Antimicrobial resistance in Campylobacter.

To the Editor: Iovine and Blaser (1) write, "This therapeutic use [of enrofloxacin] was withdrawn (2) but is now under appeal" and "Despite the restrictions on enrofloxacin use, emergence of fluoroquinolone-resistant Campylobacter species, with poultry as an important source, has been documented in the United States ... Therefore, our conclusion remains: use of enrofloxacin in poultry materially contributed to increase in human infection by fluoroquinolone-resistant Campylobacter species."

These claims propagate the following important errors. First, the therapeutic use of enrofloxacin was not withdrawn. Judge Davidson's order to withdraw the approval was an initial decision, to which exceptions were filed in 2004. A final decision rests with the US Food and Drug Administration Commissioner.

Second, poultry has not been identified as an important source of fluoroquinolone resistance in human Campylobacter isolates. The raw data of the cited Smith et al. article (3) indicate a nonsignificant negative association between chicken consumption and fluoroquinolone resistance in human isolates. Substantial resistance levels in Northern Hemisphere countries with and without enrofloxacin use, which occurred well before fluoroquinolones were ever used in animals (3-5), also suggest that attribution of such resistance to enrofloxacin is simplistic.

Finally, rational decision-making is based on probable future consequences of a decision, not past history or causes of the current situation. Iovine and Blaser's claim, "Thus the decision to withdraw therapeutic use of enrofloxacin (3) was warranted," is not implied, even if enrofloxacin use caused the emergence of fluoroquinolone resistance. If withdrawing enrofloxacin increases campylobacteriosis from airsacculitis-positive chickens, withdrawal may greatly harm human health. A rational withdrawal decision cannot be justified. In summary, Iovine and Blaser's view that enrofloxacin should be banned is not supported by the data that they have cited or by principles of sound risk management and decision-making.

Louis Anthony Cox, Jr., * Dennis Copeland, ([dagger]) and Michael Vaughn ([dagger])

* Cox Associates, Denver, Colorado, USA; and ([dagger]) Bayer HealthCare, Shawnee, Kansas, USA

References

(1.) Iovine NM, Blaser MJ. Antimicrobial resistance in Campylobacter. Emerg Infect Dis. 2004;10:1346.

(2.) Vanhoof R, Vanderlinden MR Dierickx R, Lauwers S, Yourassowsky E, Butzler JP. Susceptibility of Campylobacter fetus subsp, jejuni to twenty-nine antimicrobial agents. Antimicrob Agents Chemother. 1978;14:553-6.

(3.) Smith KE, Besser JM, Hedberg CW, Leano FT, Bender JB, Wicklund JH, et al. Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998. Investigation Team. N Engl J Med. 1999;340:1525-32.

(4.) Svedhem A, Kaijser B, Sjogren E. Antimicrobial susceptibility of Campylobacter jejuni isolated from humans with diarrhea and from healthy chickens. J Antimicrob Chemother. 1981;7:301-5.

(5.) Hollander R. [In vitro activity of 23 chemotherapeutic agents against Campylobacter jejuni/coli strains isolated from feces]. Zentralbl Bakteriol Mikrobiol Hyg [A]. 1983;256:196-201.

Address for correspondence: Louis Anthony Cox, Jr., Cox Associates, 503 Franklin St, Denver, CO 80218, USA: tax: 303-388-0609: email: [e-mail]

In Reply: Cox and colleagues raised 3 major points. For the first point, we stated (1) "This therapeutic use was withdrawn but is now under appeal." The actual language of US Federal Drug Administration Judge Davidson's ruling is "Enrofloxacin found not shown to be safe under the conditions of use upon the basis of which the application was approved as required under [section] 512(e)(1)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. [section] 360 b(e)(1)(B)]. Approval of NADA (1) for enrofloxacin ordered withdrawn" (1). The drug manufacturer now is appealing the ruling.

For the second point, the authors state that poultry has not been identified as an important source of fluoroquinolone resistance in human Campylobacter isolates. In both Denmark and Spain, introduction of fluoroquinolones into poultry led to a rapid rise in resistance to Campylobacter in both poultry and human isolates (2-5), and banning their use in Denmark led to a rapid fall in resistance (6). Cox and colleagues may maintain that there is no "proof of a causal relationship," but the relationship is sufficiently strong, temporally restricted, biologically plausible, and coherent to convince disinterested observers, including Judge Davidson and ourselves, otherwise.

For the third point, that decisions must consider probable consequences, we agree. However, Cox et al. appear to use "possible" as their standard. In fact, nearly everything is possible, including the reasoning that they offer. However, in our opinion, based on experience as scientists and microbiologists, we deem the possible consequences described by Cox et al. as insubstantial compared to the clear and present danger to human health of continuing fluoroquinolone use in poultry. Obfuscation and delay have been effective tactics used to maintain profitability even when the facts indicate a different course of action. We hope that the FDA Commissioner will carefully weigh the actual evidence of the risk to human health imposed by the use of fluoroquinolones in poultry.

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

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

(1) New Animal Drug Application

References

(1.) Daniel J. Davidson FALJ. 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.

(2.) Endtz HP, Ruijs GJ, van Klingeren B, Jansen WH, van der Reyden T, Mouton RP. Quinolone resistance in Campylobacter isolated from man and poultry following the introduction of fluoroquinolones in veterinary medicine. J Antimicrob Chemother. 1991:27:199-208.

(3.) Reina J, Borrell N, Serra A. Emergence of resistance to erythromycin and fluoroquinolones in thermotolerant Campylobacter strains isolated from feces 1987-1991. Eur J Clin Microbiol Infect Dis. 1992:11:1163-6.

(4.) Sanchez R, Fernandez-Baca V, Diaz MD, Munoz P, Rodriguez-Creixems M, Bouza E. Evolution of susceptibilities of Campylobacter spp. to quinolones and macrolides. Antimicrob Agents Chemother. 1994:38:1879-82.

(5.) Velazquez JB, Jimenez A, Chomon B, Villa TG. Incidence and transmission of antibiotic resistance in Campylobacter jejuni and Campylobacter coli. J Antimicrob Chemother. 1995:35:173-8.

(6.) Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, foods and humans in Denmark. Copenhagen: Danish Zoonosis Center, Danish Veterinary Institute; 2003.

Address for correspondence: Martin J. Blaser, Department of Medicine, NYU School of Medicine, 550 First Ave., OBV-606, New York, NY 10016, USA: lax: 212-263-3969; email: [e-mail]

The opinions expressed by authors contributing to this journal do not necessarily reflect the opinions of the Centers for Disease Control and Prevention or the institutions with which the authors are required.