In vitro pharmacokinetic/pharmacodynamic modeling of the effect of mucin on polymyxin B activity against Acinetobacter baumannii.

Abstract

The antibacterial efficacy of polymyxins in lungs may be impacted by mucin. The aim of this study was to characterize in vitro the effect of mucin on polymyxin B (PMB) activity against two multidrug-resistant Acinetobacter baumannii strains isolated from a patient before (AB121-D0) and after colistin treatment (AB122-D12), using a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. PMB binding to mucin was characterized by ultracentrifugation in cation-adjusted Mueller-Hinton broth (CAMHB) supplemented with 1% mucin. Time-kill (TK) experiments were performed in CAMHB, with 1% mucin or without as control, and with PMB total concentrations ranging from 0.25 to 512 mg/L based on the strain's minimum inhibitory concentration (MIC). For each strain, TK data were modeled based on unbound PMB concentrations. Bacterial resistance to PMB was investigated via MIC and whole genome sequencing from bacteria that regrew in the presence of antibiotics at the end of the TK experiments. PMB unbound fraction increased nonlinearly from 6% to 60% when total concentration increased from 0.5 to 512 mg/L. In addition to binding to PMB, mucin had an impact on PMB activity, which differed between the two strains. For AB121-D0, PMB activity increased in the presence of mucin resulting in a reduction of the bacterial regrowth, whereas for AB122-D12, a decrease in PMB activity was observed. Mutations in genes involved in PMB resistance appeared randomly and explained only partially the bacterial regrowth observed in TK with antibiotics. This study showed that PMB binding to mucin had a real and important impact but was not the only factor explaining the impaired PMB efficacy in the presence of mucin.