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U.S. Department of Health and Human Services

Animal & Veterinary

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Antimicrobial Drug Delivery in Food Animals and Potential Disruption of Their Intestinal Microflora

by S. Steve Yan, Ph.D. and Jeffrey M. Gilbert, Ph.D., Division of Human Food Safety, Office of New Animal Drug Evaluation, Center for Veterinary Medicine
FDA Veterinarian Newsletter January/February 2004 Volume XIX, No 6

The way an antimicrobial drug is administered to food animals may affect the intestinal microflora of the animals, and a potential consequence of the drug delivery is the selection and development of resistant bacteria among the intestinal flora. Here some of the important aspects are discussed to help the reader understand how the intestinal microflora of food animals may be affected at antimicrobial drug delivery.

Current requirements for approval of antimicrobial new animal drugs for food-producing animals (or food animals) in the United States include a rigorous evaluation to ensure that the uses of these drugs are safe and effective for the target food animals, and that they are safe to the environment and to humans that consume food products derived from these animals. Additionally, the manufacturer must demonstrate that it can produce these approved antimicrobial new animal drug products consistent in quality, strength, purity, and potency. Antimicrobial new animal drugs administered to food animals may result in drug residues in the gastrointestinal (GI) tract of the treated animals, and exposure to these drug residues may result in the disruption of the host’s intestinal microflora. This exposure may also disrupt the intestinal microflora among food animals and select for resistant bacteria that are foodborne pathogens for humans, causing human food safety concerns. Disruption of the microflora in food animals may be affected by multiple elements. Some of them are briefly described as follows.

  1. Diversity of microflora among food animals. The intestinal microflora of food animals are established following harmonized host-microorganism equilibrium and may differ significantly among animal species. Food animals include mammalian and non-mammalian species that inhabit terrestrial and aquatic environments, and they also vary widely in size from large species (cattle) to relatively small species (chicken or fish). Considerable variations in their GI anatomies and physiologic functions determine the wide spectrum of intestinal microflora associated with each animal species. Zoonotic, foodborne human pathogens can arise from the intestinal microflora of food animals, and their nature and proportion vary dependent upon animal species. For example, Campylobacter jejuni is primarily associated with poultry, while E. coli O157:H7 is mainly linked to cattle. Therefore, microbial food safety considerations may vary among different animal species with respect to their resident pathogens.
  2. Properties of antimicrobial drugs. Substantial information has been accumulated on how antimicrobial drugs work against bacteria, both at the cellular and molecular levels. The response of susceptible bacteria to antimicrobial action in vitro is morphologically visible (Figures 1 & 2). Antimicrobials may behave as bacteriostatic or bactericidal agents, and their activities on bacteria are usually drug-specific. Bactericidal or bacteriostatic killing of a given drug is sometimes influenced by measuring conditions, such as inoculum effect, medium pH, ion concentration, etc. Some antimicrobial activities are persistent (i.e., exert a post-antibiotic effect) and remain active at sub-optimal concentrations (i.e., a sub-Minimum Inhibitory Concentration [MIC] effect). Antimicrobial activity may be measured by susceptibility testing performed under standardized in vitro conditions. Additionally, many factors may contribute to the ultimate effect of an antimicrobial drug in vivo, such as drug protein binding (free drug or unbound can have activity against bacteria), tissue distribution, host immunity status, etc.
  3. Drug delivery in food animals. Drug delivery methods vary among food animal species, and depend on the purpose for which an antimicrobial is prescribed or ordered, the site of infectious disease and the target pathogen involved, and the drug’s properties and formulation. Common delivery routes include parenteral administration (intramuscular or subcutaneous), oral administration (through feed or water), and other delivery methods (intramammary, intrauterine infusion, etc.). Selection of a drug delivery route for a given disease in a given food animal species is a result of a collective consideration of factors such as effec-tive-ness, efficiency, resources, costs, labor -intensity, and available drug formulations. Strategies for delivering antimicrobial drugs to food animals will need to continue to evolve as both disease conditions and animal management practices change. Veterinary pharmaceutical companies will continue to fine tune their antimicrobial product formulations and drug delivery regimens to offer the best protection and treatment schemes with delivery systems responsive to emerging needs.
  4. Context matters. A key piece of information from an antimicrobial drug profile is how much drug will end up in the animal intestine and its effect on the continued equilibrium. This information depends on pharmacokinetic and pharmacodynamic profiles of individual drugs, affected by formulation, route of administration, bioavailability, drug absorption, and transport through the intestinal epithelium, and whether biliary excretion may occur, etc. The drug concentration available in the intestinal lumen is directly linked to whether a potential exposure of intestinal microflora to the drug will actually occur, and to what extent an exposure-response might be. Therefore, such an exposure-response of intestinal microflora needs to be evaluated in a “drug-bacterium” context.
  5. Upon exposure. A possible consequence of antimicrobial intervention is a disturbance of the intestinal microflora, and the degree of the disturbance will be determined by the individual drug, drug potency, spectrum of activity, dosage regimen, delivery method, working concentration in the intestinal lumen, target food animal species, and the associated intestinal microflora. An important issue is whether a given drug delivery system, under specified use conditions, will negatively impact intestinal microflora so that a resistant population may emerge and thrive, and/or resistant elements may develop and spread. Information is readily available to indicate that bacteria are able to acquire resistance traits through a variety of mechanisms, including a) inactivation of compounds; b) decrease in membrane permeability or activated efflux function; and c) target modifications. Resistant determinants may be carried on chromosomes or by extra-chromosomal elements, such as plasmids and transposons. Expression of resistant phenotypes may be either inducible or constitutive; thus, evaluation of microbial food safety of antimicrobial new animal drugs can become complicated.

(Note: This article is adopted and modified from a review that appeared in Advanced Drug Delivery Reviews 2004, 56:1497-1521 by the same authors. Refer-ences used for the current article are not provided due to space limitation but they are included in its original review.)

[***DESIGNER NOTE: The following captions refer to the graphic figures mentioned in this “Antimicrobial...” article.***]

Figure 1. Following in vitro exposure of streptococci to penicillin at concentration at the MIC or minimum inhibitory concentration, morphological changes (under scanned electro microscopy, at 20,000 X) were obvious in treated cells (B) as compared with controls (A).

Figure 2. After Escherichia coli in vitro exposure to a fluoroquinolone drug at a concentration above the MIC (B & C), dramatic morphological changes (under transmission electro microscopy) become visible, including disruption of the cell membrane, disintegration of cytoplasmic contents, and vacuole formation. A = control. The insert bar represents 0.4uM in length.