Safety of fluconazole in kidney transplant recipients for prevention of coccidioidomycosis.

Coccidioides is an endemic fungus that causes infections ranging from mild respiratory illness to life-threatening disease, and immunocompromised hosts such as solid organ transplant recipients are at higher risk for disseminated infection and mortality. Our center administers fluconazole prophylaxis to kidney transplant recipients residing in geographic areas with higher incidences of coccidioidomycosis. However, because drug-drug interactions occur between triazoles and immunosuppressants used in transplant medicine, we undertook a study to ascertain whether fluconazole prophylaxis was associated with any important safety outcomes in kidney transplant recipients. This retrospective study evaluated patients who had undergone kidney transplantation between 2016 and 2019. Data on patient demographics, transplant-related clinical information, use of fluconazole prophylaxis (200 mg daily for 6-12 months post-transplant), and patient outcomes were obtained. The primary outcome was mean estimated glomerular filtration rate (eGFR) at 12 months, comparing those who received fluconazole prophylaxis to those who did not. Secondary outcomes included mean eGFR at 3 months, 6 months, and 9 months post-transplant, patient survival, biopsy-proven graft rejection, graft loss, or a new requirement for post-transplant dialysis, all within 12 months post-transplant. The mean eGFR at 12 months was similar between both groups, with 66.4 ml/min/1.73 m² in the fluconazole prophylaxis group vs. 64.3 ml/min/1.73 m² in the non-fluconazole prophylaxis group (P = 0.55). Secondary outcomes were similar across both groups. Multivariable linear regression found no significant association between fluconazole use and graft function. Fluconazole prophylaxis for prevention of coccidioidomycosis was not associated with adverse graft outcomes in kidney transplant recipients.

Solid organ transplant recipients can be highly immune suppressed, and infection with Coccidioides (valley fever) after transplant can lead to severe infections in these patients. Our study showed that fluconazole was safe and effective for preventing Coccidioides in kidney transplant recipients.

Drug-Drug Interaction between Tacrolimus and Fluconazole in a Kidney Transplant Recipient.

We report a case of tacrolimus and fluconazole drug-drug interaction in a 20-year-old female kidney transplant recipient with stable kidney function. The patient's tacrolimus blood concentrations were in the therapeutic range until fluconazole was administrated for Candida albicans infection, on day 58 posttransplant. Tacrolimus blood concentration increased by 125% (18.4 ng/mL) on day 79 and by 212% (25.4 ng/mL) on day 84 posttransplant. On day 92, tacrolimus trough blood concentration returned to the therapeutic range (5.6 ng/mL), with decrease of tacrolimus daily dose by 50% (to 4 mg). After fluconazole withdrawal, the patient was returned to the initial tacrolimus daily dose (8 mg) to maintain a tacrolimus trough blood concentration in the therapeutic range. Fluconazole coadministration with tacrolimus shows a significant clinical effect on tacrolimus trough blood concentration in kidney transplant patients. Maintaining a tacrolimus trough blood concentration in the therapeutic range is crucial for these patients; therefore, physicians should be aware of fluconazole prescriptions.

Low-dose fluconazole as a useful and safe prophylactic option in patients receiving allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low-dose fluconazole (FLCZ) prophylaxis (100 mg/day). METHODS: We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low-dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post-transplant. RESULTS: Of the 107 patients, 70 received low-dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection-related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44-8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02-4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group. CONCLUSION: Low-dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation.

Comparative risk assessment studies estimating the hazard posed by long-term consumption of PPCPs in river water.

