IN-VIVO ACTIVITY AND PHARMACODYNAMICS OF AMOXICILLIN IN COMBINATION WITH FOSFOMYCIN IN FIBRIN CLOTS INFECTED WITH HIGHLY PENICILLIN-RESISTANT STREPTOCOCCUS-PNEUMONIAE

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 combinati ons in the treatment of prolonged (48-h) experimental fibrin clot infe ction 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), o r two doses 6 h apart (Amo20 x 2 and Amo50 x 2); fosfomycin IV at a fi xed dose of 50 mg/kg in one dose (Fos50) or two divided doses 6 h apar t (Fos50 x 2); or the combinations of amoxicillin and fosfomycin with the same schedules, Maximum concentrations in clots were 2.03 +/- 1.02 and 2.13 +/- 0.33 mg/liter for Amo20 regimens, 3.7 +/- 1.9 and 4 +/- 1.3 mg/liter for Amo50 regimens, and 24 +/- land 40 +/- 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 betwee n 5 and 7 h for fosfomycin, We observed the highest bacterial reductio ns (log(10) CFU/gram) for Amo50 in two divided doses with or without f osfomycin, A significantly higher bacterial reduction than that with e ach monotherapy was observed when Amo20 was combined with fosfomycin i n either one dose or two doses 6 h apart (0.16 +/- 0.8 and 1.64 +/- 1. 6 log(10) CFU/g for Amo20 in one and two doses, respectively, and 0.93 +/- 0.81 and 0.61 +/- 0.56 log(10) CFU/g for fosfomycin in one and tw o doses, respectively, versus 3.36 +/- 1.26 and 3.16 +/- 1.31 log(10) CFU/g for Amo20 plus fosfomycin in one and two doses, respectively [P < 0.001]), A time-dependent effect was observed with amoxicillin regim ens, The time of regrowth was significantly delayed when amoxicillin w as combined with fosfomycin, By using a multivariate analysis, we demo nstrated that the most important parameter correlated to efficacy of t he combination amoxicillin-fosfomycin was the length of the period dur ing which the concentration of amoxicillin remained above the MIG. We demonstrated that the in vivo efficacy of the combination of amoxicill in and fosfomycin gave higher antibacterial effect than each monothera py.