Pharmacodynamic studies of nitrofurantoin against common uropathogens

Objectives: To determine the pharmacokinetic/pharmacodynamic index that best correlates to nitrofurantoin's antibacterial effect, we studied nitrofurantoin activity against common causative pathogens in uncomplicated urinary tract infection (UTI). Methods: Five isolates [two Escherichia coli (one isolate producing the ESBL CTX-M-15), two Enterococcus faecium (including one that was vancomycin resistant) and one Staphylococcus saprophyticus] were used. The MICs of nitrofurantoin were determined by Etest. Time-kill curves with different concentrations of nitrofurantoin (based on multiples of isolate-specific MICs) were followed over 24 h. An in vitro kinetic model was used to simulate different time-concentration profiles, exposing E. coli to nitrofurantoin for varying proportions of the dosing interval. The outcome parameters reduction in cfu 0-24 h (Delta(cfu0-24)) and the area under the bactericidal curve (AUBC), were correlated with time over MIC (T->MIC) and area under the antibiotic concentration curve divided by the MIC (AUC/MIC). Results: A bactericidal effect at varying static drug concentrations was achieved for all isolates. All isolates showed similar kill curve profiles. In the kinetic model, the effect of nitrofurantoin on E. coli displayed a 4 log reduction in cfu/mL within 6 h at 8xMIC. The outcome parameters Delta(cfu0-24) and AUBC had a good correlation with T->MIC (R approximate to 0.83 and R approximate to 0.67, respectively), whereas log(AUC/MIC) was significantly poorer (R approximate to 0.39 and R approximate to 0.53, respectively). Conclusions: Nitrofurantoin was highly effective against E. coli and S. saprophyticus isolates; the killing effect against E. faecium was not as rapid, but still significant. Against E. coli, nitrofurantoin was mainly associated with a concentration-dependent action; this was confirmed in the kinetic model, in which T->MIC displayed the best correlation.