Antimicrobial use in food animals and human health (Proceedings)

This presentation attempts to summarize some of the major concerns in resistance development along with key articles explaining relevance, epidemiology, and prevalence. It is not intended to be an exhaustive review of the literature and the interested practitioner should use the cited literature herein as a basis for continued, extended reading.

My impression from the literature and sitting through and participating in meetings, debates, and outright arguments is that dissemination of resistant bacterial clones is a primary driver in what we are seeing in human and veterinary medicine. Spontaneous mutations can and do occur, but the rapid changes in resistance over broad areas, and also the similarities between isolates suggests that the spread of clones is a primary driver.

Another very basic concept is that selection for a resistant pathogen or bacteria may be due to an entirely different selection pressure than the antimicrobial in which we happen to be interested. Multiple-drug resistance mechanisms allow co-selection for resistance traits. And, it doesn't even have to be an antimicrobial in the way we typically think of them. Co-selection by environmental disinfectants can co-select for antimicrobial resistance, as demonstrated for pine oil for E. coli, and triclosan for Pseudomonas aeruginosa. The presence of pathogens such as Vancomycin-Resistant Enterococci (VRE), Pseudomonas, and Methicillin-Resistant Staphylococcus aureus (MRSA) on surfaces, pagers, and stethoscopes has been well documented in human studies.

We don't cause the original spontaneous mutations. But, once these mutations take hold in an environment, we are responsible for aiding in selection and spread. As Pogo said, "We have met the enemy and he is us".

What are the challenges on the human side of medicine?

Hospital acquired infections.

One publication gives us a quick look into the challenges in human hospitals. These data are from a Centers for Disease Control and Prevention (CDC) summary. The objective was to describe the frequency of selected antimicrobial resistance patterns among pathogens causing device-associated and procedure-associated healthcare-associated infections (HAIs) reported by hospitals in the National Healthcare Safety Network (NHSN). Data were collected on HAIs reported to the Patient Safety Component of the NHSN between January, 2006 and October, 2007. These HAIs included central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and surgical site infections. Overall, 463 hospitals reported 1 or more HAIs: 412 (89%) were general acute care hospitals, and 309 (67%) had 200-1,000 beds. There were 28,502 HAIs reported among 25,384 patients. The 10 most common pathogens accounting for 84% of reported HAIs were... Coagulase-negative staphylococci (15%), Staphylococcus aureus ( 15%), Enterococcus species (12%), Candida species (11%), Escherichia coli (10%), Pseudomonas aeruginosa (8%), Klebsiella pneumoniae (6%), Enterobacter species (5%), Acinetobacter baumannii (3%), Klebsiella oxytoca (2%). As many as 16% of all HAIs in this report were associated with the following multidrug-resistant pathogens, Methicillin-resistant Staph. aureus (8% of HAIs), Vancomycin-resistant Enterococcus faecium (4%), Carbapenem-resistant Pseudomonas aeruginosa (2%), Extended-spectrum cephalosporin-resistant Klebsiella pneumoniae (1%), Extended-spectrum cephalosporin-resistant E. coli (0.5%), Carbapenem-resistant A. baumannii, K. pneumoniae, K. oxytoca, and E. coli (0.5%).

Challenges in human resistance dissemination: Some examples

Extended-spectrum beta-lactamases

ESBLs were first documented in North America in the middle 1980's in outbreak strains of Klebsiella pneumonia, with a wide variety of genetic families documented since that time. Now, the specter of widely disseminated carbapenem resistance is becoming apparent. The realities of clonal dissemination of this resistance have been documented in the United States, for example recently with a Klebsiella pneumoniae clone in California.

Streptococcus pneumoniae

Changes in macrolide resistance incidence related to target mutation encoded by erm(B) and/or a drug efflux pump encoded by mef(A) have been documented in community-acquired pneumonia in the United States. And, penicillin-resistant Streptococcus pneumoniae has garnered enough attention that a PubMed search on this term retrieves 4277 articles. Even S. pneumoniae resistance to ciprofloxacin has been documented along with increasing prescriptions in Canada from 1997 to 2006.

