Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre,prospective cohort study

ObjectivesThe aim of the study was to measure the impact of antibiotic exposure on the acquisition of colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria (ESBL-GNB) accounting for individual- and group-level confounding using machine-learning methods.MethodsPatients hospitalized between September 2010 and June 2013 at six medical and six surgical wards in Italy, Serbia and Romania were screened for ESBL-GNB at hospital admission, discharge, antibiotic start, and after 3, 7, 15 and 30 days. Primary outcomes were the incidence rate and predictive factors of new ESBL-GNB colonization. Random forest algorithm was used to rank antibiotics according to the risk of selection of ESBL-GNB colonization in patients not colonized before starting antibiotics.ResultsWe screened 10 034 patients collecting 28 322 rectal swab samples. New ESBL-GNB colonization incidence with and without antibiotic treatment was 22/1000 and 9/1000 exposure-days, respectively. In the adjusted regression analyses, antibiotic exposure (hazard ratio (HR) 2.38; 95% CI 1.29–4.40), age 60–69 years (HR 1.19; 95% CI 1.05–1.34), and spring season (HR 1.25; 95% CI 1.14–1.38) were independently associated with new colonization. Monotherapy ranked higher als combination therapy in promoting ESBL-GNB colonization. Among monotherapy, cephalosporins ranked first followed by tetracycline (second), macrolide (fourth) and cotrimoxazole (seventh). Overall the ranking of cephalosporins was lower when used in combination. Among combinations not including cephalosporins, quinolones plus carbapenems ranked highest (eighth). Among sequential therapies, quinolones ranked highest (tenth) when prescribed within 30 days of therapy with cephalosporins.ConclusionsImpact of antibiotics on selecting ESBL-GNB at intestinal level varies if used in monotherapy or combination and according to previous antibiotic exposure. These finding should be explored in future clinical trials on antibiotic stewardship interventions.Clinical Trial registrationNCT01208519.     

Probiotics for intestinal decolonization of ESBL-producing Enterobacteriaceae: a randomized,placebo-controlled clinical trial

ObjectivesInfections with extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (EPE) are a major healthcare concern. Our goal was to investigate whether a probiotic mixture could be used for eradication therapy in patients with prolonged intestinal EPE carriage.MethodsWe performed a randomized, placebo-controlled, single-blinded clinical superiority trial in the south of Sweden between February 2017 and April 2019. Probiotic Vivomixx®, a mixture of 8 different living bacterial strains or placebo was given to adult outpatients intestinally colonized for at least 3 months with EPE. Patients with suspected active infections at the time of evaluation were excluded, and also those with immunosuppression, severe psychiatric disorder, drug abuse or dementia. Each patient in the probiotic arm was administered 2 sachets (9.0 × 10¹¹ live bacteria) twice daily for 2 months. The primary outcome was intestinal EPE eradication at the end of the 1-year follow-up, as shown by 3 consecutive negative EPE rectal swabs during the follow-up year. The per protocol follow-up for all patients was 1, 3, 6 and 12 months after the initiation of the intervention. ClinicalTrials.gov Identifier: NCT03860415.ResultsIn total, the target size of 80 patients were included. The median age was 68 years in both groups. The number of females in the probiotics group was 23 (58%) and in the placebo group 28 (70%). At the end of the trial, 12.5% (5 out of 40) of the patients in the probiotic group had achieved successful eradication of EPE, as defined by the primary outcome, in the intention to treat analysis. In the placebo group, 5% (2 out of 40) of the patients had achieved successful eradication of EPE (odds ratio 2.71; 95% confidence interval (CI), 0.49–14.9; p 0.24).ConclusionsSuccessful EPE eradication was observed in very few individuals. This trial did not support Vivomixx® as being superior to placebo for intestinal decolonization in adult patients with chronic colonization of EPE, but was limited in power.     

Infections caused by extended-spectrum β-lactamase-producing Enterobacterales after rectal colonization with ESBL-producing Escherichia coli or Klebsiella pneumoniae

ObjectivesInfections as a result of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) are considered infections with a high public health burden. In this study, we aimed to identify incidences of and risk factors for healthcare-associated infections (HAIs) after rectal colonization with ESBL-producing Escherichia coli (ESBL-EC) or Klebsiella pneumoniae (ESBL-KP).MethodsThis prospective cohort study was performed in 2014 and 2015. Patients colonized with ESBL-EC or ESBL-KP were monitored for subsequent HAI with ESBL-E and other pathogens. In the case of an ESBL-E infection, rectal and clinical isolates were compared using pulsed-field gel electrophoresis (PFGE), and whole-genome sequencing (WGS) for ESBL-KP isolates. Proportional hazard models were applied to identify risk factors for HAIs, and to analyse competing risks.ResultsAmong all patients admitted to the hospital during the study period, 13.6% were rectally screened for third-generation cephalosporin-resistant Enterobacterales (3GCREB). A total of 2386 rectal carriers of ESBL-EC and 585 of ESBL-KP were included in the study. Incidence density (ID) for HAI with ESBL-E was 2.74 per 1000 patient days at risk (95% confidence interval (CI) 2.16–3.43) among carriers of ESBL-EC, while it was 4.44 per 1000 patient days at risk (95% CI 3.17–6.04) among carriers of ESBL-KP. In contrast, ID for HAI with other pathogens was 4.36 per 1000 patient days at risk (95% CI 3.62–5.21) among carriers of ESBL-EC, and 5.00 per 1000 patient days at risk (95% CI 3.64–6.69) among carriers of ESBL-KP. Cox proportional hazard regression analyses identified colonization with ESBL-KP (HR = 1.58, 95% CI 1.068–2.325) compared with ESBL-EC as independent risk factor for HAI with ESBL-E. The results were consistent over all competing risk analyses.ConclusionsClinicians should be aware of the increased risk of ESBL-E infections among patients colonized with ESBL-KP compared with ESBL-EC that might be caused by underlying diseases, higher pathogenicity of ESBL-KP and other factors.     

