Introduction. Antimicrobial resistance in Gram-negative bacteria is one of the three greatest threats to human health according to the WHO, EU and other organisations. Multi-drug resistant Gram-negative bacteria commonly cause serious infections with a high rate of mortality and high degree of morbidity. In the past, β-lactams and aminoglycosides were successfully used to treat susceptible Gram-negative bacteria. Unfortunately, isolates emerged that are resistant to all or almost all antibiotics in monotherapy. The high rates of resistance and decline in new approved antibiotics highlight the urgent need for alternative treatment options such as rationally optimised combination therapies
Aim. To identify and rationally optimise via novel mechanism-based modelling β-lactam plus aminoglycoside combinations that synergistically kill and prevent resistance of carbapenem-resistant A. baumannii.
Methods. We studied combinations of ten β-lactams and three aminoglycosides against four A. baumannii strains, including two imipenem-intermediate (MICIPM: 4 mg/L) and one imipenem-resistant (MICIPM: 32 mg/L) clinical isolate, using high inoculum static concentration time-kill studies. We present the first application of mechanism-based modelling for bacterial killing and resistance with Monte Carlo simulations of human pharmacokinetics to rationally optimise combination dosage regimens for immune-compromised, critically-ill patients. Population pharmacodynamic modelling was performed in the S-ADAPT software and Monte Carlo simulations in Berkeley Madonna.
Results. All monotherapies achieved limited killing (≤ 2.3 log10) of A. baumannii ATCC 19606 followed by extensive regrowth for aminoglycosides. Imipenem 8 mg/L plus tobramycin yielded synergistic killing (>5 log10) and prevented regrowth against all four strains. Modelling demonstrated imipenem likely killed the aminoglycoside-resistant population and vice versa and aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant A. baumannii (MICIPM: 32 mg/L), optimised combination regimens (imipenem 4 g/day as continuous infusion plus tobramycin 7 mg/kg every 24h) were predicted to achieve >5 log10 killing without regrowth in 98.2% of patients.
Discussion. Among all tested combinations, imipenem plus an aminoglycoside provided the most extensive killing without regrowth against high inocula of susceptible, carbapenem-intermediate and carbapenem-resistant strains. Mechanism-based modelling identified both subpopulation synergy and mechanistic synergy for imipenem plus aminoglycoside. Monte Carlo simulations predicted a 98.2% success rate for clinically relevant imipenem plus aminoglycoside combination dosage regimens against a carbapenem-resistant clinical A. baumannii isolate with an MIC of 32 mg/L. Imipenem plus aminoglycoside combination regimens are highly promising and warrant further evaluation.
