In-Vitro Activity of Ceftolozane-Tazobactam in Combination With Various Antibiotics Against Multidrug-Resistant Acinetobacter Baumannii Isolated From Intensive Care Patients

Abstract

Acinetobacter species lead to nosocomial infections in immunocompromised patients hospitalized in intensive care units or services. Acinetobacter baumannii is a bacterium that is difficult to treat because it is intrinsically resistant to many antibiotics and can develop resistance afterwards. This situation limits the use of existing antibiotics and directs the clinician to new agents, different treatment options and the use of various antibiotic combinations. The aim of this study was to determine the sensitivities of doripenem (DOR), tigecycline (TGC), minocycline (MIN), amikacin (AK) and a newly developed agent ceftolozane-tazobactam (CT) in multidrug resistant A.baumannii strains which were isolated from inpatients in intensive care units and to investigate the in vitro interactions of CT/DOR, CT/TGC, CT/MIN and CT/AK combinations by using antibiotic gradient test method. Thirty-five A.baumannii strains isolated from various clinical specimens (blood, urine, sputum, tracheal aspirate, wound, abscess and catheter) between January 2017 and July 2017 were included in the study. Strains isolated from inpatients in intensive care units and resistant to at least three antibiotic classes were selected. The identification of A.baumannii isolates and the determination of routine antibiotic susceptibility profile were performed according to EUCAST 2017 criteria by the use of BD Phoenix 100 (Becton Dickinson, USA) automated system. Minimum inhibitor concentration values of CT, DOR, TGC, MIN, AK and combinations of CT with four other antibiotics (CT/DOR, CT/TGC, CT/MIN and CT/AK) were determined by antibiotic gradient test method. Fractional inhibitor concentration index (FICI) was used to determine the interactions of the combinations in vitro. According to the data obtained; the FICI was evaluated as synergy if FICI 5 0.5, additive if 0.5 > FICI <= 1, indifferent (unidentified interaction) if 1 < FICI < 2 and antagonist interaction if FICI >= 2. According to FICI results of the antibiotic combinations, the highest synergistic interaction was observed between CT/TGC as 11.4%. No synergistic interaction was observed between CT/DOR antibiotics. The highest additive interaction rates were between CT/AK (60%) and CT/MIN (45.7%), while no additive interaction between CT/DOR was observed. Antagonist interaction was observed in CT/DOR (71.4%) combination only. In conclusion, in our study it was observed that CT, a novel beta-lactam/ beta-lactamase inhibitor, did not sufficiently affect A.baumannii isolates, but was able to induce synergistic interaction in combination with TGC, AK and MIN. CT should be carefully monitored in clinical use because of the antagonist interaction detected with DOR.