Clinical Consequences of Infection in Patients With Acute Stroke Is It Prime Time for Further Antibiotic Trials? Martha Vargas; Juan P. Horcajada; Victor Obach; Marina Revilla; Álvaro Cervera; Ferrán Torres; Anna M. Planas; Josep Mensa; Ángel Chamorro Background and Purpose—It is unsettled whether stroke-associated infection (SAI) is an independent prognostic factor, and a recent clinical trial failed to show that antibiotic prophylaxis prevented SAI. Contrarily, this trial suggested that antibiotic prophylaxis impaired clinical recovery. We sought to evaluate the predisposing factors and clinical consequences of SAI to gather additional insight on the need of exploring other antibiotics in acute stroke. Methods—Between March 2001 and April 2002, 229 consecutive patients were admitted into the neurological wards within 24 hours of stroke onset. Demographics, risk factors, National Institutes of Health Stroke Scale (NIHSS) score, vital data, imaging, and laboratory findings were prospectively evaluated. SAI was treated as early as possible. Multivariate regression analyses assessed predisposing factors of SAI and the independent association between SAI and poor stroke outcome at day 7 (Rankin ⬎2). Results—Sixty (26%) patients developed SAI, most frequently chest infections, and within 3 days of stroke onset. Tube feeding (odds ratio [OR], 3.2; 95% CI, 1.3, 7.8) was the strongest predisposing factor of SAI. Poor outcome at hospital discharge was associated to baseline NIHSS score (OR, 10.0; 95% CI, 1.5, 100) and tube feeding (OR, 16.6; 95% CI, 2.9, 100.0), adjusted for confounders including antibiotic use. SAI was not independently associated to poor outcome (OR, 0.9; 95% CI, 0.9, 1.0). Conclusions—SAI is a marker of the severity of stroke without an independent outcome effect when it is promptly treated. These results support current stroke guidelines that advise prompt treatment of infection and warn against antibiotic prophylaxis. Yet, these recommendations should not prevent the performance of acute stroke trials assessing the value of antibiotics with acknowledged neuroprotective properties. (Stroke. 2006;37:461-465.) Key Words: infection 䡲 outcome assessment 䡲 stroke T he medical management of acute stroke includes measures aimed to prevent or treat systemic complications, such as stroke-associated infection (SAI), which could affect the course of the disease.1,2 Although SAI stands as one of the most frequent medical problems in patients with acute stroke,3,4 few studies5,6 have addressed the clinical consequences of septic complications. Theoretically, SAI could be deleterious by mechanisms that include electrolytic unbalance, fever, or hypoxia.7 Under these conditions, neuronal survival would be impaired within the ischemic penumbra, and this would favor larger lesions, longer hospital stay, additional costs, and delayed rehabilitation. Although current data support that SAI predominate in the most disabled patients, they do not allow to reach definite conclusions whether there is an independent association between SAI and the rate of recovery after stroke.3– 6 Clarification of this issue in patients with acute stroke is determinant to recommend when and how to use antiseptic measures, including the prophylactic administration of antibiotics. Current guidelines on acute stroke management advise against prophylactic administration of antibiotics,1 and the only randomized clinical trial of antibiotic prophylaxis recently provided evidence-based support to this recommendation because it showed that levofloxacin was not better than placebo to prevent infections.8 Unexpectedly, the Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) trial also suggested that this approach might impair clinical recovery, although the trial did not exclude that other antibiotic regimens might be beneficial.8 In light of these findings, the value of prophylactic regimens in acute stroke seems doubtful, although further testing would be justified if it were convincingly shown that stroke recovery is impaired regard- Received September 12, 2005; final revision received October 13, 2005; accepted November 2, 2005. From the Stroke Unit, Hospital Clı́nic, and Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain (A.C., V.O., M.R., A.Ch.); Infectious Diseases Unit, Hospital