Daily Sepsis Research Analysis
Analyzed 33 papers and selected 3 impactful papers.
Summary
Antimicrobial stewardship advances dominated today: a multicenter target trial emulation shows day-4 de-escalation is safe in community-onset sepsis and reduces antibiotic exposure and length of stay. A Nature Communications study quantified the bystander effects of antibiotics on the gut microbiome/resistome in Malawian adults, implicating ceftriaxone as particularly disruptive. In neonates, a territory-wide cohort found CRP performs poorly for term early-onset sepsis screening but is more informative in preterms when interpreted by gestational and postnatal age.
Research Themes
- Antimicrobial stewardship and resistance
- Diagnostic biomarker performance in sepsis
- Microbiome and bystander effects of antibiotics
Selected Articles
1. Quantifying the bystander effect of antimicrobial use on the gut microbiome and resistome in Malawian adults.
Using longitudinal stool metagenomics and Bayesian modeling in Malawi, the study quantified agent-specific bystander effects of antibiotics on gut microbiome composition and resistome. Ceftriaxone particularly increased Enterobacterales abundance and the prevalence of macrolide and aminoglycoside resistance genes; simulations from fitted models explored stewardship strategies.
Impact: First robust quantification of antibiotic bystander effects on the human gut microbiome/resistome in a low-income setting, directly informing antimicrobial stewardship policies.
Clinical Implications: Supports minimizing indiscriminate ceftriaxone use and favoring narrower-spectrum or shorter courses when appropriate to limit resistome expansion. Data-driven stewardship protocols can be tailored to local agent-specific microbiome impacts.
Key Findings
- Ceftriaxone exposure increased Enterobacterales abundance in the gut.
- Post-exposure, macrolide and aminoglycoside resistance gene prevalence rose.
- Bayesian regression linked changes to specific antibiotics; simulations explored stewardship strategies.
Methodological Strengths
- Longitudinal sampling with metagenomic deep sequencing across pre-, during-, and post-antibiotic periods
- Bayesian modeling attributing agent-specific effects with simulation capability for policy testing
Limitations
- Single-country setting with unspecified sample size may limit generalizability and precision
- Observational design without direct linkage to subsequent clinical infection outcomes
Future Directions: Multi-site cohorts to validate agent-specific effects, randomized evaluations of alternative regimens, and linkage of resistome shifts to patient-level infection and transmission outcomes.
2. Antibiotic De-Escalation in Adults Hospitalized for Community-Onset Sepsis.
In a 67-hospital target trial emulation (n=36,924), de-escalation of anti-MRSA or anti-Pseudomonas coverage on day 4 in community-onset sepsis yielded similar 90-day mortality to continued broad-spectrum therapy while reducing antibiotic days and hospital length of stay.
Impact: Large, methodologically rigorous comparative effectiveness evidence supporting the safety of standardized day-4 de-escalation in community-onset sepsis.
Clinical Implications: Hospitals can implement day-4 de-escalation protocols for empiric anti-MRSA and anti-Pseudomonas agents in community-onset sepsis without increasing mortality, reducing antibiotic exposure and length of stay.
Key Findings
- After IPTW, 90-day mortality was similar for de-escalation vs continuation (anti-MRSA OR 1.00, 95% CI 0.88-1.14; anti-PSA OR 0.98, 95% CI 0.86-1.13).
- De-escalation reduced antibiotic days to day 14 (both anti-MRSA and anti-PSA RR 0.91).
- Length of hospitalization was shorter with de-escalation (anti-MRSA RR 0.88; anti-PSA RR 0.91).
- Practice varied >2-fold across hospitals in de-escalation rates.
Methodological Strengths
- Target trial emulation with inverse probability of treatment weighting across 67 hospitals
- Large sample size with balanced covariates and multiple clinically relevant outcomes
Limitations
- Observational design with potential residual confounding despite weighting
- Generalizability limited to community-onset sepsis without MDRO evidence and to day-4 decision point
Future Directions: Pragmatic randomized trials of de-escalation timing and implementation studies to reduce inter-hospital variation; evaluate effects on C. difficile, resistance, and patient-centered outcomes.
3. The utility of C-reactive protein in neonatal early-onset sepsis screening: A territory-wide cohort analysis.
In 100,327 neonates tested within 72 hours of birth, CRP rose physiologically after 8 hours—higher in term infants—and showed superior diagnostic AUCs in preterms compared with terms for culture-confirmed EOS. Early (≤4 hours) sensitivity was low across groups; CRP >12 mg/L signaled increased meningitis risk.
Impact: A very large, territory-wide analysis clarifying gestational- and time-specific CRP performance, discouraging its screening use in term neonates and guiding age-adjusted interpretation in preterms.
Clinical Implications: Avoid using CRP for EOS screening in term neonates; in preterms, interpret CRP by gestational and postnatal age, recognizing low sensitivity in the first 4 hours. Consider CRP >12 mg/L as a red flag for meningitis risk.
Key Findings
- In uninfected neonates, CRP rose after 8 hours, peaking at 24–32 hours; term infants had higher values at 24–48 hours (median 6.2 mg/L).
- Diagnostic AUC after 4 hours was higher in preterms (<34 weeks AUC 0.88; 34–36 weeks AUC 0.83–0.92) than in term neonates (AUC 0.73–0.77).
- Sensitivity within the first 4 hours of life was low across all groups.
- CRP >12.0 mg/L was associated with increased meningitis risk.
Methodological Strengths
- Territory-wide, very large multicenter cohort with 100,327 tested neonates
- Gestational age and postnatal time-stratified ROC analyses with clinically interpretable thresholds
Limitations
- Retrospective design with potential misclassification and residual confounding
- Findings limited to culture-confirmed EOS; results may not generalize to culture-negative sepsis
Future Directions: Prospective validation of gestational- and time-adjusted CRP thresholds and integration with multivariable sepsis calculators and other biomarkers.