vivo activity and pharmacodynamics of amoxicillin in combination with fosfomycin in fibrin clots infected with highly penicillin-resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother

Using a clinical pneumococcal strain for which MICs were 4, 2, and 32 mg/liter for penicillin, amoxicillin, and fosfomycin, respectively, we studied the efficacies of these antibiotics alone and their combinations in the treatment of prolonged (48-h) experimental fibrin clot infection in rabbits. Treatments were as follows: amoxicillin IV at 20 mg/kg of body weight in one dose (Amo20), 50 mg/kg in one dose (Amo50), or two doses 6 h apart (Amo20 3 2 and Amo50 3 2); fosfomycin IV at a fixed dose of 50 mg/kg in one dose (Fos50) or two divided doses 6 h apart (Fos50 3 2); or the combinations of amoxicillin and fosfomycin with the same schedules. Maximum concentrations in clots were 2.03 6 1.02 and 2.13 6 0.33 mg/liter for Amo20 regimens, 3.7 6 1.9 and 4 6 1.3 mg/liter for Amo50 regimens, and 24 6 7 and 40 6 8 mg/liter for fosfomycin regimens, respectively. The mean half-lives of elimination from clots were between 2 and 3 h for amoxicillin regimens and between 5 and 7 h for fosfomycin. We observed the highest bacterial reductions (log10 CFU/gram) for Amo50 in two divided doses with or without fosfomycin. A significantly higher bacterial reduction than that with each monotherapy was observed when Amo20 was combined with fosfomycin in either one dose or two doses 6 h apart (0.16 6 0.8 and 1.64 6 1.6 log10 CFU/g for Amo20 in one and two doses, respectively, and 0.93 6 0.81 and 0.61 6 0.56 log10 CFU/g for fosfomycin in one and two doses, respectively, versus 3.46 6 1.26 and 3.16 6 1.31 log10 CFU/g for Amo20 plus fosfomycin in one and two doses, respectively [P < 0.001]). A time-dependen