The synergistic effect of the combination of polymyxin B and rifampicin in a murine neutropenic thigh infection model with E. coli and K. pneumoniae.

BACKGROUND: Antibiotic combination therapy is increasingly used to treat MDR pathogens. In vitro studies suggest that the polymyxin B/rifampicin combination might be synergistic. Therefore, the pharmacodynamics of rifampicin as monotherapy and combined with polymyxin B were studied in Escherichia coli- and Klebsiella pneumoniae-infected mice. METHODS: The rifampicin pharmacokinetics (oral doses 0.5-64 mg/kg) in murine plasma were studied to estimate the exposures to rifampicin. These exposures were subsequently correlated with the antibacterial effect in a sigmoid maximum-effect model. The minimum exposures needed for a static, 1 log10 and 2 log10 kill effect in two E. coli and two K. pneumoniae strains were determined for monotherapy and the combination. The pharmacodynamic interactions between polymyxin B and rifampicin were assessed using Loewe additivity and Bliss independence in both an E. coli and a K. pneumoniae strain. RESULTS: Rifampicin monotherapy resulted in a static effect in E. coli but not against K. pneumoniae. When combined with polymyxin B, rifampicin fAUC/MIC needed for stasis, 1 log10 and 2 log10 kill effect decreased with increasing polymyxin B exposures for all strains. Synergy was confirmed in Loewe additivity (interaction indices 0.11-0.51 for E. coli and 0.04-0.19 for K. pneumoniae) and Bliss independence (267% and 863%). Maximal killing (>2 log10 kill) in combination therapy was found at rifampicin/polymyxin B fAUC/MIC of 0.68/32.56 for E. coli and 0.169/16.28 for K. pneumoniae. CONCLUSIONS: These in vivo studies confirmed that there is a clear synergistic effect between polymyxin B and rifampicin, which was stronger for the K. pneumoniae strain than for the E. coli strain.