Daily Sepsis Research Analysis

UNLABELLED: Bloodstream infections (BSIs) have become increasingly challenging to treat due to emerging antimicrobial resistance (AMR). As rapid administration of appropriate antimicrobials is crucial to positive patient outcomes, clinical alternatives to slow phenotypic antimicrobial susceptibility testing (AST) must be developed. We developed an automated real-time, colorimetric assay (ChroMIC) that phenotypically determines minimum inhibitory concentrations (MICs) directly from positive blood culture. Gram-negative bacteria within positive blood cultures from 83 patients were directly analyzed with ChroMIC. Both ChroMIC MICs and the much slower VITEK 2 MICs for each of seven antibiotics were compared to broth microdilution (BMD). Direct-from-blood-culture ChroMIC MICs were obtained without the ~18-hour growth and isolation steps needed to obtain both VITEK 2 and BMD MICs. ChroMIC assays yielded >90% categorical and essential agreement within 7 h from the start of the experiment and within 4 h of initial growth detection. ChroMIC minor, major, and very major errors were all comparable to, or in the case of VMEs, better than, those from VITEK 2 ASTs-the latter being performed only after an additional ~18-hour subculturing delay. As these patient blood samples were run in parallel with VITEK 2 MICs, a retrospective impact analysis on patient care suggests that ChroMIC could have facilitated faster therapeutic decision-making in nearly all cases, saving an average of >35 and >43 h for antimicrobial escalation and de-escalation, respectively, compared to VITEK 2. IMPORTANCE: The often sluggish pace of phenotypic antimicrobial susceptibility testing (AST), relative to sepsis progression, limits flexibility in altering patient treatment. We report a new direct-from-blood culture phenotypic AST that delivers excellent results within ~7 h of blood culture positivity. This rapid and accurate determination of optimal bloodstream infection treatment was compared in a retrospective study on patient blood cultures that flagged positive for Gram-negative pathogens. Although standard clinical methods were used to guide treatment, our testing was performed in parallel and could have enabled correction of the treatment course ~40 h earlier than was actually performed. Once clinically implementable, such innovative, low-labor, automated, and accurate susceptibility determinations hold great potential for improving patient outcomes and lowering overall healthcare costs.

BACKGROUND: Despite advances in understanding sepsis pathophysiology and extensive research, few treatments effectively target its underlying immune dysfunction. Thymosin α1 (Tα1) shows promise as an immunomodulator, but its impact on sepsis remains unclear. METHODS: A search strategy was designed to include any prospective clinical studies using Tα1 for assessing 28-day mortality in patients with sepsis, excluding combination therapy studies. We conducted trial sequential analysis (TSA) to assess the robustness of meta-analyses findings. Heterogeneity of treatment effects (HTE) was conducted based on individual data from two multicenter randomized clinical trials (RCTs), with result credibility assessed through the instrument to assess the credibility of effect modification analyses (ICEMAN). RESULTS: Out of 3003 identified studies, 11 RCTs met the inclusion criteria (967 patients in Tα1 group and 960 patients in control group). The comprehensive meta-analysis demonstrated a significant reduction in 28-day mortality associated with Tα1 administration (OR 0.73, 95%CI: 0.59-0.90, CONCLUSION: Tα1 has the potential to decrease 28-day mortality rates in patients with sepsis; however, it is crucial to recognize that its efficacy differs among various subgroups. These observations underscore the significance of personalized immunotherapy strategies in forthcoming clinical trials. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42024628937.

The interleukin (IL)-15Rα receptor has crucial, protective roles in sepsis and candidiasis via binding to its ligand, IL-15. However, the underlying mechanisms remain largely unexplored. In our study, we first confirmed the protective effects of IL-15 using clinical samples from patients with sepsis and candidiasis, and also in animal models with those conditions. We therapeutically administered IL-15 to IL-15Rα-deficient mice to elucidate the roles of IL-15Rα in sepsis and candidiasis treatment. Bacterial and fungal infections expedite mortality, caused organ damage, elevated the microbial burden in organs, and impaired macrophage recruitment, and subsequent microbial killing capacity. Notably, these adverse effects were alleviated via recombinant IL-15 supplementation, but this did not improve compromised conditions in IL-15Rα-deficient mice with sepsis. We show that IL-15Rα is required for protection against both bacterial and fungal sepsis, suggesting that this receptor could become a potential target for treating clinical sepsis and may hold significant clinical therapeutic value.