title: Imipenem heteroresistance induced by imipenem in multidrug-resistant Acinetobacter baumannii: mechanism and clinical implications.
abstract: Acinetobacter baumannii has emerged as a major pathogen causing nosocomial infections, particularly in critical patients admitted to the Intensive Care Unit. Increasing resistance to carbapenems in A. baumannii has been observed worldwide. Here we report the clinical impact and mechanism of imipenem heteroresistance (imipenem minimum inhibitory concentration of 6-32 μg/mL with the presence of resistant cells inside the inhibition zone of Etest strips or disks) in multidrug-resistant A. baumannii (MDR-AB). To identify risk factors associated with the emergence of imipenem heteroresistance, a retrospective case-control study was undertaken involving cases with subsequent clinical isolates of the same genotype showing loss of imipenem susceptibility and matched controls with isolates belonging to imipenem-susceptible MDR-AB. The molecular mechanism of heteroresistance was examined. From April 2006 to March 2007, 126 consecutive isolates of MDR-AB were identified from 29 patients. Switch from imipenem susceptibility to heteroresistance was more likely to occur in successive MDR-AB derived from patients who had been exposed to imipenem (length of use 10.9 ± 6.5 days for cases vs. 5.3 ± 4.8 days for controls; P=0.02). An insertion sequence (ISAba1) was found in the promoter region of a class C β-lactamase gene (bla(ADC-29)) in most imipenem-heteroresistant MDR-AB isolates. In vitro experiments indicated that imipenem heteroresistance, which was associated with overexpression of bla(ADC-29), could be induced by imipenem. Carbapenem use was the only risk factor identified for the emergence of carbapenem-heteroresistant MDR-AB. Physicians should weigh the benefits and risks of each carbapenem-based treatment in managing carbapenem-susceptible MDR-AB infection.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Hao-Yuan
authors.initials: HY
authors.lastname: Lee
authors.forename: Chyi-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Shi-Bo
authors.initials: SB
authors.lastname: Wang
authors.forename: Lin-Hui
authors.initials: LH
authors.lastname: Su
authors.forename: Shu-Hung
authors.initials: SH
authors.lastname: Chen
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Liu
authors.forename: Tsu-Lan
authors.initials: TL
authors.lastname: Wu
authors.forename: Tzou-Yien
authors.initials: TY
authors.lastname: Lin
authors.forename: Cheng-Hsun
authors.initials: CH
authors.lastname: Chiu
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001483:Base Sequence; D015139:Blotting, Southern; D016022:Case-Control Studies; D017931:DNA Primers; D004352:Drug Resistance, Microbial / Q000235:genetics; D005838:Genotype; D006801:Humans; D015378:Imipenem / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests; D016133:Polymerase Chain Reaction; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D017931:DNA Primers; D015378:Imipenem; D001618:beta-Lactamases