Methicillin-Resistant Staph aureus (MRSA)

Methicillin is no longer commercially available in the United States. It would more accurately be considered "oxacillin resistant", as the concern is for resistance to the beta-lactam-resistant class of penicillins. When resistance is documented to this class, the organism is considered to be resistant to all beta-lactams, including the cephalosporins.

Vancomycin-intermediate and Vancomycin-Resistant Staph aureus

Vancomycin, a glycopeptide, has been a major component of therapy for MRSA. However, emergence of intermediate and resistant MRSA isolates have been a problem well documented over the last decade.

Vancomycin-resistant enterococci (VRE)

Enterococci (e.g., faecalis and faecium) have emerged as major Gram (+) pathogens in human medicine. As for MRSA, the glycopeptides are critical in therapy of these pathogens. The increasing prevalence of VRE has lead to great concerns for surgical cases with infection, and this concern is heightened as linezolid resistance is also being documented for VRE isolates.

In addition to these selected examples, world-wide concerns about resistance in diseases such as Malaria and Tuberculosis are contributing to anxiety about potentially uncontrollable epidemics.

Foodborne disease

The CDC has a listing of the most common foodborne diseases in the United States on their website. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/foodborneinfections_g.htm

The most common are Campylobacter, Salmonella, E. coli O157:H7, and also the calicivirus group, also known as the Norwalk and Norwalk-like viruses. 2008 FoodNet data indicate the following reported foodborne infections over a 10 state region. A total of 18,499 laboratory-confirmed cases were reported from a surveillance population of approximately 46 million (15% of the U.S. population). Incidence rates varied substantially between surveillance areas.

Direct transmission

This involves farm and veterinary personnel. MRSA has been a recent focus in the literature (see below).

What constitutes a link between human and veterinary medicine?

1) Concurrent use of the same compound

2) Similar structure of the antimicrobial: Cross resistance within a class

3) Similar or identical mechanism of action: "MLS" group

4) Microbial genetic association: "Cassettes"

Resistance caveats

It is important to specify the antimicrobial and the microbial agent in a discussion. Always press for clarification from anyone stating generalities based on antimicrobial class (e.g. fluoroquinolones, macrolides) or an infectious agent (e.g., MRSA).

Some highlights of information concerning

Salmonella spp

Detailed information on changes in antimicrobial susceptibility by Salmonella serotype in cattle, swine, chickens and Turkey may be accessed at the National Antimicrobial resistance Monitoring System – Enteric Bacteria Veterinary Isolates Interactive Data Query Page. http://www.ars.usda.gov//Main/site_main.htm?docid=17964

E. Coli

Is it an indicator for Salmonella? E. coli O157:H7 is not a resistance issue. Antimicrobials are not used in the treatment of Hemolytic Uremic Syndrome (HUS) because antimicrobial treatment results in increased toxin release.

Staphylococcus spp.

First it was MRSA (Methicillin Resistant Staph Aureus), now it is VISA and VRSA (Vancomycin Intermediate and Vancomycin Resistant Staph Aureus) too!

Methicillin-resistant Staph aureus (MRSA)

We should actually be calling it "oxacillin-resistant Staph aureus" since methicillin hasn't been marketed for years. Methicillin and oxacillin are in a group of beta-lactamase resistant penicillins. The susceptibility testing rule has been that if the pathogen is methicillin or oxacillin resistant, then you disregard susceptible results for other beta-lactams.

Is MRSA in animals? Yes, a 2008 review article has summarized literature on animal occurrence, including cattle, dogs, cats, sheep, chickens, horses, rabbits, seals, and psittacine birds.. There is extensive literature on types and occurrence of MRSA in farm workers. While swine workers and veterinarians have been demonstrated to have nasal carriage of the MRSA type found in swine herds, epidemiological studies suggest that colonization is primarily limited to those working with the swine and further transmission is limited to familial communities of these exposed workers. In the U.S., the human community-acquired outbreak strains are different from animal strains. In the Netherlands, a new type of MRSA (ST 398) is epidemiologically associated with pig and cattle farmers and is said to be > 20% of carriage in humans. Transmission between humans and their pets is suggested by epidemiological investigations. The USDA released a fact sheet in December, 2007 addressing MRSA in animals and humans.

Some risk assessments to evaluate

Penicillins

Cox LA, et al. Human health risk assessment of penicillin/aminopenicillin resistance in enterococci due to penicillin use in food animals. Risk Analysis 29(6), 796-805, 2009.

