Antimicrobial drug delivery in food animals and microbial food safety concerns: an overview of in vitro and in vivo factors potentially affecting the animal gut microflora

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Abstract

This review provides an overview of considerations particular to the delivery of antimicrobial agents to food animals. Antimicrobial drugs are used in food animals for a variety of purposes. These drugs may have therapeutic effects against disease agents, or may cause changes in the structure and/or function of systems within the target animal. Routes of administration, quantity, duration, and potency of an antimicrobial drug are all important factors affecting their action(s) and success. Not only might targeted pathogens be affected, but also bacteria residing in (or on) the treated food animals, especially in the intestines (gastrointestinal tract microflora). Resistance to antimicrobial agents can occur through a number of mechanisms. The extent to which resistance develops is greatly affected by the amount of drug [or its metabolite(s)] a bacterium is exposed to, the duration of exposure, and the interaction between an individual antimicrobial agent and a particular bacterium. The impact of antimicrobial agents on the emergence of resistance in vitro and in vivo may not readily correlate.

Introduction

The use of antimicrobial drugs in veterinary medicine generally parallels their uses in human medicine. Many of the antimicrobial agents approved for use in humans are approved for therapeutic and other purposes in food (or food-producing) animals. Under the current requirements for approval of new antimicrobial drugs for food animals in the United States, a rigorous evaluation process exists to ensure that the uses of antimicrobial drugs are safe and effective for the targeted food animals, and that they are safe to the environment and to humans that consume food products derived from these animals [1]. In addition, approved antimicrobial agents must have demonstrated a consistency of quality, including strength, purity, and potency.

In recent years, antimicrobial resistance associated with the use of antimicrobial drugs in food animals has received an increasing amount of public attention [1], [2], [3], and related information can be found at many organization's sites (e.g., http://www.fda.gov/cvm/antimicrobial/antimicrobial.html; http://www.cdc.gov/drugresistance/; http://www.who.int/infectious-disease-report/2000/, accessed as of August 29, 2003). Antimicrobial agents administered to animals will result in residual levels in the gastrointestinal (gastrointestinal) tract of the treated animals. This exposure to antimicrobial agents may result in the disruption of the host's intestinal microflora. This exposure may also select for resistant bacteria which may ultimately cause food safety concerns for humans. Human food safety is an important and indispensable component of any new animal antimicrobial drug application process for food animals [3].

Evaluation of the human food safety of antimicrobial drugs for use in food animals takes into consideration: (1) the evaluation of the quantitative drug residues in edible tissues and their possible toxicological effects in humans, including the potential disruption of human intestinal microflora [3]; and (2) the effect of the subject antimicrobial drug on the generation or selection of resistant, zoonotic foodborne pathogens. This latter aspect is termed microbial food safety [1]. The goal of microbial food safety evaluation is to determine whether the use of a specific antimicrobial drug in food animals, under labeled conditions of use, will create (or make worse) a state of antimicrobial resistance among foodborne or other enteric bacteria in the gastrointestinal tract of the treated animals [1], [2], [3].

This review provides an overview of what is currently known about the interactions among antimicrobial agents and bacteria in vitro. In addition, similarities and differences between in vitro and in vivo antibacterial activities of various antimicrobial drugs will be discussed. The intent of this discussion is to help further the understanding of the impact of exposure to antimicrobial agents on the gastrointestinal tract microflora in food animals.

Section snippets

An ecological system

The digestive system of animals hosts several hundred species of bacteria. These bacteria (microbial flora or microflora) in the gastrointestinal tract form a complex ecosystem [4], [5] that plays an important role in maintaining the integrity of the host's enterocyte, providing enzymes for metabolism of ingested of foods, modulation of metabolic processes for host needs (such as converting steroids and unconjugating bilirubin into more water soluble forms of urobilinogen), and protecting the

Characteristics of antimicrobial drug activities in vitro

Substantial information has been accumulated on how antimicrobial drugs work against bacteria, both at the cellular and molecular levels. For in-depth reviews in this area, readers are encouraged to refer to specialized journal articles [90], [91], [92], [93], [94]. The brief discussion below is intended to provide an overview of the in vitro activity of antimicrobial drugs for the purpose of understanding the potential effect of antimicrobial drug delivery in food animals on the microflora of

Antimicrobial drug delivery in food animals

The method of drug delivery in food animals varies with animal species, the infectious disease target, the drug formulation or purposes for which the antimicrobials are employed. Treatment can be short- or long-term, and can be applied to an individual animal or an entire herd or flock. A key microbial food safety aspect of antimicrobial drug delivery in food animals is the amount of antimicrobial that ends up in the gastrointestinal tracts of treated animals. This may potentially have an

Antimicrobial drug delivery and antimicrobial resistance

Based upon the definition set forth by the NCCLS, resistant bacterial isolates are not inhibited by usual systemic concentrations of the agent following normal dosage schedules, and/or fall in the range where specific microbial resistance mechanisms are likely and clinical effectiveness has not been reliable in treatment studies [158]. A bacterium can become resistant to a particular drug through one or more mechanisms. The term ‘reduced susceptibility’ is used to describe those organisms that

Correlation of data from in vitro and in vivo studies

In general, in vitro results cannot be simply extrapolated to in vivo conditions for antimicrobial drugs [187]. Exactly which factors determine the correlation between in vitro and in vivo data remain largely unknown. Therefore, data generated from both systems are necessary and irreplaceable. A few apparent differences between in vitro and in vivo are noticeable and worthy of mention.

Summary

Strategies for delivering antimicrobial drugs in food animals will need to continue to evolve as both disease conditions and animal management practices change. Veterinary pharmaceutical companies will continue to tune their antimicrobial product formulations and drug delivery regimens to offer the best protection and treatment schemes with delivery systems responsive to emerging needs. For some food animal species, delivery of antimicrobial drugs through feed and water is most efficient,

Acknowledgements

The authors would like to thank Drs. Julia W. Punderson, Bernadette Abela-Ridder, Karen Lampe, Ana Haydee Fernandez, Richard Ellis, Mark M. Robinson, and Robert D. Walker for their comments on the manuscript.

Note

The opinions and information in this review article are those of the authors, and do not represent the views and/or policies of the U.S. Food and Drug Administration.

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