This study assesses the risk due to Emerging Contaminants (ECs), present in Indian rivers - Ganga (650 million inhabitants), Yamuna (57 million inhabitants), and Musi (7,500,000 inhabitants), 13 ECs in total, have been used for risk assessment studies. Their concentrations (e.g., Fluconazole: 236950 µg/l, Ciprofloxacin: 31000 µg/l, Caffeine: 21.57 µg/l, etc.) were higher than the threshold concentrations for safe consumption (e.g. Fluconazole allowable level is 3.8 µg/l, and Ciprofloxacin allowable level is 0.51 µg/l). Three different pathways of emerging contaminants (ECs) transfer (oral water ingestion, oral fish ingestion, and dermal water contact) have been considered and the study is carried out in 2 ways: (i) deterministic and (ii) probabilistic approaches (using Monte Carlo iterative methods with 10000 simulations) with the aid of a software - Risk (version 7.5). The risk value, quantified by Hazard Quotient (HQ) is higher than the allowable limit of 1 for several compounds in the three rivers like Fluconazole (HQ = 18276.713), Ciprofloxacin (HQ = 278.675), Voriconazole (HQ = 14.578), Cetirizine (HQ = 1006.917), Moxifloxacin (HQ = 8.076), Caffeine (HQ = 55.150), and Ibuprofen (HQ = 9.503). Results show that Fluconazole and Caffeine pose the maximum risk in the rivers via the "oral pathway" that allows maximum transfer of the ECs present in the river (93% and 82% contribution to total risk). The risk values vary from nearly 25 times to 19000 times the United States Environmental Protection Agency (USEPA) threshold limit of 1 (e.g., Caffeine Infant Risk = 25.990 and Fluconazole Adult Risk = 18276.713). The most susceptible age group, from this study, is "Adults" (19-70 years old), who stand the chance of experiencing the adverse health hazards associated with prolonged over-exposure to the ECs present in the river waters. Musi has the maximum concentration of pollutants and requires immediate remediation measures. Further, both methods indicate that nearly 60-70% of the population in all the three study areas are at risk of developing health hazards associated with over-exposure to ECs regularly, making the areas inhabitable.

Disseminated Cryptococcus neoformans presenting with an isolated pleural effusion in a patient receiving temozolomide and long-term steroids.

Cryptococcus neoformans is a ubiquitous environmental organism found worldwide. Infection with this organism occurs predominantly in immunocompromised hosts, including persons living with HIV or those with impaired cellular immunity. Cryptococcal pleural effusions have been described in cases with extensive pulmonary involvement. Here we present the case of a woman receiving temozolomide and steroids for glioblastoma multiforme, who developed cough and dyspnoea and was found to have an uncomplicated pleural effusion. Pleural fluid culture grew Cryptococcus neoformans with negative culture on bronchoalveolar lavage. High serum cryptococcal antigen titre of 1:64 prompted lumbar puncture which demonstrated positive cerebrospinal fluid for Cryptococcus neoformans She was treated with liposomal amphotericin B and flucytosine, followed by consolidation and maintenance therapy with fluconazole. Pleural involvement in the absence of pulmonary involvement has rarely been reported. We review pulmonary and radiographic manifestations of cryptococcal infection, when to assess for disseminated infection, and management principles.

Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open-label, phase I study in healthy subjects.

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non-Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P-glycoprotein (P-gp [itraconazole]) in drug-drug interaction studies. Valemetostat is a substrate of CYP3A and P-gp in vitro. This phase I, open-label, single-sequence crossover study (JapicCTI-183902) assessed the pharmacokinetics (PK) of valemetostat when co-administered with itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) or fluconazole (a moderate CYP3A inhibitor) in healthy Japanese male participants 20-45 years of age. Participants were equally allocated to receive two doses of valemetostat 25 mg, once alone and once with either itraconazole or fluconazole (400-mg induction and 200-mg once daily maintenance). Valemetostat PK parameters with versus without itraconazole or fluconazole were compared using analysis of variance models. Overall, 32 participants were enrolled. Co-administration with itraconazole increased valemetostat peak concentration (Cmax ) by 2.9-fold and area under the plasma concentration-time curve extrapolated to infinity (AUCinf ) by 4.2-fold compared with valemetostat alone. When co-administered with fluconazole, the Cmax and AUCinf of valemetostat were each increased by 1.6-fold. No treatment-related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P-gp dual inhibitors.

Comparative cardiac effects of antimalarial drug halofantrine with or without concomitant administration of kolanut or fluconazole in healthy volunteers.

