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

International Journal of Antimicrobial Agents
Zackery P BulmanBrian T Tsuji

Abstract

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 propagat...Continue Reading

Citations

Dec 14, 2018·Journal of Clinical Microbiology·Fereshteh EzadiReza Mirnejad
Apr 1, 2020·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·P Wistrand-YuenT Tängdén
Jan 28, 2021·Infection and Drug Resistance·Xing TanZackery P Bulman
Apr 16, 2021·International Journal of Antimicrobial Agents·Luigia ScudellerEvelina Tacconelli

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