2010, Vol. 5 No. 1, Article 48

Drug Resistance in Food Animals - A Public Health Concern

Rajdeep Kaur* and Rajneesh Pathania

Department of Pharmacology & Toxicology,
College of Veterinary Science,
Guru Angad Dev Veterinary and animal Sciences University,
Ludhiana-141004

*Corresponding Author; e-mail address: [email protected]

ABSTRACT

The wide spread use of antibiotics to combat infections and promote growth in live stock and poultry has resulted into emergence of resistant bacterial strains. Product characteristics, dose, treatment interval and duration of treatment influence the selection pressure for antimicrobial drug resistance. The prevalence and persistence of antimicrobial resistance is the result of a complex interaction between antimicrobials, microorganisms, the host and the environment. Antimicrobial resistance in veterinary medicine could form a potential public health hazard. Indeed, the commensal gastro-intestinal flora of healthy animals harbors a reservoir of resistance genes that can colonize the flora of humans through the food chain or by direct contact. If the underlying resistance gene is horizontally transferred into human pathogenic bacteria, this can lead to therapeutic failure as a consequence of antimicrobial resistance.

KEY WORDS

Antimicrobial, resistance, animals, public health.

INTRODUCTION

The indiscriminate use of antimicrobial drugs in food animals may result in transfer of resistance to human, it is unlikely that the so called reverse-antimicrobial drug will be restricted to use in human medicine (Schwartz and Chaslus Dancla, 2001), antimicrobial resistance and especially the multiple resistances of Staphylococcus aureus, Pneumococci, Enterococci and Enterobacteriaceae isolated both from nosocomial and non-hospital-related infections have been found to cause therapy failure and higher morbidity and mortality rates (Acar, 1997). Major economic losses and problems in controlling animal diseases could be encountered as well if antimicrobial resistance evolves towards a comparable critical level in veterinary field. Vaccination, immuno-modulation and pre and probiotics need to be considered as alternatives for combating bacterial infection as far as possible, although they are unlikely to replace antimicrobial drugs totally (Schwarzt et al, 2001).

EPIDEMIOLOGY OF ANTIMICROBIAL RESISTANCE

The prevalence and persistence of antimicrobial resistance is the result of a complex interaction between antimicrobials, microorganisms, the host and the environment (Dowling, 1996). Pathogenic organisms are clearly the target population of antimicrobial drugs, on which, by consequence a selection pressure can be exerted. antimicrobial drugs also exert pressure on commensal bacteria present on the skin, in the upper respiratory tract and especially in the digestive system (Sorum and Sunde, 2001) (Bagbosa and Levy, 2000). Within the digestive system, the largest reservoir of bacteria is the intestinal tract, consequently, majority of studies on antimicrobial resistance target the fecal bacteria like Escherichia coli and Enterocoli because of their high prevalence in feaces of healthy animals and ability to harbor several resistance determinants (Witte, 2000).

