Semi-mechanistic PK-PD modelling of combined polymyxin B and minocycline against a polymyxin-resistant strain of Acinetobacter baumannii
Résumé
OBJECTIVES: The goal of this study was to expand on previous reports of synergy between polymyxin B and minocycline against Acinetobacter baumannii and gain insights on the qualitative and quantitative determinants of the synergy.METHODS: A semi-mechanistic PK/PD model was developed based on data from in vitro time-kill experiments data with determination of resistant bacterial count to describe the effects of polymyxin B and minocycline alone and in combination. The model was enriched by complementary experiments providing information on the characteristics of the resistant sub-population.RESULTS: The model successfully described the data and made possible quantification of the strength of interaction between the two drugs and formulation of hypotheses about the mechanisms of the observed interaction. The effect of the combination is driven by minocycline with polymyxin B acting as an helper drug; simulations at clinically achievable concentrations showed that 1.5 mg/L minocycline + 0.2 mg/L polymyxin B is expected to produce sustained killing over 30h while 0.3 mg/L minocycline + 1 mg/L polymyxin B is met by bacterial regrowth. Interaction equations show that maximal synergy is reached for polymyxin B concentrations ≥0.1 mg/L and minocycline concentrations ≥1 mg/L CONCLUSIONS: Semi-mechanistic PK/PD modelling was used to investigate the quantitative determinants of synergy between polymyxin B and minocycline on a polymyxin B resistant A. baumannii strain. The developed model, improving on usual study techniques, showed asymmetry in the drug interaction as polymyxin B acted mostly as an helper to minocycline, and provide simulations as a tool for future studies.
Origine : Fichiers produits par l'(les) auteur(s)