Background: There is rekindled interest in the cardiotoxicity of antimalarial medicines. Halofantrine is associated with QT interval prolongation. Fluconazole and kolanut alter the pharmacokinetics of halofantrine. Objectives: The study assessed the electrocardiographic changes of concomitant administration of kolanut or fluconazole with halofantrine and the effects on the QTc interval. Methods: Eighteen healthy volunteers received a single oral dose of halofantrine, halofantrine with kolanut or halofantrine with fluconazole in a crossover study. Twelve lead electrocardiography (ECG) was performed to measure the PR and QT interval (QTc). Statistical analysis was with SPSS at 5% level of significance. Results: PR intervals were shortened by halofantrine alone and halofantrine with kolanut (169.29 28.67 to 165.29 28.007 and 172.73 29.843 to 163.00 18.336ms) but was prolonged by halofantrine with fluconazole (177.70 27.394 to 186.59 44.434ms). There was prolongation of QTc (384.76 21.727 to 394.12 21.525; 381.36 22.29 to 388.30 17.26 and 382.35 20.08 to 390.84 21.97) in all the three treatment groups at 6 hours, p>0.05. One subject on halofantrine and fluconazole had QTc >440ms. Pre-treatment PR interval (PR0) correlated well with post-treatment PR6, and with PR14 r= 0.519, p= 0.014; r=0.664, p=0.013. Conclusion: Concomitant intake of kolanut with halofantrine was significantly decrease cardiac effect of halofantrine.

Case Report: Hypercalcemia as a manifestation of acute adrenal crisis precipitated by fluconazole use, and a review of the literature.

Acute adrenal crisis classically presents with vomiting, altered sensorium, and hypotension. We describe a unique case manifesting with severe hypercalcemia. Addisonian crisis was unusually precipitated by fluconazole use. We reviewed other reported cases and discuss the possible mechanisms of hypercalcemia in adrenal insufficiency. This 67-year-old man presented with fever, cough, and vomiting for 1 week and with anorexia and confusion for 3 weeks. He was hypotensive and clinically dehydrated. Investigations revealed left-sided lung consolidation, acute renal failure, and severe non-parathyroid hormone (PTH)-mediated hypercalcemia (calcium, 3.55mol/L; PTH, 0.81pmol/L). Initial impression was pneumonia complicated by septic shock and hypercalcemia secondary to possible malignancy. He received mechanical ventilation; treatment with intravenous fluids, inotropes, and hydrocortisone for septic shock; and continuous renal replacement therapy with low-calcium dialysate. Although hypercalcemia resolved and he was weaned off inotropes, dialysis, and hydrocortisone, his confusion persisted. When hypercalcemia recurred on day 19 of admission, early morning cortisol was <8 nmol/L, with low ACTH level (3.2 ng/L). Other pituitary hormones were normal. Hypercalcemia resolved 3 days after reinstating stress doses of hydrocortisone, and his mentation normalized. On further questioning, he recently received fluconazole for a forearm abscess. He previously consumed traditional medications but stopped several years ago, which may have contained glucocorticoids. He was discharged on oral hydrocortisone. Cortisol levels improved gradually, and glucocorticoid replacement was ceased after 8 years, without any recurrence of hypercalcemia or Addisonian crisis. Both hypercalcemia and adrenal insufficiency may present with similar non-specific symptoms. It is important to consider adrenal insufficiency in hypercalcemia of unclear etiology.

Vincristine Side Effects With Concomitant Fluconazole Use During Induction Chemotherapy in Pediatric Acute Lymphoblastic Leukemia.

As a mainstay of treatment for acute lymphoblastic leukemia (ALL), vincristine's side effect profile is well known. Parallel administration of the antifungal fluconazole has been shown to interfere with the metabolism of vincristine, potentially resulting in increased side effects. We conducted a retrospective chart review to determine whether concomitant administration of vincristine and fluconazole during pediatric ALL induction therapy impacted the frequency of vincristine side effects, namely, hyponatremia and peripheral neuropathy. We also evaluated whether the incidence of opportunistic fungal infections was impacted by fluconazole prophylaxis. Medical charts of all pediatric ALL patients treated with induction chemotherapy at Children's Hospital and Medical Center in Omaha, NE, from 2013 to 2021 were retrospectively reviewed. Fluconazole prophylaxis did not significantly impact the rate of fungal infections. We found no correlation between fluconazole use and increased incidence of hyponatremia or peripheral neuropathy, which supports the safety of fungal prophylaxis with fluconazole during pediatric ALL induction therapy.

Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)-report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group.

BACKGROUND: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. METHODS: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. FINDINGS: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. INTERPRETATION: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.

Real world co-prescribing contraindicated drugs with fluconazole and itraconazole.

