The Use of Drugs in Food Animals Benefits and Risks (1999) / Chapter Skim
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6 Issues Specific to Antibiotics
6 Issues Specific to Antibiotics
Pages 142-178
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From page 142... ...
Given the lack of information and consensus on the appropriate data needed to accurately assess the magnitude of risk to human health in agricultural use of antibiotics, what are the assurances that safeguard humans, animals, and the environment upon whom all medical, veterinary, and animal production drug practices have an effect? The issues can be summarized as follows: • The potential for emergence of antibiotic-resistant organisms in animal and human populations from the widespread use of antibiotics in food animals 142
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From page 143... ...
DEVELOPMENT AND FUNCTIONALITY OF ANTIBIOTIC DRUGS In general terms, antibiotic drugs are classified into the categories of broad and narrow spectrum (reviewed in Merck Veterinary Manual 1986; Kucers et al.
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From page 144... ...
In some circumstances, clever chemical modification of parent antibiotic molecules, such as penicillin, can change the spectrum of activity and more narrowly direct targeting for specific types of microorganisms. Another relevant classification for antibiotic drugs related to mode or mechanism of action is based on the killing capacity of the drug.
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From page 145... ...
Although these compounds are called antibiotics or antibiotic drugs, they are fundamentally natural products of bacteria, fungi, and molds that are secreted and released into the environment by a species of organism to give it a competitive advantage over other bacteria or molds in its particular ecology. Practically all first-generation antibiotics were developed after isolation of a mold or bacteria that produced a predominant class of antimicrobial product.
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From page 146... ...
An important point regarding the development of synthetic second- and third-generation antibiotics is that the properties of the native parent molecule that confer toxicity to the host can be eliminated even as the desired effects on pathogens are retained. An interesting development in strategies to increase the efficacy of antibiotic drugs is the concomitant administration of drug metabolism modifiers.
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From page 147... ...
Antibiotic drugs belonging to this class of compounds, called oxazolidinones, are effective against Gram-positive and Gram-negative organisms. • DNA gyrase inhibitors: The genetic code of organisms is normally a highly coiled matrix with which enzymes have difficulty interacting.
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From page 148... ...
Animal health professionals voice concern that the changes in antibiotic sensitivity of animal pathogens has created the potential for disease outbreaks to emerge for which therapeutic treatment is severely challenged. Professionals in human health care share similar concerns and cite the use of antibiotics in animal agriculture as the source of potential drug resistance emergence that would make human treatment more difficult if the patterns of resistance in animal pathogens were to be transferred to humans.
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From page 149... ...
. In the process of researching and developing new antibiotic drugs, decisions must be made that affect further development of the product.
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From page 150... ...
of the issue of subtherapeutic use of antibiotic drugs suggested that, even though increased antibiotic resistance was found after use of subtherapeutic antibiotics, no direct evidence showed a definite human hazard. A microorganism might mutate to develop or otherwise acquire resistance to antibiotic drugs, but there are several factors that determine or influence whether this will result in an increased hazard for humans.
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From page 151... ...
. A detailed discussion of the molecular events and mechanisms of antibiotic resistance is beyond the scope of this report but can be found elsewhere (Hayes and Wolf 1990; Kucers et al.
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From page 152... ...
A recent review by Levy (1998) summarized the issues he considered relevant to explaining the emergence and escalation of drug resistance emergence and the potential to control it: (1)
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From page 153... ...
. Over time, repeated exposure to various antibiotics results in multidrug resistance patterns and the same bacteria acquire resistance to new agents, as has occurred with several Staphylococcus species (Koshland 1994)
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From page 154... ...
Eighty-eight percent of antibiotic drugs used in livestock and poultry are used at concentrations below 200 g/ton of feed -- that is, at subtherapeutic concentrations -- and typically, the drugs are used for disease prevention or growth promotion (IOM 1989)
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From page 155... ...
. Some species of bacteria are intrinsically resistant or more susceptible to some antibiotic drugs simply by the mechanism of action of the drug and the physical limitations that the structure of the bacterial cell wall and membrane impose on entry of the drug into the microorganism (Brumfitt and HamiltonMiller 1988)
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From page 156... ...
Therapeutic use of drugs continues to contribute to the emergence of antibiotic resistance. In addition, the dynamics of resistance declines are much slower than are the dynamics through which resistance to the use of an antibiotic increases (Langlois et al.
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From page 157... ...
. Such preventive measures as subtherapeutic drug use reduce shedding of bacteria and subsequent contamination of the environment by pathogens; thus, the occurrence of sporadic or epidemic disease also is reduced in animals that do not receive subtherapeutic doses of drugs.
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From page 158... ...
contends that antibiotic concentrations achieved in animals fed antibiotics at many of the subtherapeutic concentrations used in the field do not reach concentrations necessary for the selection of resistant strains. Therapeutic doses have a greater inhibitory and killing capability than subtherapeutic doses, but Gordon et al.
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From page 159... ...
In swine, the diminution of drug resistance in the gut flora after withdrawal of subtherapeutic concentrations from the feed is not uniform. Antibiotic-resistant flora tend to survive longer in the upper intestinal tract.
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From page 160... ...
Within 1 week of feeding animals diets supplemented with subtherapeutic concentrations of antibiotic drugs, such as tetracyclines, most gut coliforms become resistant to the drug (Linton et al.
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From page 161... ...
HUMAN AND VETERINARY CLINICAL IMPLICATIONS OF ANTIBIOTIC RESISTANCE As discussed in Chapter 3, drug resistance can be transferred between animal and human pathogens, or animal and human pathogens could obtain drug resistance from a common pool of resistant organisms in the environment. Pathogenic animal microorganisms might acquire resistance to a variety of antibiotic drugs; the resistant organisms can be transferred to other animals or to humans.
