![]() The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). ![]() For all three strains, synergistic killing without resistance was achieved by ≥0.88× MIC imipenem in combination with a median of 0.75× MIC tobramycin (range, 0.032× to 2.0× MIC tobramycin) or 0.50× MIC amikacin (range, 0.25× to 0.50× MIC amikacin). Against this isolate, imipenem (1.5× MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded ≥2-log 10 more killing than the most active monotherapy at 48 h and prevented resistance. We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem of 16 mg/liter and MIC tobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 10 7.5 CFU/ml). ![]() We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa. ![]()
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