Does the use of antibiotics in food animals pose a risk to human health? A reply to critics

Ian Phillips1, Mark Casewell1, Tony Cox2, Brad de Groot3, Christian Friis4, Ron Jones5, Charles Nightingale6,*, Rodney Preston7 and John Waddell8

1 University of London, London, UK; 2 Cox Associates, Denver, CO; 3 Kansas State University, Manhattan, KS, and Livestock Information Services, Callaway, NE; 5 JMI Laboratories, North Liberty, IA; 6 Hartford Hospital, University of Connecticut, 80 Seymour St., Hartford, CT 06102-5037; 7 Texas Tech University, Lubbock, TX; 8 Sutton Veterinary Clinic, Sutton, NE, USA; 4 Royal Veterinary and Agricultural University, Copenhagen, Denmark

Keywords: antibiotics , animal use

Sir,

We appreciate the opportunity to reply to the criticisms15 of our review of the hypothesis that the use of antibiotics in animals poses a risk to human health.6

We are accused of error, often not defined, making specific responses challenging. However, we were correct in referring to ‘seven references’ supporting the banning of growth-promoting antibiotics, noted by Dr Tollefson,1 to which we referred in addressing ‘agricultural use of antibiotics’. And we are emphatically not in error when we question received opinion that animal antibiotic use significantly harms human health harm. We intentionally did not cite every relevant paper, but cited representative papers reaching the same conclusions. We agree that Drs Karp & Engberg3 have the correct reference for the paper by Smith et al.

We are accused of bias. We confess to a strong bias towards facts and data. We sought to ‘redress what we perceive as an imbalance’ by highlighting data that do not support the hypothesis that animal antibiotic use harms human health, often played down or even ignored by those who advise risk managers responsible for antibiotic regulation. The banning of growth-promoting antibiotics in Europe required the application of the Precautionary Principle, which conceded that data were inadequate to support such a ban, and required that good data be actively sought. In light of such data, it is our conclusion that the growth-promoter ban is still not supported by evidence that it protects human health. We believe data-based evidence to be far more important than opinion, speculation and conjecture for safeguarding human health, and accordingly biased our review toward empirical data.

Professor Collignon2 accuses us of failing to recognize that growth-promoting antibiotics do not promote growth. We refer readers to a recent review of antibiotic effects in animals, AVCARE 2003,7 which summarizes experience that shows that they often do. Professor Collignon also tells us that these same antibiotics do not prevent such infections as necrotic enteritis, citing the experience of the Danes.2 However, the Danes have commendably introduced conditions of husbandry that have minimized, but not prevented, such infections, but it is naive to suggest that Denmark had no problem when the use of therapeutic antibiotics greatly increased, so dealing with the expected morbidity and mortality that might otherwise have been apparent. In contrast, neighbouring Norway reported necrotic enteritis increasing to epidemic proportions,8 and many European countries reported increases in the use of therapeutic antibiotics after the ban.9 It remains our conclusion that growth-promoting antibiotics continue to promote growth and to prevent important infections, albeit to different degrees in different places.

We are accused of underestimating the potential harm to human health arising from animal antibiotic use. Infections of concern are salmonellosis, campylobacteriosis and those caused by resistant enterococci. We were, of course, aware of the review by Swartz10 cited by Dr Tollefson1, and of his and others' difficulties in finding direct epidemiological or microbiological or clinical evidence for human harm, and consequent reliance on speculation. We continue to believe that resistance in salmonellae may be selected in animals or humans, but that its effect has been minor to undetectable since, for example, 99.96% of patients recover in the US.11 Since systemic salmonellosis is largely a disease of the immunocompromised, some such patients succumb, although this may be more related to the underlying disease than to food-borne bacteria. Increased morbidity and mortality associated with antibiotic-resistant salmonellae in some studies seems to reflect increased virulence of resistant strains (Travers & Barza12) rather than resistance itself. When we said that resistant salmonellae come and go without much relation to current antibiotic usage (see Chiller et al.5) we referred to the epidemic behaviour of different DTs of Salmonella Typhimurium, not just DT104. Finally, we emphasized the increase of salmonella infection in humans in Denmark in 2001, to which Jensen et al. objected,4 because others ignored or denied it! Our overall aim was to demonstrate that action is needed in relation to the total problem of salmonellosis rather than to subsections of lesser relative importance.

