In vivo activity and pharmacodynamics of cefotaxime or ceftriaxone in combination with fosfomycin in fibrin clots infected with highly penicillin-resistant Streptococcus pneumoniae.

Using a clinical pneumococcal strain for which MICs were 2, 0.5, 0.5, and 16 mg/liter for penicillin, cefotaxime, ceftriaxone, and fosfomycin, respectively, we studied the efficacies of these antibiotics alone and in combination in one or two doses or in continuous infusion over6hinthetreatment of the prolonged (48-h) experimental fibrin clot infections in rabbits. Doses were chosen to obtain low antibiotic concentrations. We observed the highest bacterial reductions (change in log10 CFU per gram) with the following five regimens: combination of cefotaxime plus fosfomycin given in two divided doses 6 h apart (each at 50 mg/kg of body weight given intravenously (4.2 60.7 CFU/g), ceftriaxone (8 mg/kg given once intravenously) along with one or two doses of fosfomycin (3.79 60.6 and 3.95 60.5 CFU/g), cefotaxime alone administered in two divided doses (3.6 60.4 CFU/g), and a 6-h continuous infusion of cefotaxime (100 mg/kg) with fosfomycin (100 mg/kg) (3.5 6 0.4 CFU/g). The bacterial reductions obtained with these five regimens were all higher than those obtained with the other regimens tested (P< 0.05). The time of bacterial regrowth was significantly delayed with the two doses of the cefotaxime-fosfomycin regimens (23.2 6 11 h) compared with those with the other combinations (P< 0.05). The rate of bacterial regrowth with this regimen was even lower than that observed withcefotaximealonegivenintwodoses(P<0.05).Thecriticalconcentration,belowwhichbacterialregrowth was observed, was lower for antibiotics in the combinations; the most important decrease in this concentration was with fosfomycin: 27.3 65.6 mg/liter for fosfomycin alone versus 14.7 612 mg/liter for fosfomycin in the combinations (P< 0.05). By a multivariate analysis, the most important independent parameters for efficacy were the maximal concentrations of b-lactam antibiotics and the residual concentration of fosfomycin and, for the combinations, the log of the area under the concentration-time curve/MIC ratio for b-lactam antibiotics. From these findings, the combinations cefotaxime or ceftriaxone plus fosfomycin could be proposed for the treatment of infections caused by highly penicillin-resistant pneumococci.