Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

Abstract

Optimizing antibiotic combinations is promising to combat multidrugresistant 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 (1.5ϫ MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded Ն2-log 10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by Ն0.88ϫ MIC imipenem in combination with a median of 0.75ϫ MIC tobramycin (range, 0.032ϫ to 2.0ϫ MIC tobramycin ) or 0.50ϫ MIC amikacin (range, 0.25ϫ to 0.50ϫ 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 Ͼ2.0-log 10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, Ͼ4.0 log 10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.

Aminoglycosides Resistance among Acinetobacter baumannii Complex Isolated from Hospital Acquired Blood Stream Infections

“…These results are matched with previous reports (Yadav et al, 2015;Yadav et al, 2016). The exact mechanism for synergism is not known.…”

Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

“…The developed MBM accurately described the antibacterial effects of meropenem and ciprofloxacin in mono-and combination therapies against CW44. The requirement for both subpopulation and mechanistic synergies to describe the antibacterial effects of the combination was similar to that from a previous study with MBM for an aminoglycoside and carbapenem combination (38). Subpopulation synergy, where meropenem killed ciprofloxacin-resistant bacteria and vice versa, was attributable to meropenem and ciprofloxacin having different resistance mechanisms, such as target site mutations (ciprofloxacin), AmpC ␤-lactamase overexpression (meropenem), and an inactivation of outer membrane porin oprD (meropenem) (8).…”

“…The life cycle growth model was used to describe the growth and replication of P. aeruginosa (62)(63)(64). We evaluated subpopulation synergy (i.e., meropenem killing the bacteria resistant to ciprofloxacin and vice versa) and mechanistic synergy (i.e., ciprofloxacin enhancing the killing by meropenem against one or multiple bacterial populations) (38,63,65). A diagram of the model structure is shown in Fig.…”

Aminoglycoside Concentrations Required for Synergy with Carbapenems against Pseudomonas aeruginosa Determined via Mechanistic Studies and Modeling

“…Aminoglycosides in monotherapy have demonstrated substantial bacterial load reduction, but this was followed by rapid and extensive emergence of resistance and ultimately treatment failure (7,8). In the past, in vitro and in vivo studies on carbapenem-aminoglycoside combinations demonstrated synergy (9)(10)(11)(12)(13).…”