A pharmacokinetic and pharmacodynamic evaluation of iclaprim activity against wild-type and corresponding thymidine kinase-deficient Staphylococcus aureus in a mouse abscess model

The efficacy of iclaprim against Staphylococcus aureus ATCC 25923 and its corresponding isogenic TK-deficient mutant S. aureus strain AH 1246 mixed with cytodex beads was studied in a mouse abscess infection model. Iclaprim (2-80 mg kg^-1) administered as a single dose via the subcutaneous route (2 h post-infection) was efficacious against the TK-deficient mutant with 1 and 2 log10 c.f.u. reductions at the 24 h post initiation of treatment time point, at doses of 14.4 and 30 mg kg^-1, respectively. In contrast, poor antibacterial activity was observed against corresponding wild-type (TK-competent) S. aureus strain, ATCC 25923, at all doses tested. The PK/PD parameter which appeared to correlate best with efficacy was AUC/MIC (R²=0.91). This study showed that TK-deficient mutants may be used to evaluate DHFRi activity and PK/PD relationship in a mouse abscess model.