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The Use of Drugs in Food Animals: Benefits and Risks (1999)

Chapter: 6 Issues Specific to Antibiotics

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Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
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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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

100-fold (Torres et al. 1991; Davies 1994). Some authors believe that concentrations of antibiotics below the threshold for bacterial growth inhibition stimulate cell-to-cell contact, thereby facilitating direct DNA plasmid transfer of information (Davies 1994). Clinically, multidrug-resistant phenotypes rapidly acquire resistance to newer antibiotics, and that pattern could be profoundly important (Tomasz 1994). 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).

Further bacterial transfer might occur between animal species—on different farms, far apart—to humans working with animals, and to humans consuming processed food animals (Tauxe et al. 1989). Levy et al. (1986) reported an increased number of tetracycline-resistant E. coli in the feces of chickens after only 1 week of feeding with tetracycline-supplemented feeds. Subsequently, in more than one-third of farm family members, 80 percent of the bacterial populations had tetracycline-resistant colonies, compared with 7 percent of the bacterial population in neighbors. No active human infections with tetracycline-resistant organisms were reported. Hummel et al. (1986) found that plasmid-borne resistance to streptothricin was present in E. coli from pigs fed nourseothricin, from the employees working with the pigs, and from their family members. They also found the plasmids in fecal samples from asymptomatic humans and from people with active urinary-tract infections, all of whom had no contact with the pig farms but who lived in the region where the drug was used in agriculture. These investigators found no indication of coselection for resistance to other drugs “indispensable for therapeutic use in man,” and the authors concluded that the use of this antibiotic in animal husbandry had no clinical implications for human health.

With the occurrence of plasmid transfer across genera, concern must be raised if the patterns of resistance, which occur among the coliforms, are detected as being transferred to other species of bacteria—pathogens in particular. In that case, a serious potential for widespread infection could occur. News stories have reported widespread infections by water- and food-borne organisms that involve a virulent organism that also is resistant to multiple antibiotic drugs (Cohen 1993; Toner 1994; Tillett et al. 1998). Evidence can be cited that resistance and virulence factors can be passed on the same genetic elements (plasmids, etc.) and that the occurrence of this passage is greater than random chance would predict (Kristinsson et al. 1992; Munoz et al. 1992; Tomasz 1994). In this setting, it is plausible that morbidity and mortality would rise sharply and traditional antibiotic therapy would be made more difficult.

SUBTHERAPEUTIC VERSUS THERAPEUTIC USE OF DRUGS

The potential for increasing the growth rate of farm animals with antibiotic agents was first suggested by Moore et al. (1946). Stokstad et al. (1949) demon-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

strated the growth-promoting properties of supplemental feeding with chlortetracycline. Subsequent studies illustrated the beneficial effects of antibiotics in promoting growth in pigs (Cunha et al. 1950), poultry (McGinnis et al. 1950), and calves (Loosli and Wallace 1950). FDA approved the use of penicillin and chlortetracycline as feed additives in 1951 and oxytetracycline in 1953.

The extent and reality of a drug selection pressure depends in part on the concentrations of antibiotics to which bacteria are exposed and whether a concentration is achieved that actually can assist in selecting for the proliferation of resistant organisms. For example, for penicillins to work as antibacterials, the bacteria must be in a state of active proliferation and cell wall synthesis, and the concentrations of penicillin must be high enough that they enter the bacteria, bind to the penicillin-binding proteins, and inhibit cell wall synthesis. When penicillin concentrations are below the concentration needed, some degree of partial and residual effect on the bacterial structure facilitates increased phagocytosis of the infecting bacteria by natural host immune cells (Merck Veterinary Manual 1986). Thus, in the mechanism of action of subtherapeutic antibiotics, the interconnectivity of drug pharmacology and inherent host immune defenses must be considered.

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). When considered purely in terms of the amount of drugs used in food animals, the subtherapeutic use of penicillin, tetracycline, and other feed-additive antibiotics (40 percent of antibiotic products in the United States) is viewed as considerable pressure for selection of microorganisms resistant to the mode of action of these drugs.

