Ole Eske Heuer

Human Health Consequences of Use of Antimicrobial Agents in Aquaculture

Intensive use of antimicrobial agents in aquaculture provides a selective pressure creating reservoirs of drug-resistant bacteria and transferable resistance genes in fish pathogens and other bacteria in the aquatic environment. From these reservoirs, resistance genes may disseminate by horizontal gene transfer and reach human pathogens, or drug-resistant pathogens from the aquatic environment may reach humans directly. Horizontal gene transfer may occur in the aquaculture environment, in the food chain, or in the human intestinal tract. Among the antimicrobial agents commonly used in aquaculture, several are classified by the World Health Organisation as critically important for use in humans. Occurrence of resistance to these antimicrobial agents in human pathogens severely limits the therapeutic options in human infections. Considering the rapid growth and importance of aquaculture industry in many regions of the world and the widespread, intensive, and often unregulated use of antimicrobial agents in this area of animal production, efforts are needed to prevent development and spread of antimicrobial resistance in aquaculture to reduce the risk to human health.

Human health hazards from antimicrobial-resistant Escherichia coli of animal origin.

Because of the intensive use of antimicrobial agents in food animal production, meat is frequently contaminated with antimicrobial-resistant Escherichia coli. Humans can be colonized with E. coli of animal origin, and because of resistance to commonly used antimicrobial agents, these bacteria may cause infections for which limited therapeutic options are available. This may lead to treatment failure and can have serious consequences for the patient. Furthermore, E. coli of animal origin may act as a donor of antimicrobial resistance genes for other pathogenic E. coli. Thus, the intensive use of antimicrobial agents in food animals may add to the burden of antimicrobial resistance in humans. Bacteria from the animal reservoir that carry resistance to antimicrobial agents that are regarded as highly or critically important in human therapy (e.g., aminoglycosides, fluoroquinolones, and third- and fourth-generation cephalosporins) are of especially great concern.

Danish Integrated Antimicrobial Resistance Monitoring and Research Program

This program has led to changes in the use of antimicrobial agents in Denmark and other countries.

Human Health Hazard from Antimicrobial-Resistant Enterococci in Animals and Food

The use of antimicrobial agents in the modern farm industry has created a reservoir of resistant bacteria in food animals. Foods of animal origin are often contaminated with enterococci that are likely to contribute resistance genes, virulence factors, or other properties to enterococci IN humans. The potential hazard to human health from antimicrobial-resistant enterococci in animals is questioned by some scientists because of evidence of host specificity of enterococci. Similarly, the occurrences of specific nosocomial clones of enterococci in hospitals have lead to the misconception that antimicrobial-resistant animal enterococci should be disregarded as a human health hazard. On the basis of review of the literature, we find that neither the results provided by molecular typing that classify enterococci as host-specific organisms nor the occurrence of specific nosocomial clones of enterococci provide reasons to change the current view that antimicrobial-resistant enterococci from animals pose a threat to human health. On the contrary, antimicrobial resistance genes appear to spread freely between enterococci from different reservoirs, irrespective of their apparent host association.

The effect of discontinuing the use of antimicrobial growth promoters on the productivity in the Danish broiler production

On 15 February 1998, the Danish poultry industry voluntarily decided to discontinue the use of all antimicrobial growth promoters (AGPs). To investigate how the removal of AGPs influenced the broiler productivity in Denmark, data from 6815 flocks collected from November 1995 to July 1999 by the Danish Poultry Council were analysed. The three flock parameters were: kilogram broilers produced per square meter (per rotation), feed-conversion ratio (total kilogram feed used per rotation/total kilogram live weight per rotation) and total percent dead broilers ((number of dead broilers during the rotation/number of broilers put in the house per rotation)x100). Data were analysed using a mixed model, allowing the correlation structures in the data to be taken into account. The analyses showed that kilogram broilers produced per square meter and percent dead broilers in total were not affected by the discontinued use of AGPs. However, the feed-conversion ratio increased marginally 0.016 kg/kg and has remained at this level throughout the rest of the study period.

Antimicrobial-Resistant Enterococci in Animals and Meat: A Human Health Hazard?