Much consternation and scepticism were generated by our contention that chicken is not currently the main vehicle of human campylobacter infections. A recent paper by Stern & Robach13 shows that, in the USA, campylobacter contamination rates in processed chickens has fallen by 90% in recent years, whereas human infection rates have fallen by 26%, suggesting that even if chicken was responsible for a larger share of human campylobacteriosis 10 years ago, this is no longer the case. Our conclusions are not based primarily on differential resistance rates in Danish chickens and humans (although we are not convinced that this is explained by chicken imports) but on a reanalysis of the published data that we cited. Nor are our conclusions that chicken may be protective based on a misinterpretation of Paper V: Exposures being protective for campylobacter infection, included with Neimann's thesis (our reference 165). If our critics care to examine Tables 1 and 2 of this paper they will find a list of ‘protective factors identified in case control studies of sporadic campylobacteriosis from US, New Zealand, UK, and Norway’ which includes: eating chicken, eating chicken at home, chicken prepared at home, baked/roasted chicken, chicken purchased frozen and handling chicken bought raw with giblets. Earlier risk analyses often failed to pose the appropriate questions included in more recent surveys that now allow effects of chicken consumption per se (generally protective) to be distinguished from effects of chicken and other meats served in commercial establishments (generally risk factors).6 Furthermore, Drs Karp and Engberg3 might have continued their quotation on sources of campylobacter—‘even though other sources such as raw milk, water, and pets may contribute to human infection ... the chain of transmission is often complex’.14 A major ‘point of these arguments’1 is that if chicken is not a major source of campylobacter in human infection, the role of therapeutic use of macrolides and fluoroquinolones in chickens becomes less important than it might otherwise have been.

Despite our conclusion that chicken is not generally an important source of campylobacter infection in humans at present (and carcass contamination does not imply human infection) we are concerned about a new problem arising from the growth-promoter ban in Europe. Failure to control airsacculitis, for example, by using ‘growth-promoting’ antibiotics, results in infected, underweight birds reaching evisceration machines, which tend to tear the intestines of small birds, resulting in increased faecal and campylobacter contamination of a proportion of the carcasses leaving the plant. We alluded to this in our review, and a paper has now been published on the subject.15 The problem would not be detected in studies of mean levels of contamination, such as that of Evans & Wegener (reference 258). We are aware of no specific studies relating this phenomenon to the continually increasing campylobacter infection rates seen in Europe, and thus reject as unsupported the statement of Jensen et al.4 that our argument ‘is not correct’. However, this potential benefit to human health arising from the continued use of growth-promoting antibiotics must be set against any effects of resistance to macrolides and fluoroquinolones. As with salmonellosis, there is a suggestion that resistant Campylobacter jejuni might be more virulent and that this might account for differences in morbidity.12

We are accused of misrepresenting CDC studies,5 for example in asserting that ‘Marano et al. reported a 4 day decrease in the duration of diarrhoea (from 12 to 8 days) for patients infected with fluoroquinolone-resistant strains treated with ciprofloxacin (but paradoxically no decrease for susceptible strains—6 days for both treated and untreated patients)’.6 Our critics emphasize that Marano et al. actually reported that patients with ciprofloxacin-resistant campylobacter infections had a longer duration of diarrhoea than those with susceptible infections both among patients who took ciprofloxacin and those who did not. However, this concern may be alleviated by re-reading what we said, which subsumes the suggested correction in that both 12 and 8 are greater than 6.