Antibiotics are used at subtherapeutic concentrations to prevent diseases caused by pathogenic microorganisms and to improve animal performance (enhance profit, increase rate of weight gain, or improve efficiency of feed use) (Hays 1986). Such concentrations are often used for extended periods and are usually supplied in the diet. There are cases in which the subtherapeutic use of an antibiotic was coincident with the development of resistant populations of bacteria, and occasionally these resistant bacteria are transferred to humans, but there is no clear indication that all subtherapeutic antibiotic use causes resistance uniformly or increases the potential for zoonotic disease. Not all antibiotics are used at the same concentrations as feed additives when used for prophylaxis or growth promotion and certainly not at the same concentrations in all species for which the drug is approved. Data are lacking to specifically address antibiotic use concentrations and the emergence of clinically recognized resistance in pathogens.

Resistance to antibiotics can sometimes modify some properties of disease-causing bacteria, possibly increasing their virulence or altering their potential to develop resistance to other antibiotics (Fagerberg and Quarles 1979; Hays 1986;

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

Levy 1998). The more real and more frequently encountered hazard to human health comes from any pathogenic bacteria that can contaminate animal-derived foods, regardless of drug resistance, that proliferates to clinically significant burdens to cause disease either from toxin accumulation in the food or from direct invasive infection. Elimination of resistance would not necessarily reduce the ability of microorganisms to cause disease. Rather, elimination of resistance facilitates the treatment of the disease by making more antibiotics available. However, infection by a proliferating antibiotic-resistant organism does increase the difficulty in using conventional therapy to treat the disease in humans.

Recent examples of human disease associated with animal-derived bacterial infection are illustrated by the outbreaks of severe illness associated with the virulent E. coli strain O157:H7 and Salmonella typhimurium DT-104. E. coli O157:H7 is extremely virulent but not (to date) associated with antibiotic resistance. Whereas the origin of these bacteria is always ultimately animal, some of the most frequent outbreaks have been associated with consumption of nonanimal foods (vegetable and fruit juice). Salmonella DT-104, a pathogen of major concern in the United Kingdom, is emerging with increasing frequency in the United States and is associated with multiple-antibiotic resistance (Glynn et al 1998). A summary report by Tauxe (1986) suggests that increased risk in human and animal populations (Hird et al. 1984) to susceptibility to infection with Salmonella is associated with recent use of antibiotics within 1 to 4 weeks of exposure.

Epidemiological patterns of occurrence also suggest that household pets are significant reservoirs of these bacteria. This underscores that human behavior is a dynamic factor that must be included in the discussion on risk assessment for disease emergence. When an animal is treated with specific antibiotics, antibiotic resistance does not develop automatically in all species of bacteria that might initially be sensitive. Both the type of antibiotic and the duration of use are important in the patterns of resistance that could develop (Davies and Webb 1998). 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 Hamilton-Miller 1988). Penicillins need to enter bacteria to bind to specific penicillin-binding proteins, inhibit proper cell wall synthesis during bacterial proliferation, weaken the cell wall structure, and facilitate lysis of bacteria by osmotic water movement (Merck Veterinary Manual 1986). Thus, the relative susceptibility of Histomonas influenza, E. coli, and Pseudomonas aeruginosa differ because the bacterial cell wall permeability decreases, respectively. Thus, the concentration gradients (which drive the drug into the bacteria) differ, and the bacterial sensitivity as a function of drug concentration can be affected.

For those populations in which some susceptibility to a given antibiotic exists, relatively low antibiotic concentrations inhibit the antibiotic-susceptible

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

members of the bacterial population. In response to the decreased competition, the resistant bacteria then multiply and increase as a proportion of the total population (Gordon et al. 1959; Kobland et al. 1987).

In some instances, development of resistance is rapid, and high levels of resistance can be attained within a few days. Levy (1992) suggested that, for such a rapid change in emergence of resistance to occur, resistant organisms are probably already present in the original bacterial population. In this situation, only inhibition of the susceptible competitors needs to occur to permit the resistant organisms the opportunity to multiply and become clinically significant (Levy 1992). In other instances, resistance develops after a period in which no effect is apparent (Guinee 1971). That phenomenon might take place when resistant organisms are absent initially but develop within the treated population or are introduced from outside after antibiotic therapy is under way.

