Antimicrobial Trends and Risks

Antimicrobial drugs, a term that includes all agents that act against bacteria, viruses, fungi, and parasites, are used to prevent, control or treat disease. But they can also be used prophylactically to promote growth and enhance performance of food animals. Arguments in favor of prophylactic application (usually through animal feed or water supply) of antimicrobials at low doses are that they help maintain gut health by suppressing the bacteria that cause subclinical disease. 

Antimicrobial drugs, a term that includes all agents that act against bacteria, viruses, fungi, and parasites, are used to prevent, control or treat disease. But they can also be used prophylactically to promote growth and enhance performance of food animals. Arguments in favor of prophylactic application (usually through animal feed or water supply) of antimicrobials at low doses are that they help maintain gut health by suppressing the bacteria that cause subclinical disease. Such treatment allows nutrients to be better utilized, which means the animal more rapidly reaches its optimal production level. Prophylactic use of antibiotics has led to intensive debate about the increased risk of antibiotic resistance, which, of course, reduces a drug’s ability to fend off diseases in both animals and humans.

A well-known example of a bacterium that has acquired resistance to multiple antibiotics is Meticillin-resistant Staphylococcus aureus (MRSA), which has also adapted to colonizing livestock from where it can potentially spread to humans. Another example is Campylobacter resistance to fluoroquinolone in broiler chickens, which is a particular concern because of the importance of this class of antimicrobials in both human and veterinary medicine. Prophylactic treatment contributes to the contamination of flocks and food products by antibiotic resistant pathogens, such as Escherichia coli, Salmonella spp., Campylobacter spp. and enterococci that can colonize or infect humans via the food chain or occupational (farm) exposure. Moreover, resistance genes can be transferred from bacteria of animals to human pathogens in the intestinal flora of humans (1). 

Within the EU, the use of antibiotics as growth promoters has been phased out since January 2006. Denmark, one of the largest pork exporting countries, instituted a voluntary ban of the prophylactic use of antibiotics in 1998 that resulted in a 30 percent reduction in the use of veterinary drugs. This experience demonstrated that an efficient agricultural production system is possible without the use of growth promoters (2). A decade of surveillance in Denmark has revealed that there is a close association between antimicrobial usage and antimicrobial resistance in food animals. However, the risk to humans has been difficult to assess, in part because most of the important resistant bacterial pathogens are not related to animal farming. 

Some countries, such as the USA – where prophylactic use of antimicrobials is rather widespread – are considering a different strategy. Through voluntary measures outlined in FDA draft Guidance # 209, the US FDA envisages a reduction of antibiotic use for growth promotion and feed efficiency, better veterinary oversight of the use of antibiotics in feed, and supervision in the use of antibiotics in therapeutic applications. 

Surveillance in real time, providing faster identification of emerging antimicrobial resistance, may soon be possible using next-generation DNA sequencing tools to identify pathogens (including viruses) by complete genome sequencing. Projects such as the Global Microbial Identifier initiative (www.globalmicrobialidentifier.org) will replace conventional culturing and typing methods and lead to the establishment of a global data repository of pathogen genomes. Through active sharing of information, these initiatives should provide more efficient detection, prevention and control of endemics and emerging pathogens, including antimicrobial resistant strains.

A crude estimation, provided by combining the lists of approved substances, information from veterinary drug suppliers, internal surveys, and surveys from WHO/OIE on critically important substances, indicates that today over 450 individual veterinary drugs are available for use in animal farming (3). This is close to the number of active ingredients listed in the US FDA “Green Book”. In the EU, 120 veterinary drugs (pharmacologically active substances) for use in foodstuffs of animal origin are listed with a defined MRL. Additionally, obsolete drugs that are no longer approved may persist in the marketplace especially if they are inexpensive when compared with new drugs. Drug availability, efficacy, cost, local regulations, and degree of enforcement are the main drivers that define their use – or misuse. 

In the USA, several classes of antimicrobials are approved for use as growth promoters in food animals, some of which have counterpart drugs of similar chemical structure (and common mode of action) used in human medicine (Table 1). The tetracycline class of drugs ranks highest in terms of sales and distribution (4611 tonnes in 2009) followed by, ionophores, which include compounds such as monensin, lasalocid and salinomicin (total sales for ionophores: 3740 tonnes in 2009). 

Sales figures for antibiotics used in veterinary medicine in Switzerland show a continuous decline over the past years, dropping by 5.1% in 2011 compared with 2010. Major classes in terms of volumes are the sulfonamides, followed by penicillins and tetracyclines.

 [1] = topical application; [2] = structurally related

Up to date knowledge on the application/approvals of antimicrobials in animal food production (as exemplified in Table 1) and the target species is essential. For example, ionophores are incorporated in the feed to prevent coccidiosis in poultry and increase feed efficiency in cattle. In the production of medicated feeds, careful separation of lines is pivotal to avoid cross-contamination, for example, dogs and cats are especially sensitive to ionophores. Misuse, mixing errors, and accidental ingestion in non-target species can result in toxicity of fatal proportions. 

In dairy farms, most uses of antimicrobials are for the treatment of mastitis caused by a variety of gram-negative and gram-positive bacteria, usually administered through intramammary infusion. The majority of drugs to treat mastitis are penicillins, cepahlosporins, erythromycin and oxytetracyclines.

Finally, it cannot be assumed that drugs “reserved” for human use are not accidentally or illegally administered to animals. Chloramphenicol, admittedly used very rarely and selectively in human medicine because of its toxicity, still requires careful monitoring in certain origins of aquaculture products, meats, and honey. Knowledge on the approvals, and country sales and use data in animal species are important when establishing sampling and surveillance plans. Depending on the risks, targeted testing at the highest upstream point in the supply chain may need to be implemented.