Azole Therapy Research Articles

QTc Interval Prolongation as an Adverse Event of Azole Antifungal Drugs: Case Report and Literature Review.

QTc prolongation and torsade de pointes (TdP) are significant adverse events linked to azole antifungals. Reports on QTc interval prolongation caused by these agents are limited. In this study, we report a case of a 77-year-old male with cardiovascular disease who experienced QTc prolongation and subsequent TdP while being treated with fluconazole for Candida albicans-induced knee arthritis. Additionally, a literature review was conducted on cases where QTc prolongation and TdP were triggered as adverse events of azole antifungal drugs. The case study detailed the patient's experience, whereas the literature review analyzed cases from May 1997 to February 2023, focusing on patient demographics, underlying diseases, antifungal regimens, concurrent medications, QTc changes, and outcomes. The review identified 16 cases, mainly in younger individuals (median age of 29) and women (75%). Fluconazole (63%) and voriconazole (37%) were the most common agents. Concurrent medications were present in 75% of cases, and TdP occurred in 81%. Management typically involved discontinuing or switching antifungals and correcting electrolytes, with all patients surviving. Risk assessment and concurrent medication review are essential before starting azole therapy. High-risk patients require careful electrocardiogram monitoring to prevent arrhythmias. Remote monitoring may enhance safety for patients with implanted devices. Further studies are needed to understand risk factors and management strategies.

Disseminated Histoplasmosis in a Patient with Myelofibrosis on Ruxolitinib: A Case Report and Review of the Literature on Ruxolitinib-Associated Invasive Fungal Infections.

Ruxolitinib, a selective inhibitor of Janus kinases, is a standard treatment for intermediate/high-risk myelofibrosis (MF) but is associated with a predisposition to opportunistic infections, especially herpes zoster. However, the incidence and characteristics of invasive fungal infections (IFIs) in these patients remain uncertain. In this report, we present the case of a 59-year-old woman with MF who developed disseminated histoplasmosis after seven months of ruxolitinib use. The patient clinically improved after ten weeks of combined amphotericin B and azole therapy, and ruxolitinib was discontinued. Later, the patient received fedratinib, a relatively JAK2-selective inhibitor, without relapse of histoplasmosis. We also reviewed the literature on published cases of proven IFIs in patients with MF who received ruxolitinib. Including ours, we identified 28 such cases, most commonly due to Cryptococcus species (46%). IFIs were most commonly disseminated (39%), followed by localized lung (21%) infections. Although uncommon, a high index of suspicion for opportunistic IFIs is needed in patients receiving JAK inhibitors. Furthermore, the paucity of data regarding the optimal management of IFIs in patients treated with JAK inhibitors underscore the need for well-designed studies to evaluate the epidemiology, pathobiology, early diagnosis, and multimodal therapy of IFIs in patients with hematological malignancies receiving targeted therapies.

Concurrent Versus Sequential or No Triazole Anti-Fungal Therapy in Patients Undergoing 7+3 Plus Midostaurin Induction for FLT-3 Acute Myelogenous Leukemia

Background Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML) (Stone RM et al. NEJM 2017). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as Midostaurin through the CYP3A pathway. This could result in an increase in midostaurin concentrations and toxicities, and lead to potential dose interruptions or modifications. However, the literature is scarce on outcomes in patients who are receiving an azole antifungal with intensive induction chemotherapy in combination with midostaurin (Sechaud R et al. Cancer Chemother Pharmacol 2022). In addition to the scarcity of literature, there are no midostaurin related dose modifications that are recommended with strong CYP3A inhibitors. The primary objective of this retrospective study was to compare induction efficacy and safety outcomes in patients receiving concurrent azole antifungal to patients receiving sequential or no azole antifungal therapy. Methods: From January 1, 2017, to January 30, 2023, we retrospectively reviewed all adult patients (18 or older) with newly diagnosed AML who received midostaurin in combination with cytarabine and an anthracycline (7+3). Concurrent azole therapy was defined as patients receiving an azole antifungal therapy with midostaurin for more than 70% of the midostaurin doses. Sequential azole therapy was defined as patients receiving azole antifungal therapy with midostaurin for less than 70% of the doses or no azole antifungal therapy with midostaurin therapy. Response outcome CR and CR without hematological recovery (CRi) were defined per standard International Working Group (IWG) AML response criteria. Minimal residual disease (MRD) assessment was done on post-induction bone marrow aspirate using multiparametric flow cytometric assessment. Adverse events were graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. We compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3 AML. Mann-Whitney U test method was used to compare continuous variables between these two groups. Pearson Chi-square test or Fisher Exact test was used to compare categorical variables (count, rate or proportion) between these two groups. The choice of concurrent azole or sequential azole antifungal was determined by physician choice. Results: There were 40 patients treated with 7+3+midostaurin, 18 of whom received concurrent azole therapy, while 22 received sequential or no azole therapy. There were no significant differences in baseline characteristics (Table 1) except for more patients receiving isavuconazole (moderate CYP 3A4 inhibitor) in the concurrent group (50% vs 0%; p<0.01) and more micafungin in the sequential or no azole group (0% vs 72%; p<0.01). Overall CR/CRi rate with concurrent versus sequential or no azole was 72% (13/18) vs 77% (17/22), with no significant difference in median days to ANC recovery (27 vs 29; p=0.98), platelet recovery (28 vs 32 days; p=0.67), and non-hematologic grade 3 toxicities (22% and 45%; p=0.13), respectively. There were higher, but not significant, rates of midostaurin dose reductions (6% vs 0%; p=0.26) and holds (17% vs 14%; p=0.79) in the concurrent azole group. Conclusion: In conclusion, the addition of azole antifungal was found to be equally safe and effective in the treatment of newly diagnosed FTL3 AML. Dose modifications in midostaurin appeared not to be necessary with concurrent azole antifungal therapy. Further analysis based on a larger cohort is needed to confirm the outcomes and safety endpoints reported in the current study. Given the importance of azole anti-fungal therapy in the treatment of AML and specifically in induction therapy for AML (Cornely et al, NEJM 2007), dose modifications for this drug interaction should be studied in the future to help guide clinicians on how to appropriately dose these drugs.

