An integrative and translational PKPD modelling approach to explore the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae

Abstract

Objectives

To expand a translational pharmacokinetic–pharmacodynamic (PKPD) modelling approach for assessing the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae.

Methods

A PKPD model developed based on in vitro static time-kill experiments of one strain (ARU613) was first translated to characterize that of a more susceptible strain (ARU705), and thereafter to dynamic time-kill experiments (both strains) and to a murine thigh infection model (ARU705 only). The PKPD model was updated stepwise using accumulated data. Predictions of bacterial killing in humans were performed.

Results

The same model structure could be used in each translational step, with parameters being re-estimated. Dynamic data were well predicted by static-data-based models. The in vitro/in vivo differences were primarily quantified as a change in polymyxin B effect: a lower killing rate constant in vivo compared with in vitro (concentration of 3 mg/L corresponds to 0.05/h and 57/h, respectively), and a slower adaptive resistance rate (the constant in vivo was 2.5% of that in vitro). There was no significant difference in polymyxin B–minocycline interaction functions. Predictions based on both in vitro and in vivo parameters indicated that the combination has a greater-than-monotherapy antibacterial effect in humans, forecasting a reduction of approximately 5 and 2 log₁₀ colony-forming units/mL at 24 h, respectively, under combined therapy, while the maximum bacterial load was reached in monotherapy.

Conclusions

This study demonstrated the utility of the PKPD modelling approach to understand translation of antibiotic effects across experimental systems, and showed a promising antibacterial effect of polymyxin B and minocycline in combination against K. pneumoniae.