Consensus group on the design, analysis and reporting of antibiotic stewardship trials – MRC

Improving antibiotic stewardship [Interview] Professor Martin Llewelyn and Dr Valentijn Schweitzer discuss antibiotic stewardship and explain why there is an urgent need to develop recommendations for better research in this fiel

Oncogenic K-Ras suppresses IP₃-dependent Ca²⁺ release through remodeling of IP₃Rs isoform composition and ER luminal Ca²⁺ levels in colorectal cancer cell lines

The GTPase Ras is a molecular switch engaged downstream of G-protein coupled receptors and receptor tyrosine inases that controls multiple cell fate-determining signalling athways. Ras signalling is frequently deregulated in cancer underlying associated changes in cell phenotype. Although Ca2+ signalling pathways control some overlapping functions with Ras, and altered Ca2+ signalling pathways are emerging as important players in oncogenic transformation, how Ca2+ signalling is remodelled during transformation and whether it has a causal role remains unclear. We have investigated Ca2+ signalling in two human colorectal cancer cell lines and their isogenic derivatives in which the mutated K-Ras allele (G13D) has been deleted by homologous recombination. We show that agonist-induced Ca2+ release from intracellular stores is enhanced by loss of K-RasG13D through an increase in the ER store content and a modification of IP3R subtype abundance. Consistently, uptake of Ca2+ into mitochondria and sensitivity to apoptosis was enhanced as a result of KRasG13D loss. These results suggest that suppression of Ca2+ signalling is a common response to naturally occurring levels of K-RasG13D that contributes to a survival advantage during oncogenic transformation

Alzheimer’s disease-associated peptide Aβ₄₂ mobilizes ER Ca²⁺ via InsP₃R-dependent and -independent mechanisms

Dysregulation of Ca2+ homeostasis is considered to contribute to the toxic action of the Alzheimer’s Disease (AD) associated Amyloid β-peptide (Aβ). Ca2+ fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca2+ fluxes induced by Aβ42. Here, we investigated the contribution of Ca2+ release from the endoplasmic reticulum (ER) to the effects of Aβ42 upon Ca2+ homeostasis and the mechanism by which Aβ42 elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of Aβ42 exhibited Ca2+ mobilizing properties. The Aβ42-stimulated Ca2+ signals persisted in the absence of extracellular Ca2+ indicating a significant contribution of Ca2+ release from the ER Ca2+ store to the generation of these signals. Moreover, inositol 1,4,5-trisphosphate (InsP3) signaling contributed to Aβ42-stimulated Ca2+ release. The Ca2+ mobilizing effect of Aβ42 was also observed when applied to permeabilized cells deficient in InsP3 receptors revealing an additional direct effect of internalized Aβ42 upon the ER, and a mechanism for induction of toxicity by intracellular Aβ42

What diagnostic strategies can help differentiate cellulitis from other causes of red legs in primary care

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Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care

Although many sepsis biomarkers have shown promise in selected patient groups, only C-reactive protein and procalcitonin (PCT) have entered clinical practice. The aim of this study was to evaluate three promising novel sepsis biomarkers in unselected patients at admission to intensive care. We assessed the performance of pancreatic stone protein (PSP), soluble CD25 (sCD25) and heparin binding protein (HBP) in distinguishing patients with sepsis from those with a non-infective systemic inflammatory response and the ability of these markers to indicate severity of illness. METHODS: Plasma levels of the biomarkers, PCT and selected inflammatory cytokines were measured in samples taken from 219 patients during the first six hours of admission to intensive or high dependency care. Patients with a systemic inflammatory response were categorized as having sepsis or a non-infective aetiology, with or without markers of severity, using standard diagnostic criteria. RESULTS: Both PSP and sCD25 performed well as biomarkers of sepsis irrespective of severity of illness. For both markers the area under the receiver operating curve (AUC) was greater than 0.9; PSP 0.927 (0.887 to 0.968) and sCD25 0.902 (0.854 to 0.949). Procalcitonin and IL6 also performed well as markers of sepsis whilst in this intensive care unit (ICU) population, HBP did not: PCT 0.840 (0.778 to 0.901), IL6 0.805 (0.739 to 0.870) and HBP 0.607 (0.519 to 0.694). Levels of both PSP and PCT reflected severity of illness and both markers performed well in differentiating patients with severe sepsis from severely ill patients with a non-infective systemic inflammatory response: AUCs 0.955 (0.909 to 1) and 0.837 (0.732 to 0.941) respectively. Although levels of sCD25 did not correlate with severity, the addition of sCD25 to either PCT or PSP in a multivariate model improved the diagnostic accuracy of either marker alone. CONCLUSIONS: PSP and sCD25 perform well as sepsis biomarkers in patients with suspected sepsis at the time of admission to intensive or high dependency care. These markers warrant further assessment of their prognostic value. Whereas previously published data indicate HBP has clinical utility in the emergency department, it did not perform well in an intensive-care population

