Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Prognosis of bacterial meningitis in children

We studied the incidence and prognosis of acute neurologic complications in 281 children under 13 years of age with a diagnosis of acute bacterial meningitis. All the patients were examined daily by the same group of neurologists, using a standardized neurological examination. Patients with signs of encephalic lesions, unsatisfactory response to antibiotics or decreased level of consciousness were submitted to brain computer tomography. The overall lethality rate was 20.3% and cases whose causative agent was identified presented a higher lethality rate (23.7%) than those in which the agent was not found. The most important neurological abnormalities were meningeal signs (88.3%) followed by decreased consciousness (47.7%), irritability (35.2%), seizures (22.4%), fontanel bulging (20.6%) and cranial nerve palsy (14.2%). Seizures, cranial nerve palsy and the absence of meningeal signs were related to higher rates of lethality. Diminished consciousness, seizures, subdural effusion, abscess and hydrocephalus were the most important complications, respectively. We can conclude that acute bacterial meningitis continues to be an important health problem in developing countries and that public health measures will be necessary to minimize the impact of sequelae and reduce the mortality rate in children with that pathology.Para estudar os fatores prognósticos e incidência de complicações em meningite bacteriana, 281 crianças (idade abaixo de 13 anos) com quadro clínico e do LCR compatíveis com esse diagnóstico foram acompanhadas, durante o internamente), através de ficha de avaliação padrão. Aquelas que apresentaram sinais de lesão encefálica, resposta inadequada ao tratamento ou diminuição do nível de consciência, com Glasgow < 7, foram submetidas a tomografia computadorizada de crânio. A taxa de letalidade global foi 20,3%, sendo maior quando o agente etiológico foi identificado (23,7%). As alterações neurológicas mais encontradas foram: irritação meníngea, diminuição do nível de consciência, convulsões, irritabilidade, abaulamento de fontanela e comprometimento de nervos cranianos. Convulsões, comprometimento de nervos cranianos e ausência de irritação meníngea foram associados a maior Ietalidade. Complicações neurológicas ocorreram em 58%, sendo as mais frequentes diminuição do nível de consciência (47,7%), convulsões (22,4%), coleção subdural (3,2%), abscesso(2,5%) e hidrocefalia(2,5%). Observamos que meningite bacteriana continua sendo problema de saúde publica em países em desenvolvimento e que medidas para redução da morbidade e mortalidade desta doença são necessárias

Metalloproteinases and their inhibitors—diagnostic and therapeutic opportunities in orthopedics

Matrix metalloproteinases (MMPs) and related enzymes (ADAMs, ADAMTS) and their inhibitors control matrix turnover and function. Recent advances in our understanding of musculoskeletal conditions such as tendinopathy, arthritis, Dupuytren's disease, degenerative disc disease, and bone and soft tissue healing suggest that MMPs have prominant roles. Importantly, MMPs are amenable to inhibition by cheap, safe, and widely available drugs such as the tetracycline antibiotics and the bisphosphonates. This indicates that these MMP inhibitors, if proven effective for any novel indication, may be quickly brought into clinical practice

Dexamethasone for adult community-acquired bacterial meningitis: 20 years of experience in daily practice

The aim of the study was to assess adjunctive intravenous dexamethasone in adult community-acquired bacterial meningitis (BM) in daily practice. Analysis of consecutive patients (1990-2009) with acute community-acquired bacterial meningitis in a single centre in Zagreb, Croatia, N = 304. Adjusted relative risks [RR, dexamethasone vs. no dexamethasone (control)] of Glasgow Outcome Scale (GOS) = 1 (death) and GOS = 5 (full recovery) at discharge/end of specific treatment were estimated considering demographics; co-morbidity; BM pathogenesis and on-admission characteristics, and cerebrospinal fluid (CSF) inflammation markers; causative agent and antibiotic use. Two hundred forty (79%) patients had proven BM (43.1% Streptococcus pneumoniae, any other agent ≤ 8.2%). No independent effects of dexamethasone on GOS = 1 or GOS = 5 were observed in the entire cohort (dexamethasone n = 119, control n = 185; RR = 1.06, 95% CI 0.77-1.45 and RR = 0.99, CI 0.83-1.20, respectively), microbiologically proven disease (dexamethasone n = 104, control n = 136; RR = 0.97, CI 0.69-1.38 and RR = 1.03, CI 0.82-1.28), pneumococcal disease (dexamethasone n = 71, control n = 60; RR = 0.95, CI 0.53-1.70 and RR = 0.82, CI 0.57-1.18), and also in other BM, subgroups based on consciousness disturbance, CSF markers, prior use of antibiotics and timing of appropriate antibiotic treatment. CSF markers did not predict the outcomes. Conclusions: Our experience does not substantiate the reported benefits of adjunctive dexamethasone in adult BM. Socio-economic and methodological factors do not seem to explain this discrepancy. Empirical use of dexamethasone in this setting appears controversial