Farm-grown superbugs: While the world acts, Canada dawdles

I wish to write to applaud Barbara Sibbald for her short article on the human health implications of antimicrobials in agriculture (1). I was interested to learn about the degree to which Canada has lagged behind other countries in regulating their use. I wished to write on two points of clarification: the first relates to a statement made in the article about quinpristin-dalfopristin as the "...quinupristin-dalfopristin, [is] our last line of defence if Staphylococcus aureus or Enterococcus infections develop resistance to vancomycin"(1). The second relates to additional sources of concern regarding the potential infectious disease consequences of heavy antimicrobial use in agriculture.

With respect to the article's statement regarding S. aureus and Enterococcus sp., I would note that vancomycin-resistant Enterococcus (VRE) has been recognized for over two decades (2);strains of S. aureus with intermediate-level resistance to vancomycin were described in 1997 (3), and high-level vancomycin resistant S. aureus was described (outside the laboratory) in 2002 (4). The role that agricultural use of avoparcin played in the genesis of VRE in humans is controversial, but recognition of the potential links between avoparcin and VRE likely contributed to European decisions to remove this antibiotic from feeds, as mentioned in the article (5). Fortunately, however, quinpristin-dalfopristin is not the only agent with activity against multiresistant gram positive microbes. Daptomycin and linezolid are available in Canada, and other agents (such as ceftaroline) have been approved in the U.S. and await approval in Canada.

The article did not mention multi-drug resistant gram negative pathogens, including Acinetobacter species, Pseudomonas aeruginosa, and the Enterobacteraceae (including recently described strains with a novel plasmid-borne carbapenemase (6)), some of which have actually reached a point of being effectively pan-resistant to available antimicrobials (7). Such microbes are environmentally abundant, in agricultural runoff, surface waters, and sewage, and (particularly given the tendency of resistance determinants to cluster at the microbial level) the environmental contamination associated with agricultural antibiotic use provides a source of selective pressure that gives a competitive advantage to resistant microbes.

An additional, but more controversial, reason for concern around antimicrobial use in agriculture relates to verotoxigenic strains of E. coli, which are (at the time of writing) the source of a massive meat recall, and numerous cases of enteric illness, in Canada (8). There is (limited) evidence suggesting that the use of antibiotics and other growth promoters as linked to carriage of VTEC strains like E. coli O157:H7 (9), and if this relationship is proved may provide additional support for the restriction of antimicrobial use in food animals. I hope that the above serves to underscore the importance and timeliness of this article. Again, I write to express my gratitude to Ms. Sibbald for having written the article, and to the CMAJ for giving this issue the prominence it deserves.

Sincerely,

David N. Fisman, MD MPH FRCPC Associate Professor of Public Health (Epidemiology) Dalla Lana School of Public Health University of Toronto

References

1. Sibbald B. Farm-grown superbugs: While the world acts, Canada dawdles. CMAJ. 2012 Oct 2;184(14):1553.

2. Gold HS, Unal S, Cercenado E, Thauvin-Eliopoulos C, Eliopoulos GM, Wennersten CB, et al. A gene conferring resistance to vancomycin but not teicoplanin in isolates of Enterococcus faecalis and Enterococcus faecium demonstrates homology with vanB, vanA, and vanC genes of enterococci. Antimicrob Agents Chemother. 1993 Aug;37(8):1604-9.

3. Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robinson- Dunn B, et al. Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group. N Engl J Med. 1999 Feb 18;340(7):493-501.

4. Chang S, Sievert DM, Hageman JC, Boulton ML, Tenover FC, Downes FP, et al. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med. 2003 Apr 3;348(14):1342 -7.

5. Bonten MJ, Willems R, Weinstein RA. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis. 2001 Dec;1(5):314-25.

6. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010 Sep;10(9):597-602.

7. Walsh TR, Toleman MA. The emergence of pan-resistant Gram-negative pathogens merits a rapid global political response. J Antimicrob Chemother. 2012 Jan;67(1):1-3.

8. Public Health Agency of Canada. Public Health Notice: E coli O157 illness related to beef. Available via the Internet at http://www.phac- aspc.gc.ca/fs-sa/phn-asp/ecoli-1012-eng.php. Last accessed October 15, 2012. Ottawa, Ontario, Canada2012 [updated October 12, 2012.].

9. Lefebvre B, Diarra MS, Giguere K, Roy G, Michaud S, Malouin F. Antibiotic resistance and hypermutability of Escherichia coli O157 from feedlot cattle treated with growth-promoting agents. J Food Prot. 2005 Nov;68(11):2411-9.

Conflict of Interest:

None declared

Interesting editorial, lots of threats about the use of antibiotics in animals leading to antibiotic resistance in man. However, despite the ban on the growth promotion use of antibiotics in Sweden for many years and more recently Denmark and the EU in general, no evidence is presented that these bans are having any influence on the amount of animal derived antibiotic resistance in man only that the ban has resulted in an increase in the cost of food. The author presents no hard support for the thesis that widespread antibiotic bans in animals have any widespread beneficial effects for human health.

