ro13-9904 and Stroke

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

We report on 2 patients with cerebral vasculitis and stroke due to Lyme neuroborreliosis (LNB). Both patients had a prodromal stage involving headaches, and showed meningeal enhancement in addition to ischemic infarctions on brain magnetic resonance imaging and diffuse vasculitis on vascular imaging. Serological and cerebrospinal (CSF) fluid studies confirmed the diagnosis of active LNB. Ceftriaxone for 3 weeks led to an excellent recovery and improvements in the CSF examination findings. Stroke physicians should be aware of this rare presentation of LNB. A review of the current knowledge on cerebral vasculitis due to LNB is provided.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antibodies, Bacterial; Borrelia burgdorferi; Brain Ischemia; Ceftriaxone; Cerebral Angiography; Child; Child, Preschool; Female; Headache; Humans; Lyme Neuroborreliosis; Magnetic Resonance Angiography; Male; Middle Aged; Stroke; Treatment Outcome; Vasculitis, Central Nervous System; Young Adult

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).. 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.. 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.. 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.

Topics: Anti-Bacterial Agents; Ceftriaxone; Humans; Pneumonia; Stroke; Treatment Outcome

Aspiration, infections, and fever are common in the first days after stroke, especially in older patients. The occurrence of these complications has been associated with an increased risk of death or dependency.. PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) is an international, multi-centre, 3 × 2 factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment, which will assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, respectively, or any combination of these in the first 4 days after stroke onset improves functional outcome at 90 days in elderly patients with acute stroke.. This statistical analysis plan provides a technical description of the statistical methodology and unpopulated tables and figures. The paper is written prior to data lock and unblinding of treatment allocation.. ISRCTN registry ISRCTN82217627 . Registered on 22 September 2015. The trial was prospectively registered.

Topics: Aged; Ceftriaxone; Humans; Outcome Assessment, Health Care; Stroke; Treatment Outcome

To evaluate the cost-effectiveness of preventive ceftriaxone vs standard stroke unit care without preventive antimicrobial therapy in acute stroke patients.. In this multicenter, randomized, open-label trial with masked endpoint assessment, 2,550 patients with acute stroke were included between 2010 and 2014. Economic evaluation was performed from a societal perspective with a time horizon of 3 months. Volumes and costs of direct, indirect, medical, and nonmedical care were assessed. Primary outcome was cost per unit of the modified Rankin Scale (mRS) and per quality-adjusted life year (QALY) for cost-effectiveness and cost-utility analysis. Incremental cost-effectiveness analyses were performed.. A total of 2,538 patients were available for the intention-to-treat analysis. For the cost-effectiveness analysis, 2,538 patients were available for in-hospital resource use and 1,453 for other resource use. Use of institutional care resources, out-of-pocket expenses, and productivity losses was comparable between treatment groups. The mean score on mRS was 2.38 (95% confidence interval [CI] 2.31-2.44) vs 2.44 (95% CI 2.37-2.51) in the ceftriaxone vs control group, the decrease by 0.06 (95% CI -0.04 to 0.16) in favor of ceftriaxone treatment being nonsignificant. However, the number of QALYs was 0.163 (95% CI 0.159-0.166) vs 0.155 (95% CI 0.152-0.158) in the ceftriaxone vs control group, with the difference of 0.008 (95% CI 0.003-0.012) in favor of ceftriaxone (. Preventive ceftriaxone has a probability of 0.7 of being less costly than standard treatment per unit decrease in mRS and per QALY gained.

