Search

BACKGROUND: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection. METHODS: We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants. RESULTS: Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects. CONCLUSION: Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.

The sudden emergence of multidrug- and pan-resistant Candida auris isolates, combined with limited treatment options, poses significant global challenges in healthcare settings. Combination based therapies are promising alternative options to overcome C. auris related infections, where echinocandin and isavuconazole (ISA) combinations may be an interesting and promising approach. Understanding the molecular mechanisms underlying ISA treatment is crucial for developing novel therapeutic recommendations. Therefore, we investigated the gene transcription profiles of non-wild type (non-WT) and wild type (WT) C. auris isolates from the South Asian clade following ISA exposure using total RNA sequencing. The non-WT isolate was classified according to the previously reported tentative epidemiological cut-off value of ≤ 1 mg/L. ISA treatment resulted in the upregulation of 158 and 134 genes and the downregulation of 119 and 96 genes in the non-WT and WT isolates, respectively, compared with untreated samples. In general, ISA-treated isolates exhibited increased transcription of the transcriptional factor UPC2, the drug transporter MDR1, vacuolar calcium-ATPase PMC1, and several ergosterol biosynthesis genes. The WT isolate showed pronounced enrichment of genes involved in sphingolipid biosynthesis, adhesion, and drug transport. These findings suggest that alterations in membrane lipid composition and modulation of drug efflux transporters are critical processes contributing to ISA susceptibility in case of WT isolates. [ABSTRACT FROM AUTHOR]

Objective: Several antifungals are available for the treatment of patients with invasive aspergillosis (IA). This study aims to evaluate the relative efficacy and safety of the first-line monotherapies in primary therapy of IA through network meta-analysis (NMA). Methods: We systematically searched PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, VIP database, Wanfang database, and China Biology Medicine for randomized controlled trials (RCTs) up to July 2023 that evaluated the efficacy and safety of monotherapies. We performed NMA with a frequentist random effects model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Primary outcomes were the all-cause mortality at week 12, and secondary outcomes included overall response rate, and incidence of adverse events (AEs) and severe adverse events (SAEs). Results: A total of three RCTs involving 1,368 participants (four antifungals) were included. The NMA showed that compared to amphotericin B deoxycholate (D-AmB), the triazoles (posaconazole (POS), isavuconazole (ISA) and voriconazole (VCZ)) can improve the overall response rate in primary therapy of IA, but only VCZ and ISA can reduce the all-cause mortality at week 12 for patients with proven and probable IA (VCZ vs D-AmB: RR = 0.66, 95%CI = 0.47–0.93, moderate certainty; ISA vs D-AmB: RR = 0.52, 95%CI = 0.31–0.86, low certainty). ISA (SUCRA = 93.50%; mean rank, 1.20) seemed to be the most effective therapy in the above population. As to proven, probable, and possible IA patients, the triazoles were superior to D-AmB in terms of reducing all-cause mortality. Furthermore, the risk of AEs and SAEs was comparable for the three triazoles, but the risk of SAEs was significantly higher for D-AmB than others. Conclusion: The efficacy and safety of triazoles are more favorable than D-AmB in the primary therapy of IA, with ISA being the optimal choice. Systematic Review Registration: PROSPERO CRD42023407632. [ABSTRACT FROM AUTHOR]

AbstractWe review the case of a 58-year-old female on extracorporeal membrane oxygenation (ECMO) support diagnosed with invasive pulmonary aspergillosis (IPA). Intravenous isavuconazole was started, requiring dose escalation to achieve isavuconazole trough concentration (ISA-Cmin) within the therapeutic range (2.5–5.0 μg/mL). For more than 4 months, she maintained a dose of 200 mg q12h, with a median ISA-Cmin of 3.4 (interquartile range [IQR]: 3.1–4.9) µg/mL. Throughout this interval, 17 assessments of ISA-Cmin were performed (weekly). Of these, 82% (14/17) were within the therapeutic range, with an intra-individual variability of 36.8%. Although no signs of hepatotoxicity were observed, she experienced short-term gastrointestinal adverse events related to potential isavuconazole over-exposure (ISA-Cmin > 5.0 μg/mL). ECMO circuit changes did not appear to affect ISA-Cmin. She was not obese (IMC ≈ 25 kg/m2) and did not require other extracorporeal therapy, but hypoalbuminemia may have contributed to an increase in unbound isavuconazole fraction and consequently its clearance. [ABSTRACT FROM AUTHOR]