PURPOSE: This study aimed to investigate co-prescribing of contraindicated drugs with fluconazole and itraconazole using real-world nationwide data. METHODS: This retrospective cross-sectional study was performed using claims data collected by the Health Insurance Review and Assessment Service (HIRA) of Korea during 2019-2020. To determine the drugs that should be avoided in patients taking fluconazole or itraconazole, Lexicomp® and Micromedex® were used. The co-prescribed medications, co-prescription rates, and potential clinical consequences of the contraindicated drug-drug interactions (DDIs) were investigated. RESULTS: Of the 197 118 prescriptions of fluconazole, 2847 co-prescriptions with drugs classified as contraindicated DDI by either Micromedex® or Lexicomp® were identified. Further, of the 74 618 prescriptions of itraconazole, 984 co-prescriptions with contraindicated DDI were identified. Solifenacin (34.9%), clarithromycin (18.1%), alfuzosin (15.1%), and donepezil (10.4%) were frequently found in the co-prescriptions of fluconazole, whereas tamsulosin (40.4%), solifenacin (21.3%), rupatadine (17.8%), and fluconazole (8.8%) were frequently found in the co-prescriptions of itraconazole. In 1105 and 95 co-prescriptions of fluconazole and itraconazole, accounting for 31.3% of all co-prescriptions, potential DDIs were associated with a risk of corrected QT interval (QTc) prolongation. Of the total 3831 co-prescriptions, 2959 (77.2%) and 785 (20.5%) were classified as contraindicated DDI by Micromedex® alone and by Lexicomp® alone, respectively, whereas 87 (2.3%) were classified as contraindicated DDI by both Micromedex® and Lexicomp®. CONCLUSIONS: Many co-prescriptions were associated with the risk of DDI-related QTc prolongation, warranting the attention of healthcare providers. Narrowing the discrepancy between databases that provide information on DDIs is required for optimized medicine usage and patient safety.

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study.

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.

Induction therapy with high-dose fluconazole plus flucytosine for human immunodeficiency virus-uninfected cryptococcal meningitis patients: Feasible or not?

BACKGROUND: Cryptococcal meningitis (CM) is increasingly recognised in human immunodeficiency virus (HIV)-uninfected patients with high mortality. The efficacy and safety profiles of induction therapy with high-dose fluconazole plus flucytosine remain unclear. METHODS: HIV-uninfected CM patients who received high-dose fluconazole (800 mg/d) for initial therapy in Huashan Hospital were included in this retrospective study from January 2013 to December 2018. Efficacy and safety of initial therapy, clinical outcomes and risk factors were evaluated. RESULTS: Twenty-seven (71.1%) patients who received high-dose fluconazole with flucytosine combination therapy and 11 (28.9%) having fluconazole alone for induction therapy were included. With a median duration of 42 days (IQR, 28-86), the successful response rate of initial therapy was 76.3% (29/38), while adverse drug reactions occurred in 14 patients (36.8%). The rate of persistently positive cerebrospinal fluid (CSF) culture results was 30.6% at 2 weeks, which was significantly associated with CSF CrAg titre >1:1280 (OR 9.56; 95% CI 1.40-103.65; p = .010) and CSF culture of Cryptococcus >3.9 log10 CFU/ml (OR 19.20; 95% CI 1.60-920.54; p = .011), and decreased to 8.6% at 4 weeks. One-year mortality was 15.8% (6/38), and low serum albumin (35 g/L) was found as an independent risk factor for 1-year mortality (HR 6.31; 95% CI 1.150-34.632; p = .034). CONCLUSIONS: Induction therapy with high-dose fluconazole (800 mg/d), combined with flucytosine, effectively treated HIV-uninfected CM and was well tolerated. Long-term fluconazole treatment with continued monitoring is beneficial for patients with persistent infection.

Ibrexafungerp in the Treatment of Vulvovaginal Candidiasis.

