title: Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost-effectiveness analysis.
abstract: BACKGROUND
  Determination of the presence or absence of bacterial infection is important to guide appropriate therapy and reduce antibiotic exposure. Procalcitonin (PCT) is an inflammatory marker that has been suggested as a marker for bacterial infection.
  
  
  OBJECTIVE
  To assess the clinical effectiveness and cost-effectiveness of adding PCT testing to the information used to guide antibiotic therapy in adults and children (1) with confirmed or highly suspected sepsis in intensive care and (2) presenting to the emergency department (ED) with suspected bacterial infection.
  
  
  METHODS
  Twelve databases were searched to June 2014. Randomised controlled trials were assessed for quality using the Cochrane Risk of Bias tool. Summary relative risks (RRs) and weighted mean differences (WMDs) were estimated using random-effects models. Heterogeneity was assessed visually using forest plots and statistically using the I (2) and Q statistics and investigated through subgroup analysis. The cost-effectiveness of PCT testing in addition to current clinical practice was compared with current clinical practice using a decision tree with a 6 months' time horizon.
  
  
  RESULTS
  Eighteen studies (36 reports) were included in the systematic review. PCT algorithms were associated with reduced antibiotic duration [WMD -3.19 days, 95% confidence interval (CI) -5.44 to -0.95 days, I (2) = 95.2%; four studies], hospital stay (WMD -3.85 days, 95% CI -6.78 to -0.92 days, I (2) = 75.2%; four studies) and a trend towards reduced intensive care unit (ICU) stay (WMD -2.03 days, 95% CI -4.19 to 0.13 days, I (2) = 81.0%; four studies). There were no differences for adverse clinical outcomes. PCT algorithms were associated with a reduction in the proportion of adults (RR 0.77, 95% CI 0.68 to 0.87; seven studies) and children (RR 0.86, 95% CI 0.80 to 0.93) receiving antibiotics, reduced antibiotic duration (two studies). There were no differences for adverse clinical outcomes. All but one of the studies in the ED were conducted in people presenting with respiratory symptoms. Cost-effectiveness: the base-case analyses indicated that PCT testing was cost-saving for (1) adults with confirmed or highly suspected sepsis in an ICU setting; (2) adults with suspected bacterial infection presenting to the ED; and (3) children with suspected bacterial infection presenting to the ED. Cost-savings ranged from £368 to £3268. Moreover, PCT-guided treatment resulted in a small quality-adjusted life-year (QALY) gain (ranging between < 0.001 and 0.005). Cost-effectiveness acceptability curves showed that PCT-guided treatment has a probability of ≥ 84% of being cost-effective for all settings and populations considered (at willingness-to-pay thresholds of £20,000 and £30,000 per QALY).
  
  
  CONCLUSIONS
  The limited available data suggest that PCT testing may be effective and cost-effective when used to guide discontinuation of antibiotics in adults being treated for suspected or confirmed sepsis in ICU settings and initiation of antibiotics in adults presenting to the ED with respiratory symptoms and suspected bacterial infection. However, it is not clear that observed costs and effects are directly attributable to PCT testing, are generalisable outside people presenting with respiratory symptoms (for the ED setting) and would be reproducible in the UK NHS. Further studies are needed to assess the effectiveness of adding PCT algorithms to the information used to guide antibiotic treatment in children with suspected or confirmed sepsis in ICU settings. Additional research is needed to examine whether the outcomes presented in this report are fully generalisable to the UK.
  
  
  BACKGROUND
  This study is registered as PROSPERO CRD42014010822.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Kleijnen Systematic Reviews Ltd, York, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Westwood
authors.affiliation: Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: Ramaekers
authors.affiliation: Kleijnen Systematic Reviews Ltd, York, UK.
authors.forename: Penny
authors.initials: P
authors.lastname: Whiting
authors.affiliation: Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Florian
authors.initials: F
authors.lastname: Tomini
authors.affiliation: Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Manuela
authors.initials: M
authors.lastname: Joore
authors.affiliation: Kleijnen Systematic Reviews Ltd, York, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Armstrong
authors.affiliation: Kleijnen Systematic Reviews Ltd, York, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Ryder
authors.affiliation: Kleijnen Systematic Reviews Ltd, York, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stirk
authors.affiliation: Erasmus University Rotterdam, Rotterdam, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Severens
authors.affiliation: Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Kleijnen
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D015415:Biomarkers; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide; D002648:Child; D003362:Cost-Benefit Analysis; D004636:Emergency Service, Hospital; D006801:Humans; D007362:Intensive Care Units; D007902:Length of Stay; D018803:Models, Economic; D011498:Protein Precursors; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy* / Q000191:economics; D013673:Technology Assessment, Biomedical; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; C000606589:CALCA protein, human; D011498:Protein Precursors; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide