Evaluation of PK/PD model-based optimized combination regimens against multidrug-resistant Pseudomonas aeruginosa in a murine thigh infection model using humanized dosing schemes [PublishAheadOfPrint]

We previously optimized imipenem and tobramycin combination regimens against a double-resistant clinical P. aeruginosa isolate using in vitro infection models, mechanism-based PK/PD modeling (MBM) and Monte Carlo simulations. The current study aimed to evaluate these regimens in a neutropenic murine thigh infection model and to characterize the time-course of bacterial killing and regrowth via MBM. We studied monotherapies and combinations of imipenem with tobramycin in vivo against the double-resistant clinical P. aeruginosa isolate using humanized dosing schemes. Viable count profiles of total and resistant populations were quantified over 24h. Tobramycin monotherapy (7 mg/kg q24h as 0.5h infusions) was ineffective. Imipenem monotherapies (continuous infusion of 4 or 5 g/day with 1 g loading dose) yielded 2.47 and 2.57 log₁₀ CFU/thigh killing at 6h. At 24h, imipenem 4 g/day led to regrowth up to the initial inoculum (4.79±0.26 log₁₀ CFU/thigh), whereas imipenem 5 g/day displayed 1.75 log₁₀ killing versus the initial inoculum. The combinations (i.e. imipenem 4 or 5 g/day plus tobramycin) provided a clear benefit with bacterial killing of ≥2.51 and ≥1.50 log₁₀ CFU/thigh compared to the respective most active monotherapy at 24h. No colonies were detected on 3xMIC agar plates for combinations, whereas increased resistance (at 3xMIC) emerged for monotherapies (except imipenem 5 g/day). MBM suggested tobramycin considerably enhanced the imipenem target site concentration up to 2.6-fold. The combination regimens, rationally optimized via a translational modeling approach, demonstrated substantially enhanced bacterial killing and suppression of regrowth in vivo against a double-resistant isolate, and are therefore promising for future clinical evaluation.

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