Management of invasive candidiasis: A focus on rezafungin, ibrexafungerp, and fosmanogepix.

Management of invasive fungal infections is challenging with growing antifungal resistance. Broad antifungal use has resulted in greater intrinsic and acquired resistance among Candida spp. It is important for clinicians to recognize the relationship between host susceptibility, site of infection, Candida resistance profiles, specific drug pharmacokinetics and pharmacodynamics, and the role of novel antifungal agents. This narrative review covers the role of rezafungin, ibrexafungerp, and fosmanogepix in the management of invasive candidiasis (IC). The PubMed Database, Embase, and ClinicalTrials.gov were searched between January 2006 and January 2024 using the following terms: rezafungin, CD101, ibrexafungerp, SCY-078, fosmanogepix, APX001, candidemia, and invasive candidiasis. Review articles, prospective clinical trials, and observational studies published in the English language were reviewed. Studies evaluating pharmacology, pharmacokinetics, efficacy, and safety in animals and humans were also reviewed. Promising data continues to emerge in support of novel drug therapies for IC and candidemia. Rezafungin possesses a unique pharmacodynamic profile that might be advantageous compared to other echinocandins, with a practical, once-weekly dosing interval. Ibrexafungerp, currently approved for vulvovaginal candidiasis, has been studied off-label for use in IC and candidemia, and initial data is encouraging. Lastly, fosmanogepix, a mechanistically novel, investigational antifungal agent, may be a potential future option in the management of IC and candidemia. Future research is needed to evaluate the potential use of these agents among diverse patient populations.

Impact of time to treatment in first occurrence, non-severe Clostridioides difficile infection for elderly patients: are we waiting too long to treat?

Objective: Data evaluating timeliness of antibiotic therapy in Clostridioides difficile infections (CDI) are not well established. The study's purpose was to evaluate the impact of time-to-CDI treatment on disease progression. Methods: A case-control study was performed among hospitalized patients with CDI from 1/2018 to 2/2022. Inclusion criteria were age ≥65 years, first occurrence, non-severe CDI at symptom onset, and CDI treatment for ≥72 hours. Cases included patients who progressed to severe or fulminant CDI; controls were patients without CDI progression. Time to CDI treatment was evaluated in three ways: a classification and regression tree (CART)-defined threshold, time as a continuous variable, and time as a categorical variable. Results: 272 patients were included; 136 with CDI progression, 136 patients without. The median (IQR) age was 74 (69-81) years, 167 (61%) were women, and 108 (40%) were immunosuppressed. CDI progression patients more commonly were toxin positive (66 [49%] vs 52 [38%], P = .087) with hospital-acquired disease (57 [42%] vs 29 [21%], P < 0.001). A CART-derived breakpoint for optimal time-to-CDI treatment of 64 hours established early (184, 68%) and delayed treatment (88, 32%). When accounting for confounding variables, delayed CDI treatment was associated with disease progression (adjOR, 4.6; 95%CI, 2.6-8.2); this was observed regardless of how time-to-CDI-active therapy was evaluated (continuous adjOR, 1.02; categorical adjOR, 2.11). Conclusion: Delayed CDI treatment was associated with disease progression and could represent an important antimicrobial stewardship measure with future evaluation.

Biomarkers in the intensive care setting: A focus on using procalcitonin and C-reactive protein to optimize antimicrobial duration of therapy.

Managing the critically ill patient with infection is complex, requiring clinicians to synthesize considerable information relating to antimicrobial efficacy and treatment duration. The use of biomarkers may play an important role in identifying variation in treatment response and providing information about treatment efficacy. Though a vast number of biomarkers for clinical application have been described, procalcitonin and C-reactive protein (CRP) are the most thoroughly investigated in the critically ill. However, the presence of heterogeneous populations, variable end points, and incongruent methodology in the literature complicates the use of such biomarkers to guide antimicrobial therapy. This review focuses on an appraisal of evidence for use of procalcitonin and CRP to optimize antimicrobial duration of therapy (DOT) in critically ill patients. Procalcitonin-guided antimicrobial therapy in mixed critically ill populations with varying degrees of sepsis appears to be safe and might assist in reducing antimicrobial DOT. Compared to procalcitonin, fewer studies exist examining the impact of CRP on antimicrobial DOT and clinical outcomes in the critically ill. Procalcitonin and CRP have been insufficiently studied in many key intensive care unit populations, including surgical patients with concomitant trauma, renally insufficient populations, the immunocompromised, and patients with septic shock. We believe the available evidence is not strong enough to warrant routine use of procalcitonin or CRP to guide antimicrobial DOT in critically ill patients with infection. So long as its limitations are recognized, procalcitonin could be considered to tailor antimicrobial DOT on a case-by-case basis in the critically ill patient.

