Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and resistance prevention by carbapenem and aminoglycoside combinations, and to rationally optimize combination dosage regimens via mechanism-based modeling (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable count profiles of total and resistant populations were quantified in 48h static-concentration time-kill studies (inoculum: 107.5CFU/mL). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MICimipenem 16 mg/L, MICtobramycin 32 mg/L; i.e. both 98th percentiles of EUCAST). Against this isolate, imipenem (1.5xMIC) combined with 1-2 mg/L tobramycin (MIC 32 mg/L) or amikacin (MIC 4 mg/L) yielded ≥2 log10 more killing than the most active monotherapy at 48h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88xMIC imipenem in combination with a median [range] of 0.75x [0.032-2.0] MIC tobramycin or 0.50x [0.25-0.50] MIC amikacin. The MBM indicated aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving half-maximal of this synergistic effect required an aminoglycoside concentration of 1.34 mg/L (if the aminoglycoside MIC was 4 mg/L) and 4.88 mg/L (for MICs 8-32 mg/L). An optimized combination regimen (imipenem 5g/day continuous infusion plus 7 mg/kg tobramycin 0.5 h infusion) was predicted to achieve >2.0 log10 killing and prevent regrowth at 48h in 90.3% of patients (median bacterial killing >4.0 log10) against double resistant isolate FADDI-PA088 and was therefore highly promising.
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