Pharmacokinetic and pharmacodynamic properties of polymyxin B in Escherichia coli and Klebsiella pneumoniae murine infection models

BACKGROUND: Although polymyxin B has been in use since the late 1950s, there have been limited studies done to unravel its pharmacokinetics (PK) and pharmacodynamics (PD) index. METHODS: We determined, in neutropenic infected mice, the PK, plasma protein binding and PK/PD index best correlating with efficacy for Escherichia coli and Klebsiella pneumoniae strains. RESULTS: The pharmacokinetic profile showed non-linear PK; dose was significantly correlated with absorption rate and clearance. The inhibitory sigmoid dose–effect model for the fC(max)/MIC index of E. coli fitted best, but was only modestly higher than the R(2) of %fT(>)(MIC) and fAUC/MIC (R(2) 0.91–0.93). For K. pneumoniae the fAUC/MIC index had the best fit, which was slightly higher than the R(2) of %fT(>)(MIC) and fC(max)/MIC (R(2) 0.85–0.91). Static targets of polymyxin B fAUC/MIC were 27.5–102.6 (median 63.5) and 5.9–60.5 (median 11.6) in E. coli and in K. pneumoniae isolates, respectively. A 1 log kill effect was only reached in two E. coli isolates and one K. pneumoniae. The PTA with the standard dosing was low for isolates with MIC >0.25 mg/L. CONCLUSIONS: This study confirms that fAUC/MIC can describe the exposure–response relationship for polymyxin B. The 1 log kill effect was achieved in the minority of the isolates whereas polymyxin B PK/PD targets cannot be attained for the majority of clinical isolates with the standard dosing regimen, indicating that polymyxin B may be not effective against serious infections as monotherapy.