Clinton, NC • October 29, 2004

ANTIMICROBIAL RESISTANCE DEVELOPMENT

SHOULD WE BE CONCERNED?

 

Siddhartha Thakur and Wondwossen Gebreyes

Department of Population Health and Pathobiology

College of Veterinary Medicine
North Carolina State University

Raleigh, NC 27606

 

 

Introduction

 

            Antibiotics have been used in animal production for many years now for therapy and treatment. Shortly after discovering the potential therapeutic us of antimicrobials, their growth-promoting effects in chickens were discovered by feeding them fermented offal from the chlortetracycline production of Streptomyces aureofaciens. Since then, several antimicrobials have been used as antimicrobial growth promoters (AGP) by addition in feed. Feeds that contain these antimicrobials are also known as medicated feeds. The introduction of AGP also coincided with intensive animal rearing. The US produces approximately 50 million pounds of antibiotics each year and 40% of that is given to animals, usually as a feed additive to promote growth. The AGP increase feed efficiency in food animals and enhance growth rates. Their use also helps in decreasing the morbidity and mortality due to diseases in animals. There is an average growth promotion between 4 to 8% and an improved feed utilization by 2 to 5% (Butaye et al., 2003). Therefore, the overall use of these growth promoters contributed to the economic effectiveness of the production system.

           

            From the producer’s point of view, adding antimicrobials in feed for growth promotion presents an ideal scenario. However, the emergence of antimicrobial resistant strains of bacteria over the years gained prominence owing in part to the increased awareness in infectious diseases of public health importance. Long term use of AGP in feed may select for the resistant bacteria that continue to survive as compared to the antimicrobial susceptible bacteria. These resistant bacteria can also pass on their resistance to other bacteria. The transmission of such resistant bacteria from animals to humans has been the focus of attention for the past few years. Foods of animal origin have been implicated in many food-borne outbreaks and therefore also act as vehicles for the transmission of resistant pathogens.

 

In view of the above, it is important that we try and prevent development of resistant bacteria by the judicious use of antimicrobials in feed and for prophylaxis and therapy purposes. This presentation is aimed to increase the awareness of the swine producers to use AGP substances properly and to prevent their indiscriminate use.

 

 

Mode of Action of AGP substances

 

            Studies conducted in germ free animals have shown that the actions of these AGP substances are mediated through their antibacterial activity. There are four hypotheses to explain their effect (Butaye et al., 2003). These include: 1) antibiotics decrease the toxins produced by the bacteria; 2) nutrients may be protected against bacterial destruction; 3) increase in the absorption of nutrients due to a thinning of the intestinal wall; and 4) reduction in the incidence of sub clinical infections. However, no study has pinpointed the exact mechanism by which the AGP work in the animal intestine.

 

Antimicrobials permitted for addition in feed in swine in the US

 

The table below shows the different applications of approved medicated feed permitted for use in swine (Table 1). The Federal, Food and Cosmetic act provide the legal authority for these acts. More information about this panel regarding the dose and withdrawal periods is available at the URL: http://www.oznet.ksu.edu/library/GRSCI2/MF2042.PDF.

 


 

Table 1: Antimicrobials permitted for use in feed in the US.

 

Antimicrobial Resistance Development

 

            There are many ways by which susceptible bacteria can become resistant. Resistance against antimicrobials can be either intrinsic or extrinsic. Intrinsic resistance is due to the presence of certain resistance conferring genes that are carried by the bacteria. The other way of resistance development is extrinsic in nature and could be due to a number of reasons. The common ones include: 1) sub therapeutic use of antimicrobials, 2) changes in the genome through sudden mutations.

 

Use of antimicrobials in the sub therapeutic dose is one of the most common reasons for resistance development. It puts a “selective pressure” on the bacteria to either develop resistance or perish. The Darwinian principle of “survival of the fittest” holds true here. Over a period of time, resistant bacteria start emerging and completely dominate the gut microflora since they are able to survive against the antimicrobials. The animal then becomes a potent source of transmission of resistant bacteria to other animals in the group.

