مقاومت بالا به مروپنم در ایزوله های بالینی سودوموناس آئروژينوزا در غیاب کرباپنم ها
ABSTRACT
High-level carbapenem resistance is worryingly increasing in clinical isolates and is often attributed to carbapenemase expression. This study aimed to determine the mechanisms leading to high-level meropenem resistance in six carbapenemase-negative Pseudomonas aeruginosa isolated from cystic fibrosis (CF) patients and seven carbapenemase-positive isolates from patients suffering from hospitalacquired pneumonia (HAP). MICs were determined in the absence or presence of l-arginine or glycine– glutamate as competitive substrates for OprD (OccD1) or OpdP (OccD3), respectively, or the efflux pump inhibitor Phe-Arg β-naphthylamide (PAβN). β-Lactamases were screened by phenotypic tests and/or PCR. The oprD gene and its promoter were sequenced; protein expression was evidenced by SDS-PAGE. mexA, mexX, mexC and mexE transcripts were evaluated by real-time and semiquantitative PCR. Meropenem/ imipenem MICs were 64–128/16–32 mg/L and 128/128–256 mg/L in CF and HAP isolates, respectively; PAβN reduced meropenem MICs to 4–16 mg/L only and specifically in CF isolates; porin competitors had no effect on MICs. All isolates showed an increase in transcription levels of mexA, mexX and/or mexC and mutations in oprD leading to production of truncated proteins. AmpC-type cephalosporinases were overexpressed in CF isolates and VIM-2 was expressed in HAP isolates. Antibiotic exclusion from bacteria by concomitant efflux and reduced uptake is sufficient to confer high-level resistance to meropenem in isolates overexpressing AmpC-type cephalosporinases. As efflux is preponderant in these isolates, it confers a paradoxical phenotype where meropenem is less active than imipenem. Concomitant susceptibility testing of both carbapenems and rapid elucidation of the most probable resistance mechanisms is thus warranted.
1. Introduction
Meropenem is widely used in the treatment of pulmonary exacerbations in cystic fibrosis (CF) patients infected by multidrugresistant (MDR) Pseudomonas aeruginosa. Its consumption has promoted the emergence of high-level resistance, often ascribed to expression of carbapenemases in hospital-acquired infections [1]. Upon screening of a collection of 333 P. aeruginosa isolates from CF patients, we observed meropenem minimum inhibitory concentrations (MICs) of ≥64 mg/L in six isolates that did not express carbapenemases. This study aimed to determine the mechanism(s) leading to this high-level meropenem resistance.
چکیده
مقدمه
2-مواد و روش ها
2-1- استرین ها
2-2- تست حساسیت
2-3- غربالگری و شناسایی بتالاکتاماز
2-4- بیان پمپ جریان
2.5. بیان پورین و جهش ها
3- نتایج
4- بحث
ABSTRACT
1. Introduction
2. Materials and methods
2.1. Strains
2.2. Susceptibility testing
2.3. β-Lactamase screening and identification
2.4. Efflux pump expression
2.5. Porin expression and mutations
3. Results
4. Discussion
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