Superantigen antagonist peptides

The production of superantigenic exotoxins by Gram positive bacteria underlies the pathology of toxic shock syndrome. Future treatment strategies for superantigen-mediated diseases are likely to be directed at blocking the three-way interaction between superantigen, T cell receptor and major histocompatibility class II molecule, which inititates an excessive and disordered inflammatory response. In this article, we review the first published data to address one such strategy in the context of other recognised and experimental treatments

Overview of systematic reviews assessing the evidence for shorter versus longer duration antibiotic treatment for bacterial infections in secondary care

<div><p>Our objective was to assess the clinical effectiveness of shorter versus longer duration antibiotics for treatment of bacterial infections in adults and children in secondary care settings, using the evidence from published systematic reviews. We conducted electronic searches in MEDLINE, Embase, Cochrane, and Cinahl. Our primary outcome was clinical resolution. The quality of included reviews was assessed using the AMSTAR criteria, and the quality of the evidence was rated using the GRADE criteria. We included 6 systematic reviews (n = 3,162). Four reviews were rated high quality, and two of moderate quality. In adults, there was no difference between shorter versus longer duration in clinical resolution rates for peritonitis (RR 1.03, 95% CI 0.98 to 1.09, I² = 0%), ventilator-associated pneumonia (RR 0.93; 95% CI 0.81 to 1.08, I² = 24%), or acute pyelonephritis and septic UTI (clinical failure: RR 1.00, 95% CI 0.46 to 2.18). The quality of the evidence was very low to moderate. In children, there was no difference in clinical resolution rates for pneumonia (RR 0.98, 95% CI 0.91 to 1.04, I² = 48%), pyelonephritis (RR 0.95, 95% CI 0.88 to 1.04) and confirmed bacterial meningitis (RR 1.02, 95% CI 0.93 to 1.11, I² = 0%). The quality of the evidence was low to moderate. In conclusion, there is currently a limited body of evidence to clearly assess the clinical benefits of shorter versus longer duration antibiotics in secondary care. High quality trials assessing strategies to shorten antibiotic treatment duration for bacterial infections in secondary care settings should now be a priority.</p></div

Duration of antibiotic treatment for common infections in English primary care: cross sectional analysis and comparison with guidelines