806. Candida Gut Colonization in Critically Ill Patients

Abstract Background Candida spp. colonization is a risk factor for candidemia in intensive care unit (ICU) patients. Recent data suggest that the epidemiology of Candida infections is shifting away from C. albicans, but prospective data on the epidemiology of Candida spp. gut colonization are limited. Methods We conducted a prospective cohort study of adult patients admitted to an ICU at a tertiary care hospital. Patients had stool samples collected twice weekly for up to four weeks or until ICU discharge. A convenience sample of stool samples was plated on CHROMagar Candida Plus for 48 hours. Colonies of different morphologies were isolated on Sabouraud dextrose agar and identified with MALDI-ToF. Results A total of 102 patients were included in the cohort. We performed screening for stool Candida colonization in 12 patients: 8 (67%) men, median age 65 (IQR 54.5-68.5). Three (25%) were in shock and eight (67%) required mechanical ventilation on ICU admission. In-hospital mortality was 25%. Seven patients (58%) were colonized with Candida at ≥1 time point (Figure 1). Of 30 total time points tested (median per patient=2, range 1-5), 15 (50%) were positive for Candida spp. Most time points (9/15, 60%) were positive for C. glabrata; 4/15 (27%) were positive for both C. glabrata and C. albicans. A minority (1/15; 7%) were positive for C. albicans and C. parapsilosis alone, respectively. None had C. auris colonization. Most colonization was persistent: Of 6 colonized patients with ≥1 time point tested, 5 (83%) were colonized at multiple timepoints. Eleven patients had data collected on anti-fungal administration during the study period, and five of these received an antifungal (Figure 1). Of these five, three (60%) had no Candida colonization. One lost C. albicans colonization but had persistent C. glabrata colonization despite azole therapy, and another developed C. parapsilosis colonization despite azole and amphotericin administration. Figure 1. Results of serial stool samples tested for Candida colonization per individual patient. Conclusion Most ICU patients in this study had Candida spp. gut colonization, commonly with intrinsically azole-resistant C. glabrata. This study is limited by small sample size, and further data are needed to determine the clinical impact of antifungal-resistant Candida in ICU patients at high risk of candidemia. Disclosures All Authors: No reported disclosures

2804. Azole versus echinocandin combination therapy for the treatment of invasive mucormycosis: A case series

Abstract Background Mucormycosis is a rare and aggressive mold infection with an all-cause mortality of 54%. Treatment for mucormycosis has historically consisted of high dose liposomal amphotericin B (LAmB) as monotherapy. Recent data has emerged studying combination therapies; however, this data is conflicting, and the benefit of combination therapy remains unclear. This case series aims to explore different combination therapies utilized for the treatment of mucormycosis and their effect on mortality. Methods We report 17 cases of proven or probable mucormycosis managed with combination therapy for at least 48 hours at University Hospital between March 2020 and November 2022. Results The median age of patients was 60 years old (range 21-74), and 11 patients were male (64.7%), with a median BMI of 27.8 kg/m2. Of the 17 patients, all patients (100%) were Hispanic, nine patients (53%) had diabetes and two patients (12%) were lung transplant recipients. The most common infection site was rhino-orbital (6/17; 35%) and surgery was performed on 11 patients (64.7%) after a median of two days after hospital admission. All 17 patients received LAmB with an average initial dose of 5.13 mg/kg/day (range 2.9-6.4 mg/kg/day). All patients received combination therapy with either posaconazole (6/17; 35.2%), micafungin (4/17; 23.5%), or triple therapy (7/17; 41.2%). Duration of combination therapy was a median six days (range 2-21 days). Five of the 17 patients (29%) died of mucormycosis-related complications. Mortality observed in patients receiving combination therapy is as follows: micafungin combination (4/4; 100%), posaconazole combination (5/6; 83%), and triple therapy (0/7; 0%). Conclusion Mucormycosis is an aggressive fungal infection with high morbidity and mortality that requires immediate recognition, urgent intervention, and appropriate antifungal dosing. Combination therapy with micafungin maybe associated with higher mortality compared to posaconazole or triple therapy. In this cohort, combination may be associated with lower mortality that previously documented but further investigation is required to determine optimal combination treatment for invasive mucormycosis. Disclosures Kelly Reveles, PharmD, PhD, Ferring Pharmaceuticals: Advisor/Consultant|Ferring Pharmaceuticals: Honoraria

Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia

Introduction: Menin inhibitors are an exciting new class of agents in development for patients (pts) with acute leukemia who overexpress HOXA9 and MEIS1 genes. Although there is a growing list of fusion genes in acute leukemia that appear to be dependent on homeobox-related gene activity, menin inhibition has been shown to be particularly active in pts with NPM1 mutations (NPM1c) and KMT2A rearrangements (MLLr). DSP-5336 is an investigational, oral small molecule designed to inhibit the menin and MLL protein interaction. Methods: A Phase 1/2 study of DSP-5336 is being conducted in pts with relapsed or refractory (R/R) acute leukemia. The dose escalation portion of the study consists of two parallel arms (Arm A: without concomitant anti-fungal azole therapy; Arm B: with concomitant azole therapy). Pts were eligible with R/R AML, ALL or acute leukemia of ambiguous lineage without a limit on number of prior therapies, with a focus on those with MLLr and NPM1c. Results: Accrual is ongoing with 24 pts enrolled as of April 2023; 14 pts in Arm A at doses of 40 mg BID (n=2), 80 mg BID (n=4), 100 mg BID (n=2) and 120 mg BID (n=6), and 10 pts in Arm B at doses of 40 mg BID (n=4) and 60 mg BID (n=6). The median age was 67.0 years (range 20 - 85) and 62.5% were male. All pts had AML except for 1 pt with acute leukemia of ambiguous lineage. Pts had received a median of 3 (range 1 to 9) prior treatments, and 6 (25%) had received prior alloSCT. MLLr or NPM1c were present in 6 (25%) and 4 (17%) patients, respectively. No dose-limiting toxicities have been observed thus far. Most treatment-emergent adverse events (TEAEs) were grade 1/2. TEAEs assessed as related to DSP-5336 in ≥ 3 pts were nausea (Grade 1 or 2, n = 3 pts) and vomiting (Grade 1 or 2, n = 4 pts). Grade >3 TEAEs occurring in ≥ 3 pts included anemia (6 pts), pneumonia (5 pts), sepsis (3 pts) and hypokalemia (3 pts), all unrelated to study drug. A possible Grade 4 differentiation syndrome (DS) was observed in 1 pt with a TP53 mutation in Arm A receiving 80 mg BID although concurrent pneumonia and sepsis made a clear attribution difficult. No other DS events of any grade have been reported to date. No cardiac toxicities, and no QTc prolongation of any grade related to DSP-5336 have been observed. Out of the 6 pts enrolled with MLLr, 4 were treated at dose levels projected to be active based on preclinical modeling (≥ 60 mg BID with azoles, or ≥ 120 mg BID without azoles). Of these 4 pts, all had received prior intensive induction chemotherapy as well as a venetoclax-based regimen, and 3 had received prior allo-transplant. Of these 4 pts, 1 achieved CRi with a duration of therapy of 5.1 months, 1 achieved MLFS with a duration of therapy of 6.2 months (ongoing), and 1 achieved SD with clearance of peripheral blasts, recovery of peripheral counts, resolution of leukemic gingival infiltration, and reduction in bone marrow (BM) blasts from 85% to 31%. Of the 4 enrolled pts with NPM1c, 2 were treated at doses projected to be effective. Stable disease with complete clearance of peripheral blasts were observed in both pts, and BM blasts were reduced by 66% and 83% respectively. Preliminary pharmacokinetic (PK) analysis has demonstrated generally higher mean exposures at higher dose levels. Across all the dose levels, plasma t 1/2 ranged from 2-6 hours in Arm A and from 2-10 hours in Arm B, with T max reached within 2 hours. Little to no drug accumulation was observed with repeat dosing in both arms. Data to date suggests that azoles may not have a significant effect on DSP-5336 exposure, but enrollment and comparative analyses are ongoing. Target pharmacodynamic changes have been achieved in pts who have MLLr or NPM1m, including rapid decreases in HOXA9, MEIS1, and PBX3 with treatment and, conversely, increases in CD11b compared to pretreatment. Conclusion: DSP-5336 has been well tolerated with no DLTs to date in heavily pretreated R/R AML patients with NPM1c and MLLr AML. Importantly, no cardiac signals (including no QTcF prolongation) have been observed. PK studies have not identified a significant drug-drug interaction with azoles. Although there are early signs of clinical activity and pharmacodynamic changes during administration of DSP-5336, the study is ongoing to determine a recommended Phase 2 dose for single-agent expansion and potential combination regimens. Updated safety and efficacy data will be presented at the meeting.