Topics: Aged; Anti-Bacterial Agents; Ceftriaxone; Cost of Illness; Cost-Benefit Analysis; Health Care Costs; Humans; Middle Aged; Quality-Adjusted Life Years; Stroke; Treatment Outcome

To investigate whether admission hyperglycemia predicts poststroke infections and, if so, whether poststroke infections modify the effect of admission hyperglycemia on functional outcome in ischemic stroke.. We used data from acute ischemic stroke patients in the Preventive Antibiotics in Stroke Study (PASS), a multicenter randomized controlled trial (n = 2,550) investigating the effect of preventive antibiotics on functional outcome. Admission hyperglycemia was defined as blood glucose ≥7.8 mmol/L and poststroke infection as any infection during admission judged by an expert adjudication committee. Functional outcome at 3 months was assessed with the modified Rankin Scale.. Of 1,676 nondiabetic ischemic stroke patients, 338 (20%) had admission hyperglycemia. After adjustment for potential confounding variables, admission hyperglycemia was associated with poststroke infection (adjusted odds ratio [aOR] 2.31, 95% CI 1.31-4.07), worse 3-month functional outcome (common aOR 1.40, 95% CI 1.12-1.73), and 3-month mortality (aOR 2.11, 95% CI 1.40-3.19). Additional adjustment for poststroke infection in the functional outcome analysis, done to assess poststroke infection as an intermediate in the pathway from admission hyperglycemia to functional outcome, did not substantially change the model. In patients with recorded diabetes mellitus (n = 418), admission hyperglycemia was not associated with poststroke infection (aOR 0.49, 95% CI 0.15-1.58).. In nondiabetic acute ischemic stroke patients, admission hyperglycemia is associated with poststroke infection and worse functional outcome. Poststroke infections did not modify the effect of admission hyperglycemia on functional outcome in ischemic stroke.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Blood Glucose; Brain Ischemia; Ceftriaxone; Chi-Square Distribution; Female; Humans; Hyperglycemia; Infection Control; Infections; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Stroke

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.. 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.. 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).. 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.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Infections; Ceftriaxone; Cerebral Hemorrhage; Disability Evaluation; Drug Administration Schedule; Female; Fibrinolytic Agents; Humans; Infusions, Intravenous; Male; Middle Aged; Odds Ratio; Risk Factors; Stroke; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator; Treatment Outcome

Stroke-associated infections occur frequently and are associated with unfavorable outcome. Previous cohort studies suggest a protective effect of beta-blockers (BBs) against infections. A sympathetic drive may increase immune suppression and infections.. This study is aimed at investigating the association between BB treatment at baseline and post-stroke infection in the Preventive Antibiotics in Stroke Study (PASS), a prospective clinical trial.. We performed an exploratory analysis in PASS, 2,538 patients with acute phase of stroke (24 h after onset) were randomized to ceftriaxone (intravenous, 2 g per day for 4 days) in addition to stroke unit care, or standard stroke unit care without preventive antibiotic treatment. All clinical data, including use of BBs, was prospectively collected. Infection was diagnosed by the treating physician, and independently by an expert panel blinded for all other data. Multivariable analysis was performed to investigate the relation between BB treatment and infection rate.. Infection, as defined by the physician, occurred in 348 of 2,538 patients (14%). Multivariable analysis showed that the use of BBs at baseline was associated with the development of infection during clinical course (adjusted OR (aOR) 1.61, 95% CI 1.19-2.18; p < 0.01). BB use at baseline was also associated with the development of pneumonia (aOR 1.56, 95% CI 1.05-2.30; p = 0.03). Baseline BB use was not associated with mortality (aOR 1.14, 95% CI 0.84-1.53; p = 0.41) or unfavorable outcome at 3 months (aOR 1.10, 95% CI 0.89-1.35; p = 0.39).. Patients treated with BBs prior to stroke have a higher rate of infection and pneumonia.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Infections; Ceftriaxone; Drug Administration Schedule; Female; Humans; Immunocompromised Host; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Opportunistic Infections; Pneumonia, Bacterial; Prospective Studies; Risk Factors; Stroke; Time Factors; Treatment Outcome; Urinary Tract Infections

