Mechanism-based modelling of meropenem plus tobramycin combination regimens against clinical hypermutable Pseudomonas aeruginosa in the hollow-fibre infection model

Introduction: Hypermutable Pseudomonas aeruginosa (HYPa)strains are frequently associated with chronic respiratory infections in patients with cystic fibrosis leading to increased morbidity and mortality. HYPa have increased mutation rates resulting in multidrug-resistance and treatment failure.

Aims: To evaluate bacterial killing and resistance suppression of clinically relevant meropenem (MER) and tobramycin (TOB) dosage regimens against two clinical hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid (ELF) concentration-time profiles.

Methods: Different dosage regimens of MER and TOB alone and in combinations were investigated against CW8 (MICMER = 8 mg/L, MICTOB = 8 mg/L) and CW44 (MICMER = 4 mg/L, MICTOB = 2 mg/L) in the hollow-fibre infection model (HFIM) over 8 days. The total and less susceptible bacterial populations were quantified and subsequently described via mechanism-based modelling (MBM).

Results: Rapid regrowth occurred with the monotherapies and low dose combination regimens. The highest daily doses for MER (2 g every 8 h, 3 h infusion) and TOB (10 mg/kg every 24 h, 30 min infusion) in combination demonstrated synergistic killing and suppressed meropenem-resistant subpopulations below the high-dose monotherapy counts over 191 h for both isolates. MBM incorporating three bacterial subpopulations and direct bacterial killing by both antibiotics well described the antibacterial effects of the mono- and combination therapies in the HFIM.

Discussion: The developed MBM successfully accounted for the time course of amplification of pre-existing less-susceptible bacterial subpopulations. The synergistic combination of MER and TOB is promising against clinical HYPa strains and warrants further evaluation.