A Randomized Phase 2 Trial of 28-Day (Arm A) Versus 14-Day (Arm B) Schedule of Venetoclax + Azacitidine in Newly Diagnosed Acute Myeloid Leukemia Patients ≥ 60 Years

Background: Treatment options for older, less fit acute myeloid leukemia (AML) patients continue to be challenging, with toxicities and limited efficacy. The combination therapy of azacitidine (Aza) and the bcl-2 inhibitor venetoclax (Ven) showed superior benefit in response rates and overall survival compared to Aza alone, leading to the combination's FDA approval in newly diagnosed AML patients ≥ 75 years and younger patients ineligible for intensive chemotherapy. While Ven-Aza is a very effective and potent therapy, the 28-day continuous dosing of Ven combined with 7 days of Aza resulted in interrupted dosing or shortened dosing schedules due to persistent cytopenias in more than 50% of treated patients in the VIALE-A trial and subsequent real-world data. Furthermore, investigation of novel agents in combination with Ven-Aza has been challenging due to prolonged cytopenias even when monotherapy with the new agent shows no myelosuppression. Given that Ven-Aza is not curative, successful integration of other agents with this standard of care remains important in AML. The growing knowledge of Ven-Aza toxicities prompted attention to developing a safer dosing regimen while maintaining similar efficacy. Our study will examine the FDA label of 28 days of Ven, versus 14 days, in combination with Aza for newly diagnosed AML patients ≥ 60 years who are not candidates for intensive chemotherapy. The primary objective of this study is to compare complete remission (CR) rates with an abbreviated schedule of Ven (14 days) versus the current package insert approved schedule (28 days). We hypothesize that reducing the dosing duration of Ven would reduce the associated toxicities while maintaining a comparable response rate. Study Design and Methods: This protocol is a sub-study of the Beat AML Master Trial (NCT03013998) in which untreated AML patients age ≥ 60 are assigned an investigational therapy based on cytogenetic and central genomic analysis. Patients are randomized onto Arm A (28-day Ven-Aza schedule) or Arm B (14-day Ven-Aza schedule) stratified by age (60-74 vs. 75+ years). The primary objective is to determine the complete remission (CR) rate of patients treated in each randomized arm for up to 2 cycles. The secondary objectives will include assessments of composite complete remission (CR, CR with hematologic improvement, CR with incomplete count recovery), duration of remission, survival, and incidence of treatment-related and non-related toxicities. Additionally, the overall incidence of febrile neutropenia, grade ≥3 infections, transfusions, days of hospitalization and time to neutrophil recovery will be determined. In both arms of the study, patients will be assessed for response at day 21-28 of cycles 1 and 2. Patients who have marrow remission (< 5% blasts) will wait for count recovery of absolute neutrophil count ≥ 0.5x10 9/L and platelets ≥ 50x10 9/L before initiating the next cycle of therapy. Patients will then be followed for survival. With the exception of the Ven dosing schedule (14 vs. 28 days), the FDA approved package insert for Ven, including dose modifications for concurrent azole therapy, will be followed in both arms. The intent of the analysis is to demonstrate that the 14-day Ven-Aza regimen is at least as effective as the standard 28-day regimen. A total of 166 patients (83 per group) will provide 80% power to detect a 10% non-inferiority margin at the one-sided 5% significance level, assuming that the CR rate is 36% for the 28-day regimen, as observed in VIALE-A, and 25% higher (45%) for the 14-day regimen. In addition to assessing the frequency of adverse events such as cytopenias, safety monitoring will include an assessment of response rates after at least 25% of patients have completed 2 cycles of treatment, with consideration for stopping the study if data suggest the 14-day regimen is inferior to the standard regimen. Correlative studies will include measurement of MRD and a focus on identifying properties of leukemic cells that respond, do not respond and become resistant to therapy.

Using (1,3)-β-D-glucan concentrations in serum to monitor the response of azole therapy in patients with eumycetoma caused by Madurella mycetomatis.

(1,3)-β-D-glucan is a panfungal biomarker secreted by many fungi, including Madurella mycetomatis, the main causative agent of eumycetoma. Previously we demonstrated that (1,3)-β-D-glucan was present in serum of patients with eumycetoma. However, the use of (1,3)-β-D-glucan to monitor treatment responses in patients with eumycetoma has not been evaluated. In this study, we measured (1,3)-β-D-glucan concentrations in serum with the WAKO (1,3)-β-D-glucan assay in 104 patients with eumycetoma treated with either 400 mg itraconazole daily, or 200 mg or 300 mg fosravuconazole weekly. Serial serum (1,3)-β-D-glucan concentrations were measured at seven different timepoints. Any correlation between initial and final (1,3)-β-D-glucan concentrations and clinical outcome was evaluated. The concentration of (1,3)-β-D-glucan was obtained in a total of 654 serum samples. Before treatment, the average (1,3)-β-D-glucan concentration was 22.86 pg/mL. During the first 6 months of treatment, this concentration remained stable. (1,3)-β-D-glucan concentrations significantly dropped after surgery to 8.56 pg/mL. After treatment was stopped, there was clinical evidence of recurrence in 18 patients. Seven of these 18 patients had a (1,3)-β-D-glucan concentration above the 5.5 pg/mL cut-off value for positivity, while in the remaining 11 patients, (1,3)-β-D-glucan concentrations were below the cut-off value. This resulted in a sensitivity of 38.9% and specificity of 75.0%. A correlation between lesion size and (1,3)-β-D-glucan concentration was noted. Although in general (1,3)-β-D-glucan concentrations can be measured in the serum of patients with eumycetoma during treatment, a sharp decrease in β-glucan concentration was only noted after surgery and not during or after antimicrobial treatment. (1,3)-β-D-glucan concentrations were not predictive for recurrence and seem to have no value in determining treatment response to azoles in patients with eumycetoma.

Rapid Evolution of Multidrug Resistance in a Candida lusitaniae Infection during Micafungin Monotherapy.

Candida (Clavispora) lusitaniae is a rare, emerging non-albicans Candida species that can cause life-threatening invasive infections, spread within hospital settings, and rapidly acquire antifungal drug resistance, including multidrug resistance. The frequency and spectrum of mutations causing antifungal drug resistance in C. lusitaniae are poorly understood. Analyses of serial clinical isolates of any Candida species are uncommon and often analyze a limited number of samples collected over months of antifungal therapy with multiple drug classes, limiting the ability to understand relationships between drug classes and specific mutations. Here, we performed comparative genomic and phenotypic analysis of 20 serial C. lusitaniae bloodstream isolates collected daily from an individual patient treated with micafungin monotherapy during a single 11-day hospital admission. We identified isolates with decreased micafungin susceptibility 4 days after initiation of antifungal therapy and a single isolate with increased cross-resistance to micafungin and fluconazole, despite no history of azole therapy in this patient. Only 14 unique single nucleotide polymorphisms (SNPs) were identified between all 20 samples, including three different FKS1 alleles among isolates with decreased micafungin susceptibility and an ERG3 missense mutation found only in the isolate with increased cross-resistance to both micafungin and fluconazole. This is the first clinical evidence of an ERG3 mutation in C. lusitaniae that occurred during echinocandin monotherapy and is associated with cross-resistance to multiple drug classes. Overall, the evolution of multidrug resistance in C. lusitaniae is rapid and can emerge during treatment with only first-line antifungal therapy.

Man With Thigh Pain

A 33-year-old construction worker with diabetes presented to an emergency department in Chicago, Illinois, with thigh pain for 1 year. Physical examination revealed a large, heme-crusted, multicolored annular plaque with central atrophy and an indurated, verrucous border involving the entire circumference of the lower right thigh (Figure). Laboratory study results were significant for a sedimentation rate of 22 mm/h and a C-reactive protein level of 2.62 mg/dL. A punch biopsy, performed during a dermatology consultation, later confirmed the diagnosis. Cutaneous blastomycosis. Blastomycosis is a systemic pyogranulomatous infection, endemic to states surrounding Mississippi and the Ohio River Valley, that occurs because of inhalation of spores from Blastomyces dermatidis or Blastomyces gilchristii. Immunocompromised patients and those with diabetes are at the highest risk for infection.1Lemos L.B. Baliga M. Guo M. et al.Acute respiratory distress syndrome and blastomycosis: presentation of nine cases and review of the literature.Ann Diagn Pathol. 2001; 5: 1-9Crossref PubMed Scopus (64) Google Scholar,2Pappas P.G. Threlkeld M.G. Bedsole G.D. et al.Blastomycosis in immunocompromised patients.Med (Baltim). 1993; 72: 311-325Crossref PubMed Scopus (149) Google Scholar Although the most common site of infection is the lungs, presenting as pneumonia, hematogenous spread and extrapulmonary manifestations are common.3Azar M.M. Massi R. Relich R.F. et al.Blastomycosis in Indiana: clinical and epidemiologic patterns of disease gleaned from a multicenter retrospective study.Chest. 2015; 148: 1276-1284Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar The skin is the second most common site of infection, mimicking squamous cell carcinoma, with bone being the third, presenting as osteomyelitis.4Oppenheimer M. John M.E. Black B. et al.Blastomycosis of bones and joints.South Med J. 2007; 100: 570-578Crossref PubMed Scopus (51) Google Scholar The final diagnosis is made by histology and culture of infected tissue. Before the advent of effective antifungals, systemic blastomycosis often progressed to acute respiratory distress syndrome with high general mortality.3Azar M.M. Massi R. Relich R.F. et al.Blastomycosis in Indiana: clinical and epidemiologic patterns of disease gleaned from a multicenter retrospective study.Chest. 2015; 148: 1276-1284Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,5Martin D.S. Smith D. Blastomycosis I: a review of the literature.Am Rev Tuberc. 1939; 39: 275Google Scholar Current treatments include amphotericin B or azole therapy. Lethal cases now most commonly occur in the setting of acute pulmonary blastomycosis and associated acute respiratory distress syndrome.1Lemos L.B. Baliga M. Guo M. et al.Acute respiratory distress syndrome and blastomycosis: presentation of nine cases and review of the literature.Ann Diagn Pathol. 2001; 5: 1-9Crossref PubMed Scopus (64) Google Scholar Our patient biopsy result confirmed pulmonary blastomycosis, likely from an occupational exposure, which improved with systemic itraconazole.

Disseminated blastomycosis with an intracranial fungoma in an immunocompetent patient: illustrative case

Blastomyces dermatitidis is a fungus endemic to central and southern North America. While infection most commonly results in pneumonia, a small number of infections progress to systemic disease, which may include intracranial lesions. Progression to systemic disease is most common in immunocompromised patients, such as those with human immunodeficiency virus. The authors present a 44-year-old immunocompetent male who presented following a tonic-clonic seizure. Initial workup revealed a 19-mm enhancing intracranial mass. There was avid uptake of fluorescein sodium, and an en bloc resection of the mass was performed. Histopathology revealed B. dermatitidis. Medical management included amphotericin B and azole therapy. Postoperative recovery was uneventful, and no focal neurological deficits were appreciated. This case highlights the neurosurgical management of a rare intracranial fungal manifestation in an immunocompetent patient. A literature review was also performed to better understand the role of neurosurgery in fungal infections. There were limited cases of intracranial Blastomyces reported in immunocompetent patients, and neurosurgical management varied (no intervention, biopsy, resection) and was underreported. Too few cases are reported to suggest neurosurgical intervention for blastomycosis improves outcomes. Medical management was relatively standard with azole and amphotericin therapy.