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.. 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.. 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.. 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.. Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftriaxone; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Length of Stay; Male; Middle Aged; Netherlands; Pneumonia; Prospective Studies; Quality-Adjusted Life Years; Recovery of Function; Stroke; Treatment Outcome; Urinary Tract Infections

Stroke is a leading cause of death worldwide. Infections after stroke occur in 30% of stroke patients and are strongly associated with unfavourable outcome. Preventive antibiotic therapy lowers infection rate in patients after stroke, however, the effect of preventive antibiotic treatment on functional outcome after stroke has not yet been investigated.The Preventive Antibiotics in Stroke Study (PASS) is an ongoing, multicentre, prospective, randomised, open-label, blinded end point trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 hours intravenously for four-days, in addition to stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. Aim of the study is to assess whether preventive antibiotic treatment improves functional outcome at three months by preventing infections.. To date, 2,470 patients have been included in PASS. Median stroke severity of the first 2,133 patients (second interim analysis) is 5 (IQR 3 to 9) on the National Institutes of Health Stroke Scale (NIHSS). Due to the PROBE design, no outcome data are available yet. In the initial trial protocol we proposed a dichotomisation of the mRS as primary analysis of outcome and ordinal regression analysis as secondary analysis of primary outcome, requiring a sample size of 3,200 patients. However, ordinal analysis of outcome data is becoming increasingly more common in acute stroke trials, as it increases statistical power. For PASS, funding is insufficient for inclusion of 3,200 patients with the overall inclusion rate of 15 patients per week. Therefore we change the analysis of our primary outcome from dichotomisation to ordinal regression analysis on the mRS. Power analysis showed that with similar assumptions 2,550 patients are needed using ordinal regression analysis. We expect to complete follow-up in June 2014. A full statistical analysis plan will be submitted for publication before treatment allocation will be unblinded.. The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection. In this update, we changed our primary outcome analysis from dichotomisation to ordinal regression analysis.. Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Bacterial Infections; Ceftriaxone; Clinical Protocols; Disability Evaluation; Drug Administration Schedule; Humans; Patient Selection; Regression Analysis; Research Design; Sample Size; Severity of Illness Index; Stroke; Time Factors; Treatment Outcome

Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Ceftriaxone; Clinical Protocols; Humans; Models, Statistical; Prospective Studies; Recovery of Function; Stroke

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 still blinded for all outcomes.. The primary outcome is the score on the modified Rankin Scale (mRS), assessed by ordinal logistic regression analysis according to a proportional odds model. Secondary analysis of the primary outcome is the score on the mRS dichotomized as a favorable outcome (mRS 0 to 2) versus unfavorable outcome (mRS 3 to 6). Secondary outcome measures are death rate at discharge and 3 months, infection rate during hospital admission, length of hospital admission, volume of post-stroke care, use of antibiotics during hospital stay, quality-adjusted life years and costs. Complications of treatment, serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported as safety outcomes.. The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection and will be analyzed according to this pre-specified SAP.. Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.

Topics: Anti-Bacterial Agents; Bacterial Infections; Ceftriaxone; Clinical Protocols; Cost-Benefit Analysis; Data Interpretation, Statistical; Disability Evaluation; Drug Administration Schedule; Drug Costs; Hospital Mortality; Humans; Length of Stay; Logistic Models; Netherlands; Odds Ratio; Prospective Studies; Quality of Life; Recovery of Function; Research Design; Stroke; Time Factors; Treatment Outcome