Background: Invasive mucormycosis (IM) poses a substantial morbidity and mortality burden among immunocompromised patients. Objectives: We aim to compare the real-world effectiveness and safety of isavuconazole with those of amphotericin B in patients with IM. Patients and methods: In this observational cohort study, we enrolled patients who were diagnosed with IM and treated with either isavuconazole or amphotericin B. Results: A total of 106 patients met the study criteria. Of these, 47 received isavuconazole, and 59 received amphotericin B as the primary treatment. The two cohorts had similar baseline characteristics, including a history of malignancy, use of immunosuppressants, infection sites, and pathogens. The amphotericin B group demonstrated a significantly greater incidence of renal disorders (p < 0.001) and hypokalemia (p < 0.001) than the isavuconazole group. The proportion of patients who received salvage therapy was greater in the amphotericin B group than in the isavuconazole group (42% vs. 6%, p < 0.001). Eighteen patients in the amphotericin B group discontinued treatment because of adverse events, whereas no patients in the isavuconazole group discontinued treatment because of adverse events. A significant difference in the primary therapeutic response between the isavuconazole and amphotericin B groups was noted (p = 0.013), with a higher treatment failure rate in the amphotericin B group (68% vs. 36%, p = 0.001). However, there were no significant differences in all-cause mortality or mucormycosis-attributable mortality rates between the two groups. Conclusions: Isavuconazole outperformed amphotericin B as a first-line treatment option for IM in terms of its clinical effectiveness and safety. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) aspergillosis is a rare and fatal complication in immunocompromised patients. We present the case of a 72-year-old patient with unexplained recurrent pancytopenia who presented with fever, constipation, abdominal distention, and jaundice. Imaging revealed a mass in the ileocecal junction, and biopsy revealed Aspergillus hyphae infiltrating the bowel wall. He had no evidence of pulmonary, sinus, or central nervous system Aspergillus infection. After 1 month of antifungal treatment with oral isavuconazole, he recovered well and was discharged. The clinical manifestations of GI aspergillosis are non-specific. This case highlights the importance of increasing the awareness regarding GI aspergillosis in high-risk patients without pulmonary involvement. [ABSTRACT FROM AUTHOR]

Background: Voriconazole, isavuconazole, and amphotericin (AmB) formulations are currently recommended to treat invasive pulmonary aspergillosis (IPA). We aimed to estimate the efficacy of different antifungal drugs in the initial treatment of IPA. Methods: We included all available randomized controlled trials (RCTs) evaluating first-line treatments for IPA by searching PubMed, Medline, EMBASE, the Cochrane Library, and the ClinicalTrials.gov database. We performed a network meta-analysis to compare the relative efficacy of different drugs in treating IPA. The primary outcomes were the overall response and all-cause mortality (ACM). Results: Eight studies were identified that compared different drugs including voriconazole, isavuconazole, posaconazole, anidulafungin, liposomal AmB (L-AmB) at standard, high and low doses (3-5 mg/kg/d; 10 mg/kg/d; 1 mg/kg/d), AmB deoxycholate (dAmB) and amphotericin B colloidal dispersion (ABCD). We found that second-generation triazole antifungal drugs containing voriconazole, isavuconazole, and posaconazole exhibited significantly superior overall response to dAmB and ABCD. Voriconazole was ranked as the best drug on network rank analysis. We found no difference in efficacy between triazole antifungals and L-AmB. A combination of voriconazole with anidulafungin, isavuconazole and voriconazole showed significantly better safety than dAmB. Conclusion: The efficacy of second-generation triazole antifungal drugs for the first-line treatment of IPA is comparable with L-AmB and is better than both dAmB and ABCD. Isavuconazole may show better safety than voriconazole and posaconazole. Combination therapy with voriconazole and anidulafungin may serve as an alternative option for IPA patients with limited drug tolerance. Systematic review registration: https://inplasy.com/. [ABSTRACT FROM AUTHOR]

