Article Dans Une Revue International Journal of Antimicrobial Agents Année : 2025

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

Zhigang Wang
Christer Malmberg
Pernilla Lagerbäck
Thomas Tängdén

Résumé

Objectives: To expand a translational pharmacokinetic-pharmacodynamic (PK/PD) modelling approach for assessing the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae.
Methods: A PK/PD 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 PK/PD 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 PK/PD 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.

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Dates et versions

hal-05144878 , version 1 (04-07-2025)

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Chenyan Zhao, Sanne van den Berg, Zhigang Wang, Anna Olsson, Vincent Aranzana-Climent, et al.. An integrative and translational PK/PD modelling approach to explore the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae. International Journal of Antimicrobial Agents, 2025, 65 (3), pp.107443. ⟨10.1016/j.ijantimicag.2025.107443⟩. ⟨hal-05144878⟩

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