Plasma matrix metalloproteinase 7, CC-chemokine ligand 18, and periostin as markers for pulmonary sarcoidosis

BackgroundSome patients with sarcoidosis experience worsening of pulmonary lesions. However, no biomarker has been identified that reflects pulmonary disease status in sarcoidosis. We investigated the usefulness of potential markers of pulmonary fibrosis in patients with sarcoidosis.MethodsPlasma matrix metalloproteinase 7 (MMP-7), CC-chemokine ligand 18 (CCL-18), and periostin levels were evaluated in 60 patients with sarcoidosis and 30 healthy controls; bronchoalveolar lavage fluid levels were analyzed in 22 patients with sarcoidosis. To determine the usefulness of these markers, we explored potential correlations between these markers and sarcoidosis clinical characteristics.ResultsPlasma MMP-7, CCL-18, and periostin concentrations were significantly higher in patients with sarcoidosis than those in healthy controls. MMP-7 concentrations in plasma and bronchoalveolar lavage fluid were higher in patients with sarcoidosis with parenchymal infiltration than in those without lung lesions. Moreover, MMP-7 concentration was negatively correlated with pulmonary function.ConclusionAmong these novel biomarkers, MMP-7 most precisely reflected pulmonary sarcoidosis disease status and thus, might be useful for diagnosing and evaluating sarcoidosis, particularly in patients with pulmonary parenchymal lesions.     

High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 2: putative scenarios and timeline in case of approval,recommendations for use,implementation, and ethical considerations in France

In 2021, aducanumab, an immunotherapy targeting amyloid-β, was approved for Alzheimer's disease (AD) by the US Food and Drug Administration thanks to positive results on a putative biological surrogate marker. This approval has raised an unprecedented controversy. It was followed by a refusal of the European Medicine Agency, which does not allow the marketing of drugs solely on biological arguments and raised safety issues, and important US coverage limitations by the Centers for Medicare & Medicaid Services. Two other anti-amyloid immunotherapies showed significant results regarding a clinical outcome in phase II trials, and five drugs are being studied in phase III trials. Lecanemab is currently under examination for an ‘Accelerated Approval’ in the US, with an expected decision in January 2023. The common feature and novelty of these anti-amyloid immunotherapies, compared to those tested in previous trials of the 2010s, is their ability to induce a high clearance of amyloid load, as measured with positron emission tomography, in the brain of early-stage biomarker-proven AD patients. In the first part of this review, we underlined through a meta-analysis that the pooled data from high-clearance anti-amyloid immunotherapies trials demonstrated a significant but slight clinical effect after 18 months. Still, safety remains an issue with serious and symptomatic amyloid-related imaging abnormalities, which are seldom (～1 per 200 treated patients) but occur beyond chance. In the second part of this review, we hypothesized that there is a high probability that some phase III trials of high-clearance anti-amyloid immunotherapies in early AD will finally be unarguably positive on clinical outcomes in the next five years with acceptable safety data. This may, in turn, lead to approval by the European Medicine Agency if the risk-benefit profile is deemed favorable. Such approval would be a game-changer in managing AD patients and for the organization of memory clinics in France. We review the possible timeline and scenarios for putative approval in France and make propositions regarding putative use in clinical practice, putative implementation in a real-life setting, and ethical considerations.     

防己茯苓汤对急性肾损伤患者肾组织蛋白表达的影响

目的:观察防己茯苓汤对急性肾损伤患者肾组织蛋白表达的影响。方法:将150例急性肾损伤患者随机分为治疗组和对照组,每组75例,对照组患者均予基础治疗,包括:饮食控制、营养支持,血压及血糖管理,维持水、电解质及酸碱平衡,祛除诱因、对原发病给予治疗,停用可疑致肾损伤药物。治疗组在对照组治疗基础上加服防己茯苓汤治疗,方药组成:防己9 g,黄芪9 g,茯苓18 g,桂枝9 g,甘草6 g,每日1剂。治疗28 d后采集血液及尿液标本检测血利钠肽(natriuretic peptide,ANP)和尿β2-微球蛋白,用生化仪测定血肌酐(serum creatinine,Scr)、血清半胱氨酸蛋白酶抑制剂C(serum cystatin C,Cys C)的变化。结果:两组患者ANP、尿β2-微球蛋白、Cys C比较,差异均有统计学意义(P0.05);两组患者Scr比较,差异无统计学意义(P0.05)。结论:防己茯苓汤对急性肾损伤疗效显著,且能改善患者临床检验指标。     

White matter hyperintensities mediate the impact of amyloid ß on future freezing of gait in Parkinson's disease

BackgroundFreezing of gait (FOG) is a common symptom in Parkinson's Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid β deposition. However, there is a paucity of research on the concurrent impact of white matter damage.ObjectivesTo assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other.MethodsWe used baseline MRI and longitudinal gait data from 423 de novo PD patients from the Parkinson's Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid β were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid β on future FOG.ResultsSN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid β levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid β levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels.ConclusionsAmyloid β might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.