillance bacteria, and to significant changes in the quality of their use, as part of efforts by individual countries, the veterinary profession, and food producers to improve antimicrobial stewardship in animals within a One Health context. Global efforts to improve antimicrobial stewardship in animals by veterinarians and producers in lower‐ and middle‐income countries are discussed in Chapter 21.

Duration of Use Considerations

Subsequent to strengthening veterinary oversight and removal of growth promotion claims for antimicrobials, North American regulatory agencies are now reevaluating label directions for medically important veterinary antimicrobials in feed with unspecified or prolonged durations of use (see Chapters 21 and 23). The intent is to limit use to those times in which an antimicrobial effect is truly necessary for animal health, thus minimizing unnecessary antimicrobial use.

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