Preventive antibiotic therapy in acute stroke patients: A systematic review and meta-analysis of individual patient data of randomized controlled trials

Introduction Infection after stroke is associated with unfavorable outcome. Randomized controlled studies did not show benefit of preventive antibiotics in stroke but lacked power for subgroup analyses. Aim of this study is to assess whether preventive antibiotic therapy after stroke improves functional outcome for specific patient groups in an individual patient data meta-analysis. Patients and methods We searched MEDLINE (1946–7 May 2021), Embase (1947–7 May 2021), CENTRAL (17th September 2021), trial registries, cross-checked references and contacted researchers for randomized controlled trials of preventive antibiotic therapy versus placebo or standard care in ischemic or hemorrhagic stroke patients. Meta-analysis was performed by a one-step and two-step approach. Primary outcome was functional outcome adjusted for age and stroke severity. Secondary outcomes were infections and mortality. Results 4197 patients from nine trials were included. Preventive antibiotic therapy was not associated with a shift in functional outcome (mRS) at 3 months (OR1.13, 95%CI 0.98–1.31) or unfavorable functional outcome (mRS 3–6) (OR0.85, 95%CI 0.60–1.19). Preventive antibiotics did not improve functional outcome in pre-defined subgroups (age, stroke severity, timing and type of antibiotic therapy, pneumonia prediction scores, dysphagia, type of stroke, and type of trial). Preventive antibiotics reduced infections (276/2066 (13.4%) in the preventive antibiotic group vs. 417/2059 (20.3%) in the control group, OR 0.60, 95% CI 0.51–0.71, p < 0.001), but not pneumonia (191/2066 (9.2%) in the preventive antibiotic group vs. 205/2061 (9.9%) in the control group (OR 0.92 (0.75–1.14), p = 0.450). Discussion and conclusion Preventive antibiotic therapy did not benefit any subgroup of patients with acute stroke and currently cannot be recommended.


