Daily Sepsis Research Analysis
Three studies advanced sepsis-related science and practice today: a mechanistic paper uncovered phosphorylation-dependent, genome-wide regulation by BfmR driving Acinetobacter baumannii resistance and sepsis in vivo; a multicenter ECMO cohort defined empiric antibiotic choices for bloodstream infections with high Enterococcus involvement; and a real-world SAB study showed selective [18F]-FDG-PET/CT yields low NNT for actionable findings with clinical parameters to refine selection.
Summary
Three studies advanced sepsis-related science and practice today: a mechanistic paper uncovered phosphorylation-dependent, genome-wide regulation by BfmR driving Acinetobacter baumannii resistance and sepsis in vivo; a multicenter ECMO cohort defined empiric antibiotic choices for bloodstream infections with high Enterococcus involvement; and a real-world SAB study showed selective [18F]-FDG-PET/CT yields low NNT for actionable findings with clinical parameters to refine selection.
Research Themes
- Antimicrobial resistance mechanisms in sepsis pathogens
- Empiric therapy optimization for ECMO-associated bloodstream infection
- Imaging-based diagnostics in Staphylococcus aureus bacteremia
Selected Articles
1. A phosphorylation signal activates genome-wide transcriptional control by BfmR, the global regulator of Acinetobacter resistance and virulence.
This mechanistic study shows that phosphorylation activates BfmR to dimerize, expand genome-wide binding, and directly regulate 303 genes involved in envelope biogenesis and pilus repression, among others. Phospho-BfmR is required for antibiotic resistance and sepsis development in vivo, positioning the BfmS-BfmR system as a therapeutic target.
Impact: Identifies a phosphorylation-dependent master regulator linking resistance and virulence with direct in vivo relevance to sepsis. Provides a concrete regulon and DNA motif, enabling targetable intervention strategies.
Clinical Implications: While preclinical, the findings nominate the BfmS-BfmR signaling axis as a drug target to attenuate Acinetobacter virulence and resistance, potentially reducing sepsis severity and improving antibiotic effectiveness.
Key Findings
- Phosphorylation is required for BfmR-mediated gene regulation, antibiotic resistance, and sepsis development in vivo.
- Phosphorylation induces BfmR dimerization and increases target DNA affinity, expanding genome-wide binding sites.
- BfmR directly regulates 303 genes including capsule, peptidoglycan, and outer membrane biogenesis (activation) and pilus biogenesis (repression).
- A direct repeat DNA motif underlies BfmR recognition and is widespread in promoters; BfmR also controls non-coding sRNAs.
Methodological Strengths
- Integrated mutagenesis, ChIP-seq, transcriptomics, and in vitro phosphorylation assays
- In vivo validation linking phospho-BfmR to sepsis development
Limitations
- Preclinical bacterial and murine models may not fully capture human infection complexity
- No therapeutic inhibitor of BfmS-BfmR tested for efficacy
Future Directions: Develop and test small-molecule inhibitors of BfmS-BfmR signaling; validate regulon and phenotypes across clinical isolates and infection models; delineate host-pathogen interactions influenced by BfmR.
The nosocomial pathogen Acinetobacter baumannii is a major threat to human health. The sensor kinase-response regulator system, BfmS-BfmR, is essential to multidrug resistance and virulence in the bacterium and represents a potential antimicrobial target. Important questions remain about how the system controls resistance and pathogenesis. Although BfmR knockout alters expression of >1000 genes, its direct regulon is undefined. Moreover, how phosphorylation controls the regulator is unclear. Here, we address these problems by combining mutagen
2. Which antimicrobial treatment for patients with bloodstream infection during ECMO support?
In 182 ECMO patients with BSI, Enterococcus spp. accounted for ~37%, and MDROs were implicated in 14.3% (mainly ESBL-producing Enterobacterales). Third-generation cephalosporins would be inappropriate in most cases, whereas piperacillin/tazobactam+vancomycin or carbapenem+vancomycin achieved 85.2% and 92.3% appropriateness, respectively.
Impact: Provides multicenter real-world data to guide empiric therapy choices for a high-risk ECMO population where BSI has high mortality and atypical pathogen distribution.
Clinical Implications: For ECMO patients with suspected BSI of unknown source, empiric coverage should include vancomycin plus either piperacillin/tazobactam or a carbapenem; third-generation cephalosporins alone are likely inadequate.
Key Findings
- Enterococcus spp. were the leading pathogens (37.4%) in ECMO-associated BSI.
