title: Genetic and molecular predictors of high vancomycin MIC in Staphylococcus aureus bacteremia isolates.
abstract: An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes.
authors.affiliation: Austin Centre for Infection Research, Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia Department of Medicine, University of Melbourne, Parkville, Victoria, Australia natasha.holmes@austin.org.au.
authors.forename: Natasha E
authors.initials: NE
authors.lastname: Holmes
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia Department of Paediatrics, Pathology and Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Turnidge
authors.affiliation: Infection Management Services, Princess Alexandra Hospital, Wolloongabba, Queensland, Australia Department of Medicine, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Munckhof
authors.affiliation: Department of Microbiology and Infectious Diseases, PathWest Laboratory Medicine-WA, Royal Perth Hospital, Perth, Western Australia, Australia Australian Collaborating Centre for Enterococcus and Staphylococcus Species (ACCESS) Typing and Research, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: J Owen
authors.initials: JO
authors.lastname: Robinson
authors.affiliation: Department of Infectious Diseases, Monash Health, Clayton, Victoria, Australia Department of Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Tony M
authors.initials: TM
authors.lastname: Korman
authors.affiliation: Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia Department of Medicine, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Matthew V N
authors.initials: MV
authors.lastname: O'Sullivan
authors.affiliation: Department of Infectious Diseases, Royal Hobart Hospital, Hobart, Tasmania, Australia Department of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Anderson
authors.affiliation: Auckland District Health Board, Auckland, New Zealand.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Roberts
authors.affiliation: Department of Infectious Diseases, Royal Hobart Hospital, Hobart, Tasmania, Australia Department of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Sanchia J C
authors.initials: SJ
authors.lastname: Warren
authors.affiliation: Department of Microbiology and Infectious Diseases, PathWest Laboratory Medicine-WA, Royal Perth Hospital, Perth, Western Australia, Australia Australian Collaborating Centre for Enterococcus and Staphylococcus Species (ACCESS) Typing and Research, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Coombs
authors.affiliation: Department of Microbiology and Infectious Diseases, PathWest Laboratory Medicine-WA, Royal Perth Hospital, Perth, Western Australia, Australia Australian Collaborating Centre for Enterococcus and Staphylococcus Species (ACCESS) Typing and Research, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Hui-Leen
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Austin Centre for Infection Research, Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia Department of Microbiology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Austin Centre for Infection Research, Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia Department of Medicine, University of Melbourne, Parkville, Victoria, Australia Department of Microbiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Paul D R
authors.initials: PD
authors.lastname: Johnson
authors.affiliation: Austin Centre for Infection Research, Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia Department of Microbiology, Austin Health, Heidelberg, Victoria, Australia Department of Microbiology, Monash University, Clayton, Victoria, Australia Microbiological Diagnostic Unit, Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Howden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000382:microbiology*; D001426:Bacterial Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004361:Drug Tolerance; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D046228:Microarray Analysis; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011446:Prospective Studies; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D015534:Trans-Activators / Q000235:genetics; D014640:Vancomycin / Q000494:pharmacology*; D037521:Virulence Factors / Q000235:genetics; D055815:Young Adult
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015534:Trans-Activators; D037521:Virulence Factors; D014640:Vancomycin