title: Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality.
abstract: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide.
  
  
  
  A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling.
  
  
  
  In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp.
  
  
  
  In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine,  Cleveland, Ohio, USA.|Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rojas
authors.affiliation: Division of Infectious Diseases, Detroit Medical Center, Wayne State University, Michigan, USA.
authors.forename: Madiha
authors.initials: M
authors.lastname: Salim
authors.affiliation: Department of Infectious Diseases, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Cober
authors.affiliation: Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Richter
authors.affiliation: Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine,  Cleveland, Ohio, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Perez
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine,  Cleveland, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Salata
authors.affiliation: Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kalayjian
authors.affiliation: Department of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH , USA.|Division of Infectious Diseases, Cleveland Clinic Akron General Medical Center , Akron , OH , USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Watkins
authors.affiliation: Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Rudin
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: T Nicholas
authors.initials: TN
authors.lastname: Domitrovic
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Hujer
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Hujer
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pennsylvania, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Doi
authors.affiliation: Division of Infectious Diseases, Detroit Medical Center, Wayne State University, Michigan, USA.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Kaye
authors.affiliation: Department of Biostatistics and the Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Evans
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.|Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine,  Cleveland, Ohio, USA.|Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine,  Cleveland, Ohio, USA.|Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: Division of Infectious Diseases, University of North Carolina, Chapel Hill, USA.
authors.forename: David
authors.initials: D
authors.lastname: van Duin
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015780:Carbapenems / Q000494:pharmacology / Q000627:therapeutic use; D003091:Colistin / Q000494:pharmacology / Q000627:therapeutic use*; D015897:Comorbidity; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007710:Klebsiella Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology* / Q000401:mortality; D007711:Klebsiella pneumoniae / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010802:Phylogeny; D016016:Proportional Hazards Models; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D001618:beta-Lactamases; D003091:Colistin
keywords: Klebsiella pneumoniae; carbapenem-resistant Enterobacteriaceae; colistin; mortality; ST258