Clı́nic, Barcelona, Spain (J.P.H., M.V., J.M.); Pharmacology and Toxicology Department, Consejo Superior de Investigaciones Cientı́ficas (IIBB-CSIC), and IDIBAPS, Barcelona, Spain (A.M.P.); and Clinical Pharmacology Unit–Unitat d’Avaluació I Suport de Projectes (UASP), Hospital, Clı́nic, Barcelona, Spain (F.T.). Correspondence to Ángel Chamorro, MD, PhD, Stroke Unit, Hospital Clı́nic, Villarroel 170, 08036 Barcelona, Spain. E-mail achamorro@ub.edu © 2006 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000199138.73365.b3 461 462 Stroke February 2006 less of successful control of infections. In this study, we sought to assess the independent association between SAI and clinical outcome in stroke patients who received adequate antibiotic therapy as soon as infection was suspected. These patients were part of a prospective observational study designed in preparation of the ESPIAS study reported recently.8 Methods Study Population From March 2001 through April 2002, we performed a prospective evaluation of all incident infections occurring in patients with acute stroke admitted consecutively to the Neurology Service within 24 hours of symptom onset. Patients with transient ischemic attack, admission temperature ⱖ37.5°C, or patients who required admission into an intensive care unit or mechanical intubation were not included in the study. The study was approved by the local ethical committee, and stroke neurologists, infectious disease specialists, and research nurses worked in close collaboration to warrant a harmonized application of diagnostic and therapeutic measures. Patients had a brain computed tomography scan or brain MRI before admission, as well as the diagnostic workup aimed to identify the cause of ischemic or hemorrhagic strokes. Stroke syndromes were classified as lacunar and nonlacunar, the former including pure motor hemiparesis, sensorimotor stroke, ataxic hemiparesis, pure sensory syndrome, and dysarthria clumsy hand syndrome. Daily neurological exams were performed using the National Institutes of Health Stroke Scale (NIHSS), and particular attention was given to the occurrence of fever, vomiting, urinary retention, or swallowing abnormalities that might favor infection. Swallowing function was assessed at the bedside with the water swallowing test,9 and in patients with abnormal tests, a nasogastric tube was immediately placed to initiate feeding. Axillary temperature was assessed at least every 8 hours, and oxygenation, heart rate, blood pressure, respiratory function, serum glucose, and leukocyte count were frequently recorded in all patients. Arterial hypertension, diabetes, active smoking, alcohol intake, hypercholesterolemia, and coronary heart disease were assessed following conventional definitions. Additional historical data included chronic pulmonary obstructive disease, infections in the previous 3 months, previous strokes, cancer, and chronic renal disease. Fever was defined as axillary temperature ⱖ37.5°C in 2 separate determinations or ⱖ37.8°C in 1 single determination. Nonseptic fever was described as axillary temperature ⱖ37.5°C without symptoms or signs of infection and blood leukocyte count ⬍11.000 cell/mL or ⬎4.000 cell/mL. Acute bronchial infection included fever, bronchial purulent secretions, blood leukocyte count ⬎11.000 cell/mL or ⬍4.000 cell/mL, and normal chest x-ray films. Pneumonia was described as pulmonary infiltrates in chest radiograph, fever, respiratory symptoms (cough, dyspnea, or pleuritic pain), and blood leukocyte count ⬎11.000 cell/mL or ⬍4.000 cell/mL. Aspiration was defined as acute bronchial infection or pneumonia 24 to 48 hours after a witnessed vomit. Urinary tract infection was defined as low urinary tract symptoms with a positive urine culture for an uropathogen (⬎105 colony-forming units [cfu]/mm3) or fever with a positive urine culture for an uropathogen in absence of other infectious source. Bacteremia included a blood culture positive for a pathogen; if coagulase-negative staphylococcae were isolated from blood, confirmation was required in a second positive blood culture with the same antibiogram. Bacteremia attributable to intravenous catheter required the isolation of the same pathogen from blood and the catheter tip (⬎15 cfu) in the absence of other infectious source. Catheter-related phlebitis was