Subtherapeutic use of antibiotics as administered in animal feed has been heavily criticized (Levy 1998; Witte 1998): (1) Subtherapeutic use of antibiotics in animal feeds has been blamed as the principal cause of antibiotic-resistant bacteria. (2) If subtherapeutic use were eliminated, the level of resistance of bacteria harbored by animals would be reduced. (3) Reduced resistance to antibiotics in animals would result in an improvement in human health because the potential for transmitting antibiotic-resistant bacteria from animals to humans would be reduced. Such arguments have been advanced for many years, as reviewed by Hays and Black (1989), and were considered more speculation than data-driven fact. In addition, Walton (1986) suggested that their fundamental flaws underscore how inappropriate the recommendations of the Swann committee report (Swann 1969) actually were. Even the requirement for prescription use of antibiotics in the United Kingdom failed to limit the extent of coliform and Salmonella resistance (Dupont and Steele 1987). The IOM (1989) report on penicillin and tetracycline use in animals further summarized these lines of evidence, which suggest that the health risk posed to humans in the United Kingdom through the emergence of animal-antibiotic-associated resistance has not been changed substantively by implementation of recommendations in the Swann report. 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. 1986; Levy 1998). In the face of stopping antibiotics, resistance levels are slow to decline, and the reasons for this slowness are not well understood and are inadequately addressed in available research reports.

Ahmed et al. (1984) petitioned to ban the subtherapeutic use of penicillin and tetracyclines in animal feeds, citing an imminent hazard to public health. In the petition, they argued that, because therapeutic treatment of animals with antibiotics was episodic and of relatively short duration, it did not contribute significantly, if at all, to the long-term sustained development of antibiotic-resistant bacterial strains in food animals. On that basis, the petition suggested the inter-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

mittent use of antibiotics at therapeutic concentrations as an alternative to subtherapeutic concentrations in animal feeds.

Because of its suggested benefit in limiting the duration and extent of disease-causing bacteria and pathogen shedding (summarized and reviewed in IOM 1980, pp.130–147; 205–220), the use of subtherapeutic drug concentrations has been substantial and has been embraced by, as well as influenced by, the livestock industry (Steele and Beran 1992). The most important benefit has been protection against disease, although the effect has been less pronounced in clean, healthful, and stress-free environments (Hays 1986). 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. The beneficial effects of subtherapeutic drug use are found to be greatest in poor sanitary conditions (Speer 1982; Zimmerman 1986).

The development of de novo resistance in populations of bacteria in antibiotic-treated animals is influenced by complex interactions between the length of time and the concentrations of the drug to which bacteria are exposed (Baquero and Negri 1997a,b; Baquero et al. 1997). In contrast to the supposed propensity of long-term subtherapeutic doses to promote development of antibiotic-resistant strains of bacteria, short-term therapeutic doses are believed to act rapidly and decisively before being eliminated from the body. Therapeutic doses result in higher plasma and tissue concentrations of antibiotics than are attained with the use of the same antibiotic for growth promotion or disease prophylaxis. Characteristically, therapeutic concentrations are used for shorter times and are administered in the diet or parenterally (Ziv 1986). For example, when a systemic infection occurs, it is normal to use large doses of antibiotic to eliminate the invading organism quickly. Low doses administered over a longer time could favor emergence of resistant organisms (Jukes 1986). However, there remains the nebulous concepts of what constitutes a “low dose” and how long a dose must be present for resistant bacteria to emerge. Tracking resistance emergence is complicated because not all bacterial species or strains have the same limits at which concentration-dependent selections can occur. In addition, because the probability that resistance will emerge is based on the change in development of a favorable mutation, it can rarely be determined how long a drug must be present for the selection to occur.

An interesting relationship in the dynamics between intentional low-level antibiotic use and directed therapeutic use exists in the concentration gradients of antibiotic that form from the site of administration through diffusion and distribution. For in vivo drug distribution within tissues and body compartments, naturally occurring concentration gradients form in the pharmacokinetic processes of delivery, distribution, and elimination (Grahame-Smith and Aronson 1992). Where the elements of drug dose and exposure duration increase the likelihood for resistance to emerge in bacterial populations, these natural gradients might

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

contribute to the localized emergence of resistance (Baquero and Negri 1997a, b; Baquero et al. 1997). The so-called high-level-directed therapeutic drug concentrations can accumulate in tissues locally at relatively low concentrations, and low-level antibiotic uses might be present in pharmacokinetic compartments at concentrations that are too low to select for resistance. This is a complicated interaction, but it serves to demonstrate how reducing the terminology to “therapeutic” and “subtherapeutic” becomes confusing and inappropriate.

