Preventive ceftriaxone in patients at high risk of stroke-associated pneumonia. A post-hoc analysis of the PASS trial

PLoS One. 2022 Dec 30;17(12):e0279700. doi: 10.1371/journal.pone.0279700. eCollection 2022.


Background: Infections complicate the acute phase of stroke in one third of patients and especially pneumonia is associated with increased risk of death or dependency. In randomized trials of stroke patients, preventive antibiotics reduced overall infections, but did not reduce pneumonia or improve outcome. This may be explained by broad selection criteria, including many patients with a low risk of pneumonia. To assess the potential of selection of patients at high risk of pneumonia, we performed a post-hoc analysis in the Preventive Antibiotics in Stroke Study (PASS).

Methods: PASS was a multicentre phase 3 trial in acute stroke patients who were randomized to preventive ceftriaxone for four days within 24 hours or standard care. For this analysis patients were divided based on the ISAN risk score for pneumonia as follows: low (0-6), medium (7-14) and high (15-21). Primary outcomes were pneumonia rate during admission as judged by the treating physician, and by an independent committee; secondary outcomes were overall infections and unfavorable outcome (modified Rankin Scale ≥3). We adjusted with multivariable regression for possible confounders: age, stroke subtype and severity, pre-stroke dependency and diabetes.

Results: Pneumonia occurred more frequently in higher risk groups (25.7% (high), 9.0% (medium) 1.5%, (low)). The absolute difference in pneumonia rate between patients treated with ceftriaxone or standard care increased with the ISAN score (low: 0.5%, medium: 1.2%, high: 10.1%). After adjustment ceftriaxone reduced overall infections in the low and medium groups, not in the high-risk group. There was a trend towards reduction of pneumonia as judged by the committee (3.7% vs 13.6%, aOR = 0.164, p = 0.063) in the high-risk group.

Conclusions: This post-hoc analysis of PASS confirmed higher rates of pneumonia with higher ISAN scores, and suggests that in acute stroke patients with an ISAN score of ≥15, preventive ceftriaxone for four days may reduce pneumonia rate.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / therapeutic use
  • Ceftriaxone / therapeutic use
  • Humans
  • Pneumonia* / complications
  • Pneumonia* / drug therapy
  • Stroke* / complications
  • Stroke* / drug therapy
  • Stroke* / prevention & control
  • Treatment Outcome


  • Ceftriaxone
  • Anti-Bacterial Agents

Grants and funding

The Preventive Antibiotics in Stroke Study was funded by The Netherlands Organization for Health Research and Development (ZonMW grant no. 171002302 to DvdB and PJN; grant no. 016116358 to DvdB), The Netherlands Heart Foundation (grant no.2009B095 to DvdB and PJN), and the European Research Council (ERC Starting Grant to DvdB). WMS is supported by the European Union’s Horizon 2020 Research and Innovation Programme (grant No. 634809). HBvdW reports grants from Stryker outside the submitted work, and served as a consultant to Bayer and LivaNova, with fees paid to his institution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of this post-hoc analysis.