Stroke is a leading cause of death worldwide. Fever after stroke is a strong predictor of a poor outcome. Infections occur in up to 40% of patients with stroke and have also been associated with poor outcomes. Preventive antibiotic therapy lowers the infection rates in patients after stroke, as shown in a recent meta-analysis of randomised studies. Phase III trials evaluating the effect of antibiotic prophylaxis on clinical outcomes in sufficient numbers of patients with stroke have, however, not been performed to date. Ceftriaxone, an off-patent medicine, is an antibiotic with a broad defence against the bacteria that cause the most common infections after stroke. Preventive antibiotic therapy with ceftriaxone may potentially reduce poor outcome after acute stroke and, therefore, a randomised clinical trial is warranted.. The aim of the present study is to investigate whether the preventive use of the antibiotic ceftriaxone improves functional outcome in patients with stroke.. We will conduct a multicentre prospective, randomised, open-label, blinded end point trial of standard care with preventive ceftriaxone treatment and compare it with standard care without preventive ceftriaxone. Adult patients with stroke (both ischaemic and haemorrhagic) and a score ≥ 1 on the National Institutes of Health Stroke Scale will be included. The 3200 patients will be randomly assigned to two groups of 1600 patients. One group will receive standard care and ceftriaxone at a dose of 2 g, given every 24 h intravenously for four-days, and the other group will receive stroke-unit care without preventive antibiotic treatment.. The primary end point will be functional outcome at a three-month follow-up on the modified Rankin Scale, dichotomised as a favourable outcome (0-2) or an unfavourable outcome (3-6). Secondary outcome measures will be death rate at discharge and three-months, infection rate during hospital admission, length of hospital admission, volume of poststroke care, use of antibiotics during the three-month follow-up, functional outcome using the full ordinal scoring range of the modified Rankin Scale, quality-adjusted life years and costs.

Topics: Adult; Anti-Bacterial Agents; Bacterial Infections; Ceftriaxone; Humans; Recovery of Function; Research Design; Stroke

Vasculitis caused by neuroborreliosis is one of many rare described causes of stroke.. A female smoker in her fifties presented with dizziness due to a left cerebellar infarction, and after general stroke workup atherosclerosis was considered the probable cause. In the preceding months she had experienced nonspecific intermittent headache, neck pain and dizziness initially attributed to prior head trauma. Over the following months she presented with relapsing and additional symptoms from the posterior circulation and a new right cerebellar infarction was diagnosed. Contrast-enhanced MRI showed signs of myelitis and meningeal enhancement. CSF examination revealed leukocytes 230 · 106/L (0-4 · 106/L) with 98 % mononuclear cells, protein 3.12 g/L (0.00-0.45 g/L). Borrelia IgG and IgM antibodies were positive in serum and CSF, with ratio examinations consistent with intrathecal synthesis. She had a history of multiple tick bites, but not of erythema migrans. She had satisfactory clinical, biochemical and radiological response to antibiotic treatment with ceftriaxone.. Neuroborreliosis was considered the aetiology of her cerebellar infarctions although no definite signs of cerebral vasculitis were evident from CT angiography. Rare causes of stroke, including neuroborreliosis, should be considered in stroke patients without risk factors for cerebrovascular disease and negative primary workup, and in recurrent stroke despite secondary preventive treatment.

Topics: Anti-Bacterial Agents; Ceftriaxone; Dizziness; Female; Humans; Lyme Neuroborreliosis; Stroke

Bacterial meningitis commonly presents with symptoms such as headache, impaired consciousness, neck stiffness, and fever. In most cases, cerebrospinal fluid analysis will yield white cell counts >100/mm. The patient was admitted after being found unconscious on her bed. Upon admittance, she was considered confused, with a temperature of 39.4 °C and slight neutrophilic leukocytosis, but no neck stiffness. A neurological examination revealed bilateral horizontal nystagmus, unstable eye movements, and suspected right-sided gaze paralysis. Cerebrospinal fluid analysis revealed normal parameters, and the microscopy result was negative for bacteria. The most likely diagnosis was considered to be stroke with concomitant infection. However, cerebrospinal fluid and blood cultures subsequently were rapidly positive for pneumococci. Neither immunodeficiency nor blood contamination was considered a likely cause of this discrepancy.. This case emphasizes the need to consider a multidisciplinary approach and empirical meningitis treatment until diagnostic results from microbiological cultures are obtained.