Objectives: To evaluate antibiotic therapy durations for common infections in English primary care and to compare this with guidelines. Design: Cross-sectional study. Setting: General practices contributing to The Health Improvement Network database, 2013-2015. Participants: 931,015 consultations that resulted in an antibiotic prescription for one of the following indications: acute sinusitis, acute sore throat, acute cough and bronchitis, pneumonia, acute exacerbation of chronic obstructive pulmonary disease (COPD), acute otitis media, acute cystitis, prostatitis, pyelonephritis, cellulitis, impetigo, scarlet fever and gastroenteritis. Main outcome measures: The main outcomes were the percentage of antibiotic prescriptions with a duration exceeding the guideline recommendation and the total number of days beyond the recommended duration for each indication. Results: The most common reasons for the prescriptions were patients consulting with acute bronchitis and cough (386,972), acute sore throat (239,231), acute otitis media (83,054), and acute sinusitis (76,683). Antibiotic treatments for upper respiratory indications and acute bronchitis accounted for more than two thirds of the total prescriptions considered, and ≥80% of these treatment courses exceeded guideline recommendations. Notable exceptions were acute sinusitis, where only 9.6% (95% CI 9.4 to 9.9%) of prescriptions exceeded 7 days and acute sore throat where only 2.1% (95% CI 2.0 to 2.1) exceed 10 days (recent guidance recommends 5 days). More than half of antibiotic prescriptions were longer than guidelines recommend for acute cystitis among females (54.6%, 95% CI 54.1 to 55.0%). The percentage of antibiotic prescriptions exceeding the recommended duration was lower for most non-respiratory infections. For the 931,015 included consultations resulting in antibiotic prescriptions, approximately 1.3 million days were beyond the durations recommended by the guidelines. Conclusion: For most common infections treated in primary care, a substantial proportion of antibiotic prescriptions have durations exceeding those recommended in guidelines. Substantial reductions in antibiotic exposure can be accomplished by aligning antibiotic prescription durations with guidelines

Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life

Objectives: Data quantifying outcomes of recurrent Clostridium difficile infection (rCDI) are lacking. We sought to determine the UK hospital resource use and health-related quality of life (HrQoL) associated with rCDI hospitalisations. Patients and methods: A non-interventional study in 6 UK acute hospitals collected retrospective clinical and resource use data from medical records of 64 adults hospitalised for rCDI and 64 matched inpatient controls with a first episode only (f)CDI. Patients were observed from the index event (date rCDI/fCDI confirmed) for 28-days (or death, if sooner); UK-specific reference costs were applied. HrQoL was assessed prospectively in a separate cohort of 30 patients hospitalised with CDI, who completed the EQ-5D-3L questionnaire during their illness. Results: The median total management cost (post-index) was £7,539 and £6,294 for rCDI and fCDI, respectively (cost difference, p=0.075); median length of stay (LOS) was 21 days and 15.5 days, respectively (p=0.269). The median cost difference between matched rCDI and fCDI cases was £689 (IQR=£-1,873-£3,954). Subgroup analysis demonstrated the highest median costs (£8,542/patient) in severe rCDI cases. CDI management costs were driven primarily by hospital LOS, which accounted for >85% of costs in both groups. Mean EQ-5D index values were 46% lower in CDI patients compared with UK population values (0.42 and 0.78, respectively); EQ-VAS scores were 38% lower (47.82 and 77.3, respectively). Conclusions: CDI has considerable impact on patients and healthcare resources. This multicentre study provides a contemporaneous estimate of the real-world UK costs associated with rCDI management, which are substantial and comparable to fCDI costs

Prion diseases are efficiently transmitted by blood transfusion in sheep

The emergence of variant Creutzfeld-Jakob disease, following on from the bovine spongiform encephalopathy (BSE) epidemic, led to concerns about the potential risk of iatrogenic transmission of disease by blood transfusion and the introduction of costly control measures to protect blood supplies. We previously reported preliminary data demonstrating the transmission of BSE and natural scrapie by blood transfusion in sheep. The final results of this experiment, reported here, give unexpectedly high transmission rates by transfusion of 36% for BSE and 43% for scrapie. A proportion of BSE-infected tranfusion recipients (3 of 8) survived for up to 7 years without showing clinical signs of disease. The majority of transmissions resulted from blood collected from donors at more than 50% of the estimated incubation period. The high transmission rates and relatively short and consistent incubation periods in clinically positive recipients suggest that infectivity titers in blood were substantial and/or that blood transfusion is an efficient method of transmission. This experiment has established the value of using sheep as a model for studying transmission of variant Creutzfeld-Jakob disease by blood products in humans. (Blood. 2008; 112: 4739-4745