Meropenem prevents levofloxacin-induced resistance in penicillin-resistant pneumococci and acts synergistically with levofloxacin in experimental meningitis

The aim of the present study was to investigate the potential synergy between meropenem and levofloxacin in vitro and in experimental meningitis and to determine the effect of meropenem on levofloxacin-induced resistance in vitro. Meropenem increased the efficacy of levofloxacin against the penicillin-resistant pneumococcal strain KR4 in time-killing assays in vitro and acted synergistically against a second penicillin-resistant strain WB4. In the checkerboard, only an additive effect (FIC indices: 1.0) was observed for both strains. In cycling experiments in vitro, levofloxacin alone led to a 64-fold increase in the MIC for both strains after 12 cycles. Addition of meropenem in sub-MIC concentrations (0.25xMIC) completely inhibited the selection of levofloxacin-resistant mutants in WB4 after 12 cycles. In KR4, the addition of meropenem led to just a twofold increase in the MIC for levofloxacin after 12 cycles. Mutations detected in the genes encoding for topoisomerase IV (parC) and gyrase (gyrA) confirmed the levofloxacin-induced resistance in both strains. Addition of meropenem was able to completely suppress levofloxacin-induced mutations in WB4 and led to only one mutation in parE in KR4. In experimental meningitis, meropenem, given in two doses (2x125 mg/kg), produced a good bactericidal activity (-0.45 Deltalog(10) cfu/ml.h) comparable to one dose (1x10 mg/kg) of levofloxacin (-0.44 Deltalog(10) cfu/ml.h) against the penicillin-resistant strain WB4. Meropenem combined with levofloxacin acted synergistically (-0.93 Deltalog(10) cfu/ml.h), sterilizing the CSF of all rabbits.