Daily Sepsis Research Analysis
Two complementary analyses from the A-PLUS program show that a single intrapartum oral dose of azithromycin reduces maternal infections in low-resource settings and is likely cost-saving. A prospective ICU study provides actionable pharmacokinetic guidance for antibiotic dosing during continuous veno-venous hemofiltration in septic patients, supporting loading doses and daily TDM.
Summary
Two complementary analyses from the A-PLUS program show that a single intrapartum oral dose of azithromycin reduces maternal infections in low-resource settings and is likely cost-saving. A prospective ICU study provides actionable pharmacokinetic guidance for antibiotic dosing during continuous veno-venous hemofiltration in septic patients, supporting loading doses and daily TDM.
Research Themes
- Maternal sepsis prevention in low-resource settings
- Pharmacokinetics and dosing optimization during CRRT
- Economic evaluation to inform global health policy
Selected Articles
1. Effectiveness of intrapartum azithromycin to prevent infections in planned vaginal births in low-income and middle-income countries: a post-hoc analysis of data from a multicentre, randomised, double-blind, placebo-controlled trial.
In a post-hoc analysis of the large A-PLUS randomized trial, a single 2 g oral dose of azithromycin given intrapartum reduced maternal infections (4.0% vs 5.6%; RR 0.71, 95% CI 0.64–0.79) without increasing neonatal infections. Results were consistent across sites in low-resource settings and analyses were intention-to-treat.
Impact: This analysis strengthens the evidence base for a simple, scalable strategy to prevent maternal infections and sepsis during childbirth in LMICs, with immediate policy relevance. It complements prior mortality/sepsis results by detailing broader infectious outcomes.
Clinical Implications: Consider a single 2 g oral azithromycin dose intrapartum for women planning vaginal delivery in low-resource settings to reduce maternal infections; implement with antimicrobial stewardship oversight and monitor for resistance and local epidemiology.
Key Findings
- Maternal infection occurred in 4.0% with azithromycin vs 5.6% with placebo (RR 0.71, 95% CI 0.64–0.79, p<0.0001).
- No difference was observed in any neonatal infection between groups.
- Analysis used intention-to-treat and a Poisson model adjusted for site.
Methodological Strengths
- Large multicentre, double-blind, placebo-controlled randomized dataset with intention-to-treat analysis
- Clear, clinically relevant composite of maternal infections with site-adjusted modeling
Limitations
- Post-hoc analysis; not a prespecified primary outcome of the original trial
- Follow-up time horizon for infection ascertainment not detailed in the abstract; antimicrobial resistance outcomes not assessed
Future Directions: Prospective implementation studies with resistance surveillance, cost-effectiveness within health systems, and evaluation in diverse settings including higher-resource facilities.
2. Cost-effectiveness of intrapartum azithromycin to prevent maternal infection, sepsis, or death in low-income and middle-income countries: a modelling analysis of data from a randomised, multicentre, placebo-controlled trial.
A probabilistic decision-analytic model using A-PLUS trial inputs suggests intrapartum azithromycin averts 1,592 maternal infection/sepsis/death events per 100,000 pregnancies and is typically cost-saving (mean net savings US$32,661), with 13.2 DALYs averted. Sensitivity analyses identified readmission cost, azithromycin price, and infection probability as key drivers.
Impact: Provides robust economic evidence to inform national and global scale-up of maternal infection/sepsis prevention in LMICs, complementing clinical efficacy data.
Clinical Implications: Health systems in LMICs can consider intrapartum azithromycin adoption as an economically efficient strategy, prioritizing sites with high maternal infection burden and optimizing procurement to maintain cost-saving.
Key Findings
- Model projects 1,592 maternal infection/sepsis/death cases averted per 100,000 pregnancies (95% CI 1,139.7–2,024.1).
- Estimated mean net savings of US$32,661 per 100,000 pregnancies and 13.2 DALYs averted.
- Reductions in 248.5 facility readmissions, 866.8 unplanned clinic visits, and 1,816.2 antibiotic regimens per 100,000 pregnancies.
Methodological Strengths
- Probabilistic decision tree with 100,000 simulations informed by randomized trial data
- Extensive sensitivity analyses and healthcare sector perspective across multiple LMIC sites
Limitations
- Model-based results depend on assumptions and site-specific cost inputs; external validity may vary
- Antimicrobial resistance externalities and long-term population-level effects were not explicitly modeled
Future Directions: Country-specific budget impact analyses, integration with antimicrobial resistance surveillance, and operational research on delivery at scale.
3. Adequate posology of antimicrobial therapy in the septic critically ill in continuous veno-venous hemofiltration: a single centre prospective observational study.
In 85 septic CRRT patients with 135 TDM assessments, antibiotics showed high sieving coefficients (~75%). Linear regression linked ultrafiltrate to plasma concentrations (e.g., CUF=0.77×CP+const), Vd was highly variable, and TDM correlated with AUC/MIC, supporting loading doses and daily TDM-guided adjustments.
Impact: Provides quantitative, bedside-applicable guidance (regression equations, high sieving coefficients) for antibiotic dosing during CRRT in sepsis, a common and high-stakes clinical scenario.
Clinical Implications: Use loading doses for commonly used antibiotics in septic patients starting CRRT, anticipate ~75% sieving through the filter, and apply daily TDM with regression-based estimates of extracorporeal loss to adjust dosing.
Key Findings
- High sieving coefficient (~75%) across antibiotics during CRRT in septic patients.
- Linear regression equations quantify ultrafiltrate vs plasma ATB concentrations: CUF(trough)=0.77×CP(trough)+0.93 ng/mL; CUF(peak)=0.77×CP(peak)+3.1 ng/mL.
- Marked variability and generally increased volume of distribution; lower molecular weight/steric hindrance associated with higher elimination rate constant.
- TDM correlated with AUC and AUC/MIC, supporting bactericidal target attainment.
Methodological Strengths
- Prospective observational design with paired plasma and ultrafiltrate measurements across 135 TDM assessments
- Multidisciplinary team and PK/PD-integrated analysis linking TDM to exposure metrics (AUC, AUC/MIC)
Limitations
- Single-centre observational study without randomized comparisons or hard clinical outcomes
- Total concentrations measured; unbound fractions and antibiotic-specific nuances may limit generalizability
Future Directions: Multicentre trials linking TDM-guided dosing to clinical outcomes (mortality, microbiologic cure) and validation of regression equations across filters and antibiotic classes.