title: Association between clinical antibiotic resistance and susceptibility of Pseudomonas in the cystic fibrosis lung.
abstract: OBJECTIVE
  Cystic fibrosis patients suffer from chronic lung infections that require long-term antibiotic therapy. Pseudomonas readily evolve resistance, rendering antibiotics ineffective. In vitro experiments suggest that resistant bacteria may be treated by exploiting their collateral sensitivity to other antibiotics. Here, we investigate correlations of sensitivity and resistance profiles of Pseudomonas aeruginosa that naturally adapted to antibiotics in the cystic fibrosis lung.
  
  
  METHODS
  Resistance profiles for 13 antibiotics were obtained using broth dilution, E-test and VITEK mass spectroscopy. Genetic variants were determined from whole-genome sequences and interrelationships among isolates were analyzed using 13 MLST loci.
  
  
  RESULTS
  Our study focused on 45 isolates from 13 patients under documented treatment with antibiotics. Forty percent of these were clinically resistant and 15% multi-drug resistant. Colistin resistance was found once, despite continuous colistin treatment and even though colistin resistance can readily evolve experimentally in the laboratory. Patients typically harbored multiple genetically and phenotypically distinct clones. However, genetically similar clones often had dissimilar resistance profiles. Isolates showed mutations in genes encoding cell wall synthesis, alginate production, efflux pumps and antibiotic modifying enzymes. Cross-resistance was commonly observed within antibiotic classes and between aminoglycosides and β-lactam antibiotics. No evidence was found for consistent phenotypic resistance to one antibiotic and sensitivity to another within one genotype.
  
  
  CONCLUSIONS
  Evidence supporting potential collateral sensitivity in clinical P. aeruginosa isolates remains equivocal. However, cross-resistance within antibiotic classes is common. Colistin therapy is promising since resistance to it was rare despite its intensive use in the studied patients.
authors.affiliation: Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, Am Botanischen Garten 1-9, 24118 Kiel, Germany gjansen@zoologie.uni-kiel.de gunther.jansen@gmail.com.
authors.forename: Gunther
authors.initials: G
authors.lastname: Jansen
authors.affiliation: Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, Am Botanischen Garten 1-9, 24118 Kiel, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Mahrt
authors.affiliation: Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, Am Botanischen Garten 1-9, 24118 Kiel, Germany.
authors.forename: Leif
authors.initials: L
authors.lastname: Tueffers
authors.affiliation: Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, Am Botanischen Garten 1-9, 24118 Kiel, Germany.
authors.forename: Camilo
authors.initials: C
authors.lastname: Barbosa
authors.affiliation: Fachklinik Satteldüne, Tanenwai 32, Nebel, 25946 Amrum, Germany;
authors.forename: Malte
authors.initials: M
authors.lastname: Harjes
authors.affiliation: Fachklinik Satteldüne, Tanenwai 32, Nebel, 25946 Amrum, Germany;
authors.forename: Gernot
authors.initials: G
authors.lastname: Adolph
authors.affiliation: Department of Internal Medicine Department of Pharmacy, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Friedrichs
authors.affiliation: LADR GmbH Medizinisches Versorgungszentrum Plön, Krögen 6, 24306 Plön, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Krenz-Weinreich
authors.affiliation: Institute for Clinical Molecular Biology, University of Kiel, Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, Am Botanischen Garten 1-9, 24118 Kiel, Germany.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Schulenburg
keywords: Pseudomonas aeruginosa; antibiotics; clinical sampling depth; collateral sensitivity; cross-resistance; cystic fibrosis; multi-drug resistance