Isavuconazole in the Treatment of Chronic Forms of Coccidioidomycosis.

Coccidioidomycosis is a fungal infection with a range of clinical manifestations. Currently used antifungal agents exhibit variable efficacy and toxicity profiles that necessitate evaluation of additional therapeutic options. Improvement was observed in the majority of patients treated with isavuconazole, with clinical failures observed only in those with coccidioidal meningitis.

Tolerability of long-term fluconazole therapy.

BACKGROUND: Fluconazole is a commonly prescribed first-generation triazole antifungal. Although the toxicity profile of fluconazole has been evaluated in clinical trials, there are scant data regarding its tolerability with long-term therapy. Treatment guidelines for coccidioidomycosis recommend fluconazole therapy and severe or disseminated infections can require lifelong treatment. OBJECTIVES: To assess the prevalence of long-term fluconazole adverse effects, their consequences for antifungal therapy, time to adverse effects and the association between dosing regimen or fluconazole serum level and adverse effect status. METHODS: We conducted a single-centre, retrospective study of adult patients (≥18 years) with proven or probable coccidioidomycosis receiving long-term fluconazole therapy for an intended duration of ≥28 days. RESULTS: Out of 124 patients included, 64 (51.6%) experienced adverse effects. The most common adverse effects were xerosis (16.9%), alopecia (16.1%) and fatigue (11.3%). Of the 64 patients experiencing adverse effects, 42 (65.6%) required a therapeutic intervention such as dose reduction, discontinuation or switch to a new antifungal. Patients experiencing adverse effects were prescribed higher total daily fluconazole doses (6.7 versus 5.7 mg/kg; P < 0.01). The median therapeutic drug levels did not differ significantly between patients who experienced adverse effects and those who did not (36.1 versus 28.1 mg/L; P = 0.35). CONCLUSIONS: A significant number of patients receiving long-term fluconazole therapy for coccidioidomycosis experienced adverse effects. Of these, around two-thirds required a therapeutic change. We believe these findings are representative of the adverse effect profile of long-term fluconazole therapy as it is used in clinical practice for coccidioidomycosis as opposed to use in clinical trials.

Utility of microbial cell free DNA next-generation sequencing for diagnosis and management of infectious diseases.

Microbial cell-free DNA (mcfDNA) sequencing is a promising tool to identify infectious pathogens when traditional methods fail to identify the causative agent. We performed a retrospective observational cohort study to evaluate clinical outcomes among pediatric and adult patients who underwent mcfDNA testing. 127 mcfDNA tests were reviewed from 112 patients. Baseline characteristics included 61 (54.5 %) adults, 52 (40.9 %) tests were from female patients, and 67 (52.8 %) tests were obtained from patients designated as immunocompromised. Of all tests obtained, 59 (46.4 %) were deemed clinically relevant. 41 (32.3 %) of tests also led to a change in antimicrobial management for the corresponding patient. No statistically significant association was ascertained between patient-specific factors and clinically relevant test results. Testing in certain clinical scenarios or high-risk settings may be useful, however further studies are needed to assess the cost-benefit of this approach.

Blood culture identification (BCID) performance in polymicrobial bacteremia.

The rapid multiplex PCR (rmPCR)-based FilmArray® blood culture identification (BCID) assay reduces time from positive blood culture to organism identification. Polymicrobial bacteremia (PMB) is a known area of reduced diagnostic fidelity for BCID and remains incompletely characterized. All cases of clinically confirmed PMB at a large academic single center from a 23-month period were evaluated in a retrospective cohort analysis. A total of 207 samples were identified and studied. Overall, 49.3% (N = 102) of polymicrobial cultures were incompletely identified by FilmArray® result. There were no significant between-group differences in comorbidity status, length of stay, mortality, or source between patients with PMB who had complete versus incomplete BCID identification. Our results suggest that rmPCR-based assays frequently miss organisms in PMB and should be interpreted accordingly.

Impact of Vaccination on Cost and Course of Hospitalization Associated with COVID-19 Infection.

Objective: Examine the impact of vaccination status on hospital cost and course for patients admitted with COVID-19 infection. Design: Retrospective cohort study characterizing vaccinated and unvaccinated individuals hospitalized for COVID-19 between April 2021 to January 2022. Setting: Large academic medical center. Methods: Patients were included if they were greater than 18 years old, fully vaccinated or unvaccinated against COVID-19, and admitted for COVID-19 infection. Patients: 437 consecutively admitted patients for COVID-19 infection met inclusion criteria. Of these, 79 were excluded for unknown or partial vaccination status, transfer from an outside hospital, or multiple COVID-19 related admissions. Results: Overall, 279 (77.9%) unvaccinated patients compared to 79 (22.1%) vaccinated patients were hospitalized with a diagnosis of COVID-19. Average length of stay was significantly lower in the vaccinated group (6.47 days versus 8.92 days, P = 0.03). Vaccinated patients experienced a 70.6% lower risk of ICU admission (OR = 0.29, 95% CI 0.12-0.71, P = 0.006). The unadjusted cost of hospitalization was not found to be statistically significant ($119,630 versus $191,146, P = 0.06). After adjusting for age and comorbidities, vaccinated patients experienced a 26% lower cost of hospitalization compared to unvaccinated patients (P = 0.004). Unvaccinated patients incurred a significantly higher cost of hospitalization per day ($29,425 vs $13,845 P < 0.0001). Unvaccinated patients (n = 118, 42.9%) were more likely than vaccinated patients (n = 16, 20.3%) to require high-flow oxygen or mechanical ventilation (OR = 2.95, 95% CI 1.62-5.38, P = 0.0004). Conclusion: Vaccinated patients experienced a lower cost of hospitalization after adjusting for age and comorbidities and shorter length of stay compared to unvaccinated patients admitted for COVID-19.

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments.

Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined.

Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections.

We have a limited arsenal with which to treat invasive fungal infections caused by Aspergillus and Mucorales. The morbidity and mortality for both pathogens remains high. A triazole antifungal, isavuconazole, was recently granted approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis. A randomized double-blind comparison trial for the treatment of invasive aspergillosis found isavuconazole noninferior to voriconazole. A separate, open-label study evaluating the efficacy of isavuconazole in the treatment of mucormycosis found comparable response rates to amphotericin B and posaconazole treated historical controls. The prodrug isavuconazonium sulfate is commercially available in both an oral and intravenous formulation and is generally well tolerated. Isavuconazole's broad spectrum of activity, limited side effect profile, and favorable pharmacokinetics will likely solidify its place in therapy.

Antimicrobial stewardship programs that target only high-cost, broad-spectrum antimicrobials miss opportunities to reduce Clostridium difficile infections.

Antimicrobial stewardship programs are promoted as a strategy to reduce Clostridium difficile infections. We implemented an antimicrobial stewardship program comprised of formulary restriction plus prospective audit with feedback for high-cost and broad-spectrum antimicrobials. Subsequently, we reviewed all heath care facility-onset, health care facility-associated C difficile infections. We found that most of these infections were associated with the antecedent receipt of nonaudited, and often unnecessary, antimicrobials.