ANTIMICROBIAL DRUG RELATED FACTORS

Bacterial population is the sum of different sub populations, whose growth is inhibited by different antimicrobial drug concentrations. A rise in antimicrobial drug concentrations will increase the proportion of bacteria that are killed or inhibited in growth in a given population (Baquero et al, 1998). Above a certain concentration, known as the mutant prevention concentration (MPC), all bacteria will be killed or inhibited in growth (Drlica, 2001). When the antimicrobial drug concentration declines, the growth of more resistant subpopulation will no longer be inhibited, while this concentration is still effective for the susceptible sub population. Once the concentration drops under the critical level which is called selective concentration (SC), even the susceptible sub population will not be inhibited and selection pressure will no longer be exerted on any element of the population. Thus, a resistant sub population will be selected between SC and MPC, as demonstrated in vitro by concentration gradient studies on a variety of antimicrobial drug combinations (Dong et al, 1999).
To address the relationship between the antimicrobial resistance and the type of the drug, emphasis has been given to the distinction between time-dependent (concentration-independent) and concentration-dependent killing agents. For time dependent agents (penicillin, cephalosporin’s and macrolides) increasing the period of time above the MIC at the site of infection for a minimum of 40-60% of the dosing interval is the key parameter for clinical efficacy (Craig, 1998) and should help to prevent the emergence of resistance (Hyatt et al, 1995).
The effectiveness of pharmacokinetic/pharmacodynamic parameters as predictors for the development of antimicrobial resistance is more clearly established in concentration dependent agents (fluoroquinolones and aminoglycosides with emphasis on fluoroquinolones, both in man (Thomas et al, 1998) and animal studies (Lees and Shojaee, 1998). In concentration-dependent agents, the primary determinant of clinical efficacy is the amount of drug at the site of infection and not the frequency of dosing. Higher concentrations of a concentration dependent antimicrobial drug kill the pathogen more quickly. The two surrogate markers AUC/MIC and C_Max/MIC indicate the clinical success of the drug if their values are more than 100 and 10, respectively.
Finally, a product affects the bacterial population according to its spectrum of activity. Broad spectrum antimicrobial drugs considerably influence the fecal flora of animals (Berends et al, 2001). As a well balanced microflora prevents the establishment of resistant microbial strains, thus the use of broad spectrum antimicrobial drugs is considered a risk factor for the emergence of antimicrobial resistance (Bagbosa and Levy, 2000). In a neonatal intensive care unit the risk of intestinal colonization with resistant bacteria was calculated to be 18 times higher for broad spectrum antimicrobial drugs than for narrow spectrum products (de Man et al, 2000). Broad spectrum agents nevertheless remain the recommended initial therapy for many diseases in veterinary medicine, while waiting for the identification susceptibility profile of the pathogen involved (Schwarz et al, 2001).
Microbial Population: A resistant sub population remains prominent even in the absence of antimicrobial drug if they obtain a selective growth advantage compared with the original susceptible population (Gillespi, 2001).
The commensal flora offers protection against a potential overgrowth of pathogens such as Salmonella species. The concept of this sheltered commensal is called colonization resistance (Heimdahl and Nord, 1983).
Host: A former exposure (upto 5-6 months) to an antimicrobial drug is recognized as a risk factor for antimicrobial resistance in pathogen, at the level of individual agent. Similarly the number of animals treated is directly related to the amount of antimicrobial drugs used. Within an animal species, age is a vital factor that influences the prevalence of antimicrobial resistance. Fecal coliforms in young ones exhibit a higher prevalence of antimicrobial resistance than in adults of man/animals (Berge et al, 2003).
In general, a different localization of a bacterial species within the host is correlated with a different prevalence of antimicrobial resistance. It has been found that the population of a resistant organism in a given organ system depends on the extent to which the system is able to harbor a large commensal flora. For instance, pathogenic strains from respiratory tract in cattle have an overall high degree of acquired resistance compared with the pathogen from the udder, although local antimicrobial therapy in udder is a common practice (Dragon et al, 2001). Impaired immunity is considered a casual risk factor for antimicrobial resistance in human medicine. In swine, housing conditions influence the prevalence of resistant fecal coliforms. A higher level of resistant coli form was found in finishing unit pigs than in pigs in the farrowing house or on the pasture (Langlois et al, 1988)
Environment: A pronounced prevalence of resistant coliforms in wild animals, pets and livestock never treated with antimicrobial drugs, indicates the existence of an intensive exchange of resistant strains or determinants between different ecological niches. Horizontal transfer of resistant gene between different bacterial species is known to occur in a natural environment. A strict hygiene is an absolute necessity for contending with antimicrobial resistance in hospital settings. Seasonal changes can exert an additional influence on certain microbial populations, for example the influence of extreme fluctuation in temperature on the shedding of resistant coliforms in swine (Moro et al, 2000).

CURRENT NEW ANIMAL DRUG APPROVAL PROCESS

The Food and Drug Administration (FDA) is empowered with the regulatory responsibility of ensuring that the use of antimicrobial drugs in food- animals does not result in adverse health consequences in humans. Before any animal drug may be legally marketed in the United States, the drug sponsor must have a New Animal Drug Application (NADA) approved by the FDA. To obtain NADA approval, the drug's sponsor must demonstrate that the drug is effective and safe for the animals and the environment and can be manufactured to uniform standards of purity, strength and identity. If the animal drug product is intended for use in food- animals, the drug's sponsor must also demonstrate that edible products derived from treated animals are safe for consumers (Friedlander et al, 1999). Accordingly, for antimicrobial compounds, there are two major concerns that must be addressed: (1) the human food safety of veterinary drug residues and (2) the potential for encouraging the emergence of resistant bacteria of human health concern.