Supplemental file Preventive antibiotic therapy in subgroups of acute stroke patients: an individual patient meta-analysis
Contents Page Table S1. Search strategy 2 Table S2. Excluded studies 4 Table S3. Studies eligible but no data obtained 4 Table S4. Variables extracted from each trial on individual patient level 5 Table S5. Data definitions across trials 6-9 Table S6. Baseline characteristics of type 1 trials 10 Table S7. Baseline characteristics of type 2 trials 11 Table S8. Risk of bias assessment 12 Table S9. Outcomes for each trial 13 Table S10. Unfavorable outcome (mRS 3-6) at 3 months in all patients per trial 14 Figure S1. Unfavorable outcome (mRS 3-6) at 3 months per trial 14 Table S11. Ordinal analysis mRS in all patients per trial 15 Figure S2. mRS scores at 3 months for all patients 16 Figure S3. mRS scores at 3 months for patients included in type 2 trials 16 Table S12. Subgroup analyses for the primary outcome of functional outcome on total range of mRS for all trials 17 Table S13. Subgroup analyses for the primary outcome of functional outcome 18 on total range of mRS for type 1 trials Table S14. Subgroup analyses for the primary outcome of functional outcome 19 on total range of mRS for type 2 trials Table S15. Subgroup analyses for the primary outcome of unfavorable functional 20 outcome (mRS 3-6) for all trials.   1 cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or exp cerebrovascular trauma/ or exp intracranial arterial diseases/ or exp intracranial arteriovenous malformations/ or exp "intracranial embolism and thrombosis"/ or exp intracranial hemorrhages/ or stroke/ or exp brain infarction/ or vasospasm, intracranial/ or vertebral artery dissection/ 364994 2 (stroke$ or poststroke$ or cva$ or cerebrovascular$ or cerebral vascular).tw. 313781 3 ((cerebral or cerebellar or brain$ or vertebrobasilar) adj5 (infarct$ or isch?emi$ or thrombo$ or apoplexy or emboli$)).tw. 94335 4 ((cerebral or intracerebral or intracranial or brain or cerebellar or subarachnoid) adj5 (haemorrhage or hemorrhage or haematoma or hematoma or bleeding or aneurysm)).tw. 72576 5 1 or 2 or 3 or 4 558713 6 Antibiotic Prophylaxis/ 14374 7 exp Anti-Bacterial Agents/ 747215 8 (antibiotic$ or anti-bacterial or anti bacterial or antibacterial or bacteriocid$ or antimycobacterial or anti mycobacterial or antimycobacterial or anti-infect$ or anti infect$).tw. 427649 9 (amoxicillin or amphotericin b or ampicillin or calcimycin or cephalosporin$ or cephalothin or cephamycin$ or chloramphenicol or dactinomycin or doxycycline or erythromycin or fluoroquinolone$ or gentamicin$ or kanamycin or minocycline or neomycin or oxytetracycline or penicillin or streptomycin or tetracycline or vancomycin).tw. Embase classic + Embase (1947 -May 7th 2020) # Searches Results 1 cerebrovascular disease/ or basal ganglion hemorrhage/ or exp brain hematoma/ or exp brain hemorrhage/ or exp brain infarction/ or exp brain ischemia/ or exp carotid artery disease/ or exp cerebral artery disease/ or cerebrovascular accident/ or exp cerebrovascular malformation/ or exp intracranial aneurysm/ or exp occlusive cerebrovascular disease/ or stroke/ 782967 2 stroke unit/ or stroke patient/ 37529 3 (stroke$ or poststroke$ or cva$ or cerebrovascular$ or cerebral vascular).tw. 507145 4 ((cerebral or cerebellar or brain$ or vertebrobasilar) adj5 (infarct$ or isch?emi$ or thrombo$ or apoplexy or emboli$)).tw. 137661 5 ((cerebral or intracerebral or intracranial or brain or cerebellar or subarachnoid) adj5 (haemorrhage or hemorrhage or haematoma or hematoma or bleeding or aneurysm)).tw.
109930 6 1 or 2 or 3 or 4 or 5 939203 7 antibiotic prophylaxis/ 33976 8 exp antibiotic agent/ 1681145 9 (antibiotic$ or anti-bacterial or anti bacterial or antibacterial or bacteriocid$ or antimycobacterial or anti mycobacterial or antimycobacterial or anti-infect$ or anti infect$).tw. 615316 10 (amoxicillin or amphotericin b or ampicillin or calcimycin or cephalosporin$ or cephalothin or cephamycin$ or chloramphenicol or dactinomycin or doxycycline or erythromycin or fluoroquinolone$ or gentamicin$ or kanamycin or minocycline or neomycin or oxytetracycline or penicillin or streptomycin or tetracycline or vancomycin ((stroke$ or poststroke$ or cva$ or cerebrovascular* or cerebral vascular)):TI,AB,KY" 20732 2 (((cerebral or cerebellar or brain$ or vertebrobasilar) adj5 (infarct$ or isch?emi$ or thrombo$ or apoplexy or emboli$))):TI,AB,KY 142 3 (((cerebral or intracerebral or intracranial or brain or cerebellar or subarachnoid) adj5 (haemorrhage or hemorrhage or haematoma or hematoma or bleeding or aneurysm))):TI,AB,KY 9786 4 1 OR 2 OR 3 28984 5 ((antibiotic$ or anti-bacterial or anti bacterial or antibacterial or bacteriocid$ or antimycobacterial or anti mycobacterial or antimycobacterial or anti-infect$ or anti infect$)):TI,AB,KY 13632 6 ((amoxicillin or amphotericin b or ampicillin or calcimycin or cephalosporin$ or cephalothin or cephamycin$ or chloramphenicol or dactinomycin or doxycycline or erythromycin or fluoroquinolone$ or gentamicin$ or kanamycin or minocycline or neomycin or oxytetracycline or penicillin or streptomycin or tetracycline or vancomycin)):TI,AB,KY 20260 7 7 OR 5 OR 6 29471 8 ((infection$ or sepsis or septicaemia or septicemia or pneumonia or bacteremia or bacteraemia or inflammation or fever or blood poisoning)):TI,AB,KY 83126 9 ((prophyla$ or prevent$ or premedicat$ or incidence or occurrence)):TI,AB,KY" 132756 10 4 and 7 and 8 and 9 7 Supplemental 8°C in a single determination in patients with suggestive symptoms (ie, cough, dyspnea, pleuritic pain, urinary tract symptoms), white blood