Topics: Aged; Anti-Bacterial Agents; Ceftriaxone; Consciousness Disorders; Dexamethasone; Diagnosis, Differential; Female; Humans; Meningitis, Pneumococcal; Penicillin G; Stroke; Treatment Outcome

Topics: Ampicillin; Antibiotic Prophylaxis; Brain Injuries, Traumatic; Ceftriaxone; Cefuroxime; Cohort Studies; Coma; Disease Susceptibility; Forecasting; Humans; Pilot Projects; Pneumonia, Ventilator-Associated; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Retrospective Studies; Stroke; Sulbactam

Topics: Anti-Bacterial Agents; Ceftriaxone; HIV Infections; Humans; Male; Middle Aged; Neurosyphilis; Recurrence; Stroke

Topics: Anti-Bacterial Agents; Ceftriaxone; Female; Humans; Male; Pneumonia; Stroke; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Ceftriaxone; Emergency Service, Hospital; Female; Fever; Humans; Infant; Lethargy; Male; Meningitis, Pneumococcal; Pneumococcal Vaccines; Seizures; Serotyping; Sinus Thrombosis, Intracranial; Streptococcus pneumoniae; Stroke; Treatment Outcome; Vancomycin

The HACEK group of organisms are one of the infrequent causes of infective endocarditis. Infective endocarditis should be recognized and treated promptly to prevent excessive morbidity and mortality associated with the disease. Sometimes the diagnosis is delayed due to vague and subtle presentation. Through this case report, risk factors of Cardiobacterium hominis endocarditis and its atypical presentation is illustrated to increase the recognition of infective endocarditis as one of the differential diagnosis. [Full article available at http://rimed.org/rimedicaljournal-2016-07.asp, free with no login].

Topics: Administration, Intravenous; Aged, 80 and over; Alzheimer Disease; Anti-Bacterial Agents; Cardiobacterium; Ceftriaxone; Echocardiography; Endocarditis, Bacterial; Gram-Negative Bacterial Infections; Humans; Male; Stroke

Ischemic stroke increases the propensity to develop depression in humans and laboratory animals, and we hypothesized that such an incidence during pregnancy may increase the risk for the development of postpartum depression (PPD).. To test this hypothesis, we used bilateral common carotid arteries occlusion (BCCAO) to induce transient cerebral ischemia in pregnant rats, and evaluated its effects on subsequent development of PPD in dams. Additionally, we investigated whether ceftriaxone pretreatments before the induction of brain ischemia could alter the propensity of PPD.. We found that 15min BCCAO during pregnancy enhanced immobility time and reduced the frequency of swimming or climbing behaviors in the forced swim test, and decreased the sucrose preference in dams at postpartum day 21. Such behavioral alterations were associated with lower level of GLT-1 expression in the medial prefrontal cortical regions (mPFC) of PPD dams. Specifically, mPFC GLT-1 expression levels in dams with ischemia history were correlated with sucrose preference levels at postpartum day 21. Finally, ceftriaxone pretreatment (200mg/kg/day, 5days) before the 15min BCCAO prevented the development of PPD, and prevented the reduction of GLT-1 expression in the mPFC.. Taken together, our results suggested that ceftriaxone pretreatment before brain ischemia during pregnancy may reduce the propensity for the development of PPD by preventing the loss of GLT-1 expression in the mPFC.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Ceftriaxone; Depression, Postpartum; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Female; Prefrontal Cortex; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Stroke; Swimming

Topics: Anti-Bacterial Agents; Ceftriaxone; Female; Humans; Male; Pneumonia; Stroke; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Ceftriaxone; Female; Humans; Male; Pneumonia; Stroke; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Ceftriaxone; Female; Humans; Male; Pneumonia; Stroke; Urinary Tract Infections

The most frequent clinical manifestation of borreliosis in Switzerland is erythema migrans, with about 2500 patients each year. Neurological manifestations are rare, mostly hyperalgesic radiculitis (Bannwarth syndrome), aseptic meningitis or cranial nerve involvement. We report the first Swiss patient with meningovasculitis due to neuroborreliosis, with recurrent multiple ischemic strokes in multiple vascular territories. The treatment with ceftriaxone stopped the progression, but the patient is still suffering from severe invalidating cognitive disorders. We also comment on the pathophysiology and review the literature of other clinical cases.

