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Antimicrobial Agents and Chemotherapy, September 2009, p. 3635-3641, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00325-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Efficacy of Iclaprim against Wild-Type and Thymidine Kinase-Deficient Methicillin-Resistant Staphylococcus aureus Isolates in an In Vitro Fibrin Clot Model{triangledown}

José M. Entenza,1* Andreas Haldimann,2 Marlyse Giddey,1 Sergio Lociuro,2 Stephen Hawser,2,{dagger} and Philippe Moreillon1

Department of Fundamental Microbiology, Biophore Building, University of Lausanne, 1015 Lausanne, Switzerland,1 Arpida AG, Duggingerstrasse 23, 4153 Reinach, Switzerland2

Received 10 March 2009/ Returned for modification 14 April 2009/ Accepted 22 June 2009

Iclaprim is a novel diaminopyrimidine antibiotic that is 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. Unlike with humans, for whom thymidine levels are low, thymidine levels in rodents are high, thus precluding the 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, which were aimed at mimicking vegetation structure, were made from human or rat plasma containing either the parent AW6 or the mutant AH1252, and they were exposed to homologous serum supplemented with iclaprim (3.5 µg/ml), trimethoprim-sulfamethoxazole (TMP-SMX; 8/40 µg/ml), vancomycin (40 µg/ml), or saline, each of which was 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 most active drug against AW6 (P < 0.05), but it showed an activity similar those of 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 of animals using simulated human kinetics of iclaprim and thymidine kinase-deficient MRSA, which eliminate the thymidine-induced confounding effect, are warranted to support the use of iclaprim in the treatment of severe MRSA infections in humans.

* Corresponding author. Mailing address: Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland. Phone: (4121) 6925612. Fax: (4121) 6925605. E-mail: jose.entenza{at}unil.ch

{triangledown} Published ahead of print on 29 June 2009.

{dagger} Present address: IHMA Europe, 4 Route de la Corniche, CH-1066 Epalinges, Switzerland.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3635-3641, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00325-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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