IN-VIVO ACTIVITY AND PHARMACODYNAMICS OF CEFOTAXIME OR CEFTRIAXONE INCOMBINATION 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 fosfomyci n, respectively, we studied the efficacies of these antibiotics alone and in combination in one or two doses or in continuous infusion over 6 h in the treatment of the prolonged (48-h) experimental fibrin clot infections in rabbits, Doses were chosen to obtain low antibiotic conc entrations, We observed the highest bacterial reductions (change in lo g(10) CFU per gram) with the following five regimens: combination of c efotaxime plus fosfomycin given in two divided doses 6 h apart (each a t 50 mg/kg of body weight given intravenously (4.2 +/- 0.7 CFU/g), cef triaxone (8 mg/kg given once intravenously) along with one or two dose s of fosfomycin (3.79 +/- 0.6 and 3.95 +/- 0.5 CFU/g), cefotaxime alon e administered in two divided doses (3.6 +/- 0.4 CFU/g), and a 6-h con tinuous infusion of cefotaxime (100 mg/kg) with fosfomycin (100 mg/kg) (3.5 +/- 0.4 CFU/g). The bacterial reductions obtained with these fiv e regimens were all higher than those obtained with the other regimens tested (P < 0.05), The time of bacterial regrowth was significantly d elayed with the two doses of the cefotaxime-fosfomycin regimens (23.2 +/- 11 h) compared with those with the other combinations (P < 0.05), The rate of bacterial regrowth with this regimen was even lower than t hat observed with cefotaxime alone given in two doses (P < 0.05), The critical concentration, below which bacterial regrowth was observed, w as lower for antibiotics in the combinations; the most important decre ase in this concentration was with fosfomycin: 27.3 +/- 5.6 mg/liter f or fosfomycin alone versus 14.7 +/- 12 mg/liter for fosfomycin in the combinations (P < 0.05). By a multivariate analysis, the most importan t independent parameters for efficacy were the maximal concentrations of beta-lactam antibiotics and the residual concentration of fosfomyci n and, for the combinations, the log of the area under the concentrati on-time curve/MIC ratio for beta-lactam antibiotics, From these findin gs, the combinations cefotaxime or ceftriaxone plus fosfomycin could b e proposed for the treatment of infections caused by highly penicillin -resistant pneumococci.