Topics: Anti-Infective Agents; Blotting, Western; Borrelia burgdorferi Group; Brain Ischemia; Ceftriaxone; Cognition Disorders; Humans; Lyme Neuroborreliosis; Magnetic Resonance Imaging; Male; Meningitis; Middle Aged; Stroke; Vasculitis, Central Nervous System

Topics: Animals; Anti-Bacterial Agents; Brain Ischemia; Ceftriaxone; Disease Models, Animal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypothermia, Induced; Rats; Recombinant Proteins; Stroke; Tissue Plasminogen Activator

Ceftriaxone has been reported to reduce neuronal damage in amyotrophic lateral sclerosis and in an in-vitro model of neuronal ischaemia through increased expression and activity of the glutamate transporter, GLT1. We tested the effects of ceftriaxone on mortality, neurological outcome, and infarct size in experimental stroke in rats and looked for underlying mechanisms.. Male normotensive Wistar rats received ceftriaxone (200 mg/kg intraperitoneal) as a single injection 90 min after middle cerebral artery occlusion (90 min with reperfusion). Forty-eight hours after middle cerebral artery occlusion, infarct size (MRI) and neurological deficits were estimated. GLT1 expression was determined by real time RT-PCR, immunoblotting and promoter reporter assay, astrocyte GLT1 activity by measuring glutamate uptake. Bacterial load in various organs was measured by real time RT-PCR, neurotrophins and IL-6 by immunoblotting.. Ceftriaxone dramatically reduced early (24-h) mortality from 34.5% (vehicle treatment, n = 29) to 0% (P < 0.01, n = 19). In a subgroup, followed up for 4 weeks, mortality persisted at 0%. Ceftriaxone strongly tended to reduce infarct size, it significantly improved neuronal survival within the penumbra, reduced neurological deficits (P < 0.001) and led to an upregulation of neurotrophins (P < 0.01) in the peri-infarct zone. Ceftriaxone did not increase GLT1 expression, but increased GLT1 activity (P < 0.05).. Ceftriaxone causes a significant reduction in acute stroke mortality in a poststroke treatment regimen in animal studies. Improved neurological performance and survival may be due to neuroprotection by activation of GLT1 and a stimulation of neurotrophins resulting in an increased number of surviving neurons in the penumbra.

Topics: Animals; Anti-Bacterial Agents; Body Temperature; Brain; Brain Infarction; Ceftriaxone; Cerebrovascular Disorders; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Interleukin-6; Male; Nerve Growth Factors; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stroke; Survival Rate