Enrofloxacin in poultry

The risk assessment developed by the FDA Center for Veterinary Medicine related to the use of enrofloxacin in poultry may be accessed on the FDA/CVM website at: http://www.fda.gov/AnimalVeterinary/SafetyHealth/RecallsWithdrawals/ucm042004.htm (accessed 12-14-09). This site contains the background information for the withdrawal of enrofloxacin approval for use in poultry. Also, Cox LA, Quantifying potential human health impacts of animal antibiotic use: enrofloxacin and macrolides in chickens. Riak Anal 26(1):135-146, 2006.

Macrolides

Hurd HS, et al. A stochastic assessment of the public health risks of the use of macrolide antibiotics in food animals. Riak Anal 28(3):695-710, 2008. Also, see the Recent Guidance 152 document for Tulathromycin. (Accessed 12-14-09). (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/UCM127196.pdf)

Streptogramins

FDA Center for Veterinary Medicine Virginiamycin Risk Assessment. Available at http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm048417.htm (accessed 12-14-09)

References

Moken MC, McMurry LM, and Levy SB. Selection of Multiple-Antibiotic-Resistant (MAR) Mutants of Escherichia coli by Using the Disinfectant Pine Oil: Roles of the mar and acrAB Loci. Antimicrobial Agents and Chemotherapy. 41(2):2770-2772, 1997.

Chuanchuen R, et al. Cross-resistance between triclosan and antibiotics in Pseudomonas aeruginosa is mediated by multidrug efflux pumps: Exposure of a susceptible mutant strain to triclosan selects nfxB mutants over-expressing mexCD-Oprj. Antimicrobial Agents and Chemotherapy 45(2):428-432, 2001.

Antimicrobial-Resistant Pathogens Associated With Healthcare-Associated Infections: Annual Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infection Control and Hospital Epidemiology 29:996-1101, 2008.

Bush K. Extended-spectrum β-lactamases in North America, 1987-2006. Clin Microbial Infect 14:134-143, 2008.

Cornaglia G, Rossolini GM. The emerging threat of acquired carbapenemases in Gram-negative bacteria. Clinical Microbiology and Infection 16(2):98-101, 2010.

Le J., Castanheira M, Burgess DS, et al. Clonal dissemination of Klebsiella pneumonia carbapenemase KPC-3 in Long Beach, California. J Clin Microbiol 48(2):623-625, 2010.

Jenkins SG, Farrell DJ. Increase in pneumococcus macrolide ressitance, United States. Emerging Infectious Diseases 15(8):1260-1264, 2009.

Adam HJ, Hoban DJ, Gin AS, et al. Association between fluoroquinolone usage and a dramatic rise in ciprofloxacin-ressitant streptococcus pneumonia in Canada, 1997-2006. Int J Antimicrob Agents 34(1):82-85, 2009.

Appelbaum PC. The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. Clin Microbiol Infect 12(suppl.1):16-23, 2006.

Mazuski JE. Vancomycin-Resistant Enterococcus: Risk Factors, Surveillance, Infections, and Treatment. Surgical Infections, 9(6), 567-561, 2008.

Preliminary FoodNet Data on the Incidence of Infection with Pathogens Transmitted Commonly Through Food—10 States, 2008. MMWR 58(13):333-337,2009.

Morgan M. Methicillin0resistant Staphylococcus aureus and animals: zoonosis or humnanosis? J Antimicrobi Chemother 62(6), 1181-187, 2008.

Cuny C, et al. Nasal colonization of humans with methicillin-resistant Staphylococcus aureus (MRSA)CC398 with and without exposure to pigs. PloS One, 4(8), 2009.

Van Loo I. Emergence of methicillin-resistant Staphylococcus aureus of animal origin in humans. Emerg Infect Dis 13(12), 1834-1839, 2007.

Weese JS. Suspected transmission of methicillin-resistant Staphylococcus aureus between domestic pets and humans in veterinary clinics and in the household. Vet Microbiol 115:140-155, 2006.

USDA APHIS Info Sheet. Accessed 12-15-09 http://www.aphis.usda.gov/vs/ceah/cei/taf/emergingdiseasenotice_files/mrsa_122007.pdf