Evaluation of Activity and Emergence of Resistance of Polymyxin B and ZTI-01 (Fosfomycin for Injection) against KPC-Producing Klebsiella pneumoniae

Abstract

ZTI-01 (fosfomycin for injection) is a broad-spectrum antibiotic with a novel mechanism of action and is currently under development in the United States for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multidrug-resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing <i>Klebsiella pneumoniae</i> and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MIC of polymyxin B[MIC_PMB], 0.5 mg/liter; MIC of fosfomycin [MIC_FOF], 32 mg/liter) and BRKP67 (MIC_PMB, 8 mg/liter; MIC_FOF, 32 mg/liter) at an initial inoculum of 10⁷ CFU/ml, were evaluated over 168 h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5-mg/kg loading dose as a 2 h-infusion followed by 1.5-mg/kg dose every 12 h [q12h] as a 1-h infusion) and fosfomycin (6 g q6h as a 1-h or 3-h 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 24 h. Polymyxin B plus a fosfomycin 1-h infusion demonstrated sustained bactericidal activity by 4 h, with undetectable colony counts beyond 144 h. Polymyxin B plus a fosfomycin 3-h infusion demonstrated bactericidal activity at 4 h, followed by regrowth similar to that of the control by 144 h. PAPs revealed resistant subpopulations by 120 h. The combination of polymyxin B and a fosfomycin 1-h infusion is a promising treatment option for KPC-producing <i>K. pneumoniae</i> and suppresses the emergence of resistance. Further evaluation of novel dosing strategies is warranted to optimize therapy.