6
Issues Specific to Antibiotics

The mechanism of action of an antibiotic is the same whether it is administered to a child or a calf. However, access to and choices of antibiotics are far greater if the infection develops in a child than if the calf develops a similar infection. With human health as the standard for all health-related decisions, the cost of developing new medications for human use is of limited consideration, and the development and use of new antibiotics are largely reserved for clinically diagnosable human infections. In the past, a veterinarian might have treated a calf with a preparation specified for human use. Depending on the circumstances, this practice could be considered illegal under the provisions of the Food and Drug Administration (FDA) law governing extra-label use of nonveterinary drugs. Recently, however, modifications in the drug law authorized by Congress legalized and expanded extra-label use of many human drugs for therapeutic purposes in livestock under the supervision of a responsible veterinarian (see Chapter 4). But what are the criteria for deciding whether newly developed antibiotics can or should be used for therapeutic or subtherapeutic treatment in livestock? 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



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The Use of Drugs in Food Animals: Benefits and Risks 6 Issues Specific to Antibiotics The mechanism of action of an antibiotic is the same whether it is administered to a child or a calf. However, access to and choices of antibiotics are far greater if the infection develops in a child than if the calf develops a similar infection. With human health as the standard for all health-related decisions, the cost of developing new medications for human use is of limited consideration, and the development and use of new antibiotics are largely reserved for clinically diagnosable human infections. In the past, a veterinarian might have treated a calf with a preparation specified for human use. Depending on the circumstances, this practice could be considered illegal under the provisions of the Food and Drug Administration (FDA) law governing extra-label use of nonveterinary drugs. Recently, however, modifications in the drug law authorized by Congress legalized and expanded extra-label use of many human drugs for therapeutic purposes in livestock under the supervision of a responsible veterinarian (see Chapter 4). But what are the criteria for deciding whether newly developed antibiotics can or should be used for therapeutic or subtherapeutic treatment in livestock? 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

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The Use of Drugs in Food Animals: Benefits and Risks has been documented and has been a reason for concern. The magnitude of the actual animal-to-human transfer problem and associated development of disease is poorly characterized and varies greatly because of food-processing and consumer handling practices that are separate from animal production or antibiotic use in food production. Drug discovery and development are fueled by the need to compete with immensely adaptable adversaries, the microorganisms themselves, but the process is lengthy and expensive for manufacturing sponsors. Obtaining regulatory approval also is a time consuming process that can lengthen the time in getting new drugs to market and is expensive. Efforts to streamline the government approval process are evolving, and expanding the use of nonveterinary drugs in food animals should increase the number of uses and the availability of these products. The world is becoming a global economy, but quality standards vary greatly from one place to another. There is little uniformity in the approach to regulating drug use, and often the lack of approval centers on a socioeconomic concern rather than on concern for human health. As a result, U.S. federal regulatory agencies are reluctant to accept other nations’ data to support the approval of a drug. Harmonization efforts could be made to gain acceptance of standardized regulatory approaches and data. Are there measures that might be used to better track the potential for a pathogen to emerge as a significant disease threat, particularly as it relates to the development of resistance in humans or animals? How will new infections be controlled in food animals if not with the increased availability of antibiotics? 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. 1997). The nature of the activity spectrum reflects how specific a drug or class of drugs is in terms of its microbial-killing capacity. Broad-spectrum antibiotics are generally effective in killing bacteria or organisms across a range of species. Narrow-spectrum drugs are usually highly selective for a particular species of bacteria, very effective when the identity of the invading organism is suspected or known, and particularly useful when specifically identified as effective against bacteria with known and defined resistance to other antibiotic drugs. Another feature that affects the broad- or narrow-spectrum attributes is the drug’s mode of action (O’Grady et al. 1997). Some antibiotics, such as the penicillins and cephalosporins (called ß-lactam antibiotics because of the lactam ring structure), are particularly useful against a variety of organisms. Compounds in this class prevent the proper formation of bacterial cell walls during cell division and function to make the bacteria “leaky” and susceptible to osmotic forces. Because the biochemical paths involved in cell wall synthesis are com-

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The Use of Drugs in Food Animals: Benefits and Risks mon to a variety of organisms, these compounds have broad functional applicability. Narrow-spectrum compounds can target biochemical pathways specific to a single type or a few types of microorganisms. The scope of effectiveness of these compounds is limited. Additional layers of classification are related to chemical structure and other aspects of mode of action. 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. Bactericidal drugs have killing capacity and, when administered in therapeutic concentrations, treat infection by actively killing invading organisms (Merck Veterinary Manual 1986; Kucers et al. 1997). In contrast, bacteriostatic drugs prevent the growth of organisms, but do not kill them directly. A key feature of bacteriostatic drugs is that, with the proliferative potential of the organism impaired, the body’s natural defense mechanisms can eliminate the disease threat. Sometimes, bactericidal drugs can appear bacteriostatic if effective killing concentrations in blood and tissues are not achieved. From the standpoint of usefulness, therefore, serious consideration is given to the concentrations necessary for effective action without harming the host. The “therapeutic index” is a measure of the relative toxicity of a drug to a pathogen compared with the toxicity of a drug to an infected host (Grahame-Smith and Aronson 1992). Drugs with high toxicity to pathogens and low toxicity to animals are the most desirable. Therefore, drug developers would capitalize on fundamental biochemical differences between prokaryotes (simple cellular organisms without a membrane-bonded genetic material—bacteria) and eukaryotes (organisms whose cells contain a true nucleus—animal cells) to kill or affect pathogens and minimize danger to the host. Two readily recognizable examples of biochemical differences that might be exploited are the basic differences in cell wall and plasma membrane synthesis that allow ß-lactam antibiotics to kill bacteria and be relatively harmless to animal cells and the basic differences in the biochemical composition of protein-synthesizing ribosomes that allow aminoglycoside drugs, such as the streptomycins, to kill organisms by inhibiting prokaryotic protein synthesis, leaving eukaryotic protein synthesis intact (Kucers et al. 1997). Cell toxicity is just one measure of a drug’s potential to harm the host. On a systemic basis, whole-animal responses (for example, allergic reactions) to antibiotics and drugs must be considered. Penicillins are well noted for this problem (Dayan 1993; Grahame-Smith and Aronson 1992). Even though the penicillin molecule is too small to be an effective allergen, its ability to hydrolyze spontaneously in an aqueous environment and covalently cross-link to proteins allows it to function as an immunologically recognizable hapten determinant and thus promote sensitivity to the penicilloyl residue as coupled to a larger protein. When

