Efficacy of ME1036 against meticillin-resistant Staphylococcus aureus and vancomycin-insensitive S. aureus in a model of haematogenous pulmonary infection.
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ME1036, a novel parenteral carbapenem, was developed for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA). A model of haematogenous pulmonary infection was induced in mice by tail vein injection of MRSA strain NUMR101 or VISA Mu50 enmeshed in agar beads. After 24h of infection, mice were treated twice daily for 7 days with 200mg/kg/day vancomycin (VCM) or ME1036. Mice infected with VISA were also pre-treated with cyclophosphamide to induce an immunocompromised state. The number of viable bacteria in the lungs was counted 12h after the final drug treatment. VCM decreased the number of viable MRSA in the lungs in comparison with the control, although the difference was not significant (mean+/-standard error of the mean log(10) colony-forming units (CFU)/lung=6.876+/-0.54 vs. 8.25+/-0.41, respectively). In contrast, treatment with ME1036 resulted in a significant decrease in the number of viable MRSA (log(10)CFU/lung=2.69+/-0.44 (n=6); P<0.0001) compared with both the VCM-treated and control mice. In the VISA-infected mice, ME1036 significantly reduced the number of viable bacteria compared with VCM and control (log(10)CFU/lung=3.65+/-0.68 for ME1036 vs. 5.71+/-0.75 for VCM (P<0.05) and 7.07+/-0.45 for control (P<0.001)). ME1036 produced >3 log(10) reduction versus control against both MRSA strains (>5 log for the VCM-susceptible strain and 3.4 log for the VISA), whereas VCM produced <1.3 log for both strains.