Thus, major distinctions between the effects of subtherapeutic and therapeutic antibiotic doses on resistance present themselves in several dimensions, including the temporal aspects of the onset of resistance as well as the propagation and persistence of resistance and the number of resistant organisms maintained in the animal population (IOM 1980). There appears to be no definitive answer regarding whether subtherapeutic or therapeutic antibiotic use in farm animals causes more or less drug resistance. The absolute number of antibiotic-resistant isolate bacteria appears to be greater when subtherapeutic doses are used in animal feed than when therapeutic doses are given (IOM 1989). However, Walton (1986) 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. (1959) and Kobland et al. (1987) found that the proportion of resistant intestinal bacteria was higher with therapeutic doses than with subtherapeutic doses of antibiotics. In one experiment by Kobland et al. (1987), chickens were fed different amounts of chlortetracycline in the diet and, after 3 days of treatment, were infected artificially with a mixture of sensitive and chlortetracycline-resistant Salmonella. In chickens with no chlortetracycline in the diet, elimination of the resistant Salmonella was complete 20 days after infection. When chlortetracycline was in the diet, the chickens had not eliminated the chlortetracycline-resistant bacteria by the end of the experiment. Bacteria were eliminated more slowly with therapeutic doses than with subtherapeutic doses. However, by the end of the experiment, the proportion of the chickens still infected with resistant Salmonella was lower with therapeutic doses (which were discontinued at the end of day 22) than with subtherapeutic doses (which were supplied continuously throughout the experiment). In the presence of chlortetracycline, the resistant Salmonella persisted throughout a substantial portion of the 35- to 56-day life span of broiler chickens.

Another study was made of an isolated herd of swine that had been established by Cesarean section of the sows to avoid contamination of the piglets with antibiotic-resistant and other bacteria at birth (Langlois et al. 1986). After 9 years of intermittent therapeutic use of streptomycin, but no subtherapeutic use of any antibiotic, 73 percent of the fecal coliform bacteria tested were resistant to streptomycin. For pigs, the time from birth to marketing is about 3.5 to 5 months.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

Thus, under some circumstances, bacterial resistance from therapeutic use of antibiotics in market pigs might not disappear before slaughter.

One reason for the long residence time of antibiotic-resistant intestinal bacteria is probably continual reinfection and cross-infection of animals from fecal material (Harry 1962) and animal feeds (Durand et al. 1987). Reinfection also might contribute to the development of well-adapted strains that compete with the preexisting nonresistant strains and persist indefinitely. For example, in the herd from the Cesarean-section-derived piglets, 70 percent of the fecal coliform bacteria were found to be resistant to tetracyclines, even though the herd had been kept isolated and no tetracyclines had ever been used (Langlois et al. 1986). The resistance to tetracycline must have been derived from incidental introduction of tetracycline-resistant bacteria, because resistance to streptomycin, which had been used intermittently in therapeutic concentrations, has not been found to confer resistance to tetracycline. In regard to the potential for reinfection, even the most stringent biosecurity measures might be insufficient to guard against incidental introduction of resistant bacteria. For example, manure is a likely reservoir for microorganisms. Passage of microorganisms from farms to people by bird and rodent vectors that scavenge grain from the fecal material as well as agricultural waste runoff and refeeding of animal litter will naturally occur (Haapapuro et al. 1997).

Once an antibiotic has been introduced into animal management practice, either as a subtherapeutic feed application or as a specific therapeutic drug, the emergence of some microbial resistance is highly probable, and cessation of antibiotic use does not significantly alter the pattern of resistance. 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. When such swine are stressed, increased bacterial shedding in the feces includes bacteria from the upper tract (Moro and Beran 1993). Contamination by multiple-drug-resistant E. coli was substantially greater in carcasses of swine subjected to preslaughter stress than it was in carcasses with minimized preslaughter stress.