The value of this debate would improve if there was a real effort to quantify the actual benefits of more restrictive policies on antibiotic use in animals, rather than speculative assumptions. Having followed this debate for the past 40 years, it appears to me that the agriculture industry is more of a scapegoat for poor medical practitioner practices that poor agriculture practices. This debate will have to get beyond, no mea culpa, if truly effective policies are to be developed.

Conflict of Interest:

None declared

As members of the Ad Hoc Committee for Antimicrobial Stewardship in Canadian Agriculture and Veterinary Medicine we would like to comment on your editorial on "farm grown superbugs".

The purpose of our Committee is to press for outcomes to the action points identified at the 2011 Conference in Toronto on "Antimicrobial Stewardship in Canadian Agriculture and Veterinary Medicine: How is Canada doing and what still needs to be done?" A report of the conference (Canadian Veterinary Journal 2012; 53: 402-407) will soon be freely downloadable through PubMed.

There are some clear misunderstandings of antimicrobial use in animals in Canada in the editorial. We also disagree with your perspectives and characterizations of agricultural practices, which represent an uninformed and stereotypic view of a critically important industry globally. In the spirit of the term 'One Health", we do support your call for regulatory reform in the area of antibiotic use in animals, to bring Canada into line with international standards as detailed in World Health Organization documents on the topic (e.g., Global strategy for containment of antimicrobial resistance, 2001; The evolving threat of antimicrobial resistance, 2012). Beyond this action it is important that human and animal health continue to work together to preserve the critically important medications needed to manage disease in the future.

The regulation of antimicrobial drug use in Canada, particularly regulations around own use importation, active pharmaceutical ingredient use, and extra-label use, is by far Canada's weakest link in managing antibiotic stewardship in agriculture and veterinary medicine. As you note in the editorial, the issue is that the federal government through Health Canada regulates the pre-market assessment and licensing of antibiotics for sale while the actual use of antibiotics is controlled at the provincial level. This leaves a major gap in the framework by which animal use of antibiotics is managed, a problem that needs to be addressed seriously, and with urgency.

The committee therefore suggests that the following measures relating to regulation in animals be implemented expeditiously: Removing of the "own use importation" and "active pharmaceutical ingredient importation" loopholes in the regulations, since there is no Canadian quality or safety risk assessment involved with these products; the ability under appropriate circumstances to ban nationally the extra-label use of certain antibiotics.

We should not have to wait for a crisis in antimicrobial resistance to make the regulatory changes that are so clearly needed. What is needed in Canada is political leadership towards judicious antimicrobial use policy.

Yours sincerely,

John Prescott, Department of Pathobiology, University of Guelph

Jean Szkotnicki, Canadian Animal Health Institute, Guelph

Conflict of Interest:

None declared

The Alberta Veterinary Medical Association (ABVMA) is the professional regulatory organization responsible for the practice of veterinary medicine in Alberta, under the authority of the Veterinary Profession Act. Veterinarians registered under this act are medical practitioners with the authority to prescribe medications for the treatment of animals. Like our colleagues in the human health field, we are acutely aware of the hazards posed by the use of antimicrobial drugs. We believe every effort must be taken to maintain the utility and safety of these products both for animal and human health. The ABVMA is partnering with animal industry stakeholders in an effort to increase awareness in all sectors of the need for appropriate stewardship of this essential commodity. We have launched a program called Alberta Platform for the Responsible Use of Medications in Animals (APRUMA) and have developed a site to exchange information on this topic www.apruma.ca.

While we applaud the effect Barbara Sibbald, Deputy Editor, has had in stimulating awareness of this timely topic, we believe the published editorial also highlights some common areas of confusion. Certain antimicrobials can be and are used in animal agriculture in both a preventative and growth promoting capacity. These are not the same purpose, although one might support the other. In reality, both of these uses are in accordance with existing drug label claims as approved by Health Canada, and therefore should not be confused with "off label use". When used according to label, however, these antimicrobials do not require a prescription from a veterinarian and consequently professional supervision might be lacking.

The writer is correct in stating that the practice of veterinary medicine is regulated provincially. The classification of pharmaceuticals as either prescription only or non-prescription, however, is the federal responsibility of Health Canada. A drug classified as non-prescription is available for over the counter sales for use in animals. These then fall outside of the scope of regulated veterinary practice.

While appreciating the writers' assertion that improved agricultural practices can contribute to safer use of antimicrobials, I believe it might be more correct to say that improved standards of animal production and hygiene might lead to improved animal welfare and reduced use of antimicrobials. There is real concern that restriction of appropriate antimicrobial use might actually lead to animal welfare concerns. This apparently has been seen in other jurisdictions.

My final reservation comes from the reference to the total percentage volume of antimicrobials used in animals versus human health. These numbers are seemingly meaningless unless the biomass of patients treated is considered. These numbers are commonly discussed and I am not certain anyone has the best solution of how to report and compare volume of antimicrobial use.

Despite these reservations, I think the editorial is successful in once again raising the signal flag that our processes need to continually be reviewed and updated where necessary.

Sincerely,

Dr. Duane Landals BSc. Ag., DVM Registrar, Alberta Veterinary Medical Association Vice President, World Veterinary Association

Conflict of Interest:

None declared