Optimization of a Meropenem-Tobramycin Combination Dosage Regimen against Hypermutable and Nonhypermutable Pseudomonas aeruginosa via Mechanism-Based Modeling and the Hollow-Fiber Infection Model

Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔ mutS strain (MIC meropenem of 1.0 mg/liter and MIC tobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼10 8.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔ mutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >10 8.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log 10 bacterial killing followed by regrowth to >6 log 10 CFU/ml by day 5 and high-level resistance (MIC meropenem , 32 mg/liter; MIC tobramycin , 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log 10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to 10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.