Entenza JM, Haldimann A, Giddey M, Lociuro S, Hawser S, Moreillon P
Efficacy of Iclaprim against Wild-Type and Thymidine kinase-Deficient Methicillin-Resistant Staphylococcus aureus in an In Vitro Fibrin-Clot Model. [JOURNAL ARTICLE]
Antimicrob Agents Chemother 2009 Jun 29.
Iclaprim is a novel diaminopyrimidine antibiotic active against methicillin-resistant Staphylococcus aureus (MRSA). However, it is known that the activity of diaminopyrimidines against S. aureus is antagonized by thymidine, through uptake and conversion to thymidylate by thymidine kinase. In contrast to humans, where thymidine levels are low, thymidine levels in rodents are high, thus precluding accurate evaluation of iclaprim efficacy in animal models. We have studied the bactericidal activity of iclaprim against an isogenic pair of MRSA isolates, the wild-type parent AW6 and its thymidine kinase-deficient mutant AH1252, in an in vitro fibrin-clot model. Clots, aimed at mimicking vegetation structure, were made from human or rat plasma containing either the parent AW6 or the mutant AH1252, and exposed to homologous serum supplemented with iclaprim (3.5 microg/ml), trimethoprim-sulfamethoxazole (TMP-SMX; 8-40 microg/ml), vancomycin (40 microg/ml) or saline, added one time for 48 h. In rat clots, iclaprim and TMP-SMX were bacteriostatic against the parent AW6. In contrast, they were bactericidal (>/=3 log10 CFU/clot killing of the original inoculum) against the mutant AH1252. Vancomycin was the more active drug against AW6 (P< 0.05) but showed a similar activity when compared with iclaprim and TMP-SMX against AH1252. In human clots, iclaprim was bactericidal against both AW6 and AH1252 strains, and was as effective as TMP-SMX and vancomycin (P> 0.05). Future studies in animals using simulated human kinetics of iclaprim and thymidine kinased-deficient MRSA, which eliminate thymidine-induced confounding effect, are warranted to support the use of iclaprim in the treatment of severe MRSA infections in humans.
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