- MDROs accounted for 14.3% of BSIs, mainly ESBL-producing Enterobacterales (17/26).
- Only 32.4% of cases were susceptible to third-generation cephalosporins.
- Empiric piperacillin/tazobactam+vancomycin and carbapenem+vancomycin would have been appropriate in 85.2% and 92.3% of cases, respectively.
Methodological Strengths
- Multicenter cohort across 12 ICUs increases generalizability
- Focused inclusion on BSI of unknown source during ECMO enhances applicability to empiric therapy decisions
Limitations
- Retrospective observational design susceptible to confounding and selection bias
- European ICUs; pathogen ecology and resistance patterns may differ elsewhere
Future Directions: Prospective validation and stewardship algorithms incorporating local ecology; pharmacokinetic studies under ECMO to refine dosing for combination regimens.
OJECTIVE: We aim to describe a large, multicenter cohort of patients with bloodstream infection (BSI) acquired during extracorporeal membrane oxygenation (ECMO) support. METHODS: We conducted a retrospective observational study in 12 Europeans ICUs. Only patients who developed a BSI of unknown source during ECMO support were included in the present analysis. Primary aim was to describe BSI epidemiology in patients with ECMO support. Secondary objectives were to describe antimicrobial susceptibility of incriminated micro-or
3. Clinical revenues of selective use of [18F]-FDG-PET/CT scanning in the management of Staphylococcus aureus bacteremia.
In a real-world SAB cohort (n=397), selective PET/CT had low numbers needed to scan for detecting new foci (~2), prompting interventions (~4), and altering antimicrobials (~3). CRP >200 mg/L and persistent bacteremia at 48 h predicted PET/CT-driven interventions, while younger age and lower CRP predicted antimicrobial changes.
Impact: Quantifies actionable yield of PET/CT and identifies clinical parameters to refine selection, informing stewardship of advanced imaging in SAB.
Clinical Implications: Consider PET/CT in SAB when CRP is very high or follow-up blood cultures remain positive at 48 h; anticipate management changes and plan resources accordingly. Routine use may be unnecessary; selective ordering can be efficient.
Key Findings
- Among 397 SAB patients, 36% underwent PET/CT; new foci were detected in 73/143 (NNT ≈ 2).
- New interventions occurred in 33/143 (NNT ≈ 4), and antimicrobial therapy changed in 44/143 (NNT ≈ 3).
- CRP >200 mg/L and positive follow-up blood cultures at 48 h independently predicted interventions after PET/CT.
- Therapy changes were more common in patients <65 years and those with CRP <100 mg/L at presentation.
Methodological Strengths
- Real-world cohort with explicit consequence categories and NNT metrics
- Multivariable analysis identifies predictors for PET/CT-driven interventions
Limitations
- Single-center retrospective design limits generalizability and may introduce selection bias
- Incomplete methodological details (e.g., time window) and no randomized comparison
Future Directions: Prospective, multicenter validation of clinical selection criteria; cost-effectiveness analyses comparing selective versus routine PET/CT strategies in SAB.
PURPOSE: Although [18F]-FDG-PET/CT scanning (PET/CT) is recommended for managing Staphylococcus aureus bacteremia (SAB), its added value remains debated. This study investigated the clinical revenues of selective PET/CT use in SAB by considering three consequence-categories: detection of new infection foci, performance of new interventions, and alterations in antimicrobial therapy. METHODS: All adult patients with ≥ 1 blood culture (BC) positive with Staphylococcus aureus admitted in a Dutch academic center between 2017 RESULTS: Of 397 SAB patients, 143 (36%) underwent PET/CT. This led to detection of new foci in 73/143 patients (NNT-scan ≈ 2), new interventions in 33/143 patients (NNT-scan ≈ 4), and a change in antimicrobial therapy in 44/143 patients (NNT-scan ≈ 3). A CRP > 200 mg/L at presentation and positive follow-up BCs at 48 h were independently associated with interventions following PET/CT (adjusted OR and 95%CI 3.2 (1.2-8.3) and 2.6 (1.0-6.7) respectively). PET/CT results instigated changes in antimicrobial therapy predominantly in patients < 65 years and those with a CRP < 100 at presentation. CONCLUSIONS: Selective PET/CT ordering in real-life practice resulted in a relatively low NNT-scan across all consequence-categories. Further research is warranted to optimize patient selection for PET/CT using clinical parameters or profiles.