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The Use of Drugs in Food Animals: Benefits and Risks linked to proteins in this fashion, these penicilloyl residues alter the self-recognition of the protein, establishing a “foreign protein” status and eliciting hypersensitivity reactions in the immune system. Finally, compounds with low therapeutic index for internal use might be highly effective as topical preparations and when entry into the body is limited (Grahame-Smith and Aronson 1992; Hardman et al. 1996). IDENTIFYING AND SCREENING ANTIBIOTICS Antibiotics are generally sought through initial screening of compounds that occur naturally in nature, particularly in soils. 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. Around the world, as many as 30,000 species of microorganisms have been isolated from soils and screened for general antimicrobial activity. Techniques for identifying new antibiotics have changed over the years as information on the mechanisms of actions of different classes of antibiotics has been amassed (Brumfitt and Hamilton-Miller 1988). Older procedures called for enormous batteries of active-culture screenings using live organisms and inoculated flasks of broth or plates of agar. Modern procedures are considerably more automated and mechanistic. Current tests are based on measuring the generalized ability of culture supernatants into which test organisms secrete their antibiotic to inhibit growth of organisms and more specific capacities to affect (inhibit or compete against) a particular biochemical event in a microbial metabolic pathway. Screening often is aimed at a single enzyme target in specific prokaryotic bacteria and fungi. Discovery of the ability of a compound to affect the proliferation and viability of pathogens allows chemists, with an arsenal of chemical and biochemical modifications, to develop the spectrum of action and a therapeutic index. Chemical properties of naturally occurring antibiotics are often intentionally altered to enhance specific attributes of antibiotics (Drews 1983; Hardman et al. 1996). Starting with the basic chemical structure of a class of drugs, chemists can modify ring structures or add and substitute side-chain molecules to alter relative solubility in aqueous or lipid environments, slow or increase the metabolism and excretion of a drug, and define the site in the body for drug delivery. For example, certain antibiotics have fundamental toxicities if taken internally, but have excellent antibacterial properties. Chemical modification of those compounds can enhance their application as topical or ophthalmic ointments and suspensions. Similarly, chemical modification of sulfa drugs can make them ideal for treating

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The Use of Drugs in Food Animals: Benefits and Risks urinary-tract infections, because absorption and excretion patterns after oral administration target antibacterial action at the infection site in the process of drug excretion through the kidneys and bladder. Finally, totally synthetic classes of antibiotic drugs are being developed that are based on the chemical structure and spatial conformation of the antimicrobially active portions of the molecules. 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. In this process, the administration of an additional drug can increase the efficacy of the antibiotic by decreasing inactivation of the antibiotic or by facilitating synergistic drug interactions. For example, some forms of antibiotic resistance develop in bacteria as they acquire properties to degrade a drug enzymatically. In the evolution of bacteria, some have developed the ability to secrete ß-lactamase, an enzyme that ruptures the active lactam ring structure of penicillins and inactivates them. Addition of a compound called sublactam, along with ampicillin, provides a competitive inhibitor of the lactamase and arrests the activity of the resistance factor. Another example is the incorporation of trimethaprim with sulfa drugs to increase the bactericidal action of the sulfa. The animal health pharmaceutical industry also pursues genetic and biochemical strategies to identify compounds with novel mechanisms of action. Several of these compounds are listed below (for reviews see Kucers et al. 1997; Jungkind et al. 1997; St. Georgiev 1998). The 8-carbon-sugar keto-deoxy-octulonate (KDO) is unique to Gram-negative bacteria (Garrett et al. 1997). Gram-negative bacteria produce endotoxins, also called lipopolysaccharides, as part of their cell membrane envelopes. An important part of the toxicity of these organisms is conferred through the release of endotoxins, as occurs in septicemia, toxic shock syndrome, and sometimes in food poisoning. Bacteria that make endotoxins synthesize it in a biochemical pathway that uses the enzyme cytidine monophosphate–KDO synthetase. The development of inhibitors of this enzyme could have specificity and selected toxicity against Gram-negative bacteria. The added benefit of this approach to microbial control is that the antibiotic also would limit the toxic endotoxin production and lessen the virulence of the organism and the severity of the host response to infection. That is important because killed bacteria can release endotoxins as they decay. Other compounds that are found to interfere with endotoxin production should have similar merit as antibiotic drugs. Novel inhibitors of protein synthesis: Eukaryotic organisms (like humans) and prokaryotic organisms (like bacteria) have fundamental differences in how protein is synthesized in the cells. Proteins are synthesized from the genetic code

