Daily Sepsis Research Analysis

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is associated with impaired neutrophil migration to the infectious focus owing to G protein-coupled receptor kinase (GRK2)-dependent CXCR2 internalization. In the present study, we investigated whether paroxetine, an antidepressant that belongs to the selective serotonin reuptake inhibitor (SSRI) class of drugs and that is also identified as a GRK2 inhibitor, can improve neutrophil recruitment in the cecal ligation and puncture (CLP)-induced sepsis model. Moderate (mCLP) and severe (sCLP) polymicrobial peritonitis were induced in C57BL/6 mice. The in vivo effects of paroxetine (10 mg/kg/day) were evaluated by peritoneal neutrophil count, flow cytometry CXCR2 expression on circulating neutrophils, peritoneal bacterial load, serum quantification of chemokines/cytokines (CXCL1, CXCL2, and IL-6), heart and lung histological analysis, radiotelemetry blood pressure recording, and survival curves. The in vitro CXCR2 expression on the cellular membrane was evaluated by flow cytometry techniques using CXCL2- and LPS-stimulated murine neutrophils, CXCL2-stimulated HEK293 cells, and LPS-stimulated human neutrophils. The in vitro expression of CD11b, a marker of neutrophil activation, was evaluated in CXCL2 and LPS-stimulated murine neutrophils. Herein, we observed that paroxetine-treated mCLP mice showed improved neutrophil migration to the peritoneal cavity with a reduced presence of local bacteria, lower plasma levels of CXCL1, controlled blood pressure, and higher sepsis survival. In addition, sCLP mice post-treated with paroxetine plus antibiotics showed preserved membrane CXCR2 expression on circulating neutrophils, reduced plasma levels of CXCL2 and IL-6, attenuated leukocyte infiltration in the lungs and hearts, and a higher survival index. Finally, paroxetine also prevented LPS and CXCR2 ligands-induced reduction of CXCR2 expression in human and murine neutrophils and HEK293 cells, and increased the membrane CD11b expression in CXCL2 and LPS-stimulated murine neutrophils. Given that the pharmacokinetics and toxicology of paroxetine are already well defined, we suggest its repurposing as an adjuvant pharmacological approach in antibiotic therapy during infection management.

OBJECTIVES: Escherichia coli bacteraemias have been under mandatory surveillance in the UK for fifteen years, but cases continue to rise. Systematic searches of all features present within electronic healthcare records (EHRs), described here as an EHR-wide association study (EHR-WAS), could potentially identify under-appreciated factors that could be targeted to reduce infections. METHODS: We used data from Oxfordshire, UK, and an EHR-WAS method developed for use with large-scale COVID-19 data to estimate associations between E. coli bacteraemia cases, hospital-exposed controls, and 377 potential risk factors using Poisson regression models adjusted for potential confounders for three two-year financial year (FY) periods. RESULTS: FY2022/23-2023/24 analysis included 757 (0.3%) cases and 276,758 (99.7%) controls. We identified six broad disease areas associated with increased or decreased E. coli bacteraemia risk. Renal/urological/urinary tract infection-related variables had the largest impact, with 47% of cases theoretically removed if these factors could be minimised. Cancer-related variables were associated with higher E. coli bacteraemia risk (1.20 times higher (95%CI 1.08-1.34) per three months closer to chemotherapy in the last year), as were gastrointestinal- and infectious disease-related variables. Cardiac/respiratory-related variables were associated with lower E. coli bacteraemia risk, whereas greater healthcare exposure showed no consistent effect. Associated factors varied across periods, but broad groups remained similar. CONCLUSIONS: Applying an EHR-WAS approach, we show E. coli bacteraemias are largely driven by known risk factors and frailty, highlighting the importance of monitoring these factors and targeting modifiable risks where possible.

BACKGROUND: Echinocandins represent first-line therapy for Candida Bloodstream Infections (C-BSIs). Incidence of treatment failure (TF) remains high with unclear risk factors. AIM: to evaluate predictors of echinocandin TF for C-BSIs. METHODS: Retrospective observational multicenter study, enrolling all patients with C-BSI treated with echinocandin from 01/06/2020 to 30/06/2023 in four Italian Hospitals. PRIMARY OUTCOME: to evaluate predictors of TF defined as a composite of: i)transfer to ICU or any worsening in organ dysfunction at day 5 of therapy; ii)Persistent C-BSI; iii)Echinocandin discontinuation for any reason; iv)Onset of a new infection site by Candida spp. during treatment. SECONDARY OUTCOME: 90-day all-cause mortality. Cox regression and treatment-effect were used, along with inverse-probability of treatment-weighting (IPTW) to adjust cohort treatment-assignment bias. RESULTS: Overall, 218 patients were enrolled. Median (q1-q3) age was 72 (56-78), 55% male. In 33% and 63% of cases, septic shock at presentation and C-BSIs by non-albicans strains were reported. Importantly, 68 (31%) patients received high dosage echinocandin ("HDE": increase of 30-50% of standard dosage), according to clinical judgement. Eighty-two (38%) experienced TF; 90-day all-cause mortality was 30%, significantly higher in TF-group (P < 0.001). At multivariable Cox-regression analysis, obesity, septic shock, and increased MIC to echinocandins were predictors of TF; presence of removable intravascular devices and HDE resulted protective. After adjustment by inverse-probability of treatment-weighting, HDE still reduced TF risk in patients admitted to the ICU, with SOFA score<6, BMI>30, or with serum albumin concentration ≤2,5gr/dL. CONCLUSION: Several clinical and microbiological factors could influence the echinocandin TF. Interestingly, in patients at risk for echinocandin TF, HDE may be protective.