described as inflammatory symptoms and signs at the insertion point or subcutaneous trajectory of peripheral or central intravenous catheter. SAI was defined as infections diagnosed during the first 7 days of stroke onset to limit the confounding effect of time at risk. Infections were treated with antibiotics as judged most appropriate by specialists on infectious diseases, and antipyretics were administered if body temperature was ⬎37.5°C. Outcome was assessed at day 7 and defined as poor if the modified Rankin scale (MRS) score was ⬎2. Patients could be discharged before day 7 only when the neurological state remained stable for ⱖ48 hours. Microbiologic Methods Blood cultures were performed in the presence of fever, and urine cultures were obtained in the presence of urinary tract symptoms, or if fever was not accompanied by any focal symptoms. Samples were obtained by spontaneous micturation or from previously inserted urinary catheters. Urine culture was considered positive when 105 cfu/mL of an uropathogen was isolated. Respiratory samples were obtained in the presence of respiratory tract symptoms, and sputum samples were obtained in collaborative patients. Tracheal aspirate was obtained in patients with abundant respiratory secretions and low level of consciousness. Samples were grown on McConkey agar at 37°C and cystine lactose electrolyte deficient agar for quantification during 48 hours. Identification of isolated microorganisms was performed by standard methods.10 Antibiotic susceptibility testing was performed by the E-test method (AB Biodisk) and Kirby Bauer method following the instructions of the manufacturer, according to the National Committee for Clinical Laboratory Standards recommendations. Blood cultures were placed into 2 blood culture bottles and tested daily by means of an infrared ray (Bactec 9240) system during 5 days. Significant bacteremia was considered when a pathogenic microorganism was isolated in 1 blood culture. Statistical Analysis Dichotomous and categorical data were compared by use of Fisher exact test or the ␹2 as appropriate. Differences in continuous variables were assessed with Student’s test if normally distributed or nonparametric tests otherwise. Logistic regression modeling was used to assess statistically significant predictors of SAI during the acute phase of stroke and poor outcome at discharge. Variables with a P value ⬍0.10 on univariate testing were selected in these models. When necessary, collinearity was minimized generating interaction terms. Antibiotic use was studied as a whole group without the analysis of individual drugs. All tests of significance were 2-tailed and at 0.05 level. TABLE 1. Topography of Infection and Isolated Micro-Organisms Topography of Infection n (%) Acute bronchial 38 (63) Pneumonias 33 (5) Urinary tract 13 (22) Other locations 6 (10) Cultures Blood n⫽45 Urine n⫽52 Tracheal Aspirate n⫽17 Escherichia coli 1 13 3 Coagulase negative staph. 2 䡠䡠䡠 䡠䡠䡠 Staphylococcus aureus 1 䡠䡠䡠 Streptococcus viridans 1 䡠䡠䡠 䡠䡠䡠 2 Streptococcus pneumoniae 䡠䡠䡠 Enterococcus faecalis 䡠䡠䡠 䡠䡠䡠 1 Pseudomonas aeruginosa 䡠䡠䡠 䡠䡠䡠 Enterobacter spp. 䡠䡠䡠 Proteus mirabilis 䡠䡠䡠 䡠䡠䡠 1 䡠䡠䡠 Klebsiella oxytoca 䡠䡠䡠 1 䡠䡠䡠 Micro-organisms 1 䡠䡠䡠 1 1 Vargas et al TABLE 2. Early Infection After Acute Stroke 463 Univariate Predictors of Early Infection in 229 Stroke Patients Early Infection No n⫽169 Age y, mean (SD), y Yes n⫽60 P Value ⬍0.001 70.3 (13.1) 78.9 (7.8) Female, n (%) 75 (44) 37 (61) 0.02 Current smoking, n (%) 30 (18) 7 (12) 0.27 Alcohol (⬎60 关males兴/40 关females兴, g/d), n (%) 20 (12) 3 (5) 0.13 Diabetes, n (%) 32 (19) 12 (20) 0.85 Chronic pulmonary disease, n (%) 16 (10) 6 (10) 1.00 7 (4) 1 (2) 0.68 Hypertension, n (%) 103 (61) 35 (58) 0.76 Active cancer, n (%) 6 (4) 4 (7) 0.29 Chronic renal disease, n (%) Previous stroke, n (%) 27 (16) 10 (17) 0.17 Hours to first exam, mean (SD) 6.9 (5.7) 6.0 (5.5) 0.31 Baseline temperature °C, mean (SD) 36.1 (0.4) 36.2 (0.5) 0.76 Lacunar/nonlacunar syndrome, n (%) 32/137 (97/70) 1/59 (3/30) ⬍0.001 Hemorrhagic/ischemic stroke, n (%) 30/139 (18/82) 12/48 (20/80) 6 (3–13) 18 (11–21) Baseline NIHSS, (interquartile) Vomits on admission, n (%) Nasogastric tube feeding, n (%) 0.69 ⬍0.001 7 (4) 7 (12) 0.07 48 (28) 46 (77) ⬍0.001 In-dwelling urinary catheter, n (%) 19 (11) 11 (18) 0.12 Baseline