Preventive antibiotic therapy in acute stroke

Stroke is the second most common cause of death and the third most common cause of disability worldwide. Infections complicate stroke in about one-third of patients and they are associated with unfavourable disease outcome and mortality. This thesis is focused on the ‘Preventive Antibiotics in Stroke Study’ (PASS), a multicenter randomised clinical trial aimed at prevention of infections with antibiotic therapy to improve functional outcome in stroke patients. 2550 stroke patients were randomised to ceftriaxone in addition to standard therapy, or standard therapy alone. Preventive antibiotic therapy did not improve functional outcome at 3 months. It did prevent infections, but this was merely due to prevention of urinary tract infection, pneumonia was not prevented. We also described the cost-effectiveness analysis of the PASS in this thesis. This showed that preventive antibiotic therapy was likely to be a cost-effective treatment, although the possible costs of future antimicrobial resistance were not included in this analysis. Patients are vulnerable for infection after stroke due to immune suppression, partly mediated by the sympathetic nervous system. We also investigated whether pre-stroke use of beta-blockers could decrease infection rate, but found that infection rates were increased in patients with pre-stroke beta-blocker use. Finally, we describe a prediction rule for pneumonia and infection after stroke. This prediction rule can be used to select the patients at the highest risk for these infections for future trials. Future trials should be focused on diagnosis of post-stroke infection and combined treatment approaches for fever, infection and aspiration

Update of the Preventive Antibiotics in Stroke Study (PASS): Statistical analysis plan

Background: Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were st

Disruptions of anaerobic gut bacteria are associated with stroke and post-stroke infection: a prospective case-control study

In recent years, preclinical studies have illustrated the potential role of intestinal bacterial composition in the risk of stroke and post-stroke infections. The results of these studies suggest that bacteria capable of producing volatile metabolites, including trimethylamine-N-oxide (TMAO) and butyrate, play opposing, yet important roles in the cascade of events leading to stroke. However, no large-scale studies have been undertaken to determine the abundance of these bacterial communities in stroke patients and to assess the impact of disrupted compositions of the intestinal microbiota on patient outcomes. In this prospective case-control study, rectal swabs from 349 ischemic and hemorrhagic stroke patients (median age, 71 years; IQR: 67-75) were collected within 24 h of hospital admission. Samples were subjected to 16S rRNA amplicon sequencing and subsequently compared with samples obtained from 51 outpatient age- and sex-matched controls (median age, 72 years; IQR, 62-80) with similar cardiovascular risk profiles but without active signs of stroke. Plasma protein biomarkers were analyzed using a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Alpha and beta diversity analyses revealed higher disruption of intestinal communities during ischemic and hemorrhagic stroke compared with non-stroke matched control subjects. Additionally, we observed an enrichment of bacteria implicated in TMAO production and a loss of butyrate-producing bacteria. Stroke patients displayed two-fold lower plasma levels of TMAO than controls (median 1.97 vs 4.03 mu M, Wilcoxonp < 0.0001). Finally, lower abundance of butyrate-producing bacteria within 24 h of hospital admission was an independent predictor of enhanced risk of post-stroke infection (odds ratio 0.77,p = 0.005), but not of mortality or functional patient outcome. In conclusion, aberrations in trimethylamine- and butyrate-producing gut bacteria are associated with stroke and stroke-associated infections.Proteomic

Development and internal validation of a prediction rule for post-stroke infection and post-stroke pneumonia in acute stroke patients

Introduction Patients with acute stroke are at high risk for infection. These infections are associated with unfavourable outcome after stroke. A prediction rule can identify the patients at the highest risk for strategies to prevent infection. We aim to develop a prediction rule for post-stroke pneumonia and other infections in patients with acute stroke. Patients and methods We used data from the Preventive Antibiotics in Stroke Study, a multicentre randomised trial comparing preventive ceftriaxone vs. standard stroke care in patients with acute stroke. Possible predictors for post-stroke pneumonia or infection were selected from the literature. Backward elimination logistic regression analysis was used to construct prediction rules for pneumonia or infection. Internal validation was performed and a risk chart was constructed. We adjusted for preventive antibiotic use. Results Pneumonia was diagnosed in 159 of the 2538 included patients, and infection in 348. Pneumonia was predicted by higher age, male sex, pre-stroke disability, medical history of chronic obstructive pulmonary disease, more severe stroke, dysphagia and intracerebral haemorrhage (rather than ischaemic stroke). Infections were predicted by higher age, male sex, history of diabetes, chronic obstructive pulmonary disease, more severe stroke, dysphagia, use of bladder catheter, preventive antibiotic use and intracerebral

Supplementary Material for: Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

<i>Background:</i> The Preventive Antibiotics in Stroke Study (PASS), a randomized open-label masked endpoint trial, showed that preventive ceftriaxone did not improve functional outcome at 3 months in patients with acute stroke (adjusted common OR 0.95; 95% CI 0.82-1.09). Post-hoc analyses showed that among patients who received intravenous thrombolysis (IVT), patients who received ceftriaxone had a significantly better outcome as compared with the control group. This study aimed to gain more insight into the characteristics of these patients. <i>Methods:</i> In PASS, 2,550 patients were randomly assigned to preventive antibiotic treatment with ceftriaxone or standard care. In current post-hoc analysis, 836 patients who received IVT were included. Primary outcome included functional status on the modified Rankin Scale, analyzed with adjusted ordinal regression. Secondary outcomes included infection rate and symptomatic intracerebral hemorrhage (sICH) rate. <i>Results:</i> For all patients in PASS, the p value for the interaction between IVT and preventive ceftriaxone regarding functional outcome was 0.03. Of the 836 IVT-treated patients, 437 were administered ceftriaxone and 399 were allocated to the control group. Baseline characteristics were similar. In the IVT subgroup, preventive ceftriaxone was associated with a significant reduction in unfavorable outcome (adjusted common OR 0.77; 95% CI 0.61-0.99; p = 0.04). Mortality at 3 months was similar (OR 0.75; 95% CI 0.48-1.18). Preventive ceftriaxone was associated with a reduction in infections (OR 0.43; 95% CI 0.28-0.66), and a trend towards an increased risk for sICH (OR 3.09; 95% CI 0.85-11.31). Timing of ceftriaxone administration did not influence the outcome (aOR 1.00; 95% CI 0.98-1.03; p = 0.85). <i>Conclusions:</i> According to the post-hoc analysis of PASS, preventive ceftriaxone may improve the functional outcome in IVT-treated patients with acute stroke, despite a trend towards an increased rate of post-IVT-sICH