Willeke F Westendorp1, Jan-Dirk Vermeij1, Elles Zock2, Imke J Hooijenga1, Nyika D Kruyt3, Hans J L W Bosboom4, Vincent I H Kwa4, Martijn Weisfelt5, Michel J M Remmers6, Robert ten Houten7, A H C M Tobien Schreuder8, Sarah E Vermeer9, Ewout J van Dijk10, Diederik W J Dippel11, Marcel G W Dijkgraaf12, Lodewijk Spanjaard13, Marinus Vermeulen1, Tom van der Poll14, Jan M Prins14, Frederique H Vermeij15, Yvo B W E M Roos1, Ruud P Kleyweg2, Henk Kerkhoff2, Matthijs C Brouwer1, Aeilko H Zwinderman16, Diederik van de Beek17, Paul J Nederkoorn1. 1. Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 2. Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands. 3. Department of Neurology, Slotervaart Hospital, Amsterdam, Netherlands. 4. Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands. 5. Department of Neurology, Kennemer Gasthuis, Haarlem, Netherlands. 6. Department of Neurology, Amphia Ziekenhuis, Breda, Netherlands. 7. Department of Neurology, Medisch Centrum Alkmaar, Alkmaar, Netherlands. 8. Department of Neurology, Atrium Medisch Centrum, Heerlen, Netherlands. 9. Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands. 10. Department of Neurology, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands. 11. Department of Neurology, Erasmus MC University Medical Centre, Rotterdam, Netherlands. 12. Clinical Research Unit, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 13. Department of Medical Microbiology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 14. Infectious Diseases, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 15. Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, Netherlands. 16. Department of Clinical Epidemiology and Biostatistics, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 17. Department of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. Electronic address: d.vandebeek@amc.uva.nl.
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. FINDINGS: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 toceftriaxoneand 1275 patients to standard treatment (control group). 12 patients (seven in theceftriaxone 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. INTERPRETATION: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. FUNDING: Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.
RCT Entities:
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.
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