Daily Sepsis Research Analysis

BACKGROUND: In 2023, the Azithromycin Prevention in Labor Use (A-PLUS) trial showed intrapartum azithromycin reduces maternal sepsis or death in women with planned vaginal delivery in low-resource settings, but whether it reduces maternal infection is unknown. We aimed to evaluate the effectiveness of intrapartum azithromycin in reducing maternal infection. METHODS: We performed a post-hoc analysis of the multicentre, facility-based, randomised, double-blind, placebo-controlled A-PLUS trial. This trial compared prophylactic intrapartum single oral dose of 2 g azithromycin versus placebo on maternal morbidity and mortality in low-resource settings in southeast Asia and Africa from Sept 9, 2020, to Aug 18, 2022. The trial enrolled women in labour at 28 weeks' gestation (or later) at eight sites in the Democratic Republic of the Congo, Kenya, Zambia, Bangladesh, India, Pakistan, and Guatemala and found that azithromycin reduced the incidence of maternal sepsis or death. The primary outcome of the present analysis was the incidence of any maternal infection in the azithromycin versus placebo groups, which was defined as one or more of these infections after randomisation: chorioamnionitis, endometritis, perineal or caesarean wound infection, abdominopelvic abscess, mastitis or breast abscess, and other infections. Any neonatal infection was also analysed. All analyses were by intention to treat in all those with data available for that outcome. Relative risks (RRs) and 95% CIs were estimated with a Poisson model adjusted for treatment group and site. Subgroup analyses included a two-way interaction test between intervention group and subgroup. A-PLUS was registered at ClinicalTrials.gov, number NCT03871491. FINDINGS: 29 278 women were randomly assigned to groups: 14 590 to receive azithromycin, 14 688 to receive placebo. Baseline characteristics were similar between the azithromycin and placebo groups (43·3% vs 43·4% primiparous, 8·5% vs 8·7% high risk for infection). The presence of any maternal infection occurred less often in the azithromycin group (580 [4·0%] of 14 558) compared with the placebo group (824 [5·6%] of 14 661 women; RR 0·71, 95% CI 0·64-0·79, p<0·0001). Any neonatal infection did not differ between treatment groups. Adverse events were not detected. INTERPRETATION: Among women planning vaginal delivery, this analysis provides evidence indicating that intrapartum azithromycin is associated with a lower incidence of maternal infections than placebo. FUNDING: The Eunice Kennedy Shriver National Institute of Child Health and Human Development and Bill and Melinda Gates Foundation via Foundation of National Institutes of Health. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

BACKGROUND: Sepsis is one of the leading causes of maternal mortality globally. In 2023, the Azithromycin Prevention in Labor Use (A-PLUS) trial showed intrapartum azithromycin for women planning a vaginal birth reduced the risk of maternal sepsis or death and infection. We aimed to evaluate the cost-effectiveness of intrapartum azithromycin for pregnant people planning a vaginal birth in low-income and middle-income countries (LMICs) using A-PLUS trial data. METHODS: We compared the benefits and costs of intrapartum azithromycin versus standard care across 100 000 model simulations using data from the A-PLUS trial and a probabilistic decision tree model that included 24 mutually exclusive scenarios. A-PLUS was a randomised, double-blind, placebo-controlled trial that enrolled 29 278 women in labour at 28 weeks' gestation or more at eight sites in the Democratic Republic of the Congo, Kenya, Zambia, Bangladesh, India, Pakistan, and Guatemala. Women randomly assigned to azithromycin received a single intrapartum 2 g oral dose. In this cost-effectiveness analysis, we considered the cost of azithromycin treatment and its effects on a composite outcome of maternal infection, sepsis, or death and its individual components, and health-care use. Our analysis had a health-care sector perspective. We summarised results as an average and 95% CI of the model simulations. We also conducted sensitivity analyses. A-PLUS was registered at ClinicalTrials.gov, number NCT03871491. FINDINGS: In model simulations, intrapartum azithromycin resulted in 1592·0 (95% CI 1139·7 to 2024·1) cases of maternal infection, sepsis, or death averted per 100 000 pregnancies, yielding 248·5 (95·3 to 403·7) facility readmissions averted, 866·8 (537·8 to 1193·2) unplanned clinic visits averted, and 1816·2 (1324·5 to 2299·7) antibiotic regimens averted. Using mean health-care costs across the A-PLUS sites, intrapartum azithromycin resulted in net savings of US$32 661 (-52 218 to 118 210) per 100 000 pregnancies and 13·2 (8·3 to 17·9) disability-adjusted life-years averted. The cost of facility readmission, cost of azithromycin, and probability of infection had the greatest impact on the incremental cost. INTERPRETATION: In most cases, intrapartum azithromycin is a cost-saving intervention for the prevention of maternal infection, sepsis, or death in LMICs. This evidence supports global consideration of intrapartum azithromycin as an economically efficient preventive therapy to reduce infection, sepsis, or death among women planning a vaginal birth in LMICs. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Foundation for the National Institutes of Health through the Maternal, Newborn, and Child Health Discovery and Tools Initiative of the Bill & Melinda Gates Foundation TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

BACKGROUND: Determining the optimal antibiotic (ATB) dosage in septic critically ill patients on continuous renal replacement therapy (CRRT) is still challenging. CRRT further disrupts antibiotic PK, already altered by sepsis-induced fluid shifts, volume of distribution (VD) changes and half-life modifications. MATERIALS AND METHODS: Our multi-disciplinary team-comprising an intensivist, nephrologist and clinical pharmacologist-conducted a prospective observational cohort study to evaluate the extent of ATB removal by CRRT and to assess the pharmacokinetic/pharmacodynamic (PK/PD) parameters of the most commonly used antibiotics for treating severe infections. RESULTS: A total of 135 ATB therapeutic drug monitoring (TDM) assessments were conducted, measuring total drug concentrations (C) in both plasma (P) and ultrafiltrate in 85 septic patients undergoing CRRT. A high sieving coefficient (∼75%) was recorded for all antibiotics, with CRRT-related drug loss described by the following equations: (i) [CUF-ATB](trough level) = 0.77 × [CP-ATB](trough level) + 0.93 ng/mL; (ii) CUF-ATB = 0.77 × CP-ATB + 3.1 ng/mL. The VD exhibited wide variability, with values exceeding those reported in the literature. Lower ATB molecular weight and steric hindrance were associated with a higher elimination rate constant (Kemin⁻¹). ATB TDM consistently correlated with AUC and AUC/MIC, ensuring effective bactericidal activity. CONCLUSIONS: Despite its limitations, our study suggests to carry out a loading dose for the main antibiotics and consider the daily drug loss, as identified by the linear regression equation, along with daily TDM to guide further dosing adjustments.