Antibiotic treatment of certain disease entities has led to drug-resistant animal infections, as experienced with a case of Salmonella typhimurium (phage type 29) infections in calves (Anderson 1968; Anderson et al. 1975), in which drug-resistant disease transmission was enhanced. In this case, susceptible calves at a facility were exposed under stressful conditions to a multiresistant strain of Salmonella typhimurium. Animals were treated ineffectively for salmonellosis and transported to several farms, where they served as sources of infection for other calves, adult cattle, and humans. When the facility where the diseased calves originated ceased operation and the consolidation, exposure, and dispersal of calves ended, the farm outbreaks of salmonellosis decreased.

Results of studies by Endtz et al. (1991) suggest that the emergence of quinolone-resistant strains of Campylobacter isolated from humans result from

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

the therapeutic use of these drugs in veterinary medicine. The increased resistance of Campylobacter in the animal reservoir could result in treatment failures of enteric diseases if quinolones were to be used in therapy. Based on the time of fluoroquinolones entering the market and on serotyping patterns of emerging resistant bacteria, Endtz et al. (1991) concluded that the animals were more likely the source of resistant strains for humans.

Several reports (CAST 1981; Levy et al. 1986; IOM 1989) have shown that farm workers who have close contact with livestock can acquire, although transiently, antibiotic-resistant intestinal microflora. In addition, evidence indicates that some human diseases from resistant bacteria do occur because of the subtherapeutic use of drugs in animals. The occurrence is rare, and the finding is perhaps confounded by the difficulties associated with identifying and tracking the occurrences. The 1981 CAST report, Antibiotics in Animal Feeds, stated that, up to that point, there were only 4 instances (2 in Britain, 1 in Canada, and 1 in the United States) for which there was “evidence linking use of antibiotics in animal agriculture with diseases due to antibiotic-resistant bacteria in humans” (p. 2), and it attributed the incidents to therapeutic rather than subtherapeutic use of antibiotics. Since 1981, many more cases of zoonotic-resistance transfer have been reported. These are summarized in Chapter 3. However, even today we are faced with the challenge of documenting actual cases of resistance transfer from animals to humans in terms of pathogen and nonpathogen transfers. In large part, we do not know the sources or reservoirs for antibiotic-resistant bacteria or their potential to affect the incidence of human disease from antibiotic-resistant bacteria.

Information in the commissioned reviews supplementing the committee’s evaluation indicates that some interest is developing in the practice of rotating choices of antibiotics periodically or of using combinations of therapy (such as sulfa antibiotics and trimethoprim) to suppress the rate of the development of drug resistance. This practice might be better implemented if more rapid and extensive surveillance data were generated and used in control strategies.

Cross-resistance among classes of drugs with the same mechanism can have an effect on animal production practices. If one of the macrolide drugs, such as erythromycin, is used to treat a disease over a period, cross-resistance to others (such as tilmicosin or one of the lincosaminides) used in veterinary medicine might be expected to develop (Hickey and Nelson 1997; Levy 1998). Thus, in further treatment of diseases, antibiotics with common resistance patterns would not be the drugs of choice (Jungkind et al. 1997; Kucers et al. 1997).

For therapeutic use, antibiotic drugs should be avoided in instances in which no etiological agent has been isolated from a sick animal, because drug use might select for resistant strains among the resident gut flora. 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. 1975). Furthermore, Linton (1977) suggested that the continuous

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

use of antibiotics in pigs leads to the eventual stabilization of resistant organisms in the intestinal tract, and they could become the dominant form of microorganisms. Resistant bacteria can be found in gut flora of farm workers who have close and regular contact with food animals or with antibiotic-enriched feeds and through exposure to the fecally contaminated environment (Levy et al. 1986; Levy 1992). In addition, a given drug should be avoided when the causative organism is known (or is likely) to possess an inducible enzyme or other factor that inactivates the drug. For example, the cephalosporins should not be used to treat an infection caused by an organism that produces an inducible ß-lactamase. Cephalosporins also should be avoided in instances in which a first-generation cephalosporin or a penicillin would be effective. This practice would reduce the use of newer products and subsequently decrease the rate of development of antibiotic resistance to them.

In considering the appropriateness of precautions to lower health risks associated with drug use in animals, the effects of chemical residues must be separated from the biology of microorganisms. Setting appropriate drug withdrawal times is effective in decreasing drug residues and increasing the safety of drug use in food animals. However, withdrawal times are not intended to regulate any effect on residual bacterial populations that might have been affected by the use of the antibiotic. Hays and Black (1989) concluded that resistance of some animal intestinal bacterial flora to certain antibiotic drugs might not disappear from the animal before it is marketed, even though the drugs had not been used during most of the animal’s life span.

