title: Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.
abstract: BACKGROUND
  In critically ill patients, antibiotic therapy is of great importance but long duration of treatment is associated with the development of antimicrobial resistance. Procalcitonin is a marker used to guide antibacterial therapy and reduce its duration, but data about safety of this reduction are scarce. We assessed the efficacy and safety of procalcitonin-guided antibiotic treatment in patients in intensive care units (ICUs) in a health-care system with a comparatively low use of antibiotics.
  
  
  METHODS
  We did a prospective, multicentre, randomised, controlled, open-label intervention trial in 15 hospitals in the Netherlands. Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate. Patients who received antibiotics for presumed infection were randomly assigned (1:1), using a computer-generated list, and stratified (according to treatment centre, whether infection was acquired before or during ICU stay, and dependent on severity of infection [ie, sepsis, severe sepsis, or septic shock]) to receive either procalcitonin-guided or standard-of-care antibiotic discontinuation. Both patients and investigators were aware of group assignment. In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0·5 μg/L or lower. In the standard-of-care group, patients were treated according to local antibiotic protocols. Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment. All analyses were done by intention to treat. Mortality analyses were completed for all patients (intention to treat) and for patients in whom antibiotics were stopped while being on the ICU (per-protocol analysis). Safety endpoints were reinstitution of antibiotics and recurrent inflammation measured by C-reactive protein concentrations and they were measured in the population adhering to the stopping rules (per-protocol analysis). The study is registered with ClinicalTrials.gov, number NCT01139489, and was completed in August, 2014.
  
  
  RESULTS
  Between Sept 18, 2009, and July 1, 2013, 1575 of the 4507 patients assessed for eligibility were randomly assigned to the procalcitonin-guided group (761) or to standard-of-care (785). In 538 patients (71%) in the procalcitonin-guided group antibiotics were discontinued in the ICU. Median consumption of antibiotics was 7·5 daily defined doses (IQR 4·0-12·7) in the procalcitonin-guided group versus 9·3 daily defined doses (5·0-16·6) in the standard-of-care group (between-group absolute difference 2·69, 95% CI 1·26-4·12, p<0·0001). Median duration of treatment was 5 days (3-9) in the procalcitonin-guided group and 7 days (4-11) in the standard-of-care group (between-group absolute difference 1·22, 0·65-1·78, p<0·0001). Mortality at 28 days was 149 (20%) of 761 patients in the procalcitonin-guided group and 196 (25%) of 785 patients in the standard-of-care group (between-group absolute difference 5·4%, 95% CI 1·2-9·5, p=0·0122) according to the intention-to-treat analysis, and 107 (20%) of 538 patients in the procalcitonin-guided group versus 121 (27%) of 457 patients in the standard-of-care group (between-group absolute difference 6·6%, 1·3-11·9, p=0·0154) in the per-protocol analysis. 1-year mortality in the per-protocol analysis was 191 (36%) of 538 patients in the procalcitonin-guided and 196 (43%) of 457 patients in the standard-of-care groups (between-group absolute difference 7·4, 1·3-13·8, p=0·0188).
  
  
  CONCLUSIONS
  Procalcitonin guidance stimulates reduction of duration of treatment and daily defined doses in critically ill patients with a presumed bacterial infection. This reduction was associated with a significant decrease in mortality. Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship.
  