OBJECTIVE: To review the pharmacology, efficacy, and safety of ibrexafungerp in the management of vulvovaginal candidiasis (VVC). DATA SOURCES: Literature was sought using PubMed (1966-February 2022) and EMBASE (1973-February 2022), and clinicaltrials.gov. Search terms included ibrexafungerp, SCY-078, and VVC. STUDY SELECTION AND DATA EXTRACTION: All studies including humans and published in English with data assessing the efficacy and safety of ibrexafungerp for the treatment of VVC were evaluated. DATA SYNTHESIS: A phase 2 dose-finding study found ibrexafungerp had similar efficacy to fluconazole in the clinical cure of VVC (51.9% vs 58.3%, respectively). Two phase 3 clinical trials demonstrated ibrexafungerp had statistical superiority over placebo for clinical cure in moderate to severe VVC (P < 0.001 and P = 0.023, respectively). The most frequently reported adverse reactions in the clinical trials were gastrointestinal-related symptoms. To date, data comparing efficacy of ibrexafungerp and topical imidazoles in the treatment of VVC are nonexistent. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Topical imidazoles and oral fluconazole are effective for the treatment of uncomplicated VVC. Due to increased resistance, limited fluconazole coverage for non-Candida albicans species, and potential for significant drug interactions associated with fluconazole use, alternative treatments for VVC are needed. Ibrexafungerp is a new oral triterpenoid antifungal agent indicated for the treatment of VVC. Additional clinical trials are needed to evaluate long-term safety data as well as efficacy and safety in specialty populations. CONCLUSION: Ibrexafungerp, a recently approved triterpenoid antifungal agent, is an effective and well-tolerated option for the treatment of VVC.

Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306.

Background: Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Materials and Methods: Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and Candida species. Results: At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all p < 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; p < 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and Candida species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Conclusions: Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in >20 years. Clinical Trial Registration Number: NCT03734991.

Cryptococcal meningitis with atypical paradoxical inflammatory reactions after antifungal treatment in acquired immune deficiency syndrome: A case report.

Cryptococcal meningitis (CM) is a life-threatening disease that primarily affects patients with human immunodeficiency virus (HIV). Antifungal therapy with antiretroviral treatment (ART) usually leads to the clinical remission of CM; however, in some cases, these treatments exacerbate intracranial inflammation because of paradoxical inflammatory reaction or immune reconstitution inflammatory syndrome (IRIS). Here we report two CM cases that presented atypical clinical courses attributed to paradoxical inflammatory reactions. The first case was a 43-year-old man with headache and vertigo diagnosed with CM and HIV. The patient's CM not only was refractory to the antifungal combination therapy of liposomal amphotericin B (L-AMB) and fluconazole (FLCZ) but suddenly worsened because of a paradoxical inflammatory reaction after 18 days of treatment. He passed away from brain herniation on day 23. The second case was a 43-year-old man diagnosed with CM and HIV. After receiving antifungal therapy and ART, the patient's status was stable for more than 3 years with undetectable HIV-RNA. He suddenly presented with brain inflammation and was diagnosed with IRIS due to CM (CM-IRIS). His brain lesions were migratory and refractory to various antifungal therapies such as L-AMB, FLCZ, flucytosine, and intrathecal amphotericin B. Although the cryptococcal antigen in the patient's cerebrospinal fluid gradually diminished after continuous antifungal therapies, his cognitive function declined, and right hemiparesis persisted. These two cases of CM presented atypical clinical courses, presumably because of paradoxical inflammatory reactions. It should be noted that the onset of CM-IRIS may not necessarily depend on the timing of ART initiation.

Impact of concomitant fluconazole on direct oral anticoagulant bleeding risk.

STUDY OBJECTIVE: The aim of this study was to evaluate the effect on bleeding risk when fluconazole is administered concomitantly with direct oral anticoagulants (DOACs). DESIGN: This was a retrospective cohort study including hospitalized adult patients prescribed a DOAC with or without fluconazole. SETTING: The Ohio State University Wexner Medical Center, a tertiary care academic medical center with more than 1800 beds. PATIENTS: Hospitalized patients ages 18-89 years who received apixaban or rivaroxaban with or without fluconazole from October 1, 2016, to September 30, 2021, were included. The minimum duration of DOAC or DOAC with fluconazole therapy was 48 h. Patients were excluded if they received fluconazole <400 mg daily or a DOAC at doses outside those recommended for atrial fibrillation or venous thromboembolism treatment or prophylaxis. Patients were matched based on DOAC received. INTERVENTION: Patients who received a DOAC with fluconazole were compared with those receiving a DOAC alone. The primary outcome was a composite of major, clinically relevant nonmajor, and minor bleeding events at 30 days. MEASUREMENTS AND MAIN RESULTS: There were 216 patients included, 108 in the DOAC with fluconazole group and 108 in the DOAC alone group. More patients in the DOAC with fluconazole group experienced bleeding at 30 days compared with the DOAC alone group [35/108 (32%) vs. 21/108 (19%), respectively; p = 0.03]; however, after adjusting for proven confounding variables (hemoglobin and concomitant carvedilol) this was found not to be statistically significant [adjusted odds ratio 1.71, 95% confidence interval 0.85-3.40]. CONCLUSIONS: Patients receiving a DOAC with fluconazole were not at significantly increased risk for bleeding at 30 days compared with those receiving a DOAC alone after controlling for confounding variables. As an increasing number of patients are prescribed DOACs, the results of this study may inform clinical decision-making on the safety of concomitant DOAC and fluconazole use.

