Background: Pseudomonas aeruginosa has a large armamentarium of resistance mechanisms, enabling resistance emergence against almost all antibiotics in monotherapy. Alternative treatment options are required.
Aims: To evaluate regimens of meropenem (MER) and ciprofloxacin (CIP), alone and combined, against isogenic P. aeruginosa strains with different resistance mechanisms in a dynamic hollow fibre infection model (HFIM) and develop a mechanism-based mathematical model (MBM) accounting for the resistance mechanisms.
Methods: Four isogenic strains were used: PAOD1 (spontaneous oprD mutation/loss of porin OprD), PAΔADmexR (ampD knock-out/AmpC overexpression and mexR knockout/MexAB-OprM overexpression), PAOD1ΔmexR and PAOD1ΔAD (other combinations of the resistance mechanisms). Regimens were: MER continuous infusion (CI, 6g/day, 12g/day additionally against MER-resistant strains), CIP intermittent infusions (400mg, 8-hourly as 1-h infusions), and both combinations. The HFIM was run for 240h. MBM was performed.
Results: All monotherapies resulted in regrowth with amplification of resistant subpopulations. The combination regimens suppressed total and resistant counts of PAOD1, PAΔADmexR and PAOD1ΔAD. Against PAOD1ΔmexR, MER 6g + CIP performed synergistically from 24h-120h, while MER 12g + CIP was synergistic from 24h-192h. MER-resistant counts emerged from 72h and 168h for the respective combination regimens; CIP-resistant colonies emerged from 216h with the low-dose combination only. An MBM with subpopulation synergy was developed that described the bacterial response to antibiotic based on the resistance mechanisms for all mono- and combination therapies.
Conclusions: Combination regimens enhanced bacterial killing and suppressed regrowth and resistance overall. An MBM accounting for different resistance mechanisms well-described the impact of double mutations and combination therapies on bacterial response.