Efficacy of iclaprim against wild-type and thymidine kinase-deficient methicillin-resistant Staphylococcus aureus isolates in an in vitro fibrin clot model.

Détails

ID Serval
serval:BIB_426271D5C34A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Efficacy of iclaprim against wild-type and thymidine kinase-deficient methicillin-resistant Staphylococcus aureus isolates in an in vitro fibrin clot model.
Périodique
Antimicrobial Agents and Chemotherapy
Auteur⸱e⸱s
Entenza J.M., Haldimann A., Giddey M., Lociuro S., Hawser S., Moreillon P.
ISSN
1098-6596[electronic]
Statut éditorial
Publié
Date de publication
2009
Volume
53
Numéro
9
Pages
3635-3641
Langue
anglais
Résumé
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 microg/ml), trimethoprim-sulfamethoxazole (TMP-SMX; 8/40 microg/ml), vancomycin (40 microg/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 (> or = 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.
Pubmed
Web of science
Open Access
Oui
Création de la notice
07/10/2009 15:07
Dernière modification de la notice
20/08/2019 13:44
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