Enterococcus faecium and Enterococcus faecalis belong to the gastrointestinal flora of humans and animals. Although normally regarded harmless commensals, enterococci may cause a range of different infections in humans, including urinary tract infections, sepsis, and endocarditis. The use of avoparcin, gentamicin, and virginiamycin for growth promotion and therapy in food animals has lead to the emergence of vancomycin- and gentamicin-resistant enterococci and quinupristin/dalfopristin-resistant E. faecium in animals and meat. This implies a potential risk for transfer of resistance genes or resistant bacteria from food animals to humans. The genes encoding resistance to vancomycin, gentamicin, and quinupristin/dalfopristin have been found in E. faecium of human and animal origin; meanwhile, certain clones of E. faecium are found more frequently in samples from human patients, while other clones predominate in certain animal species. This may suggest that antimicrobial-resistant E. faecium from animals could be regarded less hazardous to humans; however, due to their excellent ability to acquire and transfer resistance genes, E. faecium of animal origin may act as donors of antimicrobial resistance genes for other more virulent enterococci. For E. faecalis, the situation appears different, as similar clones of, for example, vancomycin- and gentamicin-resistant E. faecalis have been obtained from animals and from human patients. Continuous surveillance of antimicrobial resistance in enterococci from humans and animals is essential to follow trends and detect emerging resistance.

Persistence of vancomycin-resistant enterococci (VRE) in broiler houses after the avoparcin ban

The glycopeptide growth promoter avoparcin was banned from animal production in the EU in 1997 due to concern for the spread of vancomycin-resistant enterococci (VRE) from food animals to humans. In recent Norwegian and Danish studies, extensive occurrence of VRE on broiler farms and in broiler flocks after the avoparcin ban has been reported. The present study was undertaken to investigate the epidemiology of VRE on broiler farms in the absence of the selective pressure exerted by avoparcin. Environmental samples were obtained from five broiler houses after depopulation, cleaning, and disinfection of the houses between rotations, and two consecutive broiler flocks from each house were sampled by taking cloacal swabs from the broilers at the time of slaughter. A total of 69 vancomycin-resistant Enterococcus faecium isolates obtained from broiler flocks and broiler houses were subjected to molecular typing by pulsed-field gel electrophoresis (PFGE). Forty-one PFGE-profiles were observed. VRE with indistinguishable or highly similar PFGE profiles were isolated from consecutive broiler flocks and from environmental samples from the houses in which the flocks were reared, whereas VRE-isolates from different broiler houses and from flocks reared in different houses appeared to be genetically unrelated. These findings indicated that VRE was transmitted between consecutive broiler flocks by clones of resistant bacteria surviving in the broiler houses despite cleaning and disinfection between rotations. Thus, the extensive occurrence of VRE in broiler flocks after the avoparcin ban may be explained by persistence of VRE in the broiler house environment.

Vancomycin-resistant enterococci (VRE) in broiler flocks 5 years after the avoparcin ban.

The glycopeptide growth promoter avoparcin was banned from animal production in Denmark in 1995. In this study, we investigated the occurrence of vancomycin-resistant enterococci (VRE) in broiler flocks in the absence of the selective pressure exerted by the use of avoparcin. One hundred sixty-two broiler flocks from rearing systems with different histories of avoparcin exposure were investigated for the presence of VRE. Using a direct selective plating procedure, VRE were isolated from 104 of 140 (74.3%) broiler flocks reared in broiler houses previously exposed to avoparcin on conventional and extensive indoor broiler farms. In contrast, only 2 of 22 (9.1%) organic broiler flocks reared on free-range farms with no history of previous exposure to avoparcin were VRE-positive. Furthermore, the occurrence of VRE over time in flocks reared in broiler houses previously exposed to avoparcin was investigated. Results obtained by direct selective plating showed no significant decrease in the proportion of VRE-positive flocks during the study period (1998-2001). This study demonstrated the extensive occurrence of VRE in broiler flocks more than 5 years after the avoparcin ban in Denmark, and indicates that VRE may persist in the absence of the selective pressure exerted by avoparcin. The results differ markedly from previously published Danish surveillance data on VRE in broilers. This may reflect differences in isolation procedures.