glucose mean (SD), mg/dL 142 (65) 149 (50) 0.46 Baseline creatinine mg/dL, mg/dL 1.0 (0.4) 1.0 (0.3) 0.90 Baseline C-reactive protein, mg/dL 1.8 (1.7) 3.7 (4.3) 0.14 Results SAI: Incidence, Topography, and Pathogens A total of 295 stroke patients were admitted during the study period, although patients with a delay to admission of ⬎24 hours (n⫽58) or with signs or symptoms of ongoing infection at first examination (n⫽8) were excluded. Thus, 229 patients assessed at a median delay of 4.7 (interquartile range [IQR], 2.5, 10.2) hours from stroke onset took part in the study. Median time to hospital discharge was 9 (IQR, 5, 13) days. Sixty (26%) patients developed SAI, 11 (5%) patients had bacteremia attributable to an intravenous catheter, and 22 (10%) developed nonseptic fever. Forty-five (75%) patients were diagnosed with SAI within the first 3 days of admission. Antibiotics were administered to 93 (41%) patients within 7 days of stroke onset. Antibiotics included amoxicillin (n⫽48), levofloxacin (n⫽35), cephalosporins (n⫽5), tazobactampiperacillin (n⫽3), and vancomycin (n⫽2). The topography of infections and the responsible micro-organisms were as described in Table 1. The yield of positive cultures was 11% for blood samples, 31% for urine samples, and 47% for tracheal aspirate samples, respectively. Risk Factors of Infection SAI was associated in univariate analysis to older age, female gender, higher median NIHSS on admission, vomiting at stroke onset, nonlacunar stroke, and tube feeding, as shown in Table 2. Using logistic regression analysis, tube feeding was the strongest and sole independent predictor of SAI (odds ratio [OR], 3.2; 95% CI, 1.3, 7.8; P⬍0.01). Clinical Outcome At day 7, 72 (31%) patients had an MRS score of 0 to 2, and 157 (69%) patients had an MRS score of ⬎2, including 26 (11%) patients who died because of stroke (n⫽16), sepsis (n⫽5), or cardiovascular diseases (n⫽5). As shown in Table 3, poor outcome (MRS ⬎2) was associated in univariate analysis to age, gender, admission delay, smoking, baseline NIHSS, stroke syndrome, baseline temperature, tube feeding, SAI, and antibiotic use. In a logistic regression model, only baseline NIHSS score (OR, 10.0; 95% CI, 1.5, 100) and tube feeding (OR, 16.6; 95% CI, 2.9, 100.0) remained associated to poor outcome. Contrarily, SAI (OR, 0.9; 95% CI, 0.9, 1.0) or the interaction term SAI*antibiotic use (OR, 0.8; 95% CI, 0.3, 3.0) did not enter in the logistic regression model of stroke outcome. Discussion In this prospective cohort, 26% of the patients developed SAI within the first 7 days of stroke onset, and 10% of additional patients developed nonseptic fever (ⱖ37.5°C), confirming that infections and hyperthermia are a sizable problem not only in intensive care settings11 and general wards12 but also in neurological wards. The main finding of the study was that infections diagnosed and treated with antibiotics within 7 days of stroke onset did not contribute significantly to the likelihood of poor outcome at day 7. Yet, the study confirmed that SAI was directly related to the initial severity of the stroke,12,13 occurred more frequently within the first 3 days of stroke,14,15 and in patients fed by nasogastric tube.6 Indeed, 464 TABLE 3. Stroke February 2006 Clinical Outcome at Discharge MRS Age, mean (SD) 0 –2 n⫽72 3– 6 n⫽157 P Value ⬍0.001 65.6 (12.9) 75.7 (11.0) Female, n (%) 23 (32) 89 (57) 0.001 Admission delay, mean (SD) h 8.1 (5.4) 6.5 (5.6) 0.04 Smoking, n (%) 16 (22) 21 (13) Baseline NIHSS, median (IQR) Baseline temperature, median (IQR) °C 3 (1–6) 36.0 (36.0–36.5) 13 (7–20) 36.2 (36.0–36.5) 0.008 ⬍0.001 0.08 21 (29) 12 (8) ⬍0.001 Tube feeding, n (%) 2 (3) 92 (59) ⬍0.001 Early infection, n (%) 7 (10) 53 (34) ⬍0.001 13 (18) 80 (51) ⬍0.001 Lacunar syndrome, n (%) Antibiotics, n (%) 77% of the patients fed by nasogastric tube developed an infection within 7 days of stroke onset compared with 28% of orally fed patients. These results give credit to the notion that feeding tubes offer no protection from colonized oral secretions in patients with dysphagia.16 –18 However, because tube feeding and stroke severity were collinear, contribution of additional factors cannot be excluded, such as older age, immobility, impaired pulmonary function, immunosuppression, and malnutrition.19 –21 Moreover, the