Background: Tracheobronchial mucormycosis is a fatal opportunistic infection that mainly causes airway stenosis and is difficult to manage clinically. Case presentation: We report a case of severe tracheal stenosis caused by tracheobronchial mucormycosis in a 37-year-old female with a history of hyperthyroidism. She developed agranulopenia after oral methimazole administration and subsequently experienced asthma with dyspnea. Bronchoscopy, sputum culture, colony mass spectrometry, and microscopic cotton orchid staining confirmed tracheobronchial mucormycosis. The patient received venous-venous extracorporeal membrane oxygenation (VV-ECMO) and prolonged intratracheal instillation of amphotericin B (AmBD), combined with amphotericin B liposome (L-AmB) and isavuconazole intravenous infusion, ultimately resulting in successful treatment. Conclusion: VV-ECMO combined with prolonged intratracheal instillation of AmBD is an effective method for the treatment of tracheobronchial mucormycosis. [ABSTRACT FROM AUTHOR]

Background: Invasive aspergillosis (IA) is an opportunistic infection that affects immunocompromised patients. While voriconazole is commonly used for IA treatment, it presents the risk of drug interactions, particularly in patients on polytherapy. Isavuconazole may serve as a safer alternative with fewer interactions. However, the use of isavuconazole is typically limited to the parenteral route for patients without access to the enteral route, due to recommendations against tablet handling for enteral administration. The objective of this study was to evaluate the suitability of isavuconazole administration via an enteral tube, by therapeutic drug monitoring of isavuconazole plasma concentrations. Methods: This case study examines a patient with diffuse large B-cell lymphoma who was diagnosed with IA and treated with isavuconazole via an enteral tube. Therapeutic pharmacokinetic monitoring of isavuconazole plasma concentrations was performed to assess the feasibility and safety of enteral administration. Results: The results show that isavuconazole concentrations were maintained within the therapeutic range when administered via an enteral tube. No significant deviations in plasma concentration were noted during the monitoring period. Conclusions: Administering isavuconazole through an enteral tube is a safe and viable alternative for patients that are unable to receive the drug via the oral route. Therapeutic monitoring of plasma concentrations is recommended to ensure proper dosing and efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Real-world data from multinational observational studies are required to better understand the role and performance of isavuconazole in real-world practice in Europe. Methods: A retrospective medical record review was conducted at 16 sites in Europe (France, Germany, Italy, Spain, and the United Kingdom). Eligible records were from patients aged ≥ 18 years at the time of isavuconazole initiation and received at least one dose of isavuconazole for suspected or confirmed invasive aspergillosis (IA) or invasive mucormycosis (IM) during the eligibility period (October 15, 2015 to June 30, 2019). Data were descriptively analysed. Success rates, overall survival, and times to these events were descriptively analysed. Results: Data were abstracted from 218 patients (201, IA; 17, IM) who received isavuconazole as monotherapy (initiated as infusion, 52%; oral, 46%). Isavuconazole was initiated as primary therapy in 92 patients (42.2%) and salvage therapy in 121 patients (55.5%) (unknown for five patients). Mean (standard deviation) age was 56.8 (15.6) years, 66% were men and 62% had at least three comorbidities, most frequently haematologic malignancy (62%). Estimated clinical response rate at week 24 was 54.5% (95% confidence interval [CI], 38.2–66.5%) for primary treatment and 73.5% (95% CI, 62.7–81.1%) for salvage therapy. Overall, 45 patients (21%) experienced at least one adverse event (AE). Serious AEs were experienced by 37 patients (17%), with seven related to isavuconazole; five patients (2.3%) discontinued isavuconazole monotherapy due to the serious AE. A total of 137 patients (63%) died, with 17 deaths (12.4%) related to their invasive fungal infection, 11 of whom initiated isavuconazole as salvage therapy. Conclusions: This study adds to the growing body of evidence that whether used as first-line therapy or after the failure of other antifungal therapies, isavuconazole appears to have a promising clinical response and a good safety profile as an antifungal agent in patients with varied underlying conditions. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Isavuconazole is a broad-spectrum antifungal drug used for the treatment of serious infections caused by invasive aspergillosis and mucormycosis in adults. With the continuous use of this drug, its safety and environmental impact have received increasing attention. However, information on the adverse effects of the drug is very limited. Fish is a particularly important model for assessing environmental risks. In this study, the aquatic vertebrate zebrafish was used as a model to study the toxic effects and mechanisms of isavuconazole. We exposed zebrafish embryos to 0.25, 0.5, and 1 mg/L of isavuconazole 6 h after fertilization. The results showed that at 72 hpf, isavuconazole exposure reduced heart rate, body length, and survival of zebrafish embryos compared to controls. Secondly, when isavuconazole reached a certain dose level (0.25 mg/L), it caused morphological changes in the Tg(elavl3:eGFP) transgenic fish line, with the head shrunk, the body bent, the fluorescence intensity becoming weaker, the abnormal motor behaviour, etc. At the same time, exposure of zebrafish embryos to isavuconazole downregulated acetylcholinesterase (AchE) and adenosine triphosphate (ATPase) activities but upregulated oxidative stress, thereby disrupting neural development and gene expression of neurotransmitter pathways. In addition, astaxanthin partially rescued the neurodevelopmental defects of zebrafish embryos by downregulating oxidative stress. Thus, our study suggests that isavuconazole exposure may induce neurodevelopment defects and behavioural disturbances in larval zebrafish. [ABSTRACT FROM AUTHOR]

