Fluoroquinolone use in food animals.

To the Editor: Two recent articles (1,2) show that fluoroquinolone use in food animals is associated with infections by antimicrobial drug-resistant strains of Campylobacter in humans. These infections cause problems in treating illnesses as well as increased rates of illness and death (3). Despite a large body of scientific evidence and a judicial review (1-3) that show harmful results in many persons, some members of the poultry and pharmaceutical industries argue that fluoroquinolone use in food animals has no adverse effects in humans (4) and continue to supply these drugs for use in poultry (2,5). The use of these drugs has caused rapidly increasing resistance rates in most countries. In the United States, 19% of Campylobacter isolates from humans are now ciprofloxacin resistant (2), and resistance rates >80% are seen in Spain (5). By contrast, in Australia, where fluoroquinolones were never approved for use in food animals, domestically acquired infections with fluoroquinolone-resistant Campylobacter spp. are rarely found in humans (6). Drug-resistant Escherichia coli is also of concern. In Spain, humans frequently acquire fluoroquinolone-resistant E. coli associated with fluoroquinolone use in poultry (7).

In the United States, better controls in meat and poultry slaughter and processing, as well as improved foodsafety education campaigns, have resulted in 28% fewer Campylobacter infections annually since 1996 (8). However, [approximately equal to] 1.8 million persons (600 per 100,000) are likely to contract symptomatic Campylobacter infections per year (3,8), and fluoroquinolone resistance is now 19% (2). Thus, the risk of a person's contracting fluoroquinolone-resistant Campylobacter infection is 114 per 100,000 per year. If 80% of Campylobacter infections are foodborne (3), and 90% of these infections are acquired from poultry (9), then [approximately equal] 82 of 100,000 persons per will contract ciprofloxacin-resistant Campylobacter infections from poultry each year. Most persons with Campylobacter infections would not benefit from antimicrobial drug therapy. However, if only 10% of infected persons would benefit from antimicrobial drug therapy, fluoroquinolone use in poultry could cause [approximately equal to] 82 persons per million to have a compromised response to therapy. In the United States (population 300 million), this number translates to >24,000 persons annually.

Data on the number of animals that receive fluoroquinolones are difficult to find. Bayer (manufacturer of the only fluoroquinolone used in poultry in the United States) states that Baytril (enrofloxacin) is used in <1% of US broiler flocks (4). This statistic allows us to estimate how many persons will potentially have an adverse outcome compared to the number of animals receiving fluoroquinolones. If 24,000 persons in the United States have an adverse outcome annually after <84 million chickens (1% of 8.4 billion) are treated with enrofloxacin, then [approximately equal to] 285 persons are at risk of having an adverse outcome for every 1 million chickens treated.

This risk seems needless. In Australia, consequences from not using these agents in food animals (i.e., neither therapeutic nor prophylactic use is approved) have not been seen. Thus, I do not agree with Iovine and Blaser (1), who would allow fluoroquinolones to be used to treat sick food production animals. Bayer claims that "Baytril is used for therapeutic purposes only ..." (4). Thus, continuation of fluoroquinolone use for these therapeutic purposes will allow the consequent development of resistant bacteria in humans, which will include resistant strains of Campylobacter, E. coli, and Salmonella. Discontinuing fluoroquinolone use by mass dosing (the current practice for poultry [10]) would decrease the amount of the drug used. However, why use fluoroquinolones at all? Narrower spectrum antimicrobial drugs (e.g., sulfonamides, amoxicillin) could be used to adequately treat sick animals. Surely E. coli drug resistance in food animals in the United States cannot be at a level that makes fluoroquinolones indispensable. If resistance levels to narrower spectrum antimicrobial drugs are at high levels, does this finding not imply that major changes concerning antimicrobial drug use in food animals are needed?

Better methods are needed to accurately estimate how many persons are negatively affected annually because of the misuse of antimicrobial drugs in food animals. Compromised therapeutic outcomes occur in many persons throughout the world because of fluoroquinolone-resistant Campylobacter infections (10). Fluoroquinolone use is not essential for food animal production or the welfare of animals. Many ways to keep animals healthy and productive exist other than treating or trying to prevent infections with the mass use of antimicrobial drugs such as fluoroquinolones.

Peter Collignon, Canberra Hospital, Garan, Australian Capital Territory, Australia

References

(1.) Iovine NM, Blaser MJ. Antibiotics in animal feed and spread of resistant Campylobacter from poultry to humans. Emerg Infect Dis. 2004;10:1158-9.

(2.) Gupta A, Nelson JM, Barrett TJ, Tauxe RV, Rossiter SP, Friedman CR, et al. Antimicrobial resistance among Campylobacter strains, United States, 1997-2001. Emerg Infect Dis. 2004;10:1102-9.

