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

Chenyan Zhao; Sanne van den Berg; Zhigang Wang; Anna Olsson; Vincent Aranzana-Climent; Christer Malmberg; Pernilla Lagerbäck; Thomas Tängdén; Anouk E Muller; Elisabet I Nielsen; Lena E Friberg

doi:10.1016/j.ijantimicag.2025.107443

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

Int J Antimicrob Agents. 2025 Jan 8:107443. doi: 10.1016/j.ijantimicag.2025.107443. Online ahead of print.

Affiliations

¹ Department of Pharmacy, Uppsala University, SE-75123, Uppsala, Sweden.
² Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
³ Department of Medical Sciences, Uppsala University, SE-75185, Uppsala, Sweden.
⁴ Université de Poitiers, INSERM U1070, PHAR2, Poitiers, France.
⁵ Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; Department of Medical Microbiology, Haaglanden Medisch Centrum, P.O. Box 432, 2501 CK, The Hague, the Netherlands.
⁶ Department of Pharmacy, Uppsala University, SE-75123, Uppsala, Sweden. Electronic address: lena.friberg@uu.se.

PMID: 39793934
DOI: 10.1016/j.ijantimicag.2025.107443

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.

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 log₁₀ 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.

Keywords: antibiotic combination; minocycline; polymyxin B; semi-mechanistic pharmacokinetic-pharmacodynamic model; translational pharmacokinetic-pharmacodynamic modelling.