One recourse and alternative to deal with the problem of resistance is to develop more antibiotic drugs for food animals. The question is whether that strategy resolves the problem or perpetuates it, forcing continued perseverance in the search for new drug alternatives. Regardless of the incidence of drug resistance that arises from the use of antibiotics in food animals, the efficacy of the drugs has remained for disease eradication and growth promotion.

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. Humans can then transfer these drug-resistant pathogens to other humans or back to animals. Additionally, organisms that are neither pathogenic to animals nor to humans might acquire resistance. Human or animal exposure to these nonpathogenic organisms can result in transference of their resistance plasmids to pathogenic organisms. Because of the interrelationship between drug-resistant organ-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

isms that infect animals, humans, and the environment, any substantial interference in that cycle might contribute significantly to the overall problem of resistance.

Several reports have described antibiotic drug resistance in food-animal pathogens. Berghash et al. (1983) reported on a study of antibiotic resistance in nonlactating dairy cows that were treated for bovine mastitis. In that study, investigators evaluated the use of dry-cow treatment in 22 dairy herds in New York State. These herds were divided into two groups: one group (12 herds, 365 cows) had antibiotic infusions into the udder at the cessation of each lactation cycle (high-use rate); the other (9 herds, 324 cows) had no use of antibiotics during the nonlactating period (low-use rate). The investigators observed increased resistance to 13 antibiotics in Streptococcus agalactiae isolates from the high-use group. These 13 antibiotics were penicillin G, ampicillin, methicillin, cephalosporin C, cephalothin, tetracycline, streptomycin, kanamycin, gentamicin, erythromycin, lincomycin, novobiocin, and chloramphenicol. There was little difference between the two groups in the resistance patterns of the other bacterial species examined.

In another study, Blackburn et al. (1984) described the antibiotic resistance of Salmonella isolated from chickens (425 animals sampled), turkeys (749 sampled), cattle (1,307 sampled), and swine (974 sampled) in the United States from October 1981 through September 1982. The study was based on Salmonella isolate samples submitted to the National Veterinary Services Laboratory of the USDA Animal and Plant Health Inspection Service (APHIS) for serotyping. In all 3,500 isolates were tested for drug resistance and susceptibility. The drugs tested were ampicillin, chloramphenicol, carbenicillin, cephalothin, erythromycin, gentamicin, kanamycin, neomycin, penicillin G, streptomycin, triple sulfonamides, and tetracycline. High rates of drug resistance were observed. Three cultures were resistant to all the drugs, and 30 percent were resistant to each drug except chloramphenicol, cephalothin, and gentamicin. Multiple resistance was observed in 80 percent of the cultures. Higher percentages were observed in cultures from swine, and more isolates from chickens were resistant to more drugs than were isolates from other domestic animal species sources.

Cases have been documented in which plasmid-resistance patterns were used to epidemiologically trace the animal-to-human transfer of Salmonella via tainted hamburger. In a study by Spika et al. (1987), chloramphenicol-resistant Salmonella newport was traced through hamburger to dairy herds. This particular study was important because the specific strains of chloramphenicol-resistant Salmonella newport found in humans were the same strains that were traced back to the dairy farms. The drug resistance to chloramphenicol from those animal pathogens might have been transferred to humans in the zoonotic transfer of the bacteria from the animals to humans. Furthermore, they showed that the resistance resulted directly from illegal use of chloramphenicol on the farm at which the disease emerged. Chloramphenicol resistance was observed in Salmonella

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

newport in a study of California dairies by Pacer et al. (1989). Other animal-to-human transmissions are clearly documented and reproducible (Holmberg et al. 1984a). The interconnectivity of the animal and human ecosystems is clearly demonstrated by Lyons et al. (1980). A drug-resistant Salmonella heidelberg was identified and traced from ill veal calves to a farmer, his daughter, her infant, and companion infants in a hospital nursery.