Abstract Background Mucormycosis is an opportunistic fungal infection which is associated with poor prognosis. Only a few antifungals are available in the arsenal against mucormycosis. The global guidelines for diagnosing and managing mucormycosis recommend high doses of liposomal amphotericin B (LAmB) as the first-line treatment. Isavuconazole is another potential treatment option for mucormycosis. Main body This systematic review aims to consolidate and analyse existing evidence concerning the efficacy and safety of isavuconazole in treating mucormycosis alone or in combination with LAmB. For data aggregation, comprehensive searches were conducted across various electronic databases, such as PubMed, Science Direct, Trip, Google Scholar, the Cochrane Library, and Open-Gray. Furthermore, we explored the gray literature, employing tailored keywords. The reference lists of the selected articles were scrutinized to identify additional pertinent publications. Articles reporting any studies, case series, or case reports on any form of mucormycosis exclusively involving human subjects published in English were included. There were no time restrictions involved. We extracted crucial data, such as publication year, country, disease form, isavuconazole dosage, frequency, duration, overall outcomes, and reported adverse effects. A total of 31 articles, which included four case series, 24 case reports, one open-label trial, one randomized controlled trial, and one non-interventional registry study, were included in the final analysis. 135 adult patients and 14 children were treated with isavuconazole as primary monotherapy, primary combination therapy, nonprimary monotherapy, or nonprimary combination therapy. The mortality rate following LAmB monotherapy, amphotericin B plus azole, amphotericin B followed with azole, posaconazole only and isavuconazole only was 32%, 6.6%, 13.7%, 17.2% and 24.6%, respectively. The heterogeneity of the studies did not allow for a comparison of the different treatment strategies (primary mono- vs. primary combination, etc.). Short conclusion The use of isavuconazole in combination therapies during the acute phase via intravenous administration alongside LAmB or other triazoles, followed by long-term monotherapy via the oral route, has yielded promising recovery rates. Adverse events associated with the use of isavuconazole are infrequently reported.

Mucormycosis is a severe mycotic infection with high mortality among immunocompromised patients. Its in- cidence in solid organ transplant recipients is 2–8% of all invasive fungal infections. In most cases, it occurs in the late posttransplant period. Risk factors in this patient cohort are graft-versus-host disease (GvHD) and use of immunosuppressive drugs. The article describes clinical cases of mucormycosis and analysis of literature data on the problem of invasive mucormycosis in solid organ transplant recipients. It also reviews the main methods of diagnosis and treatment of the disease according to international guidelines.

Abstract Background Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort. Methods The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro. Results Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0→t), AUC(0→∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib. Conclusions Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.

Background & objectives The emergence of drug resistance in leishmaniasis has remained a concern. Even new drugs have been found to be less effective within a few years of their use. Coupled with their related side effects and cost-effectiveness, this has prompted the search for alternative therapeutic options. In this study, the Computer Aided Drug Design (CADD) approach was used to repurpose already existing drugs against Leishmania major. The enzyme lanosterol 14-alpha demethylase (CYP51), in L. major , was chosen as the drug target since it is a key enzyme involved in synthesizing ergosterol, a crucial component of the cell membrane. Methods A library of 1615 FDA-approved drugs was virtually screened and docked with modeled CYP51 at its predicted binding site. The drugs with high scores and high affinity were subjected to Molecular Dynamics (MD) simulations for 100 ns. Finally, the compounds were tested in vitro using an MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] assay against the promastigotes of L. major. Results Computational screening of FDA-approved drugs identified posaconazole and isavuconazole as promising candidates, as both drugs target the CYP51 enzyme in fungi. Molecular dynamics (MD) simulations demonstrated that both drugs form stable complexes with the target enzyme. In vitro studies of posaconazole and isavuconazole against promastigotes of L. major demonstrated significant efficacy, with IC50 values of 2.062±0.89 µg/ml and 1.202±0.47 µg/ml, respectively. Interpretation & conclusions The study showed that the existing FDA-approved drugs posaconazole and isavuconazole can successfully be repurposed for treating L. major by targeting the CYP51 enzyme, demonstrating significant efficacy against promastigotes. [ABSTRACT FROM AUTHOR]