Astrocytic glutamate transporters are considered an important target for neuroprotective therapies as the function of these transporters is abnormal in stroke and other neurological disorders associated with excitotoxicity. Recently, Rothstein et al., [Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73-77] reported that beta-lactam antibiotics (including ceftriaxone, which easily crosses the blood-brain barrier) increase glutamate transporter 1 (GLT-1) expression and reduce cell death resulting from oxygen-glucose deprivation (OGD) in dissociated embryonic cortical cultures. To determine whether a similar neuroprotective mechanism operates in more mature neurons, which show a different pattern of response to ischemia than primary cultures, we exposed acute hippocampal slices obtained from rats treated with ceftriaxone for 5 days (200 mg/kg; i.p.) to OGD. Whole-cell patch clamp recording of glutamate-induced N-methyl-d-aspartate (NMDA) currents from CA1 pyramidal neurons showed a larger potentiation of these currents after application of 15 microM dl-threo-beta-benzyloxyaspartic acid (TBOA; a potent blocker of glutamate transporters) in ceftriaxone-injected animals than in untreated animals, indicating increased glutamate transporter activity. Western blot analysis did not reveal GLT-1 upregulation in the hippocampus. Delay to OGD-induced hypoxic spreading depression (HSD) recorded in slices obtained from ceftriaxone-treated rats was longer (6.3+/-0.2 vs. 5.2+/-0.2 min; P<0.001) than that in the control group, demonstrating a neuroprotective action of the antibiotic in this model. The effect of ceftriaxone was also tested in organotypic hippocampal slices obtained from P7-9 rats (>14 days in vitro). OGD or glutamate (3.5-5.0 mM) damaged CA1 pyramidal neurons as assessed by propidium iodide (PI) fluorescence. Similar damage was observed after pre-treatment with ceftriaxone (10-200 microM; 5 days) and ceftriaxone exposure did not result in GLT-1 upregulation as assayed by Western blot. Treatment of slice cultures with dibutyryl cAMP (100-250 microM; 5 days) increased GLT-1 expression but did not reduce cell damage induced by OGD or glutamate. Thus we confirm the neuroprotective effect of antibiotic exposure on OGD-induced injury, but sugge

Topics: Analysis of Variance; Animals; Animals, Newborn; Anti-Bacterial Agents; Aspartic Acid; Ceftriaxone; Cell Death; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Glutamic Acid; Hippocampus; Hypoxia; Membrane Potentials; Neurons; Neuroprotective Agents; Organ Culture Techniques; Patch-Clamp Techniques; Rats; Stroke; Time Factors

The central nervous system (CNS) may be affected in up to 50% of patients with Whipple's disease and this can occur even with little or no gastrointestinal involvement. We describe a 63-year-old patient in whom CNS involvement with Whipple's disease had the clinical and imaging features of a brain infarction. Treatment with aspirin and ceftriaxone followed by trimethoprim-sulfamethoxazole resulted in a good neurological recovery and complete remission of the malabsorption syndrome. Cerebral Whipple's disease resembling a stroke syndrome has so far been reported in only two other patients and in both cases it represented the first presentation of the disease. Arterial or arteriolar fibrosis, thrombosis and thickening associated with the inflammation of adjacent brain parenchyma and leptomeninges, and cerebral vasculitis caused by the hematogenous spread of Tropheryma whippelii to the brain may all be important triggers of brain infarction in patients with Whipple's disease. Our case report highlights the important point that cerebral Whipple's disease with the features of a stroke syndrome, if recognized early and treated aggressively with antibiotics, could have a favorable course with no long-term disability sequelae.

Topics: Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Brain Diseases; Ceftriaxone; Cerebral Infarction; Drug Therapy, Combination; Humans; Male; Middle Aged; Stroke; Trimethoprim, Sulfamethoxazole Drug Combination; Whipple Disease

Lyme neuroborreliosis is diagnostically challenging because of its diverse manifestations. The well-documented neurologic spectrum includes lymphocytic meningitis, cranial neuropathy, and radiculoneuritis in the early disseminated stage; and peripheral neuropathy, chronic encephalomyelitis, and mild encephalopathy in the late persistent stage. This case report describes a 74-year-old man who developed progressive left hemiparesis and facial palsy. The patient was hospitalized to rule out a cerebral vascular accident. The diagnosis of Lyme borreliosis was established with serologic studies. The patient was treated with intravenous ceftriaxone and responded with rapid clinical and functional recovery. Lyme neuroborreliosis presenting as hemiparesis has rarely been reported. Prompt diagnosis and treatment appear to facilitate symptomatic relief and prevent persistent neurologic deficits.

Topics: Aged; Ceftriaxone; Cephalosporins; Disease Progression; Humans; Lyme Neuroborreliosis; Male; Paresis; Stroke