Daily ReportSep 26, 2026
Sepsis, September 26 edition
We read 57 papers and selected 3.
Summary
Today’s most impactful sepsis research spans a clinically actionable meta-analysis, a mechanistic study identifying a potentially protective succinate–GPR91 pathway in sepsis-associated acute kidney injury, and a systematic review showing that evidence is insufficient to support tigecycline for ventilator-associated pneumonia in preterm infants. Together, these studies emphasize precision antimicrobial selection, therapeutic target validation, and the importance of negative evidence in high-risk populations.
Research Themes
- Precision antimicrobial therapy for carbapenem-resistant Enterobacterales
- Metabolic and receptor-mediated mechanisms of sepsis-associated acute kidney injury
- Evidence gaps and safety constraints in neonatal salvage antimicrobial therapy
Selected Articles
1. Succinate Ameliorates Sepsis-Associated Acute Kidney Injury by Mediating Inflammation via GPR91.
Using patient samples, GPR91-knockout mice, and lipopolysaccharide-induced acute kidney injury models, the study found that circulating succinate was increased during sepsis-associated acute kidney injury. Exogenous succinate reduced renal inflammation and tissue injury through GPR91, with mechanistic evidence implicating suppression of PI3K–AKT signaling.
Impact: This is the first reported demonstration in the provided dataset that the succinate–GPR91 axis can exert a protective effect in sepsis-associated acute kidney injury. The combination of human observations, genetic receptor deletion, and in vivo mechanistic validation provides a credible basis for future metabolic or receptor-targeted therapies.
Clinical Implications: The findings do not yet justify clinical administration of succinate, but they identify GPR91 and downstream PI3K–AKT signaling as candidate therapeutic targets. Translation will require dose, timing, safety, and efficacy studies in clinically relevant sepsis models and prospective human studies.
Key Findings
- Circulating succinate levels were elevated in both patients with sepsis-associated acute kidney injury and experimental models.
- Exogenous succinate reduced renal inflammation and histopathological injury in septic mice.
- GPR91 deletion abolished the protective effect of succinate, while mechanistic studies linked the effect to suppression of PI3K–AKT signaling.
Methodological Strengths
- Integrated human observations with complementary genetic and experimental mouse models.
- Used GPR91 knockout animals to test receptor dependence rather than relying only on pharmacological association.
- Provided a proposed molecular mechanism linking the receptor axis to renal inflammation.
Limitations
- The experimental models were primarily based on lipopolysaccharide-induced injury and may not reproduce the heterogeneity of human infection-associated sepsis.
- The abstract does not establish whether succinate treatment improves survival or long-term renal outcomes.
- Clinical translation may be limited by uncertainty regarding dose, timing, and systemic metabolic effects.
Future Directions: Future studies should validate the pathway in polymicrobial and clinically representative sepsis models, determine whether GPR91-selective modulation is safer than systemic succinate administration, and evaluate effects on survival, renal recovery, and other organs.
Succinate is a key metabolic intermediate in the tricarboxylic acid (TCA) cycle, which participates in energy metabolism. It accumulates under various pathological conditions and exerts regulatory effects through binding to its specific receptor GPR91. However, its specific function in sepsis-associated acute kidney injury (SA-AKI) remains unknown. Herein, we utilized GPR91 knockout (GPR91-/-) mice and LPS-induced SA-AKI mouse models to elucidate the role and mechanisms of the succinate-GPR91 axis in SA-AKI. The results demonstrated significantly elevated succinate levels in the circulation of both SA-AKI patients and mice. Exogenous succinate supplementation markedly mitigated renal inflammatory responses and histopathological damage in SA-AKI mice.
2. Novel β-Lactam/β-Lactamase Inhibitors Versus Best Available Therapy on the Mortality-Related Carbapenem-Resistant Enterobacterales Infection: A Systematic Review and Meta-Analysis.
This systematic review and meta-analysis included nine studies involving 2,892 patients, including six randomized controlled trials and three observational cohorts. Compared with best available therapy, novel β-lactam/β-lactamase inhibitor combinations were associated with a 27% reduction in all-cause mortality, although the effect varied according to the specific drug, comparator regimen, and resistance mechanism.
Impact: The analysis synthesizes the strongest comparative evidence in the provided dataset for a major sepsis-associated antimicrobial resistance problem. Its mortality signal supports preferential use of active novel combinations when the resistance mechanism and susceptibility profile are appropriate, while highlighting the need for rapid molecular diagnostics.
Clinical Implications: For adults with CRE infection, clinicians should consider active novel β-lactam/β-lactamase inhibitor combinations when supported by susceptibility testing and the underlying carbapenemase mechanism. Treatment selection should remain individualized, particularly for metallo-β-lactamase-producing organisms, for which major therapeutic gaps persist.
Key Findings
- Nine studies involving 2,892 patients were included, comprising six randomized controlled trials and three observational cohorts.
- Novel β-lactam/β-lactamase inhibitor combinations reduced all-cause mortality compared with best available therapy, with a pooled risk ratio of 0.73.
- The mortality benefit depended on the specific β-lactam/β-lactamase inhibitor, comparator regimen, and resistance mechanism.