Background/Objectives. Pulmonary aspergillosis is a severe respiratory infection caused by Aspergillus spp., whose resistance profiles and invasive attitude complicate therapeutical strategies. Several aspergillosis cases emerged as superinfections during the SARS-CoV-2 pandemic when isavuconazole and amphotericin B became essential antifungal alternatives. The main purpose of the present study was to investigate a possible synergic activity between these molecules against Aspergillus spp. isolated from respiratory samples. Methods. The gradient test method detected isavuconazole and amphotericin B MIC values, prompting an arrangement of their combination into an R.P.M.I. agar medium. According to Liofilchem s.r.l. instructions, the FIC index was used to establish synergy, additivity, indifference, or antagonism. Results. Among 36 Aspergillus spp. isolates, only A. fumigatus strains showed both synergy and additivity episodes. A. niger reported the highest antagonism percentage, while A. terreus revealed several indifference episodes. Conclusions. Isavuconazole and amphotericin B remain fundamental therapeutical alternatives, including a possible synergic effect against A. fumigatus. On the basis of this species-related difference, further studies will be essential to investigate different antifungal drug combinations against filamentous fungi isolates. [ABSTRACT FROM AUTHOR]

Background Cerebral aspergillosis (CA) is associated with high mortality. According to the European Conference on Infections in Leukemia and the European Society of Clinical Microbiology and Infectious Diseases guidelines, the recommended first-line treatment for all forms of aspergillosis is voriconazole or isavuconazole. However, little is known about the efficacy and safety of isavuconazole in CA. Methods We conducted a European multicenter retrospective study of patients treated with isavuconazole for proven or probable CA between 2014 and 2022 and compared the outcomes with those of weighted control groups from the previously published French national cohort of CA, the Cerebral Aspergillosis Lesional Study (CEREALS). Results Forty patients from 10 countries were included. The main underlying conditions were hematological malignancies (53%) and solid-organ transplantation (20%). Isavuconazole was administered as a first-line treatment to 10 patients, primarily in combination therapy, resulting in control of CA in 70% of these cases. Thirty patients received isavuconazole after a median of 65 days on another therapy, mostly because of side effects (50%) or therapeutic failure (23%) of the previous treatment. Predominantly given as monotherapy, it achieved control of CA in 73% of the patients. Seventeen patients (43%) underwent neurosurgery. When measured, isavuconazole levels were low in cerebrospinal fluid but adequate in serum and brain tissue. Isavuconazole toxicity led to treatment interruption in 7.5% of the patients. Twelve-week mortality was 18%. Comparison with the CEREALS cohort showed comparable survival in patients receiving isavuconazole or voriconazole as a first-line treatment. Conclusions Isavuconazole appears to be a well-tolerated treatment. Mortality of CA treated with isavuconazole is similar to that reported with voriconazole. [ABSTRACT FROM AUTHOR]