Intravaginal Combination Therapy of Acetic and Lactic Acid in premenopausal women with recurrent vulvovaginal candidiasis: A randomized, double-blind placebo-controlled feasibility trial.

Recurrent vulvovaginal candidiasis management primarily entails azole therapy used as required or as an extended daily or weekly maintenance therapy for 6 months or more. Unfortunately, relapse within 3-6 months of ceasing maintenance therapy is experienced for more than half the patients, for whom indefinite treatment is required. To explore the feasibility of trial design examining a prophylaxis treatment to prevent recurrent vulvovaginal candidiasis symptomatic episodes and reduce adverse effects. A double-blinded randomized controlled feasibility trial was conducted in Australia. Women with recurrent vulvovaginal candidiasis were enrolled. An intravaginal prophylaxis application of lactic acid and acetic acid (Intravaginal Combination Therapy of Acetic and Lactic Acid) was compared with placebo. Primary outcomes comprised recruitment and retention, compliance to study medications and study assessments. Secondary outcomes included the reduction of symptomatic recurrence over the trial period and the acceptability, satisfaction, safety and tolerability of the intervention. The feasibility of quality-of-life measures was also explored. Fifteen participants were enrolled and randomized (active = 9, placebo = 6). Consent rate was 23.4%. Eight participants were lost to follow-up (active = 5, placebo = 3). Forty-seven per cent of participants (n = 7) were 100% compliant with the intervention, six of which completed the trial with good assessment compliance. The blinding process was effective. The study demonstrated a reduction in relapse in both active and placebo groups with only four participants across both groups reporting symptomatic episodes while enrolled. The intervention demonstrated good tolerability. Quality-of-life data showed minimal variance with a high quality-of-life measure. This trial assesses the feasibility of conducting a large-scale study exploring the efficacy of the Intravaginal Combination Therapy of Acetic and Lactic Acid intravaginal intervention and hints on the importance of psychological support through appropriate disease-specific communication and clinical attention. Consideration of the reported recruitment challenges, the inclusion of suitable quality-of-life measures and digital data collection is warranted for adaptation to a fully powered trial.

Role of Aspergillus Specific IgG Titres as a Therapeutic Target for Chronic Pulmonary Aspergillosis: A Longitudinal Study

Introduction: Chronic Pulmonary Aspergillosis (CPA) continues to be an enigma to clinicians in regions with a high prevalence of pulmonary tuberculosis and is often misdiagnosed as the latter, attributable to the significant overlap in symptoms and radiology. Moreover, although the diagnostic criteria for CPA have been standardised, the role of serological markers in monitoring disease activity and response to therapy is still not well characterised. Aim: To understand the characteristics, risk factors and treatment outcomes in patients developing CPA and to determine the role of serological markers as indicators of disease activity. Materials and Methods: The present longitudinal study was conducted in the Department of Respiratory Medicine, University College of Medical Sciences and its associated Guru Teg Bahadur Hospital, Delhi, India from February 2021 to June 2022. Study included 46 patients suspected of harbouring CPA attributable to their clinico-radiological presentation. The diagnosis of CPA was made using the established criteria. Patients with a confirmed diagnosis of CPA received oral azole antifungals for 6 months and were monitored at 3-monthly intervals for reduction in baseline parameters to determine treatment success/failure. Paired and unpaired parametric variables were compared using the t-test and non parametric methods were compared using the Chisquare test. Results: The diagnosis of CPA was established in 31 (67.4%) patients of whom 77.6% were males and the mean age was 47.3±2.2 years. These patients had been symptomatic for 5.8±1.2 years. Underlying risk factors (such as the history of tuberculosis, chronic obstructive pulmonary disease, diabetes mellitus, history of long-term glucocorticoid use etc.) had been present for 6.9±1.3 years. Patients harboured an average of two risk factors with tuberculosis and diabetes mellitus being the most common local and systemic affliction, respectively. Patients with tuberculosis (p-value=0.001) and chronic steroid use (p-value=0.029) were significantly at higher risk of developing CPA. 6 months of azole therapy led to significant reduction in specific IgG titres (p-value=0.001), and serum precipitins (p-value=0.004). Two patients on itraconazole relapsed within 12 months but were successfully treated with voriconazole. Conclusion: Tuberculosis was the most significant local risk factor leading to the development of CPA, which developed soon after diagnosis of another systemic risk factor. Six months of azole therapy was adequate to induce remission of the disease, activity of which can be monitored though the measurement of serum IgG antibody titres.

