title: The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial.
abstract: BACKGROUND
  In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke.
  
  
  METHODS
  In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176.
  
  
  RESULTS
  Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group.
  
  
  CONCLUSIONS
  Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke.
  
  
  BACKGROUND
  Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Willeke F
authors.initials: WF
authors.lastname: Westendorp
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Jan-Dirk
authors.initials: JD
authors.lastname: Vermeij
authors.affiliation: Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands.
authors.forename: Elles
authors.initials: E
authors.lastname: Zock
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Imke J
authors.initials: IJ
authors.lastname: Hooijenga
authors.affiliation: Department of Neurology, Slotervaart Hospital, Amsterdam, Netherlands.
authors.forename: Nyika D
authors.initials: ND
authors.lastname: Kruyt
authors.affiliation: Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands.
authors.forename: Hans J L W
authors.initials: HJ
authors.lastname: Bosboom
authors.affiliation: Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands.
authors.forename: Vincent I H
authors.initials: VI
authors.lastname: Kwa
authors.affiliation: Department of Neurology, Kennemer Gasthuis, Haarlem, Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Weisfelt
authors.affiliation: Department of Neurology, Amphia Ziekenhuis, Breda, Netherlands.
authors.forename: Michel J M
authors.initials: MJ
authors.lastname: Remmers
authors.affiliation: Department of Neurology, Medisch Centrum Alkmaar, Alkmaar, Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: ten Houten
authors.affiliation: Department of Neurology, Atrium Medisch Centrum, Heerlen, Netherlands.
authors.forename: A H C M Tobien
authors.initials: AH
authors.lastname: Schreuder
authors.affiliation: Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Vermeer
authors.affiliation: Department of Neurology, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: van Dijk
authors.affiliation: Department of Neurology, Erasmus MC University Medical Centre, Rotterdam, Netherlands.
authors.forename: Diederik W J
authors.initials: DW
authors.lastname: Dippel
authors.affiliation: Clinical Research Unit, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Marcel G W
authors.initials: MG
authors.lastname: Dijkgraaf
authors.affiliation: Department of Medical Microbiology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Spanjaard
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Marinus
authors.initials: M
authors.lastname: Vermeulen
authors.affiliation: Infectious Diseases, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Infectious Diseases, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Prins
authors.affiliation: Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, Netherlands.
authors.forename: Frederique H
authors.initials: FH
authors.lastname: Vermeij
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Yvo B W E M
authors.initials: YB
authors.lastname: Roos
authors.affiliation: Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands.
authors.forename: Ruud P
authors.initials: RP
authors.lastname: Kleyweg
authors.affiliation: Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Kerkhoff
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. Electronic address: d.vandebeek@amc.uva.nl.
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
authors.affiliation: Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Nederkoorn
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D057194:Intention to Treat Analysis; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011014:Pneumonia / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D011446:Prospective Studies; D019057:Quality-Adjusted Life Years; D020127:Recovery of Function; D020521:Stroke / Q000150:complications* / Q000628:therapy*; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*
chemical_list: D000900:Anti-Bacterial Agents; D002443:Ceftriaxone