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The Use of Drugs in Food Animals: Benefits and Risks in the messenger RNA (mRNA) on granules called ribosomes. The ribosomes and mRNA processing differ in people and bacteria, for example. Compounds have been developed that interfere with the association of the bacterial mRNA with the ribosomes, making it impossible for the bacteria to synthesize proteins and thus survive. 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. Relaxation of specific regions of the supercoiled DNA in bacteria is accomplished by a class of enzymes called topoisomerases or gyrases. Quinolones inhibit bacterial gyrases, and further chemical modification with bridging to the isothiazole ring increases the gyrase-inhibiting properties. When gyrase is inhibited, the bacteria can no longer perform molecular functions dependent on the unfolding of DNA. Bacterial cell division targets: A novel target might exist within the morphogenic system that determines septum formation in bacteria, and a large number of gene products might participate in septum initiation and formation. Septum formation is believed to be easily perturbed. Multiple targets are believed to exist in Gram-negative and Gram-positive bacteria. Inhibitors of protein secretion: All bacteria translocate essential proteins outside their cytosol. Selective inhibitors of an enzyme, such as signal peptidase I, which cleaves the signal peptide during translocation of the peptide, would theoretically exhibit broad-spectrum antimicrobial activity. Defensins: These are a family of naturally occurring microbicidal peptides found in several major tissues and in circulating immune cells in the body of most animal species. High concentrations of defensins are located in the oral cavity associated with the tongue and other structures. The first antimicrobial peptide, bovine lingual antimicrobial peptide, was isolated from bovine tongue. The antimicrobial mechanism of action of many of these peptides is associated with their basic hydrophobic character, which enables them to penetrate microbial membranes (to the exclusion of eukaryotic membrane penetration), and with the open porous channels that disrupt ion gradients within the bacteria. Many of these peptides are being cloned as the genetic sequences for their structures are discovered. Cloning could facilitate the production of clinically effective defensins as recombinant products. The use of multiple antibiotics simultaneously has some advantages in specific situations, but knowledge of the mechanism of action of antibiotics is essential for the correct choice to be made. Bactericidal drugs are usually synergistic when coadministered, having efficacy greater than that conferred by single drugs alone, because one drug increases the susceptibility of the organism to the effects of the other. Bacteriostatic drugs are additive in effect. Generally, in multiple-antibiotic therapy, a bacteriostatic drug is never administered simultaneously

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The Use of Drugs in Food Animals: Benefits and Risks with a bactericidal drug. Bactericidal drugs often function to kill bacteria during some aspect of replication (from DNA processing to membrane synthesis). For example, penicillins kill replicating bacteria by preventing proper formation of cell walls. Sulfa, a bacteriostatic drug, diminishes the effectiveness of penicillin because sulfa blocks replication. From the standpoint of professional knowledge of modes of action and tissue-specific sites of action, the proper choice of bactericidal or bacteriostatic drugs and routes of body clearance of drugs is critical in special circumstances. Bacteriostatic drugs would be poor choices in animals or humans whose reduced immune capacity makes them unable to effectively destroy the invading pathogens. Similarly, it is imprudent to administer drugs with renal or hepatic toxicity when kidney or liver function is impaired. BACTERIAL RESISTANCE Antibiotic drugs are administered to animals and humans to eliminate the threat to internal homeostasis that invading microorganisms present to a host, the result of which is sickness. Since the initial widespread use of antibiotics in the 1940s, situations have been recognized in which an antibiotic has lost its effectiveness in controlling infection, even when the dose is increased. Microorganisms that managed to evolve to escape the action of the drug were called “resistant.” The one certainty in the battle against microbial infection is that with time, antibiotic resistance will develop in some population of microorganisms. The question of how this resistance will affect human and animal health is important. The problem of emergence of bacterial resistance to a drug is a driving force behind the move to increase antibiotic drug discovery and development. Because of increasing development of antibiotic resistance, new antibiotics are considered necessary for animal and human health care personnel to choose from when more traditional therapy would be ineffective. With more choices, a plan of drug administration can be implemented to increase the chances of eliminating an infection caused by an organism resistant to other drugs. The committee noted in commissioned papers and report presentations that the animal pharmaceutical, production, and health professional organizations are concerned that government restrictions on the use and limited availability of antibiotics is a problem that approaches crisis proportions (AHI 1982; 1992). The immediate consequences of use restrictions are perceived as the loss of strategies and treatments to ensure the health and well-being of animals. 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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The Use of Drugs in Food Animals: Benefits and Risks The suggested shortage in antibiotics is not a shortage in the amount available but in the number of classes of newer antibiotics for use in food animals. Three main factors were summarized in the commissioned reports and seen by the committee as reasons for the perceived shortage: (1) the emergence of resistance that compromises the utility of many established and traditional antibiotics for specific applications and pharmacological indications, (2) the federal laws that regulate the legal administration of available drugs to food animals, and (3) the cost per dose to administer many of the new antibiotics and other classes of drugs. The last point is important. For the animal producer, the profit margin is slim after all costs of production are weighed against the sale value of the reared animals. The “traditional” antibiotics continue to be important in livestock production because they are still effective in most applications, and they are profitable even though resistant microorganisms emerge. Manufacturers of those drugs market them relatively inexpensively; new drugs are prohibitively expensive for widespread use in agriculture. Drug research, development, and approval time and costs, combined with the current problems of antibiotic choice and availability for animals, are believed by some to have far-reaching consequences for the American public. Diseases are appearing in animals and humans for which there are no approved or available treatments. Diseases once thought eradicated are reappearing with the emergence of microbial strains of increased virulence and multiple-drug resistance (for example, Salmonella DT-104; see Murray 1991; CDC 1994). Industries that produce sheep, goats, and minor species, such as deer, quail, catfish, exotic and zoo animals, and companion animals, have probably been affected most significantly by the lack of available drug choices. In some instances, the market is so small that no pharmaceutical operation will invest time and money to develop a needed remedy—certainly not within the period in which producers would like the product to be marketed. Several companies are developing and marketing new antibiotics, but industry representatives state that the intended application for these compounds is treatment of human diseases. It is estimated that it takes 11 years and tens of millions of dollars to bring a new food-animal drug to market. Only 1 compound in 7,500 tested for initial activity reaches the market (AHI 1993). In the process of researching and developing new antibiotic drugs, decisions must be made that affect further development of the product. Drug manufacturers must consider the lifetime of the product (how long it will be on the market and in use before microbial resistance emerges and limits its usefulness), the potency of the compound, the overall cost of production, the size of the antimicrobial spectrum of activity, withdrawal times, marketing advantages, and the potential for bacteria to develop cross-resistance to other compounds in the same class.

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The Use of Drugs in Food Animals: Benefits and Risks ANTIBIOTIC-RESISTANT BACTERIA AND ANIMAL MANAGEMENT Continued use of antibiotic drugs in animal feeds or as therapeutic agents in standard agricultural–veterinary practices provides conditions favorable to the selection of antibiotic-resistant bacterial strains in food animals. This selection pressure is enhanced by (1) the large concentration of animals with similar disease susceptibilities and exposure and, thus, similar therapies; (2) the social behavior of livestock, which promotes transmission; (3) poor environmental hygiene, which promotes the survival, reproduction, and transmission of bacteria in water, feed, and bedding; (4) inadequate control over individual dose and treatment duration; (5) the rapid turnover of animal populations, ensuring new groups of susceptible animals if facilities are not disinfected between groups; and (6) the wide movement of carrier animals as breeding and feeding stock. Antibiotic resistance does not in itself create the ability of bacteria and other organisms to cause disease; it does make treatment of the disease more difficult by increasing morbidity, mortality, and cost. Holmberg et al. (1984a) reported mortality that was 20 times higher for antibiotic-resistant Salmonella species than for antibiotic-sensitive species. They also showed that food animals were the source of the bacteria in more than 65 percent of resistant Salmonella strains and 45 percent of sensitive strains. The difficulty and the expense of treating resistant infections were discussed in an Institute of Medicine (IOM 1992) summary, “Emerging Infections: Microbial Threats to Health in the United States.” As early as l984, more prudent selection and use of antibiotic drugs as therapeutic agents and production enhancers in animals was recommended (Levy 1984). A detailed review by IOM (1989) 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. First, is the microorganism zoonotic, that is, can a human acquire a disease from the animal? Second, is there a misstep in the normal safety procedures in processing and handling of animal-derived foods that could enhance the risk of transmission of zoonotic microorganisms to humans, whether or not they are resistant to antibiotics? Third, if transmitted to humans from an animal source, is the microorganism more virulent than in its less-antibiotic-resistant form? Fourth, is a zoonotic disease treatable with other antibiotics? Last, are there enough new antibiotics in development to combat resistance built up from past patterns of antibiotic use and abuse? The answers will show whether there is an increased hazard for humans. Therapeutic applications of antibiotics in fowl and livestock require doses high enough to achieve blood, organ, or tissue concentrations guaranteed to ex-

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The Use of Drugs in Food Animals: Benefits and Risks ceed (usually by 4 to 5 times) the minimal inhibitory concentration (MIC, the concentration of an antibiotic that arrests the growth of a particular organism) needed to treat an existing disease. The amount of antibiotic administered to attain MIC will vary according to the clearance rate in the body and the physiological status of the animal. Subtherapeutic concentrations of antibiotics are often administered in the diet or parenterally for more than 2 weeks and can be used at concentrations ranging from 1 to 200 g per ton of feed (Gustafson 1986). When a systemic infection occurs, the usual method is to use large therapeutic doses of antibiotic intramuscularly, intravenously, or by oral bolus to eliminate the invading organism quickly. The published MICs of a given antibiotic vary from organism to organism and within species by strain. According to summarized information on MICs in the Merck Veterinary Manual (1986), the reported MIC for a particular bacterial species is not consistent. Methodology, different strains (regional), media used, growth (regrowth) time, bacteriostatic vs. bactericidal concentrations, rate of drug diffusion in the media, and degree of bacterial inhibition required for effective therapy are all significant considerations. It may not even be necessary to maintain inhibitory concentrations of antimicrobial drugs at all times during treatment periods. Persistent antibacterial effects at subinhibitory concentrations, which facilitate removal of affected bacteria by host defense mechanisms, have been demonstrated … [for many antibiotics] … Organisms damaged by antibiotics are more susceptible to leukocidal activity. (P. 1510) The last phrase offers some explanation of how subtherapeutic concentrations of antibiotics administered to animals with competent immune systems help the animals fend off disease under current intense production systems (as referenced in Chapter 3). 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. 1997; St. Georgiev 1998). To summarize, resistance of microorganisms to antibiotics develops through several mechanisms (reviewed in Davies and Webb 1998; Hickey and Nelson 1997; O’Grady et al. 1997): (1) when the targeted gene product for the antibiotic’s action in the microbe is altered, making the drug incapable of affecting biochemical pathways that otherwise would result in the death or dormancy of a susceptible microbe, (2) when microbes develop enzymatic capability to degrade a drug and lessen its potency, (3) when an altered uptake system prevents entry of the drug into the cell, (4) when a cell develops a mechanism to excrete the drug minimizing its effect, and (5) when the organism can no longer metabolize the drug into the actual inhibitory compound. Once resistance to an antibiotic is established through the probability of a random mutational event, many genetic aspects of resistance inheritance are chromosomally integrated and as such are passed to subsequent bacterial generations in the process of replication. An additional mechanism of resistance acqui-

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The Use of Drugs in Food Animals: Benefits and Risks sition is the incorporation and expression of resistance genes from one bacterium to another by means of plasmid transfer (Hickey and Nelson 1997). Plasmid transfer between bacteria can be further subdivided into several possible mechanisms. DNA transfer between bacteria can be accomplished by transfer of “free DNA” fragments (a process called transformation), by a form of sexual transfer of genetic material between organisms (conjugation), by phage (bacterial or viral) mediated transfer of genetic material, and by a newly defined class of DNA genes (transposons) easily shuttled between plasmids and chromosomal DNA. Within the nature of bacterial genetics, some organisms can transfer genetic material at higher than normal efficiencies. They are called high-frequency recombinants. Some aspects of the transmission and development of resistance do warrant comment. 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) Given sufficient time and use, resistance at some level will emerge in sensitive organisms. (2) Evidence suggests that resistance may be progressive and can evolve through levels of susceptibility to the drug. (3) There is a propensity for bacteria resistant to one drug to become resistant to others. (4) Once resistance appears, the decline in its frequency is slow. (5) The use of antibiotics by one person affects others in the immediate environment. Levy contends that an effective recourse to the development of resistance is to replace resistant strains with susceptible ones. Although curbing misuse of these drugs in humans and animals will be instrumental in limiting new resistance, education of the public, health professionals (animal and human), and the food animal industry in what constitutes proper use is considered essential. Multiple-antibiotic resistance can be acquired by bacteria from extra-chromosomal DNA in the form of plasmids. These self-contained pieces of DNA might well represent natural evolution in the sense that many early antibiotics are either derived or modified from natural compounds (Gabay 1994). Resistance to compounds toxic to the biochemical processes of bacteria is a mechanism of survival. Most bacteria do not contain resistant genes, but a small portion of bacteria within a given colony is theorized to have, develop, or acquire resistance. In fact, to date, the true reservoir of bacterial resistance remains unidentified. Until it is defined, the reservoir should be considered ubiquitous. New data contradict early microbiology dogma that exchange of genetic information occurs only between bacteria of the same species. With greater prevalence of antibiotic-resistant organisms, resistance seems to be transferred not only within species but also between genera. Frieden et al. (1993) described a vancomycin-resistant gene found among Enterococcus species and additional reports characterized cross-genera transfer of the resistance to vancomycin both in vitro and in vivo (Leclercq et al. 1989; Patterson and Zervos 1990; Noble et al. 1992). Even more alarming is that certain antibiotics, including the extensively studied tetracycline, can increase the gene-transfer rate of resistant transposons

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The Use of Drugs in Food Animals: Benefits and Risks chickens and swine in England and Denmark. In addition, a substantive link between the agricultural use of avoparcin in animals and the emergence and transmission of avoparcin–vancomycin-resistant organisms to humans is asserted (Bates et al. 1994; Aarestrup 1995; Witte and Klare 1995; Aaerstrup et al. 1996). The avoparcin concern does not appear to apply in the United States, because such drugs are not approved for use in food animals here. Several European countries also prohibit its use in food animals. The avoparcin–vancomycin issue is specifically relevant because of several factors. A relatively new class of antibiotics, the naladixic acid derivatives called fluoroquinolones, is coming under scrutiny both here and in Europe for use in food animals. Because of the history of antibiotic issues in the United Kingdom and throughout continental Europe, most of the data cited in the arguments for and against the expanded use of fluoroquinolones in the United States come from public health laboratories in Europe. Resistance to these drugs as well as to others, such as avoparcin, has been monitored for a longer time in Europe than it has in the United States. A logical question is, “If the agricultural use of avoparcin contributed to the emergence of vancomycin resistance in human bacterial isolates, could this occur with the fluoroquinolones?” 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. The Fluoroquinolones Issue1 Fluoroquinolones are synthetic antimicrobial agents (bacterial gyrase inhibitors) that are structurally associated with naladixic acid (reviewed by Hooper and Wolfson 1993). Effective against a broad range of bacteria, fluoroquinolone antibiotics are useful in the treatment of enteric diseases, and in other countries, they have been used in the prophylaxis and treatment of bacterial diarrhea. Particularly effective in combating infections that are difficult to eradicate, these antibiotics are considered a last line of defense in human medicine in the fight against antibiotic-resistant and difficult-to-manage life-threatening infections. 1   During the course of this study, committee member R. Gregory Stewart changed employment to become affiliated with a pharmaceutical firm that has a drug approval application pending before FDA for a fluoroquinolone antibiotic. As a result, Dr. Stewart excused himself from the committee discussion and deliberations pertaining to this class of antibiotics.

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The Use of Drugs in Food Animals: Benefits and Risks They have added practical considerations of reducing the need, duration, and expense for hospitalization. The ß-lactam (penicillin class) or aminoglycoside (gentamicin, tobromycin) antibiotics have resistance factors transmittable by nucleic acid plasmids. In contrast, resistance to fluoroquinolones (naladixic acid derivatives) is mostly associated with random chromosomal mutation in specific bacterial genes, with the resistant phenotype transferred to daughter bacteria in the process of simple multiplication and proliferation under the selection pressure of the drug. While quinolone resistance via plasmid vectors can be demonstrated in the laboratory, this mode of acquisition has not been demonstrated in clinical settings (Hooper and Wolfson 1993). Two main modes of resistance have been identified for fluoroquinolone drugs in bacteria: reduced binding to and inhibition of DNA gyrases and reduced access to the gyrase inside the bacteria. Eleven specific amino acid substitution mutations in the DNA gyrase GYR-A protein have been documented (Hooper and Wolfson 1993), and the substitution at a specific amino acid site has resulted in different degrees of resistance as estimated by the relative increase in the MICs for naladixic acid (NA) and ciprofloxacin (CIP). Depending on the site of the mutation, MICs are reported to increase from 2.5 to 128 μg/ml and from 4 to 32 μg/ml for NA and CIP, respectively. Additional mutations with correspondingly lesser effects on MIC are reported for mutations in the DNA gyrase B protein and mutations that result in changes in the accessibility of the drug for the target enzyme. Two fluoroquinolone resistance mechanisms in E. coli have been identified to account for reduced access to the gyrase enzymes inside bacteria: physical blocking of the entry of the drug into the bacteria at the surface membrane and energy-dependent active excretion of the drug by the bacteria (Piddock 1995). The position of the mutation and the concurrence of multiple-site amino acid substitutions will affect the clinical significance of the resistance event. Whereas a single mutation event has been suggested to result in relatively low-level fluoroquinolone resistance (MIC <2–4 μg/ml), the development of 2-site mutations, especially in different mechanisms of action, results in high-level resistance (MIC >32 μg/ml) and complicates treatment of incurred disease (Piddock 1995). Similar double mutations resulting in high-level fluoroquinolone resistance have been detected in human and veterinary (cattle) Salmonella isolates in Germany (Heisig et al. 1995). In that study the authors suggested that the cattle and human Salmonella isolates were identical. They also suggested that human and veterinary reservoirs for this multiple-site-resistant organism exist, although no epidemiological link between them could be established. Dual-mutation high-level quinolone-resistant organism populations also have become established. 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. There is considerable controversy and disagreement among animal and human health care professionals regarding the widespread use of these drugs in food

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The Use of Drugs in Food Animals: Benefits and Risks animals. The major argument put forth by the medical community against the use of these drugs in food animals is that the drugs would be needed for humans if resistance to other antibiotics were to become a problem (Levy 1998; IOM 1998). The critics contend that widespread use of fluoroquinolones in food animals, in conjunction with negligent and irresponsible use, would cause fluoroquinolone resistance in organisms to emerge that would pose a significantly increased risk to human health. The concern about greater risk is because of the resistance to fluoroquinolone drugs emerging in organisms such as Salmonella DT-104, where resistance to other classes of antibiotics already exists. If realized at the level that some health workers suggest (Threlfall et al. 1996; Glynn et al. 1998), the emergence of fluoroquinolone resistance would make invasive disease by multidrug-resistant microorganisms significantly more difficult to treat. However, Kuschner et al. (1995) described effective therapy against ciprofloxacin-resistant Campylobacter with the use of azithromycin, a broad-spectrum, new-generation macrolide (erythromycin-like) antibiotic given to U.S. military personnel stationed in Thailand, where the occurrence of ciprofloxacin resistance in Campylobacter is high. Based on the observed effect of generalized therapeutic use for farm animals in the United Kingdom, Germany, and the Netherlands, many health experts in the United States suggest that further approvals for this drug are not prudent. Therapeutic uses need to be justified, carefully documented, and controlled. Contributing to the disparate views is the definition of resistance. The National Committee for Clinical Laboratory Standards (NCCLS) has established 4 μg/ml concentrations of ciprofloxacin (MIC) as the cutoff to define clinically significant resistance that influences the effectiveness of treatment. The complication in interpretation arises when resistance is assessed in vitro and demonstrated at MICs lower than the NCCLS clinical definition, and when this lower MIC is used to support the emergence of resistance. Thus, defining resistance is critical to documenting changes in the patterns and the magnitude of resistance emergence associated with the use of antibiotics in animal production. 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. In the United States, there is currently no significant threat of disease outbreak in humans that can be tracked and associated with the passage of quinolone-resistant organisms from animals to humans. However, because of the relative newness of this drug’s use in food animals, FDA and the Centers for Disease Control and Prevention (CDC) (PHS 1995) recommend and support a cautious approach to quinolone use in agriculture, and they are sensitive to the possibility that resistance could become a significant problem in the future. It was largely outside the charge of this committee to assess the accuracy of the many reports in the literature used to support or refute claims for altered health risk associated with the use of quinolone antibiotics in food animals. To

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The Use of Drugs in Food Animals: Benefits and Risks maintain a balance in presenting the views on the issue it is useful to refer to and summarize some of the information available. The work cited in many arguments is published in the peer-reviewed literature and in non-reviewed or critiqued formats and abstracts in scientific society proceedings. Each source of information and opinion serves to shape the character of the issues and controversies surrounding it. The authors’ and stakeholders’ interpretations of data contribute to the controversy and fuel the arguments that are frequently put forward by opponents to challenge the rigor of the science used in the studies, the statistical robustness of the analysis, or the sizes of the populations studied. Authors of some scientific publications in the United Kingdom, Spain, and the Netherlands have suggested that the licensing and use of fluoroquinolone drugs for use in animals in those countries was a significant factor in the development of fluoroquinolone resistance in Campylobacter and Salmonella from food animals (Endtz et al. 1991; Perez-Trallero et al. 1997; Threlfall et al 1996; van den Bogaard et al. 1997). For example, many health officials in federal regulatory agencies look to the data from Europe as evidence that the greater introduction of fluoroquinolone antibiotics into agricultural food-animal applications increases the risk of transfer of fluoroquinolone-resistant pathogens from animals to humans. The magnitude of the reported resistance can be striking as in the case of the Campylobacter isolates from humans who suffered from food-borne illness in Spain in 1996. It was reported that more than 80 percent of these isolates were resistant to nalidixic acid (Perez-Trallero et al. 1997), using the NCCLS standard. There is confusion about the definition of resistance used in many of the studies cited and about the current standard for clinically significant resistance levels to fluoroquinolones set by NCCLS at 4 μg/ml. The NCCLS resistance level is 8 to 16 times greater than that assigned by Threlfall et al. (1996), 0.25 to 0.5 μg/ml. The Animal Health Institute has summarized its position on the relevance of the resistance data in stating that Manufacturers believe that these antibiotics are ideally suited for therapeutic use and would serve a critical need in enhancing animal health and contributing to a healthy food supply … The issue of antibiotic resistance has been debated for more than 30 years. Studies show that if animal-to-human transfer actually happens, it is a rare occurrence. There is no evidence to show that transferred organisms actually thrive or cause disease in humans …. (AHI 1997) There are in fact several reports of transfer of drug-resistant pathogens from animals to humans (summarized in Chapter 3), and there is evidence that the passage of fluoroquinolone-resistant bacteria from animals to humans is possible, just as is the case for avoparcin-resistant bacteria (Witte and Klare 1995). Two lines of evidence are cited in the scientific literature to substantiate the development of fluoroquinolone resistance in animals and transferred to humans: First, patterns of emergence of fluoroquinolone-resistant Campylobacter in the Netherlands in humans and poultry were strongly linked with the introduction of fluoro-