477. Evaluation of Electrocardiogram (ECG) Monitoring Practice in Newly Initiated Azole Antifungal Therapy

Abstract Background Azole antifungals are first-line options in the management of many fungal infections, but most are known to cause corrected Q-T interval (QTc) prolongation. There is a lack of guidance on which patients on azoles warrant ECG monitoring, potentially leading to discordant clinical practices. We aimed to determine factors associated with ECG monitoring of patients on systemic azole therapy. Methods We performed a retrospective cohort study of hospitalized adult patients who received at least five days of inpatient azole therapy. Pregnant patients, those on azoles prior to admission or with a gap in azole therapy > 3 days were excluded. Only the first admission with azole use per patient over the study period was included. The primary outcome was any ECG measurement within 5 days of starting azole therapy. We calculated adjusted odds ratios (aOR) for the association between patient and treatment characteristics and likelihood of ECG measurement using multivariable logistic regression. Figure 1.Study Flow Diagram Results 4,126 patients met inclusion criteria over 9 years (Figure 1). Most were admitted to the Hematology/Oncology service (49%), followed by Transplant (20.4%). Azole therapy was initiated for medical prophylaxis in 61.7% and for treatment in 27.9%. Fluconazole (FLU) was the most utilized azole (75.2%), followed by voriconazole (VOR) (18%). Overall, 1,454 patients (35.24%) had at least one ECG measured within 5 days of starting azole therapy. Patients were more likely to have an ECG monitored if they received VOR (48.1%) compared to FLU (31.1%), or were on the transplant service (53.9%) vs medicine (37%). On multivariate analysis (Figure 2), likelihood of having an ECG measured was greater among patients (1) receiving posaconazole (POS, aOR 1.75, 95% CI 1.31-2.34) or VOR (aOR 1.34, 95% CI 1.10-1.63) versus FLU, (2) with a baseline ECG (aOR 2.07 (1.76-2.43), and (3) who received concomitant QT-prolonging medications (aOR 1.22, 95% CI 1.01-1.48) or diuretics (aOR 1.38 95% CI 1.16-1.63). Figure 2.Odds Ratio for Primary Outcome QT-prolonging medication use during azole therapy: Antibiotics (ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, azithromycin), HIV meds (protease inhibitors), CV meds (amiodarone, disopyramide, dofetilide, procainamide, quinidine, sotalol), anti-emetics (chlorpromazine, metoclopramide, ondansetron), chemotherapy (nilotinib, sunitinib), psychiatric meds (haloperidol, risperidone, ziprasidone), miscellaneous (methadone); Diuretics/electrolyte disturbing agents used during azole therapy: Furosemide, bumetanide, torsemide, sulfamethoxazole-trimethoprim, amphotericin Conclusion Use of POS or VOR, baseline ECG monitoring, concomitant QT-prolonging medications, and electrolyte abnormalities, were associated with greater likelihood of ECG monitoring. These results can help target guidance for ECG monitoring in patients on azoles. Disclosures Conan MacDougall, PharmD, MAS, Merck: Advisor/Consultant Sarah B. Doernberg, MD, MAS, Basilea: Clincal events committee|Genentech: Advisor/Consultant|Gilead: Grant/Research Support|Regeneron: Grant/Research Support|Shinogi: Clincal events committee.

Liposomal amphotericin B-the present.

Most invasive fungal infections are opportunistic in nature but the epidemiology is constantly changing, with new risk groups being identified. Neutropenia is a classical risk factor for fungal infections, while critically ill patients in the ICU are now increasingly at risk of yeast and mould infections. Factors to be considered when choosing antifungal treatment include the emergence of rarer fungal pathogens, the risk of resistance to azoles and echinocandins and the possibility of drug-drug interactions. Liposomal amphotericin B has retained its place in the therapeutic armamentarium based on its clinical profile: a broad spectrum of antifungal activity with a low risk of resistance, predictable pharmacokinetics with a rapid accumulation at the infection site (including biofilms), a low potential for drug-drug interactions and a low risk of acute and chronic treatment-limiting toxicities versus other formulations of amphotericin B. It is a suitable choice for the first-line empirical or pre-emptive treatment of suspected fungal infections in neutropenic haematology patients and is an excellent alternative for patients with documented fungal disease who can no longer tolerate or continue their first-line azole or echinocandin therapy, both in the haematology setting and in the ICU. Moreover, it is the first-line drug of choice for the treatment of invasive mucormycosis. Finally, liposomal amphotericin B is one of the few antifungal agents approved for use in children of all ages over 1 month and is included in paediatric-specific guidelines for the management of fungal disease.

S10.4b Pathophysiology, diagnosis, and management of chronic pulmonary Aspergillosis

S10.4 Emerging antifungal resistant fungi, September 24, 2022, 10:30 AM – 12:00 PM Chronic pulmonary Aspergillosis (CPA) is a complex disease that is difficult to diagnose and resistant to treatment. Many cases are missed and have unfortunate outcomes in clinical settings. Although CPA has long been classified into several types based on pathological findings, it is not always possible to make a pathological diagnosis in all cases, so a clinical diagnosis is often made. In addition, many have an underlying respiratory disease and complications by infections caused by other microorganisms, making treatment further difficult. The diagnosis of CPA requires clinical symptoms and findings, radiological, serological, pathological, and microbiological approaches, and standardization of these diagnostic criteria is challenging. The mainstay of treatment is outpatient oral therapy with azoles, and indications and therapeutic evidence for echinocandins, and polyenes are limited. The development of novel antifungals with different mechanisms of action from conventional agents is also awaited. Azole-resistance of Aspergillus caused by long-term treatment is also an issue. It has been reported that resistant strains have been found in CPA patients treated with long-term azole therapy, mutations in the cyp51A and others have also been identified and longer exposure to azoles are correlated with higher MIC values of them. This presentation will focus on epidemiology, pathogenesis, diagnosis, and management including drug resistance in CPA patients.

