High-level resistance to meropenem in clinical isolates of Pseudomonas aeruginosa in the absence of carbapenemases: role of active efflux and porin alterations
(2016) International Journal of Antimicrobial Agents — Vol. 48, n° 6, p. 740-743 (2016)
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- High-level carbapenem resistance is worryingly increasing in clinical isolates and often attributed to carbapenemase expression. This study aims at determining the mechanisms leading to high-level resistance to meropenem in six carbapenemase-negative Pseudomonas aeruginosa isolated from cystic fibrosis patients (CF), compared with seven carbapenemase-positive isolates from patients suffering from hospital-acquired pneumonia (HAP). MICs were determined in the absence or in the presence of L-Arginine or Glycine-Glutamate as competitive substrates for OprD (OccD1) or OpdP (OccD3), respectively, or of the efflux pump inhibitor Phe-Arg-β-naphthylamide (PAβN). Beta-lactamases were screened by PCR and/or phenotypic tests. 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 semi-quantitative PCR, respectively. Meropenem/imipenem MICs were 64-128/32 mg/L and 128/128-256 mg/L in CF and HAP isolates, respectively; PAβN reduced only meropenem MICs to 4-16 mg/L specifically in CF strains; 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 porin leading to the production of truncated proteins. AmpC was derepressed in CF strains and VIM-2 expressed in HAP strains. Antibiotic exclusion from bacteria by concomitant efflux and reduced uptake is as effective as carbapenemases in conferring high-level resistance to meropenem in strains expressing AmpC. As efflux is preponderant in these strains, 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.
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Chalhoub, H., Sáenz, Y., Rodriguez-Villalobos, H., Denis, O., Kahl, B. C., Tulkens, P., & Van Bambeke, F. (2016). High-level resistance to meropenem in clinical isolates of Pseudomonas aeruginosa in the absence of carbapenemases: role of active efflux and porin alterations. International Journal of Antimicrobial Agents, 48(6), 740-743. https://doi.org/10.1016/j.ijantimicag.2016.09.012 (Original work published 2016)