title: Increase of efflux-mediated resistance in Pseudomonas aeruginosa during antibiotic treatment in patients suffering from nosocomial pneumonia.
abstract: Increases in antibiotic minimum inhibitory concentrations (MICs) for Pseudomonas aeruginosa during treatment are commonly observed but their relationship to efflux overexpression remains poorly documented. In this study, pairs of first [at time of diagnosis (D0)] and last [during treatment (DL)] P. aeruginosa isolates were obtained from patients treated for suspicion of nosocomial pneumonia. Pair clonality was determined by repetitive extragenic palindromic PCR. Overexpression of mexA and mexX was assessed by real-time PCR, and expression of mexC and mexE was assessed by PCR. Antibiotics received by patients before and during treatment were determined from clinical charts. For D0 isolates, 24% were from patients without antibiotics for 1 month and 64% were negative for mexA/mexX overexpression and mexC/mexE expression. For DL isolates, approximately one-half of the patients had received piperacillin/tazobactam, amikacin, meropenem and/or cefepime, and 17% had received ciprofloxacin (alone or in combination); 38% did not show changes in expression of the four genes, whereas 38% showed increased expression for one gene (mainly mexA or mexX), 19% for two genes (mainly mexA and mexX) and 5% for three or four genes. Isolates overexpressing mexA or mexX had median MICs above EUCAST clinical resistance breakpoints for ciprofloxacin, cefepime and meropenem, or for ciprofloxacin, amikacin, cefepime and meropenem, respectively. mexA or mexX overexpression was statistically significantly associated with patients' exposure to ciprofloxacin and meropenem or cefepime and meropenem, respectively. Overexpression of genes encoding antibiotic transporters in P. aeruginosa during treatment is frequent and is associated with increases in MICs above EUCAST clinical susceptibility breakpoints.
authors.affiliation: Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Riou
authors.affiliation: Coris BioConcept, Gembloux, Belgium.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Avrain
authors.affiliation: Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Carbonnelle
authors.affiliation: Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium; Laboratoire de microbiologie, CHU Dinant-Godinne UCL Namur, Yvoir, Belgium.
authors.forename: Farid
authors.initials: F
authors.lastname: El Garch
authors.affiliation: Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Neder-over-Heembeek, Brussels, Belgium.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pirnay
authors.affiliation: Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Neder-over-Heembeek, Brussels, Belgium.
authors.forename: Daniel
authors.initials: D
authors.lastname: De Vos
authors.affiliation: Laboratoire de bactériologie, Faculté de médecine, Université de Franche-Comté, Besançon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Plésiat
authors.affiliation: Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
authors.affiliation: Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. Electronic address: francoise.vanbambeke@uclouvain.be.
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001692:Biological Transport; D024881:Drug Resistance, Bacterial; D015870:Gene Expression; D020869:Gene Expression Profiling; D005798:Genes, Bacterial; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000382:microbiology*; D016133:Polymerase Chain Reaction; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D026901:Membrane Transport Proteins
keywords: EUCAST breakpoints; Efflux; MexAB–OprM; MexXY–OprM; Pseudomonas aeruginosa; Resistance