Meropenem-tobramycin combination regimens combat carbapenem-resistant pseudomonas aeruginosa in the hollow-fiber infection model simulating augmented renal clearance in critically ill patients

Augmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance amplification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-day hollow-fiber infection model (HFIM). Pharmacokinetic profiles representing substantial ARC (creatinine clearance of 250ml/min) were generated in the HFIM for meropenem (1g or 2g administered every 8 h as 30-min infusion and 3g/day or 6g/day as continuous infusion [CI]) and tobramycin (7mg/kg of body weight every 24 h as 30-min infusion) regimens. The time courses of total and less-susceptible bacterial populations and MICs were determined for the monotherapies and all four combination regimens. Mechanism-based mathematical modeling (MBM) was performed. In the HFIM, maximum bacterial killing with any meropenem monotherapy was ∼3 log10 CFU/ml at 7h, followed by rapid regrowth with increases in resistant populations by 24h (meropenem MIC of up to 128mg/liter). Tobramycin monotherapy produced extensive initial killing (∼7 log10 at 4h) with rapid regrowth by 24h, including substantial increases in resistant populations (tobramycin MIC of 32mg/liter). Combination regimens containing meropenem administered intermittently or as a 3-g/day CI suppressed regrowth for ∼1 to 3 days, with rapid regrowth of resistant bacteria. Only a 6-g/day CI of meropenem combined with tobramycin suppressed regrowth and resistance over 7 days. MBM described bacterial killing and regrowth for all regimens well. The mode of meropenem administration was critical for the combination to be maximally effective against carbapenem-resistant P. aeruginosa. Copyright © 2019 American Society for Microbiology. All Rights Reserved.