Efficacy of ME1036 against meticillin-resistant Staphylococcus aureus and vancomycin-insensitive S. aureus in a model of haematogenous pulmonary infection

Abstract

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 24 h of infection, mice were treated twice daily for 7 days with 200 mg/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 12 h 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.