Changes in Antimicrobial Resistance in Salmonella enterica Serovar Typhimurium.

To the Editor: The conclusion by Davis and colleagues (1) that use of antimicrobial agents in agriculture is unlikely to have contributed to the emergence of multidrug-resistant Salmonella serotype Typhimurium DT104 (MR-DT104) is contrary to available evidence. Use of antimicrobial agents in aquaculture in Asia may have contributed to the emergence of DT104. The resistant determinants of MR-DT104 reside on the chromosome, apparently within a transferrable element (2-4). Chloramphenicol resistance in MR-DT104 is due to floR, a florfenicol resistance gene (5); florfenicol is a veterinary antimicrobial agent that, although not approved in the United States until 1996, has been used in aquaculture in Asia since the early 1980s. FloR was first identified in Photobacterium damsela, a bacterium found in fish (5). Furthermore, tetracycline resistance in MR-DT104 is due to et class G resistance gene first identified in Vibrio anguillarum, a pathogen of fish (4,6). The molecular sequence where the class G and floR determinants reside on the DT104 chromosome is closely related (94% identity) to a plasmid in Pasteurella piscicida, another pathogen of fish (7). These data suggest that the resistance determinants of MR-DT104 may have emerged among bacteria in aquaculture and been horizontally transferred to S. Typhimurium DT104.

Spread of MR-DT104 between regions during international travel, as Davis and colleagues suggest, is unlikely because in industrialized countries Salmonella is seldom transmitted from person to person (8). Once MR-DT104 emerged, it spread rapidly to many regions through unknown means. The rapid emergence of MR-DT104 suggests a means of spread more efficient than person-to-person transmission. Possibilities include movement of infected breeding or "multiplier" stock or shipment of contaminated feed ingredients; such movements may not be as limited as Davis et al. suggest. For example, the international spread of Salmonella serotype Agona was traced to the global distribution of contaminated fish meal from Peru (9).

Once MR-DT104 is introduced into food animals in a region, use of antimicrobial agents in animals would contribute to further dissemination of MR-DT104 (8). If MR-DT104 is present on a farm, the use on the farm of any antimicrobial agent to which MR-DT104 is resistant would contribute to its persistence. An example of such use in cattle in the United States is the tetracycline-containing milk "replacement" commonly fed to dairy calves. This product could kill susceptible gastrointestinal flora while allowing tetracycline-resistant flora such as MR-DT104 to survive and proliferate. Once MR-DT104 proliferates on a farm, dissemination to other farms in the region is facilitated, particularly if the other farms are using an antimicrobial agent to which MR-DT104 is resistant.

Increasing antimicrobial resistance in Salmonella contributes to its spread and threatens the use of clinically important antimicrobial agents. To slow the emergence and dissemination of resistant Salmonella, measures should be implemented to ensure that antimicrobial agents are used prudently in food-producing animals (10).

References

(1.) Davis MA, Hancock DD, Besser TE, Rice DH, Gay JM, Gay C, et. al. Changes in antimicrobial resistance among Salmonella enterica serovar Typhimurium isolates from humans and cattle in the Northwestern United States, 1982-1997. Emerg Infect Dis 1999;5:802-6.

(2.) Sandvang D, Aarestrup FM, Jensen LB. Characterisation of integrons and antibiotic resistance genes in Danish multiresistant Salmonella enterica Typhimurium DT104. FEMS Microbiol Let 1998;160:37-41.

(3.) Ridley A, Threlfall EJ. Molecular epidemiology of antibiotic resistance genes in multiresistant epidemic Salmonella typhimurium DT104. Microb Drug Resist 1998;4:113-8.

(4.) Briggs CE, Fratamico PM. Molecular characterization of an antibiotic resistance gene cluster of Salmonella typhimurium DT104. Antimicrob Agents Chemother 1999;43:846-9.

(5.) Bolton LF, Kelly LC, Lee MD, Fedorka-Cray PI, Maurer H. Detection of multidrug-resistant Salmonella enterica serotype typhimurium DT104 based on a gene which confers cross-resistance to florfenicol and chloramphenicol. J Clin Microbiol 1999;37:1348-51.

(6.) Zhao J, Aoki T. Nucleotide sequence analysis of the class G tetracycline resistance determinant from Vibrio anguillarum. Microbiol Immunol 1992;36:1051-60.

(7.) Kim EH, Aoki T. Drug resistance and broad geographical distribution of identical R plasmids of Pasteurella piscicida isolated from cultured yellowtail in Japan. Microbiol Immunol 1993;37:103-9.

(8.) Cohen ML, Tauxe RV. Drug-resistant Salmonella in the United States: an epidemiologic perspective. Science 1986;234:964-9.

(9.) Clark GM, Kaufmann AF, Gangrosa EJ. Epidemiology of an international outbreak of Salmonella agona. Lancet 1973;490-3.

(10.) Centers for Veterinary Medicine, U.S. Food & Drug Administration. Proposed framework for evaluating and assuring the human safety of the microbial effects of antimicrobial new animal drugs intended for use in food-producing animals. Washington: FDA; 1999 Jan 6. Available from: URL:http//www.fda.gov/ cvm/fda/infores/vmac/antim18.htm

Frederick J. Angulo and Patricia M. Griffin Centers for Disease Control and Prevention, Atlanta, Georgia, USA