Synergistic activities of ceftazidime-avibactam in combination with different antibiotics against colistin-nonsusceptible clinical strains of Pseudomonas aeruginosa

Background: This study aims to analyse the effect of ceftazidime-avibactam plus various antibiotics against multidrug-resistant (MDR) Pseudomonas aeruginosa isolated from Intensive Care Units. Methods: 40 non-duplicate P. aeruginosa isolates were screened for their MICs of ceftazidime, ceftazidime-avibactam, colistin, levofloxacin, doripenem and tobramycin. MICs were determined by the broth microdilution method. The in vitro bactericidal activities of ceftazidime-avibactam compared to studied antibiotics were also determined by time-kill curve assays both at 1xMIC and at 4xMIC against carbapenemase-producing or -not producing six colistin-nonsusceptible MDR clinical strains of P. aeruginosa. Additionally, synergistic interactions were investigated by the time-kill curve assay. Results: The MIC90 values for ceftazidime, ceftazidime-avibactam, colistin, levofloxacin, doripenem and tobramycin against MDR P. aeruginosa isolates were found to be >256, 64, 8, 64, 128, and >256 mg/L, respectively. The minimum bactericidal concentration90 values for those antibiotics were also >256, 64, 16, 128, 256, and >256 mg/L, respectively. While doripenem, tobramycin and levofloxacin were bactericidal (>3 log10 killing) against the 2/6, 3/6 and 1/6 P. aeruginosa isolates at 4xMIC concentrations, respectively, levofloxacin and tobramycin were bactericidal against only one isolate (1/6) at 1xMIC concentrations at 24 h. The synergistic interactions of these antimicrobial agents were also achieved with ceftazidime/avibactam + colistin (4/6), ceftazidime/avibactam + tobramycin (3/6), and ceftazidime/avibactam + levofloxacin (3/6) combinations. No antagonism was observed against studied P. aeruginosa strains. Conclusions: The findings of this study suggest that ceftazidime/avibactam with colistin, or tobramycin, were effective against colistin-nonsusceptible strains. This combination therapy could be an alternative antibiotic therapy for resistant P. aeruginosa strains.