Finally, resistant enterococci. We have little to add to our review. However, we would like to remind our critics that appropriate vancomycin resistance genes have been found in commensal intestinal bacteria, and these might be a source for similar genes in enterococci.6 We also emphasize that while genetic studies have found related, but rarely indistinguishable, resistant enterococci in animals, animal-derived meat and human faeces (although we have seen no information about how long they stay there—hence our plea for shoe-leather epidemiology), resistant enterococci infecting humans have many differences, as outlined in our review.6 We continue to believe that the truth about transfer of resistance in the intestine remains beyond our grasp.

Our overriding concern is that risk management actions taken to reduce current uses of animal antibiotics may not, in fact, benefit human health if animal antibiotics prevent or control illness in food animals, reduce consequent loads of food-borne pathogens, and thus potentially reduce human illness and the need for antibiotic therapy in humans. Furthermore, we are concerned that well-meaning efforts to avert hypothetical dangers may create real ones.

Footnotes

* Corresponding author. Tel: +1-860-545-2865; Fax: +1-860-54-5112; Email: cnighti{at}harthosp.org

References

1 . Tollefson, L. (2004). Factual errors in review article. Journal of Antimicrobial Chemotherapy 54, DOI: 10.1093/jac/dkh267.

2 . Collignon, P. (2004). Antibiotic growth promoters. Journal of Antimicrobial Chemotherapy 54, DOI: 10.1093/jac/dkh266.

3 . Karp, B. E. & Engberg, J. (2004). Comment on: Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. Journal of Antimicrobial Chemotherapy 54, DOI: 10.1093/jac/dkh265.

4 . Jensen, V. F., Neimann, J., Hammerum, A. M. et al. (2004). Does the use of antibiotics in food animals pose a risk to human health? An unbiased review? Journal of Antimicrobial Chemotherapy 54, DOI: 10.1093/jac/dkh264.

5 . Chiller, T. M., Barrett, T. & Angulo, F. (2004). CDC studies incorrectly summarized in ‘critical review’. Journal of Antimicrobial Chemotherapy 54, DOI: 10.1093/jac/dkh263.

6 . Phillips, I., Casewell, M., Cox, T. et al. (2004). Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. Journal of Antimicrobial Chemotherapy 53, 28–52.[Abstract/Free Full Text]

7 . Avcare (2003). The role of enteric antibiotics in livestock production. [Online.] http://www.avcare.org.au/default.asp?V_DOC_ID=877 (26 April 2004, date last accessed).

8 . Kaldhusdal, M. & Lovland, A. (2002). Clostridial necrotic enteritis and cholangiohepatitis. [Online.] http://www.poultry-health.com/fora/inthelth/kaldhusdal02.htm (26 April 2004, date last accessed).

9 . Casewell, M., Friis, C., Marco, E. et al. (2003). The European ban on growth-promoting antibiotics and emerging consequences for human and animal health. Journal of Antimicrobial Chemotherapy 52, 159–61.[Abstract/Free Full Text]

10 . Swartz, M. N. (2002). Human disease caused by foodborne pathogens of animal origin. Clinical Infectious Diseases 34, Suppl. 3, S111–22.[CrossRef][ISI][Medline]

11 . Economic Research Service, United States Department of Agriculture (2003). Economics of foodborne disease: salmonella. [Online.] http://www.ers.usda.gov/Briefing/FoodborneDisease/salmonella/salmonellatree.htm (15 March 2004, date last accessed).

12 . Travers, K. & Barza, M. (2002). Morbidity of infections caused by antimicrobial-resistant bacteria. Clinical Infectious Diseases 34, Suppl. 3, S131–4.[CrossRef][ISI][Medline]

13 . Stern, N. J. & Robach, M. C. (2003). Enumeration of Campylobacter spp. in broiler feces and in corresponding processed carcasses. Journal of Food Protection 66, 1557–63.[ISI][Medline]

14 . Engberg, J., Aarestrup, F. M., Taylor, D. E. et al. (2001). Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates. Emerging Infectious Diseases 7, 24–34.[ISI][Medline]

15 . Russell, S. M. (2003). The effect of airsacculitis on bird weights, uniformity, fecal contamination, processing errors, and populations of Campylobacter spp. and Escherichia coli. Poultry Science 82, 1326–31.[ISI][Medline]





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