Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance

Fosfomycin resistance occurs rapidly with monotherapy. This study systematically investigated bacterial killing and emergence of fosfomycin resistance with fosfomycin combinations against Pseudomonas aeruginosa. Four clinical isolates and a reference strain of P. aeruginosa were employed. Combinations of fosfomycin plus polymyxin B, tobramycin or ciprofloxacin were examined over 24 h using time-kill studies (inocula similar to 10(6) cfu/mL) incorporating clinically relevant concentrations (fosfomycin, 30, 150 or 300 mg/L; polymyxin B, 0.5, 1 or 2 mg/L; tobramycin, 0.5, 1.5 or 4 mg/L; ciprofloxacin, 0.5, 1 or 2.5 mg/L). Microbiological response was examined by log changes and population analysis profiles. Against susceptible isolates, monotherapy produced varying degrees of initial killing followed by rapid regrowth. Fosfomycin plus polymyxin B or tobramycin produced greater initial killing (up to similar to 4 log(10) cfu/mL) with many concentrations compared with monotherapy against fosfomycin-susceptible (FOFS) isolates. With these combinations, synergy or additivity was observed in 54 (67%) and 49 (60%) of 81 cases (nine combinations across three isolates at three timepoints) for polymyxin B and tobramycin, respectively. Substantial improvements in killing were absent against fosfomycin-resistant (FOFR) isolates. For fosfomycin/ciprofloxacin combinations, synergy or additivity was observed against FOFR isolates in 33 of 54 (61%) cases (nine combinations across two isolates at three timepoints), while improvements in killing were largely absent against FOFS isolates. No combination prevented emergence of fosfomycin resistance. Against P. aeruginosa, fosfomycin in combination with polymyxin B or tobramycin (FOFS isolates) or ciprofloxacin (FOFR isolates) increased bacterial killing, but did not suppress emergence of fosfomycin resistance.