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The Use of Drugs in Food Animals: Benefits and Risks quinolones in veterinary medicine (Endtz et al. 1991). Second, animals are considered the principal reservoir of the chromosomally encoded, multidrug-resistant Salmonella DT-104 and Campylobacter (Wall et al. 1995; ERS 1996b; Glynn et al. 1998), and there appear to be cases of fluoroquinolone resistance emerging in these organisms with resistant isolates found in humans. A recent outbreak of 13 cases of food poisoning in the United Kingdom was documented when people contracted a fluoroquinolone-resistant Salmonella DT-104 infection from turkeys that had been previously treated with fluoroquinolones. Epidemiological tracking suggested the outbreak was traced directly to the poultry, confirming the potential for transfer of this resistance pattern to humans from animals (Wall, P. 1997, Public Health Laboratory Service, England, personal communication). The critical factor associated with the outbreak, however, was improper thawing of the turkey prior to cooking and subsequent inadequate cooking to kill the proliferating microorganisms. This is another example of the link between the presence of drug-resistant organisms and augmentation of the disease risk being caused, in part, by irresponsible handling of food. In the U.K. resistance issue, the Salmonella DT-104, while significant as a pathogen, is brought into the scenario not as a pathogen as such, but in terms of what it offers as a microbial sentinel to aid in tracking the passage of fluoroquinolone resistance from animals to humans. 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) Salmonella DT-104 increased from 259 in 1990 to 4,006 in 1996 (CDR 1997). It concerns health officials that, since 1994, resistance to trimethoprim and ciprofloxacin is increasing in a significant proportion of Salmonella DT-104 isolates from humans (Threlfall et al. 1998). The increase in ciprofloxacin resistance in human Salmonella isolates is shown in Figure 6–1. Approvals for uses of fluoroquinolone antibiotics in food animals in the United Kingdom have continued. Some stakeholders in the United States cite this fact and question FDA for placing a moratorium on further approvals of fluoroquinolone drugs in food animals. FDA has responded that the approval and monitoring processes in the United Kingdom are substantially different from those in the United States. Treatment of animals with fluoroquinolones is relatively new in the United States, where its use is restricted to poultry. Data on any patterns of emergence of bacterial resistance to fluoroquinolones in animals, and especially data on the resistance in terms of MIC, are few. A recent summary of the surveillance data reviewed by FDA and CDC experts (Glynn et al. 1998) stated that, at the time of the review, there were no isolates of Salmonella DT-104 that were resistant to

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The Use of Drugs in Food Animals: Benefits and Risks FIGURE 6–1 Salmonella DT-104 Ciprofloxacin-Resistant Human Isolates Confirmed in the United Kingdom. Source: CDR Weekly 1997; Wall, PHLS, personal communication. ciprofloxacin. One isolate was resistant to nalidixic acid, but it did not present the 5-drug resistance pattern typical of Salmonella DT-104. The paper concluded that incidences of the 5-drug resistant DT-104 isolates increased from 0.6 percent in 1979 to 34 percent in 1996. Similarly, the paper also stated that the sources for the Salmonella DT-104 remained undetermined. The database could not provide evidence that the increase in Salmonella DT-104 isolates over the years was related to continued subtherapeutic use of antibiotics in food animals, a combination of subtherapeutic and therapeutic use as factors establishing an environment that could select for these bacteria, or a proliferation and passage of an established population of these organisms persisting perhaps even where antibiotic use is minimal. Furthermore, without data on the relationship between Salmonella DT-104 detection in isolates and clinical disease, there is a gap in the information needed to link disease outbreaks to factors that predispose humans to greater risk of infection with this pathogen. However, the absence of detectable fluoroquinolone resistance in Salmonella DT-104 in the study isolates serves as a base and timeline from which emergence of fluoroquinolone resistance in bacterial populations can be monitored and referenced. The final decision for restricted use of fluoroquinolones in food animals in the United States resides with the CVM director, who has restricted further use of

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The Use of Drugs in Food Animals: Benefits and Risks these antibiotics in food animals. To assist in the decision-making process, a surveillance board has been established to track and oversee the effect of antibiotics in the development of bacterial resistance. Currently, the oversight of resistance surveillance is in the public sector. Board members are associated with FDA (CVM, Center for Food Safety and Applied Nutrition, Center for Drug Evaluation and Research, and the Office of the Commissioner), USDA (ARS, APHIS, and Food Safety and Inspection Service [FSIS]), CDC, and academic institutions. 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). The purpose of the program is: (1) to gather data on the extent and trends over time in antimicrobial susceptibility in Salmonella and other enteric microorganisms and to monitor several antibiotics for such resistance patterns, (2) to increase the flow of data on resistance emergence in animals and humans, (3) to identify new areas for research, and (4) to prolong the useful life of approved antibiotic drugs. The fluoroquinolones and other standard antibiotics are used as test compounds, with specific bacteria such as E. coli and Salmonella spp. used as sentinel organisms. A relevant issue that contributes still further to some aspects of this controversy relates accountability for antibiotic drug use. This probably is more of a problem worldwide than in the United States. It is an understatement to say that this issue is complex. However, the reality is that antibiotics are widely available for use in animals as well as humans through unauthorized routes of distribution. Inappropriate antibiotic use and lack of accountability are insidious and difficult to document. Not only is there a burden of increased risk to human and animal health, but when present and detected as a problem, unorthodox use of antibiotics can skew the interpretation of data and compromise the objectivity of the decision-making process. When a greater-than-expected incidence of resistance to a drug occurs in a population where the regulated use of the drug is weak, how can the source of the problem be accurately assessed? Is it from animal use? Is it from overprescription by licensed practitioners? Is it driven by the illicit-market economics? Unfortunately, assessing the magnitude of the consequences of misuse can be done only retrospectively, usually through epidemiological investigation, when the process has already become an established problem with established health consequences. In regard to the potential for transfer of resistant organisms from food animals to humans, perhaps increased attention should be given to reducing the incidence of induction and proliferation of resistant organisms on the farm. Strategies should reflect the need to limit the overuse of antibiotics. In addition, the benefit of using antibiotics in managed farm operations should be more widely

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The Use of Drugs in Food Animals: Benefits and Risks appreciated. Similarly, consumer education efforts are necessary, so the public will more readily accept modern food safety techniques, such as irradiation and surface sterilization. When properly used, these methods are efficient at stopping the proliferation of microorganisms that can be introduced inadvertently at the time of slaughter (Lagunas-Solar 1995; Osterholm and Potter 1997). Pharmaceutical developers and manufacturers are watching the fluoroquinolone resistance and approval issue with great interest because of the ramifications for development of animal antibiotics that will be scrutinized in terms of human or environmental safety. The economic incentive for discovery and introduction of new antibiotics could be compromised if human health issues of resistance development and issues of food-animal use and accountability cannot be resolved. This entire issue, driven by elements of disparate views, nonuniform use of definitions and standards, data that are less than clear-cut, and subjective opinion on both sides, is likely to be revisited each time an antibiotic is presented for use in both human medicine and animal agriculture. The importance of resolving these issues rapidly underscores the need for increased communication among stakeholders and for openness in decision making. Much of the burden of weighing the issues and integrating the available surveillance data could be lifted by the development of an oversight board that would collate and integrate information, without bias, to support science-based regulatory decisions. The Virginiamycin Issue The most recent example of agricultural versus human use of antibiotics is just unfolding (Okie 1998). Virginiamycin is an antibiotic that has been used for almost 20 years in the control of infection and growth of swine, cattle, and poultry. Virginiamycin is a member of the streptogramin class of antibiotics. Until recently, streptogramins were not used in human medicine so their use in food animals was of relatively little concern. 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. In the case of the streptogramins, the approval for use in animals was granted first. Now that a need for use in humans has developed, the question is how much debate will ensue that will challenge the continued use of these drugs in animals. Approved use of virginiamycin for animal production in the United States, along with an absence of similar or related streptogramin drugs in the human population, offers a unique opportunity to assess some of the controversial issues associated with drug use in food animals.