Trimethoprim (TMP) is a synthetic antimicrobial adjunct that is used in human and veterinary medicine against a wide range of bacteria, including E. coli and other members of the family Enterobacteriaceae. The addition of this compound to a sulfonamide preparation such as sulfamethoxazole (SMX), increases the efficacy of the sulfa by imparting a sequential blockade of bacterial tetrahydrofolate synthesis. The combination is often referred to as a “potentiated sulfonamide.” This combination is thought to be a reliable bactericide and less likely to produce resistant organisms. However, studies by Hariharan et al. (1989) showed that E. coli in calves and pigs with diarrhea were resistant to this combination of drugs (Table 6–1). What is even more worrisome is the fact that the TMP–SMX resistance found in E. coli isolates was accompanied by resistance to 4 other commonly used drugs (Table 6–2). 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.

In an experimental study, Wray et al. (1990) showed the effects on physical performance and antibiotic sensitivity of gut flora caused by feeding to calves waste milk that contained differing concentrations of antibiotic (as a consequence of cows being treated for mastitis) or an antibiotic-free milk substitute. In the first trial of that study, one-third of the calves were fed waste milk that contained antibiotics, one-third were fed the same milk previously heated and fermented (penicillin concentrations ranged from 0 to 0.24 μg/ml; streptomycin concentra-

TABLE 6–1 E. colia Resistance to TMP–SMX

Distribution

Isolates Tested

Resistant Isolates (%)

Porcine

134

52 (39)

Bovine

86

40 (46)

Total

220

92 (42)

Porcine ETECb

88

32 (36)

Bovine ETEC

38

19 (50)

aIsolated from calves and pigs with diarrhea.

bETEC = Enterotoxigenic E. coli.

Source: Hariharan et al. 1989.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

TABLE 6–2 Resistance of TMP–SMX-Resistant E. coli Isolates to Other Antimicrobial Agents

 

Resistant Isolates (%)

Drug

Total (na = 92)

Porcine (n = 52)

Bovine (n = 40)

Tetracycline

98

96

100

Neomycin

80

71

92

Ampicillin

74

67

82

Nitrofurans

30

40

18

an = Number of tested isolates.

Source: Hariharan et al. 1989.

tions were from 0 to 3.8 μg/ml for unfermented and from 0 to 1.8 μg/ml for fermented milk), and one-third were fed a milk substitute that did not contain antibiotics. Fecal E. coli were monitored for antibiotic resistance. In the second trial 60 calves were divided into 2 groups, 1 group was fed antibiotic-free milk substitute and the other milk from antibiotic-treated cows (penicillin concentrations ranged from 0.01 to 700 μg/ml). The investigators found streptomycin resistance in calves that were fed antibiotic-contaminated milk, but no resistance developed in the control group. However, a complication in the interpretation of these data was the observation that the milk from treated cows already harbored populations of contaminating bacteria, such as E. coli, various Enterococci, and some Staphylococci, and the patterns of antibiotic resistance and susceptibility of these organisms as they existed in the waste milk were not characterized. Additional antibiotic resistance of E. coli strains isolated from calves with enteritis has been reported in many countries, including the United States, Canada, and France (Fairbrother et al. 1978; Coates and Hoopes 1980; Martel et al. 1981; Prescott and Baggot 1993; Prescott et al. 1984) and is summarized in Table 6–3.

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. Wray et al. (1993), summarized the emerging trends in England and Wales. Clear increases in bacterial resistance between 1981 and 1989 were evident for some bacteria and some antibiotics, especially ampicillin, chloramphenicol, apramycin and trimethoprim resistance in Salmonella typhimurium. (Table 6–4). The authors stated that more than 40 percent of Salmonella typhimurium cultures remained sensitive to all antibiotics tested, yet resistance was a rare event in Salmonella dublin and Salmonella enteriditis. In the S. typhimurium isolated from cattle, pigs, poultry and sheep, where increases in resistance were evident, the increases were appar-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

TABLE 6–3 Antimicrobial Resistance of E. coli Strains Isolated from Enteritis in Calves in the United States, Canada, and France

 

Percentage of Resistant Isolates

Antimicrobial Drug

United Statesa

Canadab

United Statesc

Franced

Cephalothin

20

27

e

Ampicillin

59

83

75

89

Chloramphenicol

13

79

22

88

Neomycin

71

79

87

Kanamycin

75

77

87

81

Gentamicin

0

1

3

0

Tetracycline

90

100

95

83

Nitrofurazone

6

4

15

40

Triple sulfa

94

95

87

86

TMP–SMX

40

3

aCoates and Hoopes 1980.

bPrescott et al. 1984.

cFairbrother et al. 1978.

dMartel et al. 1981.

eNot tested.