  
  BACKGROUND
  Thermo Fisher Scientific.
authors.affiliation: VU University Medical Center, Amsterdam, Netherlands. Electronic address: ev.dejong@vumc.nl.
authors.forename: Evelien
authors.initials: E
authors.lastname: de Jong
authors.affiliation: Elisabeth Tweesteden Hospital, Tilburg, Netherlands.
authors.forename: Jos A
authors.initials: JA
authors.lastname: van Oers
authors.affiliation: VU University Medical Center, Amsterdam, Netherlands; Medisch Spectrum Twente, Enschede, Netherlands.
authors.forename: Albertus
authors.initials: A
authors.lastname: Beishuizen
authors.affiliation: Elisabeth Tweesteden Hospital, Tilburg, Netherlands.
authors.forename: Piet
authors.initials: P
authors.lastname: Vos
authors.affiliation: Medisch Spectrum Twente, Enschede, Netherlands.
authors.forename: Wytze J
authors.initials: WJ
authors.lastname: Vermeijden
authors.affiliation: Diakonessen Hospital, Utrecht, Netherlands.
authors.forename: Lenneke E
authors.initials: LE
authors.lastname: Haas
authors.affiliation: Martini Hospital, Groningen, Netherlands.
authors.forename: Bert G
authors.initials: BG
authors.lastname: Loef
authors.affiliation: Atrium Hospital, Heerlen, Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Dormans
authors.affiliation: Medical Centre Haaglanden, Haaglanden, The Hague, Netherlands.
authors.forename: Gertrude C
authors.initials: GC
authors.lastname: van Melsen
authors.affiliation: Elisabeth Tweesteden Hospital, Tilburg, Netherlands.
authors.forename: Yvette C
authors.initials: YC
authors.lastname: Kluiters
authors.affiliation: University Medical Centre Utrecht, Utrecht, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Kemperman
authors.affiliation: St Lucas Andreas Hospital, Amsterdam, Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: van den Elsen
authors.affiliation: Canisius Wilhelmina Hospital, Nijmegen, Amsterdam, Netherlands.
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Schouten
authors.affiliation: Bronovo Hospital, The Hague, Netherlands.
authors.forename: Jörn O
authors.initials: JO
authors.lastname: Streefkerk
authors.affiliation: Medisch Spectrum Twente, Enschede, Netherlands.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Krabbe
authors.affiliation: Isala Hospital, Zwolle, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Kieft
authors.affiliation: Slotervaart Hospital Amsterdam, Netherlands.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Kluge
authors.affiliation: Westfries Gasthuis Hoorn, Netherlands.
authors.forename: Veerle C
authors.initials: VC
authors.lastname: van Dam
authors.affiliation: University Medical Centre, University of Groningen, Groningen, Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: van Pelt
authors.affiliation: Atrium Hospital, Heerlen, Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Bormans
authors.affiliation: Diakonessen Hospital Utrecht, Utrecht, Netherlands.
authors.forename: Martine Bokelman
authors.initials: MB
authors.lastname: Otten
authors.affiliation: Martini Hospital, Groningen, Netherlands.
authors.forename: Auke C
authors.initials: AC
authors.lastname: Reidinga
authors.affiliation: Diakonessen Hospital Utrecht, Utrecht, Netherlands.
authors.forename: Henrik
authors.initials: H
authors.lastname: Endeman
authors.affiliation: VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Jos W
authors.initials: JW
authors.lastname: Twisk
authors.affiliation: St Antonius Hospital, Nieuwegein, Netherlands.
authors.forename: Ewoudt M W
authors.initials: EMW
authors.lastname: van de Garde
authors.affiliation: University Medical Centre, University of Groningen, Groningen, Netherlands.
authors.forename: Anne Marie G A
authors.initials: AMGA
authors.lastname: de Smet
authors.affiliation: University Medical Centre Utrecht, Utrecht, Netherlands.
authors.forename: Jozef
authors.initials: J
authors.lastname: Kesecioglu
authors.affiliation: VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Armand R
authors.initials: AR
authors.lastname: Girbes
authors.affiliation: University Medical Centre, University of Groningen, Groningen, Netherlands.
authors.forename: Maarten W
authors.initials: MW
authors.lastname: Nijsten
authors.affiliation: University Medical Centre Utrecht, Utrecht, Netherlands.
authors.forename: Dylan W
authors.initials: DW
authors.lastname: de Lange
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000401:mortality; D015415:Biomarkers / Q000097:blood; D002116:Calcitonin / Q000097:blood*; D015740:Calcitonin Gene-Related Peptide; D016638:Critical Illness; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007362:Intensive Care Units; D008875:Middle Aged; D009426:Netherlands; D011446:Prospective Studies; D012772:Shock, Septic / Q000401:mortality
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide