In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa

Background: The use of fosfomycin for treatment of systemic infections due to MDR Pseudomonas aeruginosa is increasing. However, pharmacodynamic data for fosfomycin are limited. Methods: Sixty-four clinical isolates of P. aeruginosa (MDR and non-MDR) from two Australian hospitals were collected; 59 isolates were from patients with cystic fibrosis and 5 isolates were from critically ill patients. The in vitro pharmacodynamic properties of fosfomycin (disodium) were investigated via MICs (all isolates) and, for selected isolates, via time-kill kinetics (static and dynamic models; concentration range, 1-1024 mg/L), population analysis profiles (PAPs) and post-antibiotic effect (PAE). Two inocula (similar to 10(6) and similar to 10(8) cfu/mL) were included in static time-kill studies to examine the effect of inocula on bacterial killing. Results: MICs ranged from 1 to >512 mg/L, with 61% of isolates considered fosfomycin susceptible (MIC <= 64 mg/L). The MIC distributions for MDR and non-MDR isolates were similar. Baseline PAPs indicated heteroresistance in all isolates tested. Time-kill studies showed moderate (maximum killing similar to 3 log(10) cfu/mL), time-dependent killing at the low inoculum with regrowth at 24 h. Most concentrations resulted in complete replacement of fosfomycin-susceptible colonies by fosfomycin-resistant colonies. Bacterial killing was virtually eliminated at the high inoculum. The PAE ranged from 0.3 to 5.5 h. Conclusions: These data suggest monotherapy with fosfomycin may be problematic for the treatment of infections caused by P. aeruginosa. Further investigation of fosfomycin combination therapy is warranted.