Polymyxin B and ZTI-01 (fosfomycin for injection) against KPC-producing Klebsiella pneumoniae: Evaluation of activity and emergence of resistance [PublishAheadOfPrint]

ZTI-01 (fosfomycin for injection) is a broad spectrum antibiotic with a novel mechanism of action and is currently under development in the USA for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multi-drug resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing K. pneumoniae and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MICPMB: 0.5mg/L, MICFOF: 32mg/L) and BRKP67 (MICPMB: 8mg/L, MICFOF: 32mg/L) at initial inoculum of 10⁷ CFU/mL were evaluated over 168h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5mg/kg loading dose as a 2h infusion followed by 1.5mg/kg q12h as a 1h infusion) and fosfomycin (6g q6h as a 1h or 3h infusion) regimens alone and in combination. Population analysis profiles (PAPs), and MIC testing were performed to assess emergence of resistance. Polymyxin B or fosfomycin monotherapy was ineffective and selected for resistance by 24h. Polymyxin B plus fosfomycin 1h infusion demonstrated sustained bactericidal activity by 4h with undetectable colony counts beyond 144h. Polymyxin B plus fosfomycin 3h infusion demonstrated bactericidal activity at 4h followed by regrowth similar to control by 144h. PAPs revealed resistant subpopulations by 120h. The combination of polymyxin B and fosfomycin 1h infusion is a promising treatment option for KPC-producing K. pneumoniae and suppresses the emergence of resistance. Further evaluation of novel dosing strategies is warranted to optimize therapy.

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