Pharmacokinetic-pharmacodynamic modeling using combined time-kill data for meropenem and colistin or polymyxin B combination effects in Acinetobacter baumannii

Acinetobacter baumannii is a high-priority pathogen with increasing antimicrobial resistance levels, requiring combination treatment. We aimed to develop a pharmacokinetic-pharmacodynamic model of meropenem with colistin/polymyxin B against A. baumannii based on a systematic review of time-kill experiments to inform the effectiveness of this combination. PubMed was systematically searched for all studies describing time-kill experiments of meropenem and colistin/polymyxin B combinations against A. baumannii . Time-kill data and strain metadata were extracted. A pharmacokinetic-pharmacodynamic model with logistic growth, sigmoidal Emax killing functions of monotherapies, time-dependent attenuation of drug effect, and general pharmacodynamic interaction for the combination effect was fitted. Simulations were performed to produce dose recommendations. A total of 21 eligible papers were found reporting data from 369 experiments on 53 strains. Minimum inhibitory concentration (MIC) on EC50 (concentration achieving half-maximum killing), inoculum on Emax (maximum killing rate), and beta-lactamases on Emax for meropenem were covariates and both drugs. EC50 of both drugs included interisolate variability. The model showed that colistin/polymyxin B increased meropenem Emax and decreased its EC50. No interisolate variability in the interaction was supported by the model. Simulations showed that in pneumonia, undetectable growth at 24 h can be achieved with a probability of >90% only in strains with meropenem MIC ≤16 mg/L. The model suggests that colistin/polymyxin B enhances meropenem activity across a diverse set of strains but does not achieve adequate target attainment in resistant strains (colistin/polymyxin B MIC ≥1 mg/L and/or meropenem MIC >8 mg/L). The presence of acquired beta-lactamases reduces the effect of meropenem.