Synergistic Activity of Colistin/Fosfomycin Combination against Carbapenemase-Producing<i> Klebsiella pneumoniae</i> in an<i> In Vitro</i> Pharmacokinetic/Pharmacodynamic Model

Abstract

Carbapenemase-producing <i>Klebsiella pneumoniae</i> is globally recognized as one of the greatest threats to public health, and combination therapy may be the chemotherapeutic option. In the present study, we aimed to evaluate the antibacterial effects of colistin/fosfomycin combination against carbapenemase-producing <i>K. pneumoniae</i>. The antibacterial effects were determined in a one-compartment <i>in vitro</i> pharmacokinetic model over a period of 24 h. The initial inoculum was 10⁸ CFU/mL. Low, medium, and high <i>C</i>_max values of colistin at 0.5, 2, and 5 mg/L as well as <i>C</i>_max of fosfomycin at 100 mg/L were simulated in the model. Doses of both colistin and fosfomycin were given every 8 h until 24 h. For the colistin- and fosfomycin-susceptible isolate KP47, three combination regimens showed greater killing effect compared with colistin monotherapy. The greatest killing effect was observed in combination regimen containing 5 mg/L colistin. For colistin-heteroresistant and fosfomycin-susceptible isolate KP79, combination regimen containing low dose colistin (0.5 mg/L) showed no synergistic or additive effects. However, combination regimens containing 2 and 5 mg/L colistin maintained the bactericidal effect until 24 h compared with colistin monotherapy. For colistin-heteroresistant and fosfomycin-resistant isolates KP42 and KP11, bactericidal activity was barely enhanced by combination regimens. Moreover, combination regimen containing 5 mg/L colistin could only prevent the emergence of colistin-resistant subpopulation in colistin and fosfomycin-susceptible isolate. It is necessary to know the resistant patterns of the <i>K. pneumoniae</i> before using combination of colistin and fosfomycin in clinical practice.