Daily Sepsis Research Analysis

BACKGROUND: Prelabor rupture of membranes is a risk factor for maternal and neonatal infectious morbidity. Ampicillin is indicated for patients with unknown group B Streptococcus status and prelabor rupture of membranes ≥18 hours. Although ampicillin-resistant Enterobacteriaceae contribute to maternal and neonatal infectious morbidity, current guidelines on intrapartum antibiotic prophylaxis primarily target group B Streptococcus and do not adequately cover Enterobacteriaceae. OBJECTIVE: To compare maternal and neonatal infectious morbidity between 2 antibiotic regimens: ampicillin and gentamicin vs ampicillin alone. STUDY DESIGN: This randomized controlled trial was conducted between November 2022 and March 2024 in a tertiary university-affiliated hospital. Inclusion criteria were a term singleton pregnancy ≥37 0/7, vertex presentation, unknown group B Streptococcus status, and prelabor rupture of membranes without active labor. Exclusion criteria included penicillin/gentamicin allergy, contraindications for vaginal delivery, and current antibiotic treatment. The participants were randomized at 12 to 18 hours post prelabor rupture of membranes to receive ampicillin and gentamicin (n=102) or ampicillin alone (n=102). They were blinded from the allocation until antibiotics initiation at 18 hours post prelabor rupture of membranes. The antibiotics were administered until delivery. The primary outcome was clinical chorioamnionitis. Secondary maternal outcomes were puerperal endometritis, peripartum infections, intrapartum fever, and a composite of postpartum maternal morbidity, defined as the presence of puerperal endometritis, postpartum antibiotic treatment exceeding 24 hours, wound infection, or infection-related hospitalization >5 days. A neonatal composite adverse outcome included culture-proven neonatal sepsis, admission to the neonatal intensive care unit, empiric antibiotic treatment in the neonatal intensive care unit, performance of a sepsis workup, and infection-related hospitalization >5 days. Microbiologic findings were assessed from chorioamniotic swab cultures. An intention-to-treat analysis was performed. The number needed to treat was calculated for the primary outcome. Multivariate logistic regression was conducted to predict clinical chorioamnionitis, after controlling for antibiotic regimen, prelabor rupture of membranes duration, delivery number, body mass index, delivery week, maternal age, meconium staining, and diabetes mellitus. RESULTS: Ampicillin and gentamicin treatment was associated with lower rates of clinical chorioamnionitis (1/102 [1.0%] vs 8/102 [7.8%], P=.035), intrapartum fever (8/102 [8.0%] vs 18/102 [18.0%], P=.036), and overall peripartum infections (1/102 [1.0%] vs 10/102 [9.8%], P=.005). The number needed to treat to prevent 1 case of clinical chorioamnionitis was 14.7 (95% confidence interval, 10.2-27.0). The rate of the composite postpartum maternal complications was also lower in the ampicillin and gentamicin group (0/102 [0%] vs 6/102 [5.9%], P=.029). Ampicillin and gentamicin treatment was associated with lower rates of the composite neonatal adverse outcome (11/102 [10.8%] vs 22/102 [21.6%], P=.036) and sepsis workups (8/102 [7.8%] vs 18/102 [17.6%], P=.036) and a shorter median neonatal intensive care unit stay (3.0 vs 3.5 days, P=.047). The frequency of positive Enterobacteriaceae cultures in chorioamniotic swab samples was lower following ampicillin and gentamicin (17/85 [20%] vs ampicillin alone 45/89 [51%], P<.001). CONCLUSION: In term prelabor rupture of membranes, ampicillin and gentamicin prophylaxis, compared to ampicillin alone, resulted in lower rates of clinical chorioamnionitis, maternal postpartum complications, and neonatal adverse outcomes. It is time to reconsider the antimicrobial prophylactic regimen in term prelabor rupture of membranes.

Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights into HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2. Our findings suggest that HK2 modulates ISGylation of ACSL4 in sepsis-induced microglial cells, indicating that therapeutic targeting of HK2 may constitute a promising strategy for SAE.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary condition with significant mortality, largely due to a lack of therapeutic interventions grounded in its molecular pathophysiology. Immune checkpoint regulators, such as the V-domain Ig Suppressor of T cell Activation (VISTA), may provide novel immunotherapeutic strategies for ARDS by modulating the immune response, a concept extensively explored in cancer and autoimmune diseases. Investigating VISTA in the context of ARDS could unveil new therapeutic avenues. METHODS: We used a mouse model of indirect ARDS by subjecting C57BL/6J mice to hemorrhage followed by cecal ligation and puncture. Systemic and localized inflammatory conditions were assessed using samples from blood, lung, and peritoneal fluid. Lung pathology was quantified by scoring hematoxylin and eosin-stained sections. Flow cytometry, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction analyses concentrated on macrophages, neutrophils, endothelial cells, and epithelial cells to elucidate VISTA expression patterns. RESULTS: Hemorrhage or cecal ligation and puncture-treated mice exhibited hallmark symptoms of indirect ARDS, including elevated levels of inflammatory cytokines and chemokines. Notably, VISTA expression was substantially upregulated on various cell types, including blood monocytes, lung macrophages, and both circulating and lung-infiltrating neutrophils, as well as on pulmonary epithelial cells and endothelial cells. CONCLUSIONS: Our model replicates critical inflammatory and physiologic changes leading to ARDS, with the elevated expression of VISTA on immune and parenchymal cells suggesting its central involvement in lung injury. The findings propose VISTA as both a potential biomarker for lung damage and as a promising target for ARDS therapy.