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U.S. Department of Health and Human Services

Animal & Veterinary

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FDA Veterinarian Newsletter July/August 2000 Volume XV, No IV

By David D. Wagner, Ph.D. and Patrick F. McDermott, Ph.D.

Antibiotics have been widely utilized for therapeutic and production purposes in animal agriculture for about 50 years. Some of this antibiotic use has served as a valuable tool in maximizing the efficiency of nutrient conversion to edible, high quality protein. Today there are twenty antibacterials approved for use in animal production as feed additives for either improvement of production efficiency or for therapeutic treatment. Some estimate that 30 to 50 percent of antibiotics produced annually in the United States are used in animal production.

For over 30 years, from about the time of the Swann Committee report (1) the question of what impact the use of these drugs in agriculture has on human health has been pending. To date, there have been no long-term efforts to answer this question. The agricultural use of antibiotics remains controversial because of the possibility that antibacterials used on the farm will select drug resistant strains that can be transferred to humans via ingestion of contaminated food. The transfer of resistant bacteria from an animal-derived food product to the consumer is complicated by the fact that a direct transfer of the bacterium itself need not occur for a potential problem to arise. Bacteria are very adept at sharing the genetic information necessary to survive in an environment where antibiotics are used. This propensity to exchange genes causes concern for the possible spread of antibiotic resistance determinants from commensal organisms in animals and man to human pathogens. Resistance genes can spread rapidly within a genus and to unrelated families of organisms. Even if an ingested bacterium is only in the intestine for a short time, it has the opportunity to donate its resistance genes to pathogenic bacteria.

The biological principle underlying the development and proliferation of antibiotic resistance is the Darwinian idea of "survival of the fittest." In any large population of bacteria, a few cells will be present that harbor physiological traits that enable them to survive in the presence of drug. The susceptible organisms (i.e., those not carrying these traits), will be killed leaving the resistant ones behind. With long-term drug use in the same environment, the microbial ecology will change dramatically, with more resistant organisms gaining ascendancy. Understanding the effects of these drugs in the animal production environment is made more difficult by the fact that the ecosystem is extremely complex, containing thousands of bacterial species interacting and adapting to many variables in addition to the drug itself. Changes in temperature, moisture, seasons, animal species, and sanitation practices, contribute to a constantly evolving milieu.

FDA's Center for Veterinary Medicine (CVM) completed a draft risk assessment on the human health risks associated with fluoroquinolone use in the poultry production environment. This risk assessment addressed the human health impact of fluoroquinolone resistance development in Campylobacter, an organism commonly associated with poultry and the most frequently reported cause of foodborne illness in the United States. The draft report of this risk assessment is posted on the Center’s Home Page.

Currently, the Center is conducting a risk assessment to examine the association between quinupristin/dalfopristin (Synercidä ) resistant Enterococcus faecium in humans and the use of virginiamycin in food-producing animals. Enterococci are gram-positive fecal streptococci commonly associated with animals and man and widespread in the environment. Although not considered an aggressive pathogen, the enterococci are a frequent cause of urinary tract infections and bacterial endocarditis. Within the past 10 years they have become the third most common cause of nosocomial bacteremias (2), many of which are multi-drug resistant. Enterococci survive well under adverse conditions, and are notorious for their capacity to acquire and transfer genetic determinants. This includes transfer of resistance genes to human pathogens such as Staphylococcus.

Both virginiamycin and Synercid are members of the streptogramin class of antibiotics, and resistance to one confers resistance to the other. Virginiamycin has been approved for use in animals for more than 25 years. It is approved for some therapeutic purposes and for use in animal feeds to increase production efficiency (rate of gain and feed conversion). The FDA recently approved Synercid for treatment of vancomycin-resistant Enterococcus faecium (VREF) infections in humans. Synercid is one of the few antimicrobials with activity against VREF. The risk assessment seeks to address the concern that virginiamycin resistant enterococci arising on the farm may compromise human therapy using Synercid.

A second objective of the current risk assessment is to evaluate Enterococcus as a model organism for understanding the development of antibiotic resistance in environmental gram-positive organisms in general. The Campylobacter risk assessment looked at the spread of resistant organisms per se. The current risk assessment will examine the spread of transferable resistance genes. Enterococci possess an efficient system of bacterial mating (conjugation) that can spread resistance genes to other bacterial species. Conjugation occurs when small circular DNA elements called plasmids are transferred from donor to recipient organisms by direct contact. Plasmids often carry genes that impart some selective advantage to the cell, such as resistance to antibiotics or heavy metals, or factors that facilitate infection. Plasmids may carry a second type of mobile genetic element, the transposon or "jumping gene", which can relocate resistance determinants from one DNA site to another within the cell. Enterococci have a specialized element termed a conjugative transposon (3) that combines the attributes of these two mechanisms resulting in a high rate of gene transfer. In examining environments in which antimicrobials are used, the characteristics of the enterococci make it an appealing organism for modeling the biology of resistance spread within human and animal populations.

A number of genes conferring streptogramin resistance in E. faecium have been characterized. High-level resistance is due in part to the presence of an enzyme (acetyl-transferase) that inactivates the drug by chemical modification. The gene for this enzyme is present on a plasmid, and, therefore, can be transferred to other bacteria. In the resistant isolates examined so far, however, many harbor an unknown resistance determinant(s). In CVM's Division of Animal and Food Microbiology, we are presently analyzing isolates obtained from animals, animal production environments, retail meat products and humans for streptogramin and other resistances. We have shown the same streptogramin resistance genes in organisms from retail meats, and the production environment; we are in the process of looking at isolates from humans. A large proportion of strains is lacking either of the known genes. Since bacteria and their genes move easily from one ecological niche to another, finding common strains is not surprising. To present a thorough comparison of human and animal strains, it will be necessary to uncover the unknown resistance mechanisms and determine whether they can be transferred to other bacteria.

The question of how much resistance among human isolates is a consequence of virginiamycin use on the farm remains vexing. After 26 years of use, approximately 65 percent of isolates from the farm environment are streptogramin resistant. In fecal isolates from healthy humans, collected before Synercid was used in human therapy, less that 2 percent are resistant. The threat this carriage rate poses to successful Synercid therapy in humans is not known. Most of what is known about Enterococcus comes from the study of human clinical strains. There is no historical database describing the dynamics of antibiotic-resistant microorganisms in the environment. The Center’s current priority is to gather research results from all possible data sources for use in modeling risk. This information will provide a better understanding of the microbial ecology in the animal production environment in which antibiotics have been regularly used, and how this use may impact human health. Ultimately, this will allow users to adopt rational interventions and drug use strategies to control resistance development and spread.

  • Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine, Her Majesty 's Stationery Office London 1969.
  • Garbutt, J. M., Ventrapragada, M., Littenberg, B., and Mundy, L. M. Association between resistance to vancomyin and death in cases of Enterococcus faecium bacteremia.
  • Salyers, A.A., Shoemaker, N.B., Stevens, A.M., Li, L.Y. Conjugative transposons: an unusual and diverse set of integrated gene transfer elements. Microbiol Rev. 1995 Dec;59(4):579-90. Review.