Creation and Internal Validation of a Clinical Predictive Model for Fluconazole Resistance in Patients With Candida Bloodstream Infection.

BackgroundFluconazole is recommended as first-line therapy for candidemia when risk of fluconazole resistance (fluc-R) is low. Lack of methods to estimate resistance risk results in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial or early step-down fluconazole would be appropriate.MethodsRetrospective analysis of hospitalized adult patients with positive blood culture for Candida spp from 2013 to 2019. Multivariable logistic regression model was performed to identify factors associated with fluc-R. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals (CIs). We used receiver operating characteristic curves to assess performance across the probability spectrum.ResultsWe identified 539 adults with candidemia and 72 Candida isolates (13.4%) were fluc-R. Increased risk of fluc-R was associated with older age, prior bacterial bloodstream infection (odds ratio [OR], 2.02 [95% CI, 1.13–3.63]), myelodysplastic syndrome (OR, 3.09 [95% CI, 1.13–8.44]), receipt of azole therapy (OR, 5.42 [95% CI, 2.90–10.1]) within 1 year of index blood culture, and history of bone marrow or stem cell transplant (OR, 2.81 [95% CI, 1.41–5.63]). The model had good discrimination (optimism-corrected c-statistic 0.771), and all of the selected variables were stable. The prediction model had a negative predictive value of 95.7% for the selected sensitivity cutoff of 90.3%.ConclusionsThis model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive first-line or early step-down fluconazole.

Tolerability of Extended Multi-Drug Fungal Prophylaxis After Lung Transplant

<h3>Purpose</h3> Lung transplant patients are at risk of fungal infections post-transplant and require anti-fungal prophylaxis (AFP). However, utilization and duration of these agents can be limited by adverse effects. The purpose of this evaluation was to assess the tolerability and duration of AFP post-lung transplant at a large academic medical center. <h3>Methods</h3> This single-center retrospective review included lung transplant patients transplanted from August 2017 to August 2018 who received at least 7 days of AFP and were followed for three years. Patients received a combination of an azole anti-fungal agent, inhaled amphotericin B lipid complex (iABLC), and nystatin suspension immediately post-transplant. Pre-transplant colonization rates, prior fungal infections, transplant indication and baseline characteristics were collected. The primary outcome was tolerability of AFP. Secondary outcomes assessed were adherence and duration of AFP. <h3>Results</h3> Forty patients were included and one patient was excluded from the azole analysis due to a history of liver hyperplasia precluding therapy (Table 1). Patients remained on an azole, iABLC, and nystatin therapy a median of 13.9, 36.6, and 32 months post-transplant, respectively. The most common reason for AFP discontinuation was provider decision to end prophylaxis coverage (Table 2). Seven (19.4%) patients in the azole group, one (4.8%) patient in the iABLC group, and one (4.3%) patient in the nystatin group discontinued therapy due to intolerable side effects and adverse reactions. Patient reported adherence rates were highest in the azole group (87.2%), followed by iABLC (67.5%) and lowest with nystatin (45%). <h3>Conclusion</h3> Despite an extended duration of broad AFP, most patients tolerated therapy without limiting adverse effects. Oral AFP of shorter duration yielded the highest patient reported adherence.

Aspergillus endocarditis in the recent years, report of cases of a multicentric national cohort and literature review.

(1) To describe the incidence, clinical characteristics, treatment and outcome of Aspergillus Endocarditis (AE) in a nationwide multicentric cohort (GAMES). (2) To compare the AE cases of the GAMES cohort, with the AE cases reported in the literature since 2010. (3) To identify variables related to mortality. We recruited 10 AE cases included in the GAMES cohort (January 2008-December 2018) and 51 cases from the literature published from January 2010 to July 2019. 4528 patients with infectious endocarditis (IE) were included in the GAMES cohort, of them 10 (0.2%) were AE. After comparing our 10 cases with the 51 of the literature, no differences were found. Analysing the 61 AE cases together, 55.7% were male, median age 45years. Their main underlying conditions were as follows: prosthetic valve surgery (34.4%) and solid organ transplant (SOT) (19.7%). Mainly affecting mitral (36.1%) and aortic valve (29.5%). Main isolated species were as follows: Aspergillus fumigatus (47.5%) and Aspergillus flavus (24.6%). Embolisms occurred in 54%. Patients were treated with antifungals (90.2%), heart surgery (85.2%) or both (78.7%). Overall, 52.5% died. A greater mortality was observed in immunosuppressed patients (59.4% vs. 24.1%, OR=4.09, 95%CI=1.26-13.19, p=.02), and lower mortality was associated with undergoing cardiac surgery plus azole therapy (28.1% vs. 65.5%, OR=0.22, 95%CI=0.07-0.72, p=.01). AE accounts for 0.2% of all IE episodes of a national multicentric cohort, mainly affecting patients with previous valvular surgery or SOT recipients. Mortality remains high especially in immunosuppressed hosts and azole-based treatment combined with surgical resection are related to a better outcome.

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond.

Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.