Treatment of Cryptococcal Meningitis: How Have We Got Here and Where are We Going?

Cryptococcal meningitis is a devastating brain infection cause by encapsulated yeasts of the Cryptococcus genus. Exposure, through inhalation, is likely universal by adulthood, but symptomatic infection only occurs in a minority, in most cases, months or years after exposure. Disease has been described in almost all tissues, but it is the organism's tropism for the central nervous system that results in the most devastating illness. While invasive disease can occur in the immunocompetent, the greatest burden by far is in immunocompromised individuals, particularly people living with human immunodeficiency virus (HIV), organ transplant recipients and those on glucocorticoid therapy or other immunosuppressive drugs. Clinical presentation is variable, but diagnosis is usually straightforward, with cerebrospinal fluid microscopy, culture, and antigen testing proving significantly more sensitive than diagnostic tests for other brain infections. Although disease incidence has reduced since the advent of effective HIV therapy, mortality when disease occurs remains extremely high, and has changed little in recent decades. This Therapy in Practice review is an update of a talk first given by JND at the European Congress on Clinical Microbiology and Infectious Diseases in 2019 in the Netherlands. The review contextualizes the most recently published World Health Organization (WHO) guidelines for the treatment of HIV-associated cryptococcal meningitis in terms of the data from large, randomized, controlled trials published between 1997 and 2022. We discuss the rationale for induction and maintenance therapy and the efficacy and undesirable effects of the current therapeutic armamentarium of amphotericin, flucytosine and fluconazole. We address recent research into repurposed drugs such as sertraline and tamoxifen, and potential future treatment options, including the novel antifungals fosmanogepix, efungumab and oteseconazole, and non-pharmaceutical solutions such as neurapheresis cerebrospinal fluid filtration.

Ibrexafungerp: A new triterpenoid antifungal.

PURPOSE: The pharmacology, microbiology, pharmacokinetics, pharmacodynamics, efficacy, safety, and role of ibrexafungerp in the treatment of fungal infections are reviewed. SUMMARY: Ibrexafungerp is the first triterpenoid antifungal. Similarly to echinocandins, it inhibits the synthesis of 1,3-ß-d-glucan. However, it binds to a different site on the enzyme than echinocandins, resulting in limited cross-resistance. Ibrexafungerp exerts concentration-dependent fungicidal activity against Candida species and retains in vitro activity against most fluconazole-resistant strains. It is also active against Aspergillus species. Ibrexafungerp has been shown to be safe and effective in the treatment of vulvovaginal candidiasis caused by Candida albicans in phase 2 and phase 3 clinical trials. It is approved for vulvovaginal candidiasis in adult and postmenarchal pediatric females and is given as two 150-mg tablets orally, administered 12 hours apart. Ibrexafungerp is contraindicated in pregnancy. The most commonly reported adverse reactions were diarrhea, nausea, abdominal pain, dizziness, and vomiting. Ibrexafungerp should be avoided with strong or moderate CYP3A inducers, and the dose should be reduced with strong CYP3A inhibitors. Ibrexafungerp may be useful for patients who are not able to receive fluconazole or prefer oral therapy for the treatment of vulvovaginal candidiasis. However, it is more expensive than the 150-mg tablet of generic fluconazole, which is the current standard of care for vulvovaginal candidiasis. Clinical trials are ongoing for recurrent and complicated vulvovaginal candidiasis as well as invasive candidiasis and pulmonary aspergillosis. CONCLUSION: Ibrexafungerp is an alternative to fluconazole for the treatment of vulvovaginal candidiasis in nonpregnant females. It has the potential to be useful for recurrent and complicated vulvovaginal candidiasis as well as certain invasive fungal infections.