Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing K. pneumoniae and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae . The rate and extent of killing with polymyxin B (1-128mg/L), rifampin (2-16mg/L), and meropenem (10-120mg/L) were evaluated against polymyxin B-susceptible (PB S ) and -resistant (PB R ) clinical isolates using 48h static time-kills. Additionally, humanized triple drug regimens of polymyxin B (C ss : 0.5, 1, 2mg/L), rifampin 600mg every 12 or 8h, and meropenem 1 or 2g every 8h dosed as an extended 3h infusion were simulated over 48h using a one-compartment in vitro dynamic infection model. Serial bacterial counts were measured to quantify pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PB S isolate followed by regrowth by 48h. Bactericidal activity was sustained at all polymyxin B concentrations ≥2 mg/L in combination with meropenem. No two-drug combinations were effective against the PB R isolate, but all simulated triple-drug regimens showed early bactericidal activity by 8h that was sustained over 48h against both strains. PAPs did not reveal the emergence of resistant subpopulations. The triple drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PB R KPC-producing K. pneumoniae . Further investigation is warranted to optimize triple combination therapy