cell count >11 000/mL or <4000/mL, pulmonary infiltrate on chest x-rays, or cultures positive for a pathogen. Otherwise, temperature >37.8°C was classified as noninfectious hyperthermia. Infection was further classified as early, if it occurred within the first 7 days after stroke, and late, when it supervened between days 8 and 90 after stroke. For the current analysis infection within 7 days was used. Harms et al: modified CDC criteria within 11 days. Chang et al: imaging, leukocytosis, fevers, clinical deterioration during follow-up (until 90 days) Blacker et al: routine clinical diagnosis, rather than strict criteria; eg urine cultures showing white cells and bacteria in associated with appropriate clinical symptoms, or cough and sputum in association with changes seem on chest X-ray to diagnose respiratory infections, or skin redness, warmth and tenderness to diagnose cellulitis or phlebitis within 7 days post stroke. Kohler et al: routine clinical diagnosis, rather than strict criteria; eg urine cultures showing white cells and bacteria in associated with appropriate clinical symptoms, or cough and sputum in association with changes seem on chest X-ray to diagnose respiratory infections, or skin redness, warmth and tenderness to diagnose cellulitis or phlebitis within 7 days post stroke. Blacker et al: telephone interview by researchers from another hospital, blinded to the treatment allocation; standardized questionnaire to assess for recurrent vascular events; modified Rankin score to assess outcome; personnel were trained in modified Ranking scoring. Kohler et al: telephone interview by researchers from another hospital, blinded to the treatment allocation; standardized questionnaire to assess for recurrent vascular events; modified Rankin score to assess outcome; personnel were trained in modified Ranking scoring. Preventive antibiotic therapy name When preventive antibiotic was given to a patient, name of antibiotic Antibiotic therapy class When preventive antibiotic was given to a patient, class of antibiotic. Class of antibiotic: 1=tetracyclin (minocyclin), 2=cefalosporins (ceftriaxone), 3=fluorchinolon (levofloxacin, moxifloxacin) 4= penicillin + macrolide (amoxicillin + clarithromycin) Type of antibiotics Kalra et al: treating physician was able to choose the type of antibiotic, but a recommendation was made for amoxicillin or co-amoxiclav, together with clarithromycin, these were named 'trial antibiotics'. Patients were classified as having had penicillin + macrolide when these trial antibiotics were given at least 2 consecutive days in the first 4 days (regardless of other additional antibiotics). When no trial antibiotics were given, but other preventive antibiotics were given at least 2 times within the first 4 days, this was coded as 'other antibiotics, type unknown', since no data was present on what type of antibiotic was given when these were not the recommended trial antibiotics. Other trials: one type of antibiotic was used for all patients randomized to preventive treatment, patients were classified in the corresponding group for the antibiotic (tetracyclins, cefalosporins, fluorchinolones, penicillin + macrolide). Antibiotic therapy dose When preventive antibiotic therapy was given to a patient, dose of antibiotic therapy per day in milligrams Antibiotic therapy DDD When preventive antibiotic therapy was given to a patient, the dose of antibiotic therapy converted to defined daily dosis (https://www.whocc.no/atc_ddd_index/) Antibiotic therapy no of days The number of days that each individual patient received preventive antibiotic therapy Was the total treatment with preventive antibiotic therapy administered according to study protocol / per protocol Whether each patient separately was treated according to the study protocol of the study in which patient was included: -Kalra et al: in this trial antibiotic choice at intervention centres conformed to local antibiotic policy, but amoxicillin or co-amoxiclav, together with clarithromycin for 7 days were recommended if no restrictions applied. Treatment was considered as per protocol when the start of antibiotic therapy was initiated within 48 hours, and a patient was treated for at least 6 days of medication (day 0,2 and 4 or 2,4 and 6). If antibiotic therapy was stopped due to discharge or death before completing 6 days this was also considered treatment as per protocol. -Westendorp et al: patients who received the complete 4 days treatment or patients who did not receive the complete 4 days treatment due to death, discharge or switch of antibiotic therapy due to infection were considered as being treated per protocol. -Harms et al: patients were included in the per protocol analysis of the trial when they received the total treatment (eg patients who died within 11 days, were deblinded for medical reasons, were given less than 5 days study medication regardless of reason) were excluded. For the current analysis, per protocol was defined as total treatment but discontinuation of treatment due to death or infection was seen as treatment per protocol.
-Chamorro et al: days 500 mg/100 mL levofloxacin or an identical volume of placebo (0.9% physiological serum) intravenously, treatment was withdrawn in case of diagnosis of infection or death. For the current analysis, the patients that were excluded from per protocol population in the primary article were included in de per protocol population of this metaanalysis because treatment was discontinued due to prespecified reasons, eg infection, death or fever and this was considered as per protocol in the current meta-analysis.

