Objectives: Hypermutable Pseudomonas aeruginosa 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).
Methods: The PAO1 wild-type strain and its isogenic hypermutable PAOmutS strain (MICmeropenem 1.0 mg/liter, MICtobramycin 0.5 mg/liter, for both) were assessed using 96-h static concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum ~108.4 CFU/ml). MBM of SCTK data was performed to predict expected HFIM outcomes. Regimens studied in the HFIM were: meropenem 1 g 8-hourly (0.5h infusion), meropenem 3 g/day continuous infusion, tobramycin 10 mg/kg 24-hourly (1h infusion) and both combinations; meropenem regimens delivered the same total daily dose. Time-courses of total and less-susceptible populations and MICs were determined.
Results: For PAOmutS in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near complete replacement by less-susceptible bacteria by day 3. Meropenem 8-hourly with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6-log10 CFU/ml by day 5 and high-level resistance (MICmeropenem 32 mg/liter, MICtobramycin 8 mg/liter). Continuous infusion meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4-log10 over 7-9 days, with both combination regimens achieving near eradication.
Conclusions: A 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.
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