(3.) Mead PS, Slutsker L, Dietz V, McCaig LF, Bresee JS, Shapiro C, et al. Food-related illness and death in the United States. Emerg Infect Dis. 1999;5:607-25.

(4.) Bayer Animal Health Care. Baytril for poultry poses no public health threat. [cited 2004 Jun 28]. Available from http://www.bayer-ah.com/web_docs/BA2169b 1 Accessed June 28, 2004.

(5.) Prats G, Mirelis B, Llovet T, Munoz C, Miro E, Navarro F. Antibiotic resistance trends in enteropathogenic bacteria isolated in 1985-1987 and 1995-1998 in Barcelona. Antimicrob Agents Chemother. 2000;44:1140-5.

(6.) Unicomb L, Ferguson J, TV Riley TV, Collignon P. Fluoroquinolone resistance in Campylobacter absent from isolates, Australia. Emerg Infect Dis. 2003;9:1482-3.

(7.) Garau J, Xercavins M, Rodriguez-Carballeira M, Gomez-Vera JR, Coll I, Vidal D, et al. Emergence and dissemination of quinolone-resistant Escherichia coli in the community. Antimicrob Agents Chemother. 1999;43:2736-41.

(8.) Centers for Disease Control and Prevention. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food--selected sites, United States, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:338-43.

(9.) Hurd H, Doores S, Hayes D, Mathew A, Maurer J, Silley P, et al. Public health consequences of macrolide use in food animals: a deterministic risk assessment. J Food Prot. 2004;67:980-92.

(10.) Nelson JM, Smith KE, Vugia DJ, Rabatsky-Ehr T, Segler SD, Kassenborg HD, et al. Prolonged diarrhea due to ciprofloxacin-resistant campylobacter infection. J Infect Dis. 2004; 190:1150-7.

Address for correspondence: Peter Collignon, PO Box 11, Woden, ACT, 2607, Australia; fax: [phone]; email: peter.collignon@ ct.gov.au

In response: We agree with Dr Collignon's view that using fluoroquinolones in the poultry industry imposes a "needless risk" of harm to humans by promoting the emergence of fluoroquinolone-resistant Campylobacter infections and consequent increased illness in humans (1). We support the therapeutic use of fluoroquinolones in poultry if only animals that are ill are treated (2). The widespread practice of adding fluoroquinolones to the drinking water of a hen house with thousands of birds, or of an entire flock, promotes the emergence of resistant Campylobacter strains. Unless veterinary practices limit fluoroquinolone use exclusively to sick birds, the only responsible recourse is to ban the use of fluoroquinolones in the poultry industry altogether, in agreement with the Food and Drug Administration's decision (3).

Nicole M. Iovine * and Martin J. Blaser * ([dagger])

* New York University School of Medicine, New York, New York, USA; and ([dagger]) Department of Veterans Affairs, New York, New York, USA

References:

(1.) Collignon P. Fluoroquinolone use in food animals. Emerg Infect Dis. 2005;11: 1789-90.

(2.) Iovine NM, Blaser MJ. Antibiotics in animal feed and spread of resistant Campylobacter from poultry to humans. Emerg Infect Dis. 2004;10:1158-9.

(3.) Davidson DJ. In the matter of enrofloxacin for poultry: withdrawal of approval of Bayer Corporation's new animal drug application 1 (NADA) 140-828 (Baytril). In: FDA Docket No. 00N-1571; 2004.

Address for correspondence: Martin J. Blaser, Department of Medicine, New York University School of Medicine, 550 First Ave, OBV-606, New York, NY 10016, USA; fax: [phone]; email: [e-mail]

In response: We thank Dr Collignon for his comments regarding the human health impact after fluoroquinolone use in food animals (1) Similar conclusions concerning the human health consequence of using fiuoroquinolones in poultry in the United States were reached by the US Food and Drug Administration (FDA) in a quantitative risk assessment in 2000 (1). FDA concluded that fluoroquinolone use in poultry has resulted in the emergence and dissemination of fluoroquinolone-resistant Campylobacter that infects thousands of persons each year in the United States. Therefore, since 2000, FDA has sought to discontinue the use of fluoroquinolones in poultry. On July 25, 2005, FDA announced the withdrawal of fluoroquinolones for use in poultry effective as of September 12, 2005.

The debate regarding the use of antimicrobial agents in food animals and their impact on human health has been longstanding. For many years, public health officials have raised concern regarding the use of antimicrobial drugs in food animals that are of importance to human health. Industry representatives have stated that these concerns are unfounded. In our study, we found no fluoroquinolone resistance among a sample of Campylobacter jejuni strains collected from persons in 1990 (2). In 1995, fluoroquinolone use was approved in the United States for food animal use, specifically for poultry. Between 1997 and 2001, we noted a significant increase in fluoroquinolone resistance among human Campylobacter strains in the United States, monitored through Centers for Disease Control and Prevention surveillance (13%-19%, logistic regression odds ratio 2.4, 95% confidence interval 1.4-4.1). This finding means that despite a 31% decline in the overall incidence of Campylo-bacter infections from 1997 to 2001, the incidence of fluoroquinolone-resistant Campylobacter infections increased (3,4). More recently published data show that persons with fluoroquinolone-resistant infection have a longer duration of diarrhea and are more likely to have invasive disease or die than persons with fluoroquinolone-susceptible infections (5,6). These data demonstrate, as Dr Collignon indicates, the human health consequences of increasing fluoroquinolone resistance among Campylobacter.