Use of urinary cathether
Data in % (n/N), median with interquartile range or mean with standard deviation COPD = chronic obstructive pulmonary disease; mRS = modified Rankin Scale; NIHSS = National Institute of Stroke Severity Scale; TIA = Transient Ischemic Attack  Analysis adjusted for age and stroke severity. * for this trial only unadjusted analysis possible (number per events rule), it was excluded for the adjusted pooled analysis. Adjusted for age and stroke severity (in categories) ** only unadjusted possible. Table S12.

Subgroup analyses for the primary outcome of functional outcome on total range of mRS for all trials
The odds ratio represents the pooled odds ratio of the effect of antibiotic therapy vs standard therapy for each subgroup of patients within all trials. An odds ratio larger than one favors control/placebo

Subgroup analyses for the primary outcome of functional outcome on total range of mRS for type 1 trials
The odds ratio represents the pooled odds ratio of the effect of antibiotic therapy vs standard therapy for each subgroup of patients within type 1 trials. An odds ratio larger than one favors control/placebo

Subgroup analyses for the primary outcome of functional outcome on total range of mRS for type 2 trials
The odds ratio represents the pooled odds ratio of the effect of antibiotic therapy vs standard therapy for each subgroup of patients within type 2 trials. An odds ratio larger than one favors control/placebo Subgroup analyses for the primary outcome of unfavorable functional outcome (mRS 3-6) for all trials.
The odds ratio represents the interaction effect (the effect of antibiotic treatment vs placebo/standard care compared between both subgroups) the p-value represents the p-value for interaction.

Subgroup analyses for the primary outcome of unfavorable functional outcome (mRS 3-6) for type 1 trials
The odds ratio represents the interaction effect (the effect of antibiotic treatment vs placebo/standard care compared between both subgroups) the p-value represents the p-value for interaction.

Subgroup analyses for the primary outcome of unfavorable functional outcome (mRS 3-6) for type 2 trials
The odds ratio represents the interaction effect (the effect of antibiotic treatment vs placebo/standard care compared between both subgroups) the p-value represents the p-value for interaction.   -3 (7.7%) vs 0 -1 (5%) vs 0 (nausea) --3 (7.1%) vs 2 (4.4%) (headache) -Data reported as no. (%) of patients randomized to antibiotic therapy vs. no. (%) patients randomized to placebo/ standard care * Fouda et al: 'minocycline was well tolerated', study did not mention adverse events separately. ** Amiri-Nikpour et al: 'During 90-day follow-up, no adverse outcomes including myocardial infarction, recurrent stroke, and mortality were observed in the both groups', study did not mention adverse events separately.