 

Antibiotic Resistance is on the Rise

 

            Salmonella causes 1.4 million illnesses and 580 deaths annually in the U.S (Mead et al., 1999). Salmonella is resistant to more than five different antibiotics and are important cause of food-borne infections. Resistant bacterial infections increase health care costs by at least $4 billion per year in the U.S. A temporal association has been noted between lessened susceptibility to fluoroquinolones among Salmonella enterica serotype Typhimurium Definitive Type 104 (DT104) and the approval and use of a fluoroquinolone for veterinary therapeutic use in the United Kingdom. Another important bacterial pathogen is Campylobacter which accounts for 2.4 million illnesses and over 120 deaths each year in the U.S. High resistance is also seen in Campylobacter, the most common cause of bacterial food-borne infections, is resistant against fluoroquinoles like ciprofloxacin which are important for human treatment. Just six years ago, before fluoroquinolones were approved for use in poultry, such resistance was negligible.

 

Should we ban use of AGP in feed?

 

A good example to answer the above question is the isolation of glycopeptide (vancomycin) resistant enterococci from pigs and poultry first in Great Britain and subsequently in Denmark and Germany (Bager et al., 1997). The food animals were suggested as possible reservoirs and raised a great alarm in Europe and the US since this group of bacteria was resistant to almost all the antimicrobials (Wagener, 2003). An association between the use of the drug avoparcin as a growth promoter in food animals and the development of the resistant strains was suggested. As a result of this, avoparcin was banned from Europe in 1997.

 

Following recommendations from other similar studies, other AGP drugs (virginiamycin and tylosin) were subsequently banned. The result of this step is now being seen (Figure: 1). The banning of drugs for growth promotion led to a decrease in the selective pressure that favors the occurrence of resistant bacteria in the animal gut. This led to a reduction in the occurrence of AGP resistant bacteria in foods and was followed by a similar reduction in the human carriage of Enterococci resistant strains. This study highlights the importance of not adding AGP in feed of animals.

 

 

 

              

 

Figure 1: Volumes of active AGP used in food-animals in Denmark and prevalence of Enterococcus faecium resistant to important drugs in stool samples from healthy animals at slaughter 1995-2001. Data from DANMAP 2002. (Adapted from Wegener, 2003).

 

 

Recommendations for judicious use of antimicrobials

 

            Use of antimicrobials as growth promoters should be avoided. Priority should be on maintaining proper hygiene conditions and incorporating good management practices. Alternatives for AGP should be used. These include:

 

1)      In-feed enzymes

These are fermentation products of fungi and bacteria and are used for the breakdown of glucans and proteins, which are difficult for the animal to digest.

 

2)      Probiotics

These are microbes that aid in digestion and also colonize the gut thereby preventing the pathogens for doing so. They also stimulate the immune system

 

3)      Good Management Practices

Most important of all the measures. Maintain healthy conditions for the pigs. These include good air space per pig, proper feeding, appropriate stocking densities, type of flooring and serological testing on incoming swine to monitor their health status are a few of them. Confine therapeutic drugs to the appropriate disease conditions only. Extra label use of these drugs should be absolutely avoided.

 

 

Conclusions

The routine use of AGP in animal feed is one of the main reasons for the development of resistance among pathogens. This is a serious public health problem and is especially true in those cases where the same class of antimicrobials is also used in humans. The best alternative to AGP is to ban their use in growth promotion and work for the general improvement of conditions for animals that produce our food. Medically important antibiotics must be prohibited from use in a growth promotional role as a matter of immediacy. Even though the greatest problem is due to the use of antimicrobials in human hospitals, resistance development at any level is a concern. We can play an important role ourselves by judiciously using antimicrobials.

 

References

 

1. Butaye,P., Devriese, L.A. and Haesebrouck, F. 2003. Antimicrobial growth promoters used in animal feed: Effects of less well known antibiotics on Gram-positive bacteria. Clinical Microbiology Reviews. 16 (2): 175-188.

 

2. Mead, P.S., Slutsker, L., Dietz, V., McCaig, L.F., Bresee, J.S., Shapiro, C., Griffin, P.M., Tauxe, R.V. Food-Related Illness and Death in the United States. 1999.  Emerging Infectious Diseases; 5:607-625

 

3. Wegener,H.C. Antibiotics in animal feed and their role in resistance development. 2003. Current Opinion in Microbiology. 6: 439-445.

 

4. Kansas State University Agricultural Experiment Station and Cooperative Extension Service. Feed additive guidelines for swine. www.oznet.ksu.edu/library/GRSCI2/MF2042.PDF.

 

SOURCES OF MORE INFORMATION
1.
American Association of Swine Practitioners
    www.aasp.org

2. National Pork Producers Council
    www.nppc.org