Antimicrobial Efficacy of Doripenem Colistin Combination on Carbapenem - Resistant Acinetobacter Baumanii Isolates by E-Test Agar Dilution and Ultrastrastructural Methods

Abstract

Background: Acinetobacter baumannii (A.baumannii) is a serious nosocomial pathogen and a threat for hospitalized patients especially in intensive care units (ICUs). Infections caused by the bacteria are difficult to treat owing to the frequent development of resistant strains which are mostly multidrug resistant (MDR). Emerging resistance to carbapenems is an alarming issue. As treatment options are limited so the discovery of new therapies, including combination therapy, is required. Doripenem is a new carbapenem, which is more stable against carbapenemases. Colistin remains a last line treatment for MDR A.baumannii and its combined use with cabapenems may present a possible strategy for treatment of serious bacterial infections. Objective: In this study we evaluated the efficacy and antibacterial activity of doripenem monotherapy versus doripenem combination therapy with colistin against carbapenem-resistant A. baumannii isolates in vitro. Methodology: Thirty two carbapenem non-susceptible A. baumannii clinical isolates were identified and antimicrobial susceptibility testing (AST) and minimum inhibitory concentration (MIC) determination were done by using VITEK2 compact system (bioMerieux, France). Phenotypic detection of MBLs was assessed using MBL E-test strips. Synergy testing was performed by agar dilution E-test method using doripenem E-test strips and colistin at 1/2 MIC values. Morphological changes were evaluated by scanning electron microscopy (SEM). Results: All 32 A. baaumannii isolates were resistant to carbapenems including doripenem and 23/32 (72%) were resistant to colistin. The colistin doripenem combination displayed synergy in (27/32; 84%) among carbapenem resistant isolates while antagonism was detected in 5/32 (16%). Metallo-f-lactamase (MBL) production was detected in 24 isolates (75%); however the MBL status did not affect the synergistic activity of the combination therapy. Electron microscopy on selected isolates showed major morphological changes after exposure of A. baumannii to doripenem and colistin combination confirming synergy between the 2 drugs. Conclusion: This study confirms the superiority of doripenem colistin combination at 1/2 MIC over doripenem or colistin monotherapy in both carbapenem resistant and carbapenem colistin resistant A. baumanni isolates. This combination could be a life-saving alternative for treatment of serious infections that improves the clinical outcome of critically ill patients in ICU. This should be further examined in clinical studies.