Daily Sepsis Research Analysis

SUMMARYBloodstream infections (BSIs) are a significant cause of mortality and morbidity. Rapid identification of pathogens and detection of a few resistance markers from positive blood cultures are now possible through the increased availability of commercial rapid diagnostic tests, including nucleic acid amplification tests and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. This document describes the clinical utility of rapid diagnostics performed on positive blood cultures and provides evidence-based laboratory medicine guidelines for using rapid tests to diagnose BSIs in hospitalized adult and pediatric patients. This guideline was developed for use by medical (a.k.a. clinical) microbiologists, medical laboratory professionals, infectious disease clinicians, pharmacists, hospital administrators, healthcare providers, and other stakeholders associated with BSIs. A panel of experts, including medical microbiologists and experts in systematic literature review, was assembled to formulate the Population-Intervention-Comparison-Outcome (PICO) question, review the literature, and provide recommendations for using rapid tests to diagnose BSI and improve patient outcomes. A comprehensive literature search of four electronic bibliographic databases (MEDLINE, Embase, CINAHL, and Cochrane) was conducted to identify studies with measurable outcomes. The panel followed a systematic process, which included a standardized methodology for rating the certainty of the evidence and strength of recommendations using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. The panel evaluated the literature to answer the question: Does using rapid diagnostic tests improve clinical outcomes in adult and pediatric patients hospitalized with a BSI? Peer-reviewed literature was available to address three outcomes, including time to targeted therapy, mortality, and length of hospital stay. In general, the quality of the evidence was low to moderate due to the paucity of controlled, randomized clinical trial studies. However, eight recommendations were made based on evidence derived from the systematic review of the published literature. To answer the PICO question, the expert committee recommended using rapid diagnostic tests combined with active communication to decrease the time to targeted therapy and length of stay (strong recommendation). While the strength of the evidence for the impact on mortality is low, the panel supports using rapid tests to impact these outcomes. A summary of the recommendations is listed in the Executive Summary, which includes a detailed description of the background, methods, evidence summary, and rationale that supports each recommendation in the full text.

BACKGROUND AND OBJECTIVES: Early-onset sepsis (EOS) poses a significant morbidity and mortality risk in neonates, for which early diagnosis and adequate antibiotic therapy is crucial. Amoxicillin and benzylpenicillin combined with aminoglycosides are often prescribed empirically for neonatal EOS but optimal dosing regimens are lacking. To evaluate the pharmacokinetics (PK), PTA and toxicity of amoxicillin and benzylpenicillin in (pre)term neonates with EOS, and define optimal dosing regimens. METHODS: One hundred forty-five neonates [gestational age (GA): 24-42 weeks] with EOS treated with intravenous amoxicillin or benzylpenicillin, dosed as per the Dutch Pediatric Formulary (DPF), were included. Amoxicillin and benzylpenicillin were quantified in left-over samples during the first 48 h of life. First, the performance of nine paediatric amoxicillin and benzylpenicillin population PK models was evaluated. Second, the most appropriate models were used for simulation-based PTA and toxicity analyses, evaluating eight international neonatal dosing regimens. Third, simulation-based dose optimization was conducted. RESULTS: The Bijleveld (amoxicillin) and Padari (benzylpenicillin) models adequately described the obtained PK data (N = 252). For amoxicillin, all regimens showed >90% PTA up to 100%fT > MIC but displayed GA-dependent toxicity potential (concentrations >110 mg/L), the DPF regimen excepted. By contrast, all benzylpenicillin regimens showed suboptimal PTA, often accompanied with GA-dependent toxicity potential (concentrations >50 mg/L). Simulations indicated GA-based intermittent dosing or continuous infusion as options to further optimize benzylpenicillin therapy. CONCLUSIONS: (Pre)term neonates with EOS can be adequately treated with amoxicillin dosed as per the DPF regimen. By contrast, further optimization is warranted for benzylpenicillin, for which GA-based intermittent dosing or continuous infusion pose potential alternatives.

BACKGROUND: Previous studies analyzing differences in mortality associated with carbapenemase type in patients with a variety of infections caused by carbapenemase-producing Enterobacterales (CPE) have produced conflicting results. METHODS: We performed a multinational multicenter retrospective cohort study. Adult patients with blood-stream infections (BSI) caused by CPE between 2015 and 2020 were included. The primary outcome was 14-day mortality; 28-day mortality and microbiological failure were secondary outcomes. Clinical and microbiological data were collected and analyzed using conditional logistic regression. RESULTS: A total of 360 patients were identified of whom 226 had infections caused by KPC-producing isolates, 109 by NDM-producing isolates and 25 by other carbapenemases. Definitive therapy was colistin-based in 35.1% of patients, ceftazidime/avibactam ± aztreonam (CAZ/AVI ± A) in 28.2% and other in 23.4%. Overall 14-day mortality was 28.1%; carbapenemase type was unassociated with mortality in univariate or multivariate analyses. Antimicrobial therapy was significantly associated with 14-day mortality: patients treated with CAZ/AVI ± A had an adjusted hazard ratio of 0.172 (95% confidence interval 0.063-0.473) for death as compared to patients treated with colistin-based therapy. At 28 days, overall mortality was 35.3%; no association was observed between carbapenemase type and 28-day mortality or microbiological failure. CONCLUSION: After controlling for antimicrobial therapy, we did not find evidence of an association between carbapenemase type and mortality. Ceftazidime/avibactam was associated with a greater than 80% reduction in mortality as compared with colistin. We analyzed differences in mortality associated with different carbapenemase types in patients with infections caused by carbapenemase-producing Enterobacterales. No evidence of an association was found, however therapy with ceftazidime/avibactam was associated with a reduction in mortality as compared with colistin.