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

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.

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 to 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 log CFU/mL at 24 hours, respectively, under combined therapy, while in monotherapy the maximum bacterial load was reached.

Conclusions: The 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.