title: Rapid Molecular Diagnostics, Antibiotic Treatment Decisions, and Developing Approaches to Inform Empiric Therapy: PRIMERS I and II.
abstract: BACKGROUND
  Rapid molecular diagnostic (RMD) platforms may lead to better antibiotic use. Our objective was to develop analytical strategies to enhance the interpretation of RMDs for clinicians.
  
  
  METHODS
  We compared the performance characteristics of 4 RMD platforms for detecting resistance against β-lactams in 72 highly resistant isolates of Escherichia coli and Klebsiella pneumoniae (PRIMERS I). Subsequently, 2 platforms were used in a blinded study in which a heterogeneous collection of 196 isolates of E. coli and K. pneumoniae (PRIMERS II) were examined. We evaluated the genotypic results as predictors of resistance or susceptibility against β-lactam antibiotics. We designed analytical strategies and graphical representations of platform performance, including discrimination summary plots and susceptibility and resistance predictive values, that are readily interpretable by practitioners to inform decision-making.
  
  
  RESULTS
  In PRIMERS I, the 4 RMD platforms detected β-lactamase (bla) genes and identified susceptibility or resistance in >95% of cases. In PRIMERS II, the 2 platforms identified susceptibility against extended-spectrum cephalosporins and carbapenems in >90% of cases; however, against piperacillin/tazobactam, susceptibility was identified in <80% of cases. Applying the analytical strategies to a population with 15% prevalence of ceftazidime-resistance and 5% imipenem-resistance, RMD platforms predicted susceptibility in >95% of cases, while prediction of resistance was 69%-73% for ceftazidime and 41%-50% for imipenem.
  
  
  CONCLUSIONS
  RMD platforms can help inform empiric β-lactam therapy in cases where bla genes are not detected and the prevalence of resistance is known. Our analysis is a first step in bridging the gap between RMDs and empiric treatment decisions.
authors.affiliation: Center for Biostatistics in AIDS Research and the Department of Biostatistics, Harvard University, Boston, Massachusetts.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Evans
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Hujer
authors.affiliation: Center for Biostatistics in AIDS Research and the Department of Biostatistics, Harvard University, Boston, Massachusetts.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Hujer
authors.affiliation: Ibis Biosciences, an Abbott Company, Carlsbad, California.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hall
authors.affiliation: Ibis Biosciences, an Abbott Company, Carlsbad, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Marzan
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jacobs
authors.affiliation: Ibis Biosciences, an Abbott Company, Carlsbad, California.
authors.forename: Rangarajan
authors.initials: R
authors.lastname: Sampath
authors.affiliation: Ibis Biosciences, an Abbott Company, Carlsbad, California.
authors.forename: David J
authors.initials: DJ
authors.lastname: Ecker
authors.affiliation: Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark.
authors.forename: Claudia
authors.initials: C
authors.lastname: Manca
authors.affiliation: Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Chavda
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Pan
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Helen
authors.initials: H
authors.lastname: Fernandez
authors.affiliation: Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Mediavilla
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Hill
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio.
authors.forename: Federico
authors.initials: F
authors.lastname: Perez
authors.affiliation: Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Caliendo
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
authors.affiliation: University of California, San Francisco General Hospital.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Chambers
authors.affiliation: Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D060005:Genotyping Techniques / Q000379:methods; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests / Q000379:methods*; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D013997:Time Factors; D018440:beta-Lactam Resistance
chemical_list: D000900:Anti-Bacterial Agents
keywords: empiric therapy; molecular diagnostics; β-lactams