Evaluation of Pharmacokinetic/Pharmacodynamic Model-Based Optimized Combination Regimens against Multidrug-Resistant Pseudomonas aeruginosa in a Murine Thigh Infection Model by Using Humanized Dosing Schemes.

We previously optimized imipenem and tobramycin combination regimens against a double-resistant clinical isolate by using infection models, mechanism-based pharmacokinetic/pharmacodynamic 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 against the double-resistant clinical isolate by using humanized dosing schemes. Viable count profiles of total and resistant populations were quantified over 24 h. Tobramycin monotherapy (7 mg/kg every 24 h [q24h] as a 0.5-h infusion) was ineffective. Imipenem monotherapies (continuous infusion of 4 or 5 g/day with a 1-g loading dose) yielded 2.47 or 2.57 log CFU/thigh killing at 6 h. At 24 h, imipenem at 4 g/day led to regrowth up to the initial inoculum (4.79 ± 0.26 log CFU/thigh), whereas imipenem at 5 g/day displayed 1.75 log killing versus the initial inoculum. The combinations (i.e., imipenem at 4 or 5 g/day plus tobramycin) provided a clear benefit, with bacterial killing of ≥2.51 or ≥1.50 log CFU/thigh compared to the respective most active monotherapy at 24 h. No colonies were detected on 3×MIC agar plates for combinations, whereas increased resistance (at 3×MIC) emerged for monotherapies (except imipenem at 5 g/day). MBM suggested that 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 against a double-resistant isolate and are therefore promising for future clinical evaluation.