title: Efficacy of trimethoprim in murine experimental infection with a thymidine kinase-deficient mutant of Escherichia coli.
abstract: The antimicrobial activity of trimethoprim is antagonized by thymidine in in vitro susceptibility tests. The purpose of this investigation was to determine whether this antagonism also occurred during experimental infection in mice, which have high serum thymidine concentrations. We derived a mutant strain of Escherichia coli, TT-48, incapable of utilizing exogenous thymidine from parent strain E. coli KC-14 and then investigated the in vitro and in vivo antimicrobial activities of trimethoprim, sulfamethoxazole, cefdinir, and ofloxacin against these strains. E. coli TT-48 lacked the activity of thymidine kinase, which catalyzes the conversion of thymidine to thymidylate, but its growth curve remained close to that of the parent strain. The MICs of all of the antimicrobial agents tested, except cefdinir, for the mutant strain were slightly inferior to those for the parent strain. The bactericidal effect of trimethoprim against the parent strain was antagonized by thymidine at concentrations of more than 1 microg/ml, while that against the mutant strain was not affected by thymidine even at the highest concentration (10 microg/ml). The therapeutic efficacy of trimethoprim in experimental murine infections was significantly higher when the mutant rather than the parent strain was used, whereas the therapeutic efficacy of cefdinir or ofloxacin, whose antimicrobial action is independent of folic acid synthesis, was the same with both strains. Unexpectedly, sulfamethoxazole also had similar efficacy against both strains. Thus, high thymidine concentrations antagonized the antimicrobial activity of trimethoprim in vitro and in vivo.
authors.affiliation: Department of Microbiology, Kyoto Pharmaceutical University, Yamashina-ku, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tokunaga
authors.forename: K
authors.initials: K
authors.lastname: Oka
authors.forename: A
authors.initials: A
authors.lastname: Takemoto
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtsubo
authors.forename: N
authors.initials: N
authors.lastname: Gotoh
authors.forename: T
authors.initials: T
authors.lastname: Nishino
mesh_terms: D000818:Animals; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D004927:Escherichia coli Infections / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D013936:Thymidine / Q000494:pharmacology; D013937:Thymidine Kinase / Q000172:deficiency*; D014295:Trimethoprim / Q000037:antagonists & inhibitors / Q000627:therapeutic use*
chemical_list: D014295:Trimethoprim; D013937:Thymidine Kinase; D013936:Thymidine