Antimicrobials are valuable therapeutics whose efficacy is seriously compromised by the emergence and spread of antimicrobial resistance. The provision of antibiotics to food animals encompasses a wide variety of nontherapeutic purposes that include growth promotion. The concern over resistance emergence and spread to people by nontherapeutic use of antimicrobials has led to conflicted practices and opinions. Considerable evidence supported the removal of nontherapeutic antimicrobials (NTAs) in Europe, based on the "precautionary principle." Still, concrete scientific evidence of the favorable versus unfavorable consequences of NTAs is not clear to all stakeholders. Substantial data show elevated antibiotic resistance in bacteria associated with animals fed NTAs and their food products. This resistance spreads to other animals and humans-directly by contact and indirectly via the food chain, water, air, and manured and sludge-fertilized soils. Modern genetic techniques are making advances in deciphering the ecological impact of NTAs, but modeling efforts are thwarted by deficits in key knowledge of microbial and antibiotic loads at each stage of the transmission chain. Still, the substantial and expanding volume of evidence reporting animal-to-human spread of resistant bacteria, including that arising from use of NTAs, supports eliminating NTA use in order to reduce the growing environmental load of resistance genes.

Food Animals and Antimicrobials: Impacts on Human Health

Environmental pollution by antibiotics and by antibiotic resistance determinants

Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.

Antibiotics and Bacterial Resistance in the 21st Century

The use of antibiotics in food animals selects for bacteria resistant to antibiotics used in humans, and these might spread via the food to humans and cause human infection, hence the banning of growth-promoters. The actual danger seems small, and there might be disadvantages to human and to animal health. The low dosages used for growth promotion are an unquantified hazard. Although some antibiotics are used both in animals and humans, most of the resistance problem in humans has arisen from human use. Resistance can be selected in food animals, and resistant bacteria can contaminate animal-derived food, but adequate cooking destroys them. How often they colonize the human gut, and transfer resistance genes is not known. In zoonotic salmonellosis, resistance may arise in animals or humans, but human cross-infection is common. The case of campylobacter infection is less clear. The normal human faecal flora can contain resistant enterococci, but indistinguishable strains in animals and man are uncommon, possibly because most animal enterococci do not establish themselves in the human intestine. There is no correlation between the carriage of resistant enterococci of possible animal origin and human infection with resistant strains. Commensal Escherichia coli also exhibits host-animal preferences. Anti-Gram-positive growth promoters would be expected to have little effect on most Gram-negative organisms. Even if resistant pathogens do reach man, the clinical consequences of resistance may be small. The application of the 'precautionary principle' is a non-scientific approach that assumes that risk assessments will be carried out.

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Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data

Due to the increased demand of animal protein in developing countries, intensive farming is instigated, which results in antibiotic residues in animal-derived products, and eventually, antibiotic resistance. Antibiotic resistance is of great public health concern because the antibiotic-resistant bacteria associated with the animals may be pathogenic to humans, easily transmitted to humans via food chains, and widely disseminated in the environment via animal wastes. These may cause complicated, untreatable, and prolonged infections in humans, leading to higher healthcare cost and sometimes death. In the said countries, antibiotic resistance is so complex and difficult, due to irrational use of antibiotics both in the clinical and agriculture settings, low socioeconomic status, poor sanitation and hygienic status, as well as that zoonotic bacterial pathogens are not regularly cultured, and their resistance to commonly used antibiotics are scarcely investigated (poor surveillance systems). The challenges that follow are of local, national, regional, and international dimensions, as there are no geographic boundaries to impede the spread of antibiotic resistance. In addition, the information assembled in this study through a thorough review of published findings, emphasized the presence of antibiotics in animal-derived products and the phenomenon of multidrug resistance in environmental samples. This therefore calls for strengthening of regulations that direct antibiotic manufacture, distribution, dispensing, and prescription, hence fostering antibiotic stewardship. Joint collaboration across the world with international bodies is needed to assist the developing countries to implement good surveillance of antibiotic use and antibiotic resistance.

Antibiotic Use in Agriculture and Its Consequential Resistance in Environmental Sources: Potential Public Health Implications

The prevalence of resistance in enterococci to antibiotics, commonly used for therapy in poultry or as antimicrobial growth promoters (AMGPs), was determined in faecal samples of two chicken populations: broilers in which antibiotic and AMGP use is common and laying-hens with a low antibiotic usage. In addition faecal samples were examined from three human populations: broiler farmers, laying-hen farmers and poultry slaughterers. MICs of an extended panel of antibiotics for a randomly chosen gentamicin- or vancomycin-resistant enterococcal isolate from each faecal specimen were also determined. The prevalence of resistance for all antibiotics tested was higher in broilers than in laying-hens. Resistance in faecal enterococci of broiler farmers was for nearly all antibiotics higher than those observed in laying-hen farmers and poultry slaughterers. The overall resistance in broilers was correlated with the resistance in broiler farmers and in poultry slaughterers. No correlation between the results obtained in the laying-hens with any of the other populations was found. The 27 gentamicin-resistant isolates all showed high-level resistance to gentamicin and two of these isolates, both Enterococcus faecium, were resistant to all antibiotics tested, except vancomycin. The 73 vancomycin-resistant enterococci (VRE) isolated from the five populations belonged to four different species and in all isolates the vanA gene cluster was detected by blot hybridization. The pulsed-field gel electrophoresis (PFGE) patterns of these vancomycin-resistant enterococci were quite heterogeneous, but Enterococcus hirae isolates with the same or a closely related PFGE pattern were isolated at two farms from the broiler farmer and from broilers. Molecular characterization of vanA-containing transposons of these isolates showed that similar transposon types, predominantly found in poultry, were present. Moreover, similar vanA elements were not only found in isolates with the same PFGE pattern but also in other VRE isolated from both humans and chickens. The results of this study suggest transmission of resistance in enterococci from animals to man. For VRE this might be clonal transmission of animal strains, but transposon transfer seems to occur more commonly.

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Antibiotic resistance of faecal Escherichia coli in poultry, poultry farmers and poultry slaughterers

Faecal samples from 180 patients on admission and 108 patients at discharge were analysed for the prevalence and degree of resistance of Escherichia coli and enterococci. Discharged patients had received 24 h cefazolin prophylaxis and had a mean hospital stay of 10 +/- 5 days. The prevalence of resistance of E. coli to amoxicillin (P 7 days) hospitalization, being significant for amoxicillin only (P < 0.05). No significant changes were observed for the enterococci.

C.A.G.G. Driessen

Papers

Antibiotic resistance of faecal Escherichia coli in poultry, poultry farmers and poultry slaughterers

Influence of cefazolin prophylaxis and hospitalization on the prevalence of antibiotic-resistant bacteria in the faecal flora