Optimization of synergistic combination regimens against carbapenem- and aminoglycoside-resistant clinical Pseudomonas aeruginosa isolates via mechanism-based pharmacokinetic/pharmacodynamic modeling

Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa. 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). 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 48-h static-concentration time-kill studies (inoculum, 10^7.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MIC_imipenem] of 16 mg/liter and MIC_tobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5x MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded ≥2-log₁₀ more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88x MIC_imipenem in combination with a median of 0.75x MIC_tobramycin (range, 0.032x to 2.0x MIC_tobramycin) or 0.50x MIC_amikacin (range, 0.25x to 0.50x MIC_amikacin). 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). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve >2.0-log₁₀ killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, >4.0 log₁₀ CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.