Acquired resistance to macrolides in Pseudomonas aeruginosa from cystic fibrosis patients

Muhammad-Hariri Mustafa, Shaunak Khandekar, Michael M Tunney, J Stuart Elborn, Barbara C Kahl, Olivier Denis, Patrick Plésiat, Hamidou Traore, Paul M Tulkens, Francis Vanderbist, Françoise Van Bambeke

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Abstract

Cystic fibrosis (CF) patients receive chronic treatment with macrolides for their antivirulence and anti-inflammatory properties. We, however, previously showed that Pseudomonas aeruginosa, considered as naturally resistant to macrolides, becomes susceptible when tested in a eukaryotic medium rather than a conventional broth.We therefore looked for specific macrolide resistance determinants in 333 CF isolates from four European CF centres in comparison with 48 isolates from patients suffering from hospital-acquired pneumonia (HAP).Minimum inhibitory concentrations (MICs) of macrolides and ketolides measured in eukaryotic medium (RPMI-1640) were higher towards CF than HAP isolates. Gene sequencing revealed mutations at three positions (2045, 2046 and 2598) in domain V of 23S rRNA of 43% of sequenced CF isolates, but none in HAP isolates. Enzymes degrading extracellular polymeric substances also reduced MICs, highlighting a role of the mucoid, biofilm-forming phenotype in resistance. An association between high MICs and chronic azithromycin administration was evidenced, which was statistically significant for patients infected by the Liverpool Epidemic Strain.Thus, ribosomal mutations are highly prevalent in CF isolates and may spread in epidemic clones, arguing for prudent use of oral macrolides in these patients. Measuring MICs in RPMI-1640 could be easily implemented in microbiology laboratories to phenotypically detect resistance.

Original languageEnglish
JournalEuropean Respiratory Journal
Volume49
Issue number5
Early online date19 May 2017
DOIs
Publication statusEarly online date - 19 May 2017

Keywords

  • Administration, Oral
  • Adolescent
  • Adult
  • Anti-Bacterial Agents/therapeutic use
  • Cell Membrane/metabolism
  • Child
  • Child, Preschool
  • Chronic Disease
  • Cystic Fibrosis/drug therapy
  • Drug Resistance, Bacterial/genetics
  • Europe
  • Humans
  • Infant
  • Ketolides/therapeutic use
  • Macrolides/therapeutic use
  • Microbial Sensitivity Tests
  • Middle Aged
  • Mutation
  • Permeability
  • Phenotype
  • Pseudomonas Infections/drug therapy
  • Pseudomonas aeruginosa/genetics
  • Ribosomes/metabolism
  • Sequence Analysis, DNA
  • Young Adult

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  • Cite this

    Mustafa, M-H., Khandekar, S., Tunney, M. M., Elborn, J. S., Kahl, B. C., Denis, O., Plésiat, P., Traore, H., Tulkens, P. M., Vanderbist, F., & Van Bambeke, F. (2017). Acquired resistance to macrolides in Pseudomonas aeruginosa from cystic fibrosis patients. European Respiratory Journal, 49(5). https://doi.org/10.1183/13993003.01847-2016