Evaluating the impact of severe sepsis 3-hour bundle compliance on 28-day in-hospital mortality: A propensity adjusted, nested case-control study.

OBJECTIVES: The Centers for Medicare and Medicaid Services Severe Sepsis and Septic Shock Management Bundle (SEP-1) assesses antibiotic administration, lactate measurement, and blood culture collection within 3 h of severe sepsis onset. The impact of the SEP-1 3-hour bundle among patients with severe sepsis is not extensively described. This investigation aimed to describe the impact of 3-hour bundle compliance on 28-day in-hospital mortality in patients with severe sepsis. STUDY DESIGN: This was a retrospective, propensity adjusted, nested case-control study assessing the impact of compliance with a 3-hour sepsis bundle among patients with severe sepsis. SETTING: This study was conducted at a large, academic, tertiary care medical center in Detroit, Michigan from July 1, 2017 to December 31, 2019. PATIENTS: Cases were defined as those suffering 28-day in-hospital mortality. Controls were defined as those surviving at or discharged by 28 days. Patients were separated based on 3-hour bundle compliance or noncompliance. Nested and overall cohorts were assessed. Severe sepsis time zero was manually validated. Patients with shock, requiring vasopressors within 8 h of time zero, or those not meeting SEP-1 inclusion criteria were excluded. INTERVENTION: The primary outcome was the propensity adjusted odds of 28-day in-hospital mortality among 3-hour bundle compliant versus noncompliant patients. Secondary outcomes included mortality for individual bundle element compliance, progression to septic shock, and predictors of mortality according to logistic regression. RESULTS: A total of 325 compliant and 325 noncompliant patients were included. The median Sequential Organ Failure Assessment (SOFA) score was three in each group. There was no difference in propensity adjusted odds of mortality among those compliant versus noncompliant with the 3-hour bundle (odds-ratio [OR] 1.039; 95% CI: 0.721-1.497; p = 0.838) or with individual bundle elements. SOFA score and female sex were predictors of mortality. CONCLUSIONS: Three-hour bundle compliance did not impact 28-day in-hospital mortality in patients with severe sepsis. Further research is needed to understand the impact of 3-hour bundle compliance on mortality in severe sepsis.

Evaluating interprofessional socialization: Matched student self-assessments surrounding underserved clinic participation.

INTRODUCTION: To determine if an existing tool, the Interprofessional Socialization and Valuing Scale (ISVS), can be used to measure student perceptions of interprofessional (IP) socialization and teamwork in a cohort of pharmacy, medicine, physical therapy, and social work students volunteering in a student-run free clinic (SRFC). METHODS: The ISVS was distributed to these health professions students before and after participation at the SRFC. After a one-month pilot, the plan was to collect data for 12 months. A power analysis determined a minimum sample size was 15 students (power = 0.8). Student surveys were matched utilizing unique alphanumeric identifiers. Results of IP socialization were analyzed by total group and health profession. RESULTS: A mean value for each ISVS domain was compared before and after the IP SRFC experience over 11 months; the pilot was not included in the final data set. Significant improvement in interprofessional socialization was observed across all ISVS factors including Self-Perceived Ability to Work with Others (p < 0.001), Value in Working with Others (p = 0.002), and Comfort in Working with Others (p < 0.001). Pharmacy and social work disciplines met the threshold for statistical significance for at least one factor. CONCLUSIONS: Utilizing the ISVS in an IP SRFC setting can detect changes in professional development that is influenced by beliefs, behaviors, and attitudes as self-assessed in our student population. Engaging students in such a clinic demonstrates educational value and potentially leads to significant improvement in their interprofessional socialization and teamwork skills.