title: Association of daptomycin use with resistance development in Enterococcus faecium bacteraemia-a 7-year individual and population-based analysis.
abstract: OBJECTIVE
  In this study we aimed to analyse the association between use of daptomycin and MICs of daptomycin in Enterococcus faecium bacteraemia.
  
  
  METHODS
  We prospectively enrolled patients aged ≥18 years with E. faecium bacteraemia hospitalized at the University Hospital Basel from 2008 to 2014. We determined daptomycin MICs by Etests and used pulsed field gel electrophoresis to determine clonal relatedness. We recorded the defined daily dosages of daptomycin (DDDs) per 100 patient-days and clinical data from charts. We correlated daptomycin MIC with use of daptomycin in patients with recurrence/persistence.
  
  
  RESULTS
  In 195 E. faecium bacteraemias originating from 162 patients the median MIC for daptomycin was 2 mg/L (IQR 2-3); 30% (15.4%) isolates had a MIC ≥4 mg/L and 6 (3.1%) were resistant (MIC >4 mg/L) according to CLSI criteria. The usage of daptomycin increased more than four-fold from 0.36 DDDs/100 patient-days in 2008 to 1.6 in 2014. In 13 of 28 (42.9%) patients with a relapsing or persisting bacteraemia, the daptomycin MIC of the second isolate increased from a median of 2.0 to 2.5 mg/L (p 0.010); 3/13 (23.1%) developed resistance. All patients with the same clone in the first and second episode and an increase of daptomycin MIC had been treated with daptomycin (6/6 versus 1/7 p 0.005).
  
  
  CONCLUSIONS
  Daptomycin MICs and Daptomycin usage increased over time. On an individual patient level daptomycin exposure was associated with an increased MIC in subsequent bacteraemia episodes. Diversity did not indicate a clonal origin and argues for a de novo development of resistance.
authors.affiliation: Clinical Microbiology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland; Applied Microbiology Research, Department Biomedicine, University of Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Egli
authors.affiliation: Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Schmid
authors.affiliation: Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland; Epidemiology, Biostatistics and Prevention Institute, University of Zürich, Zürich, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Kuenzli
authors.affiliation: Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.
authors.forename: A F
authors.initials: AF
authors.lastname: Widmer
authors.affiliation: Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Battegay
authors.affiliation: Hospital Pharmacy, University Hospital Basel, Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Plagge
authors.affiliation: Clinical Microbiology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Frei
authors.affiliation: Applied Microbiology Research, Department Biomedicine, University of Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Achermann
authors.affiliation: Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland; Department of Clinical Research, University Hospital Basel, Basel, Switzerland. Electronic address: maja.weisser@usb.ch.
authors.forename: M
authors.initials: M
authors.lastname: Weisser
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016470:Bacteremia; D015897:Comorbidity; D017576:Daptomycin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D024881:Drug Resistance, Bacterial; D016984:Enterococcus faecium / Q000187:drug effects*; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000453:epidemiology* / Q000382:microbiology*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011159:Population Surveillance; D012189:Retrospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin
keywords: Daptomycin resistance; Defined daily dosage; Enterococcus faecium; Minimal inhibitory concentration; Pulsed field gel electrophoresis