Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae

KPC-producing Klebsiella pneumoniae causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing K. pneumoniae. The activities of combination antimicrobials were also determined by the checkerboard method. The MIC50 and MIC90 of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (fT > MIC). The monotherapy MIC(50)s and MIC(90)s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC(50)s and to 1/8 to 1/16 the MIC(90)s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC50 and MIC90 had better chances of achieving >= 90% probability of target attainment (PTA) of 70% fT > MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40% fT > MIC for MIC50 but not MIC90. The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing K. pneumoniae.