TABLE 6–4 Antibiotic Resistance in Salmonella from Animals, Percentage of Cultures Showing Resistance

 

 

Salmonella typhimurium

Salmonella enteritidisa

Antibiotic

Disk 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.

bND = not done.

Source: Wray et al. 1993.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

ent in all species (Table 6–5). Resistance to neomycin was the only instance in which decreases were evident. Data from the French experience in resistance surveillance monitoring (Martel and Coudert 1993) demonstrated that the age of the animal population was an important determinant in assessing the emergence of resistance characteristics in animal populations. Resistance emergence in young calves exceeded that of adult animals principally because calf populations are greater recipients of antibiotics because they are more susceptible to bacterial disease than are adult animals. Further summarized by Espinasse (1993), 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. However, there are pitfalls that must be avoided or at least accounted for: “The interpretation of data on resistance of bacteria towards antimicrobial drugs is difficult, since both methods applied and interpretation, influence the result.” (Wiedmann 1993). For example, care must be exercised in comparing epidemiological data between different countries because the “definition” of resistance varies from country to country as determined by MIC or microbiological break-point analysis. The definition of ampicillin resistance in E. coli is <2, <4, <8, and <16 mg/ml for Sweden, Germany, the Netherlands, and the United States, respectively (Wiedemann 1993). Functionally, that translates into the observation that only 2 percent of isolated E. coli strains are sensitive in Sweden whereas 78 percent of the same strains are called sensitive in the United States. Endtz et al. (1991) reported drug resistance in Campylobacter caused by fluoroquinolone use in food animals. Again, the reporting of this emergence of resistance is a function of how the definition of resistance is interpreted and, thus, factors into the human health risk associated with the use of antibiotics in food animals.

CASES TO TEST THE SYSTEM

The future of antibiotic development and use is less than clear. Regulatory issues regarding approval of antibiotics for humans and animals have become more complicated than in the past, largely because of the tremendous capacity for bacteria to adapt to antibiotics and to become more difficult to control. Insight into the complexity of this issue is readily obtained by reviewing the concerns associated with the use of members of the fluoroquinolone class of antibiotics.

Approximately 30 years after the issues that brought attention to the applications and uses of penicillins and tetracyclines in food animals, the controversy has expanded to newer antibiotics. Additional concern for the role of antibiotic use in food animals evolved from the detection of avoparcin (glycopeptide, vancomycin-like) resistant bacteria in manure and in some food products derived from

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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)

55

24

52

43

75

34

75

58

Chloramphenicol (10)

14

<1

24

3

54

2

4

16

Ampicillin (10)

13

2

26

a

67

5

24

42

Neomycin (10)

14

1

26

2

<1

4

Trimethoprim (25)

16

1

37

29

58

8

34

27

Furazolidone (15)

2

<1

2

<1

2

8

Apramycin (15)

9

<1

3

2

Number of cultures

1146

236

46

35

809

905

115

45

aNot tested.

Source: Wray et al. 1993.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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-

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
×

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.

Suggested Citation:"6 Issues Specific to Antibiotics." National Research Council. 1999. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: The National Academies Press. doi: 10.17226/5137.
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The Use of Drugs in Food Animals: Benefits and Risks Get This Book
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The use of drugs in food animal production has resulted in benefits throughout the food industry; however, their use has also raised public health safety concerns.

The Use of Drugs in Food Animals provides an overview of why and how drugs are used in the major food-producing animal industries--poultry, dairy, beef, swine, and aquaculture. The volume discusses the prevalence of human pathogens in foods of animal origin. It also addresses the transfer of resistance in animal microbes to human pathogens and the resulting risk of human disease.

The committee offers analysis and insight into these areas

  • Monitoring of drug residues. The book provides a brief overview of how the FDA and USDA monitor drug residues in foods of animal origin and describes quality assurance programs initiated by the poultry, dairy, beef, and swine industries.
  • Antibiotic resistance. The committee reports what is known about this controversial problem and its potential effect on human health.

The volume also looks at how drug use may be minimized with new approaches in genetics, nutrition, and animal management. November

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