title: Genomic analysis of teicoplanin resistance emerging during treatment of vanB vancomycin-resistant Enterococcus faecium infections in solid organ transplant recipients including donor-derived cases.
abstract: OBJECTIVE
  We noted four cases of apparent in vivo emergence of teicoplanin resistance during failed therapy for initially teicoplanin-susceptible vanB vancomycin-resistant Enterococcus faecium (VREfm) infections in solid organ transplant recipients at our institution over a 12 month period. We investigated if in vivo emergence of resistance had occurred, if transplant-related vancomycin-resistant Enterococcus (VRE) infections had occurred and identified clinical predictors of resistance emergence.
  
  
  METHODS
  Whole genome sequencing was performed on nine VREfm isolates for phylogenetic analysis and to identify determinants of teicoplanin resistance. Clinical treatment details were compared with other patients who received teicoplanin for confirmed vanB VRE infections but did not develop resistance during the same year at our institution.
  
  
  RESULTS
  A high-resolution, core genome phylogeny was inferred for nine VREfm isolates and confirmed in vivo development of resistance during failed therapy in four cases. Four different non-synonymous single nucleotide polymorphisms (SNPs) were observed in the vanRS genes of teicoplanin-resistant strains compared with the index teicoplanin-susceptible strains, and these SNPs were predicted to confer teicoplanin resistance. VREfm within a cluster of early transplant-related infections were phylogenetically identical at the core genome level, indicating a common source donor. Focus eradication and absence of prosthetic material were characteristics of those patients treated successfully.
  
  
  CONCLUSIONS
  Clinicians should be cautious of resistance emerging during teicoplanin therapy for vanB VRE, particularly in immunosuppressed patients or where source control is difficult.
authors.affiliation: Austin Centre for Infection Research, Department of Infectious Diseases, Austin Health, Heidelberg, VIC 3084, Australia.
authors.forename: Natasha E
authors.initials: NE
authors.lastname: Holmes
authors.forename: Susan A
authors.initials: SA
authors.lastname: Ballard
authors.forename: Margaret M C
authors.initials: MM
authors.lastname: Lam
authors.forename: Paul D R
authors.initials: PD
authors.lastname: Johnson
authors.forename: M Lindsay
authors.initials: ML
authors.lastname: Grayson
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Stinear
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Howden
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D024881:Drug Resistance, Bacterial; D016984:Enterococcus faecium / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D005260:Female; D016680:Genome, Bacterial; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017334:Teicoplanin / Q000008:administration & dosage / Q000494:pharmacology*; D014180:Transplantation; D017211:Treatment Failure; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C079913:VanB protein, Enterococcus; D017334:Teicoplanin; D014640:Vancomycin
keywords: single nucleotide polymorphisms; vanRS; whole genome sequencing