Reproducible Infection Model for Clostridium perfringens in Broiler Chickens

Abstract Experiments were carried out to establish an infection and disease model for Clostridium perfringens in broiler chickens. Previous experiments had failed to induce disease and only a transient colonization with challenge strains had been obtained. In the present study, two series of experiments were conducted, each involving four groups of chickens with each group kept in separate isolators. A coccidial vaccine given at 10 times the prescribed dosage was used to promote the development of necrotic enteritis. In the first experiment, cultures of C. perfringens were mixed with the feed at day 9, 10, 11, and 12, and the coccidial vaccine was given at day 10, whereas in the second experiment, C. perfringens cultures were mixed with the feed at day 17, 18, 19, and 20, and the coccidial vaccine was given at day 18. Chickens were examined at day 9, 11, 12, and 15 (Experiment 1), and at day 17, 18, 20, and 24 (Experiment 2). There was no mortality in any of the groups; however, chickens in the groups receiving both coccidial vaccine and C. perfringens developed the subclinical form of necrotic enteritis, demonstrated by focal necroses in the small intestine, whereas chickens in control groups or groups receiving only coccidial vaccine or only C. perfringens cultures developed no necroses. The results underline the importance of predisposing factors in the development of necrotic enteritis.

Antimicrobial drug consumption in companion animals.

To the Editor: During the last decade, use of antimicrobial drugs for growth promotion and therapeutic treatment in food animals has received much attention. The reservoir of resistant bacteria in food animals implies a potential risk for transfer of resistant bacteria, or resistance genes, from food animals to humans. Subsequent emergence of infections in humans, caused by resistant bacteria originating from the animal reservoir, is of great concern. These unintended consequences of antimicrobial drug use in animals led to termination of antimicrobial growth promoters in food animals in countries in the European Union, including Denmark, where the consumption of antimicrobial drugs by production animals was reduced by 50% from 1994 to 2003 (1). In Denmark, the VetStat program monitors all veterinary use of medicines for animals. VetStat is based on reporting from the pharmacies and from veterinary practitioners and contains detailed information, such as animal species, reason for prescription, and dosage on each prescription. In Denmark, antimicrobial drugs can be obtained only by prescription and only at pharmacies. So far, use of antimicrobial drugs in companion animals has received little attention; monitoring programs have focused on antimicrobial drug consumption in food animals. According to data generated by the VetStat program in 2003, consumption of fluoroquinolones and cephalosporins in companion animals was substantial when compared to consumption in food animals (1). Fluoroquinolones and cephalosporins are antimicrobial drugs ranked by the U.S. Food and Drug Administration as critically important in human medicine, and for which emergence of resistant bacteria is especially undesirable (2). Considering the shared environment of humans and companion animals, transfer of resistant bacteria or mobile resistance determinants from companion animals to humans would be possible, and emergence of resistance to fluoroquinolones and cephalosporins in companion animals should be a matter of concern. Several scientific publications have reported the occurrence of the same resistance genes in companion animals and in humans (3–6) and the possible transfer of bacteria between companion animals and humans (3–9). Companion animal owners and their families are likely in close contact with their animals daily, which provides the opportunity for transfer of bacteria between companion animals and humans. A large proportion of the human population presumably has daily contact with companion animals, not only in Denmark but also in other countries. In Denmark, 20% of families own dogs and 16% own cats (10). In 2002, legal restrictions aimed to reduce the usage of fluoroquinolones in food animals were imposed in Denmark. The total annual consumption of fluoroquinolones in animals (companion and food animals) in Denmark was reduced from 183 kg in 2001 to 53 kg in 2003 (1). Of these 53 kg of fluoroquinolones, almost half (24 kg) was used in companion animals (data based on reporting on use in veterinary practice and sales from pharmacies on prescription). These data document that fluoroquinolones remain widely used for infections in companion animals, even though the emergence of fluoroquinolone resistance in bacteria is especially undesirable and regarded as a human health hazard. A similar situation exists with cephalosporins. The total consumption of cephalosporins in animals (companion and food animals) in Denmark in 2003 was 461 kg, of which more than half (254 kg) was consumed by companion animals (1). Thus, a comparatively small number of companion animals (550,000 dogs and 650,000 cats) (10) consume approximately the same amount of fluoroquinolones and cephalosporins as consumed annually in the much larger population of food animals in Denmark (23 million slaughter pigs, 130 million broiler chickens, and 1.2 million cattle and dairy cows) (10). We do not believe that antimicrobial drugs are more generously prescribed for companion animals in Denmark than in other industrialized countries. Rather, the data presented here reflect the apparent contrast between policies of antimicrobial drug use for food animals and policies for companion animals. The use of these antimicrobial drugs is avoided or restricted in food animals to minimize spread of resistance, while in companion animals prescription continues unimpeded. This situation may create undesirable antimicrobial drug resistance in bacteria, which may subsequently spread to humans from the previously neglected reservoir in companion animals.