Campylobacter is a zoonotic pathogen and most often associated with consumption of poultry. Our study found that in 1999, 10% of grocery store-purchased chickens yielded fluoroquinolone-resistant Campylobacter (2). More recently, retail food testing in 2002 performed by FDA found that 14% of retail chicken samples were contaminated by fluoroquinolone-resistant Campylobacter (7). Studies of commercial poultry flocks before, during, and after fluoroquinolone treatment found that only a small proportion of flocks had fluoroquinolone-resistant Campy-lobacter infections before fluoroquinolone treatment, but that fluoroquinoloneresistant strains quickly emerged during treatment and often persisted after treatment (8,9). As Dr Collignon describes, in Australia, fluoroquinolone-resistant Campylo-bacter strains have not been detected in domestically acquired human infections; this finding has been attributed to the fact that fluoroqninolones are not licensed for use in food animals (10). We agree with Dr Collignon that convincing data indicate that use of antimicrobial agents that are of human importance among food animals has an adverse human health impact and that the time has come to find alternatives that promote food-animal health while minimizing the induction of antimicrobial resistance.

* Amita Gupta, ([dagger]) Robert V. Tauxe, and ([dagger]) Frederick J. Angulo

* Johns Hopkins University, Baltimore, Maryland, USA; and ([dagger]) Centers for Disease Control and Prevention, Atlanta, Georgia, USA

References

(1.) Collignon P. Fluoroquinolone use in food animals. Emerg Infect Dis. 2005;11: 1789-90.

(2.) US Food and Drug Administration. The human health impact of fluoroquinolone-resistant Campylobacter attributed to the consumption of chicken. [cited 2005 Jun 23]. Available from http://www.fda.gov/ cvm/documents/revisedRA.pdf

(3.) US Food and Drug Administration. Final decision of the FDA commissioner. Withdrawal of approval of the new animal drug application for enrofloxacin in poultry. Rockville (MD): Center for Veterinary Medicine, US Food and Drug Administration; July 27, 2005. Docket no. 2000N1571. [cited 2005 Sep 16]. Available from http://www.fda.gov/oc/antimicrobial/baytri l.pdf

(4.) Gupta A, Nelson JM, Barrett TJ, Tauxe RV, Rossiter SP, Friedman CR, et al. Antimicrobial resistance among Campylobacter strains, United States, 1997-2001. Emerg Infect Dis. 2004; 10:1102-9.

(5.) Nelson JM, Baker N, Theriot C, Vugia DJ, Beebe JL, Rabatsky-Ehr T, et al. Increasing incidence of ciprofloxacin-resistant Campylobacter: Foodnet and NARMS 1997-2001. [cited 2005 Jun 23]. Available from http://www.cdc.gov/narms/publications/2003/Nelson_2003.pdf

(6.) Helms M, Simonsen J, Olsen KE, Molbak K. Adverse health events associated with antimicrobial drug resistance in Campylobacter species: a registry-based cohort study. J Infect Dis. 2005;191:1050-5.

(7.) Nelson JM, Smith KE, Vugia DJ, Rabatsky-Ehr T, Segler SD, Kassenborg HD, et al. Prolonged diarrhea due to ciprofloxacin-resistant Campylobacter infection. J Infect Dis. 2004;190:1150-7.

(8.) National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS). NARMS retail meat annual report, 2002. Rockville (MD): Center for Veterinary Medicine, US Food and Drug Administration; 2002. [cited 2005 Jun 23]. Available from http://www.fda.gov/cvm/ coversheet.htm

(9.) Griggs DJ, Johnson MM, Frost JA, Humphrey T, Jorgensen F, Piddock LJ. Incidence and mechanism of ciprofloxacin resistance in Campylobacter spp. isolated from commercial poultry flocks in the United Kingdom before, during, and after fluoroquinolone treatment. Antimicrob Agents Chemother. 2005;49:699-707.

(10.) Unicomb L, Ferguson J, Riley TV, Collignon P. Fluoroquinolone resistance in Campylobacter absent from isolates, Australia. Emerg Infect Dis. 2003;9:1482-3.

Address for correspondence: Amita Gupta, Johns Hopkins University, Division of Infectious Diseases, Jefferson 2-121B, 600 North Wolfe St, Baltimore, MD 21287, USA; fax: [phone]; email: [e-mail]