independent association between poor outcome and tube feeding was mostly explained by the greater severity of stroke at baseline in patients who required tube feeding. Unlike the predominance of urinary tract infections, which are more frequent during the chronic phase of stroke,12 chest infections predominated during the earliest phase of stroke. However, unlike series that included mechanical ventilated subjects,11 the predominant chest complications were acute bronchial infections rather than pneumonias. Overall, one fourth of the infections yielded positive cultures, particularly in tracheal aspirate samples, and revealed micro-organisms that are commonly acquired in the community. In contrast with previous tertiary analysis,5 series of mechanically ventilated patients,11 and studies that disregarded the effect of confounding factors,12 SAI did not emerge in our study as an independent prognostic factor. Outcome assessment in the study did not evaluate longlasting effects. However, the study accounted prospectively for the effect of decisive prognostic factors, such as age, baseline stroke severity, stroke subtype, delay to admission, tube feeding, and body temperature. Moreover, strict operational criteria were set at the outset of the study to minimize underreporting or misclassification of infectious events.5 The administration of antibiotics was not randomized, but their effect was accounted for in the prediction models. However, to avoid the creation of small subgroups, the effect of individual antibiotics was not measured. Although the strict control of fever might have also lessened the consequences of infection,22 a small randomized controlled trial of early antipyretic therapy recently showed only modest benefits in acute stroke.23 Therefore, the most likely explanation for the lack of independent association that we found between SAI and poor outcome was the prompt initiation of an antibiotic therapy. Admission temperature did not emerge as an independent prognostic factor in our study, most likely because patients with elevated temperature at stroke onset (ⱖ37.5°C) were not included. Empirically, current stroke therapy guidelines recommend to watch carefully for the appearance of infection and to treat rapidly with antibiotics all emergent infections.1,2 Our results showing that expeditiously treated infections were not detrimental are in support of these guidelines. Antibiotics have also been given prophylactically to patients with acute stroke.8 The rationale of such approach was that infections could decrease the degree of recovery,5 whereas early preventive measures might avoid it. However, antibiotics given during the early phase of brain ischemia could do more than kill bacteria because the ESPIAS trial showed less recovery in patients treated with levofloxacin than placebo,8 a finding that was attributed to the effects of this drug on ␥-aminobutyric acid and glutamate neurotransmission.24,25 Notwithstanding, certain antibiotics might theoretically provide clinical benefits in acute stroke in relation to previously unrecognized effects on the central nervous system. Thus, moxifloxacin26 and minocycline27 have demonstrated marked neuroprotective effects after focal brain ischemia in mice and rats. Indeed, an ongoing clinical trial is evaluating the effect of moxifloxacin in patients with acute stroke. Several ␤-lactam antibiotics have also shown protection against the dysfunctional effects of the neurotransmitter glutamate by activating the expression of a glutamate transporter in in vitro models of ischemic injury.28 Given the relevance of glutamate in stroke, ␤-lactam antibiotics are a promising option for future acute stroke trials in patients with or without SAI. In summary, the study shows that SAI is a very common complication after stroke that does not contribute independently to the likelihood of poorer outcome. These results support current stroke guidelines that advise prompt treatment of infection and reinforce the advise against antibiotic prophylaxis in this clinical condition. However, these recommendations should not be an obstacle to the performance of acute stroke trials that assess the outcome effects of antibiotics with acknowledged neuroprotective properties. References 1. 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