HUMAN SAFETY OF VETERINARY DRUG RESIDUES

To determine residual effect of an antimicrobial product, the drug sponsor conducts a standard battery of toxicological tests. This battery includes studies that examine the effect of the product on systemic toxicity, genotoxicity/mutagenicity, and reproductive and developmental toxicity. The toxicological studies are designed to identify a dose that causes a toxic effect and a dose that causes no observed effect. Once the no-observed-effect level is established for all the toxicity end points, sponsors must identify the most sensitive effect in the species, deemed to be the most predictive effect in humans. This no-observed-effect level is divided by a safety factor (both to account for uncertainty in extrapolating from animals to humans and to adjust for potential inter-individual variability) to calculate an acceptable daily intake (ADI) of drug residues. The ADI represents the amount of drug residues that can be safely consumed daily for as long as a lifetime. Once the ADI is established, the drug's sponsor conducts drug metabolism and depletion studies. The tissue in which the drug depletes the slowest is established as the target tissue and the amount of drug that can be measured with a regulatory method is established as the tolerance. When the drug residue in the target tissue depletes below the tolerance, all edible tissues are considered safe for human consumption. There are special food safety concerns for the residues of antimicrobial drugs. It is known that the therapeutic doses of these agents can cause adverse effects on the human intestinal microflora. Therefore, the agency has determined that issues of public health concern include the impact of drug residues in food on the selection of resistant bacteria, perturbation of the barrier effect within the human intestine, changes in intestinal enzymatic activity and alteration in intestinal bacterial counts. A disturbance in the barrier effect is of great concern because the gut microflora provides a barrier against the overgrowth and invasion of pathogenic bacteria. When an anti-infective agent destroys this barrier, overgrowth of pathogenic bacteria may occur.

HUMAN FOOD SAFETY OF DRUG-RESISTANT PATHOGENS

As per the guide lines of FDA (1999) it is mandatory to consider the potential human health impact of the antimicrobial effects associated with uses of all classes of new antimicrobial drugs that are intended for use in food-producing animals.
Minimizing the emergence of antimicrobial-resistant bacteria in animals and their subsequent spread to humans through the food supply is a complex problem requiring a coordinated, multifaceted approach. Unfortunately, unlike the clearly defined mechanism for ascertaining the toxicological safety of drug residues in food, no such predictive models currently exist to precisely estimate the rate and extent of bacterial resistance that may emerge from the use of antimicrobial drugs in food-producing animals. Despite the current lack of such models, certain information can be generated to support a pre-approval antimicrobial resistance safety assessment.
The relationship of the use of antimicrobial drugs in food-producing animals and the emergence of resistant bacteria in the food chain has been the subject of numerous national and international consultations. The prevention and control of antimicrobial resistance in human and veterinary medicine requires a concerted effort by all stakeholders, including regulatory agencies, the veterinary pharmaceutical industry, veterinarians, and livestock producers.

PUBLIC HEALTH CONCERN

Antimicrobial resistance in veterinary medicine could form a potential public health hazard. Indeed, the commensal gastro-intestinal flora of healthy animals harbors a reservoir of resistance genes that can colonize the flora of humans through the food chain or by direct contact. If the underlying resistance gene is horizontally transferred into human pathogenic bacteria, this can lead to therapeutic failure as a consequence of antimicrobial resistance. Nevertheless, the impact of the veterinary use of antimicrobial drugs on resistance problems in human medicine needs to be put into perspective. Veterinary medicine is responsible with certainty for the resistance problems in zoonotic pathogens such as and some Enteroccoci.
From the above discussion, it is quite clear that, antimicrobial resistance is a major problem in veterinary field leading to rise of related problems in human medicine, such as the appearance of multi-resistant food-borne pathogens. If the prevalence of resistance in the commensal faecal flora of livestock to a certain antimicrobial drug increases rapidly, the antimicrobial agent in question can be banned from use. It’s the need of current era to think about alternate option of antimicrobials and to optimize the use of antimicrobials. Certainly, the veterinary profession will be required to change the current practices. There are some encouraging signs that this change is occurring at least in developed countries. Fish farming is using new techniques such as immunization instead of antimicrobials. There is also a dire need to keep a sharp eye on the development of resistance in animals and to tap alternatives of antimicrobial therapy.

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