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The Use of Drugs in Food Animals: Benefits and Risks A human population sampling of bacterial isolates screened for virginiamycin resistance would be a valuable component in a drug resistance database. The general human population should be relatively devoid of streptogramin resistance because it has only recently been approved for human use as a therapeutic drug and its use is not nearly as widespread as is the use of some other drugs, such as the penicillins. The ability to detect specific virginiamycin resistance (as well as MIC) would provide good information on whether prior use of a drug as a feed additive affects human health or threatens the effectiveness of streptogramins for future therapeutic use in humans. SUMMARY OF FINDINGS AND RECOMMENDATIONS The presence of antibiotics in the microbial environment constitutes a natural initiating selection pressure that allows bacteria, which have changed phenotypically so that they are less affected by the antibiotic, to survive. The development of antibiotic resistance occurs because populations of microorganisms acquire a beneficial mutation or plasmid transfer and proliferate. The emergence of resistance is highly variable and is affected by intrinsic factors—the antibiotic used, the duration of use, the dose, the bacterial species—as well as extrinsic factors, such as farm hygiene and biosecurity. Antibiotic resistance is an important issue in human and veterinary medicine in part because of the way it is defined. There is conflict in the interpretation of absolute and clinically relevant resistance. How this is defined and exactly what MICs constitute a “resistant” organism are at the heart of the controversy. Antibiotic drug resistance is increasing in food-animal populations, particularly in bovine, swine, avian, ovine, and catfish species. Similarly, drug resistance is noted in equine, canine, and feline populations. Part of the increase results from greater use of antibiotics in animals, but a large portion of the increase also is the result of significant improvements in surveillance, detection, and screening for antibiotic-resistant organisms. Antibiotic resistance patterns tend to be against more than one drug. Furthermore, resistance has been noted in organisms that are pathogenic in animals only, in zoonotic organisms, and in nonpathogenic organisms. Although little attention had been paid to resistance development in nonpathogenic bacteria (largely because of the difficulty of that task), the occurrence of resistance in these bacteria constitutes a potential area of concern. The exact magnitude and extent of antibiotic drug resistance is difficult to estimate because of a lack of comprehensive surveillance programs in veterinary medicine in the United States and elsewhere and because of the different ways resistance is defined. 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. Therefore, any increase in resistance to these drugs limits practitioners’ choices to treat animals or conduct prophylactic

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The Use of Drugs in Food Animals: Benefits and Risks programs to improve animal health. The same is true for nonfood animals. Alternative means of controlling or slowing drug resistance must be sought, and research should be encouraged in this area. Recommendations The committee recommends establishment of an integrated national database to support a rational, visible, science-driven decision-making process and policy development for regulatory approval and antibiotic usage in food-producing animals. This will further ensure the safety of these drugs as well as foods of animal origin. The openness and accessibility of this information are critical to the success and validity of decisions that will affect veterinary and human medicine. Information contained in such a database should include the following: approved drugs in use and defined MICs that affect the clinical significance of resistance in animals and humans and available resources for treatment; volume of usage of approved drugs and incidence of misuse, and resistance patterns in important pathogens and sentinel marker organisms on the farm and at slaughter; prevalence of human pathogens in foods of animal origin and the incidence of food-borne infections from food-animal products, with particular reference to resistant organisms. The committee strongly recommends the further development and use of antibiotics in human medicine and food-animal practices have oversight by a panel of experts, interdisciplinary in composition, representing the regulatory agencies and the veterinary–animal health industry, the human medical community, consumer advocates, the animal production industry, researchers, and epidemiologists. 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. Monitoring the data from international sources where a given drug has more history than it has in the United States also would be necessary. The release of data and the ability for others to access them will be important to the oversight process. The private sector and federal regulatory agencies need to share the cost and resources as a part of the resistance-monitoring process. Ultimately, the number of zoonotic-pathogen sentinel organisms will need to be expanded as will the number of antibiotics surveyed. Resistance issues will need to be characterized with regard to the incidence of detectable resistance versus clinically significant, disease-producing resistance, based on

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The Use of Drugs in Food Animals: Benefits and Risks minimal inhibitory concentrations. These data should provide a growing base from which to develop models and predict resistance emergence. The committee recommends that basic research, which explores and discovers new or novel antibiotics and mechanisms of action of antibiotics, should receive increased funding. In particular, funding is needed to develop more rapid and wide-screen diagnostic tests to increase the capability of more accurately tracking emerging trends in antibiotic resistance and zoonotic disease and to transfer this information to the larger database. Funding should come from federal and private sources. The committee recommends that the drug development industry continue to seek new approaches to identify and capitalize on novel microbial–biochemical processes for antibiotic drug development to control the spread of infection. Because resistance development to one antibiotic poses a significant threat for resistance to emerge against others in the same parent class (cross-resistance), the discovery and development of new classes of antibiotics is essential to ensure infection control in the future. The committee recommends that increased education about issues, practices, and concepts of antibiotics and their uses should be made available in school, industry, home, and professional venues. The misuse of antibiotics through lack of awareness can no longer be tolerated. 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. The committee recommends that, to aid in the accountability process, identification of the source of drug resistance would be enhanced substantially by using individual identification systems, such as microchips, in all food animals.