- The findings support rapid molecular diagnostics and underscore the need for additional therapies against metallo-β-lactamase-producing organisms.
Methodological Strengths
- Included randomized trials and observational evidence across multiple databases.
- Considered microbiological, genetic, and resistance-mechanism factors rather than treating CRE as a biologically uniform group.
- Focused on mortality, a clinically decisive outcome.
Limitations
- The pooled evidence combines different drugs, comparator regimens, resistance mechanisms, and study designs, creating clinical and methodological heterogeneity.
- The abstract does not provide complete heterogeneity statistics, risk-of-bias results, or drug-specific effect estimates.
- Evidence for metallo-β-lactamase-producing organisms remains limited, so the overall mortality estimate may not apply uniformly to all CRE phenotypes.
Future Directions: Future trials should stratify patients by carbapenemase mechanism, compare specific active agents with standardized control regimens, and integrate rapid molecular resistance testing with patient-level pharmacokinetic and pharmacodynamic optimization.
BACKGROUND/OBJECTIVES: Carbapenem-resistant Enterobacterales (CRE) infections represent a critical global health threat with limited therapeutic options and high mortality rates. Novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations have emerged, but their comparative impact on survival versus best available therapy (BAT) remains to be comprehensively assessed. This systematic review evaluates the mechanistic, microbiological, and genetic factors affecting treatment success. METHODS: Randomized controlled trials (RCTs) and observational reports published up to December 2025 were included. An intensive search strategy was conducted through PubMed/Medline, Embase, Scopus, Cochrane, and Web of Science databases. The trials compared novel BL/BLI agents ceftazidime/avibactam (CAZ-AVI), Meropenem/Vaborbactam (MER-VABO), and Imipenem/Cilastatin/Relebactam (IPM-CIL-REL) to BAT for CRE infections that reported all-cause mortality in adult hospitalized patients (≥18 years).
3. Evidence for the Efficacy and Safety of Tigecycline for the Treatment of Ventilator-Associated Pneumonia in Preterm Infants: A Systematic Review.
This PRISMA 2020 systematic review found no randomized trial, controlled observational study, or dedicated comparative study supporting tigecycline for ventilator-associated pneumonia in preterm infants. Direct evidence was limited to two case reports, and the review concluded that tigecycline should be considered only as a last-resort combination salvage option for culture-confirmed highly resistant infections when safer alternatives are unavailable.
Impact: The paper provides an important negative finding in a vulnerable population exposed to a drug with substantial safety concerns. By separating index evidence from contextual reports and refusing inappropriate quantitative pooling, it prevents overinterpretation of anecdotal treatment success.
Clinical Implications: Tigecycline should not be considered routine therapy for ventilator-associated pneumonia in preterm infants. If used at all, it should be restricted to culture-confirmed pan-drug-resistant or extensively drug-resistant infections without safer alternatives, preferably within a registry or clinical study and with intensive monitoring of hematologic, hepatic, and coagulation parameters.
Key Findings
- No randomized controlled trial, controlled observational study, or dedicated study of tigecycline for ventilator-associated pneumonia in preterm infants was identified.
- Direct evidence consisted of only two case reports involving extremely preterm infants treated with tigecycline-based salvage combination therapy.
- Reported adverse signals included thrombocytopenia, hypofibrinogenemia, and elevated hepatic enzymes.
- The overall certainty of evidence was very low, and quantitative meta-analysis was inappropriate.
Methodological Strengths
- Used a structured PRISMA 2020 search across bibliographic databases, trial registries, regulatory sources, and reference lists.
- Applied eligibility re-review to distinguish direct VAP evidence from contextual neonatal infection reports.
- Explicitly assessed publication bias and avoided quantitative pooling when the evidence base was unsuitable.
Limitations
- The available direct evidence was limited to two case reports, preventing reliable estimation of efficacy or safety.
- The review cannot exclude benefit in exceptional rescue situations, but it also cannot exclude clinically important harm.
- The rarity and heterogeneity of neonatal multidrug-resistant infections make comparative trials difficult, but the absence of comparative data remains a major limitation.
Future Directions: Prospective neonatal pharmacokinetic and pharmacodynamic studies, safety registries, and carefully designed comparative studies are needed. Any future evaluation should include standardized infection definitions, pathogen susceptibility, dosing exposure, hematologic and hepatic monitoring, and mortality outcomes.
BACKGROUND: Ventilator-associated pneumonia (VAP) is a common and serious nosocomial infection in mechanically ventilated preterm infants and is increasingly caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative organisms. Tigecycline, a glycylcycline with broad activity against many such pathogens, is not approved below 18 years of age and carries a boxed warning for excess mortality that is most pronounced in hospital-acquired and ventilator-associated pneumonia. Its role, if any, in preterm infants with VAP is undefined. OBJECTIVES: To systematically identify and appraise all human evidence on the efficacy (clinical cure, microbiological eradication, survival) and safety (adverse events, mortality) of tigecycline used to treat VAP or nosocomial pneumonia during mechanical ventilation in preterm infants and neonates. METHODS: A PRISMA 2020 structured search of PubMed/MEDLINE, Cochrane CENTRAL, Scopus, trial registries, regulatory documents, Google Scholar and reference lists was designed without language or date restrictions.