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From page 162... ...
(1984) described the antibiotic resistance of Salmonella isolated from chickens (425 animals sampled)
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From page 163... ...
. Again, those findings indicate the complexity involved in drug resistance transfer in animal populations and the clinical complications that might result in reduced choices of drugs to use.
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From page 164... ...
Studies of the European experience with the use of antibiotics in veterinary medicine and animal production and surveillance efforts provide an opportunity to observe patterns of bacterial antibiotic resistance.
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From page 165... ...
TABLE 6–4 Antibiotic Resistance in Salmonella from Animals, Percentage of Cultures Showing Resistance Salmonella Salmonella typhimurium enteritidisa Disk Antibiotic Content (µg) 1981 1989 1990 1988 1989 1990 Ampicillin 10 12 32 30 1 5 4 Chloramphenicol 10 12 23 23 0 0 0 Apramycin 15 0 5 4 0 0 0 Neomycin 10 12 3 2 0 <1 0 Streptomycin 25 NDb 22 26 26 1 4 Sulphonamides 500 ND 46 49 2 3 5 Tetracyclines 10 48 50 51 1 6 6 Trimethoprim 25 14 28 28 0 2 4 Furazolidone 15 <1 <1 1 0 <1 <1 Nalidixic acid 30 0 0 <1 0 0 0 Sensitive to all ND 47 44 97 89 87 Total 1,146 2,151 2,522 585 1,815 3,758 a1981: only 28 incidents.
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From page 166... ...
, trends in antibiotic resistance before and after 1982 suggest similar increases in antibiotic resistance in food-animal bacteria that were statistically significant for ampicillin and sulfa-trimethoprim and significant decreases in resistance patterns for streptomycin, neomycin, chloramphenicol, and furans. Reviewing the data from other countries provides the opportunity for some informative comparisons of data and events that affect the resistance–disease issue.
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From page 167... ...
TABLE 6–5 Antibiotic Resistance in Salmonella typhimurium from Animals, Percentage of Cultures Showing Resistance 1981 1990 Antibiotic disk content (µg) Cattle Poultry Swine Sheep Cattle Poultry Swine Sheep Tetracylines (10)
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From page 168... ...
" Analogies between the avoparcin issue and fluoroquinolone use could be drawn, and the importance of public health concerns regarding the emergence of fluoroquinolone resistance in pathogenic bacteria and the zoonotic transmission of these microbes from animals to humans cannot be ignored. It is not known whether this heightened concern is premature, but it substantively shapes and molds the complex arguments that influence the fate of antibiotic development and use in food animals in the United States.
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From page 169... ...
In the United States, the FDA Center for Veterinary Medicine (CVM) approved fluoroquinolone antibiotics for use in therapeutic treatment of coliform disease and pasteurellosis in poultry, as directed by prescription by a veterinarian.
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From page 170... ...
It is important to point out that the mere presence of drug resistance does not constitute a clinical threat to human health or drug efficacy for therapeutic remediation of disease. This is true as long as the recommended dose of the drug is well above its MIC.
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From page 171... ...
. The issue of antibiotic resistance has been debated for more than 30 years.
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From page 172... ...
The United Kingdom is especially interesting to epidemiologists because the use of these drugs in food animals has been approved for a longer time than in other countries and new data are being analyzed that suggest more than a casual link between the use of these drugs in animals and the development of fluoroquinolone resistance in humans. According to the Public Health Laboratory Services of the United Kingdom, the incidence of disease cases in humans by the 5-drug-resistant (ampicillin, chloramphenicol, streptomycin, sulfonamide, tetracycline)
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From page 173... ...
ciprofloxacin. One isolate was resistant to nalidixic acid, but it did not present the 5-drug resistance pattern typical of Salmonella DT-104.
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From page 174... ...
The project is called "National Surveillance for Antibiotic Resistance in Zoonotic Enteric Pathogens." In 1996, CDC, FDA, and ARS established the National Antimicrobial Monitoring System to prospectively monitor changes in antimicrobial susceptibilities of zoonotic pathogens from human and animal clinical specimens, from healthy farm animals, and from food-producing animals at slaughter (Tollefson 1996; CDC 1996)
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From page 175... ...
The recent development of a streptogramin for use in human medicine is hailed as the newest "drug of last resort" to combat life-threatening, drug-resistant infections -- vancomycin-resistant infections in particular. This is an interesting example of what might be called "reverse concern." Usually, an antibiotic is developed for human use, use for food animals is approved years later, and the debate arises as to the soundness of the decision to approve the drug for animal use, with all of the ramifications of availability, accountability, and resistance emergence.
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From page 176... ...
A host of clinical complications in veterinary medicine results from the rise of antibiotic drug resistance. Only a small number of antibiotic drugs are approved for use in food-animal species.
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From page 177... ...
The mission of this panel would be to undertake scheduled reviews of the data that address the concerns of antibiotic resistance development in animals and humans and to advise regulatory agencies in the development and use of antibiotics in agriculture and human medicine. These tasks require the development of specific databases that encompass surveillance data on antibiotic use and effectiveness patterns, resistance emergence patterns, and trends in sentinel organisms in the United States.
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From page 178... ...
• The committee recommends the characterization of the relative risk to consumers between chronically ill or carrier food animals and antibiotic resistance in microbes residing in food animals. Increased educational efforts in this regard and development of strategies for optimizing the balance between the two also are needed.
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