Polymyxin B and fosfomycin thwart KPC-producing Klebsiella pneumoniae in the hollow-fibre infection model

Polymyxin B (PMB) and fosfomycin are two 'old' antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, the use of each antibiotic in monotherapy has been associated with high rates of treatment failure. Therefore, the objective of this study was to investigate the combinatorial pharmacodynamics of PMB and fosfomycin against KPC-producing K. pneumoniae (KPC-Kp). PMB front-loading (3.33 mg/kg for one dose, followed by 1.43 mg/kg every 12 h starting 12 h later) and burst (5.53 mg/kg for one dose, with no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4 g every 8 h) against KPC-2-producing K. pneumoniae ST258 in a hollow-fibre infection model over 120 h. Population analysis profiles were used to track the temporal PMB and fosfomycin resistance profiles. Against isolate KPC-Kp 9A (PMB MIC = 0.5 mg/L; fosfomycin MIC ≤ 8 mg/L), monotherapies resulted in >3 log10 CFU/mL killing within 3 h but re-growth and proliferation of resistant subpopulations within 48 h. PMB combinations with fosfomycin demonstrated rapid bacterial killing (>6 log10 CFU/mL reductions) while preventing propagation of PMB and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC = 0.5 mg/L; fosfomycin MIC = 32 mg/L), a PMB burst and fosfomycin combination caused a >6 log10 CFU/mL reduction within 1 h, although bacterial re-growth occurred with the amplification of fosfomycin-resistant subpopulations. PMB in combination with fosfomycin may provide a practicable treatment strategy against KPC-Kp and warrants further investigation.