Background New antifungal agents are required to mitigate against azole-resistant Aspergillus and drug-resistant non- Aspergillus moulds. The novel orotomide, olorofim (F2G, Manchester, UK), has potent fungicidal activity against Aspergillus including azole-resistant Aspergillus fumigatus, Lomentospora prolificans and Scedosporium spp. Development of olorofim-specific clinical breakpoints/epidemiological cut-off values requires reliable MIC data. Objectives Determine the in vitro activity of olorofim compared with standard antifungals against mould pathogens at an Australian hospital. Materials and methods Olorofim MICs were determined for 507 clinical mould isolates using the CLSI M38-A3 standard. MICs of amphotericin B, anidulafungin, posaconazole, voriconazole and isavuconazole were obtained using Sensititre™ YeastOne YO10 and AUSNMRCI panels (Thermo-Fisher Scientific). Results A. fumigatus sensu stricto was the commonest species (33.3%) followed by L. prolificans (18.3%), Scedosporium (11.4%) and Fusarium (6%) species. Olorofim modal MICs were ≤0.25 mg/L (MIC90 0.25 mg/L) for all Aspergillus except Aspergillus Section Usti (1 mg/L); MICs for nine azole-resistant/non-wild-type A. fumigatus ranged from 0.008 to 0.125 mg/L. The MIC90 of olorofim for L. prolificans was 0.5 mg/L, 0.25–0.5 mg/L for Scedosporium spp. and 8 mg/L for the F. solani complex but with modal MICs of 0.25 and 0.008 mg/L for F. oxysporum and F. proliferatum complexes, respectively. For Verruconis gallopava (n  = 10), the olorofim MIC90 was 0.06 mg/L (voriconazole MIC90 2 mg/L, isavuconazole MICs of 4–>8 mg/L). Olorofim had little activity against other dematiaceous moulds including Exophiala species. Conclusions Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus , L. prolificans , Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava. [ABSTRACT FROM AUTHOR]

Introduction: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear. Case Presentation: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy. Conclusion: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment. [ABSTRACT FROM AUTHOR]

Background: Isavuconazole (ISA) has a favorable side effect profile that makes it attractive for treatment of invasive fungal infections (IFI). It carries FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data for other organisms and non-pulmonary infections. We conducted this review to investigate how ISA performed at treating IFI, with an especial interest in these non-approved indications. Methods: We retrospectively identified and reviewed 131 patients who received ISA as treatment for IFI at our institution, some of whom received ISA as their first anti-fungal therapy and others who received ISA as either step-down therapy or salvage therapy. We identified the microbiologic cause of infection as well as the anatomic site involved for each patient. We then classified patients according to their response to ISA: namely cured, partially responded, or stabilized. Results: The majority of patients were immunocompromised (n = 76, 58%). ISA was used primarily as a secondary therapy (n = 116, 89%); either as a step-down/switching from other agents, or as salvage therapy. The most common reasons for switching to ISA were toxicities with prior agents followed by QT prolongation. Although pulmonary aspergillosis and mucormycosis were represented in more than half of the cohort, ISA was also used off-label for treatment of other organisms such as endemic fungi (n = 19, 15%) as well as central nervous system (CNS) infections (n = 15, 11%). We have described the detailed clinical characteristics of these CNS infections cases. The overall clinical response rate varied by type of infection and site involved (57–73% response rate). Conclusions: We demonstrated encouraging clinical responses, particularly outside the FDA-approved indications, as well as good tolerability. This report highlights the critical need for expanded scope of prospective studies to delineate the efficacy of this better-tolerated agent, especially in central nervous system infections. [ABSTRACT FROM AUTHOR]

Invasive fungal infections (IFIs) present significant challenges in managing hospitalized and immunocompromised pediatric patients, contributing to high morbidity and mortality. Despite advancements in diagnostics and treatment, outcomes remain suboptimal due to unique clinical epidemiology, lack of pediatric-specific trials, and varied pharmacokinetics. The emergence of new antifungal classes and agents has expanded our options for preventing and treating IFIs in children, enhancing the safety and effectiveness of antifungal therapy. The oral formulations of ibrexafungerp, fosmanogepix and olorofim along with the extended dosing intervals of rezafungin show promising features for effective antifungal treatment in pediatrics. Despite the promising potential of novel antifungal drugs, their performance in heavily immunosuppressed patients remains unstudied. Until then, dedicated antifungal stewardship programs for high-risk patients are essential to optimize therapeutic outcomes, improve patient care, and limit the emergence of resistance. [ABSTRACT FROM AUTHOR]

Background: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort. Methods: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro. Results: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0→t), AUC(0→∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib. Conclusions: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib. [ABSTRACT FROM AUTHOR]

Objective To recommend precision dosing and improve therapeutic efficacy against invasive fungal disease, a physiologically based pharmacokinetic model (PBPK) of oral isavuconazole (ISA) was established and used to explore its disposition across populations in different physiological and pathological states. Methods Twenty-five pharmacokinetic (PK) studies of oral ISA were identified through a systematic search of PubMed. Concentration–time data were extracted using WebPlotDigitizer. Physiochemical parameters were obtained from published literature and DrugBank. Model development and simulation used the Simcyp population-based simulator, and visual predictive check and predictive error were used for the model evaluation. Probability of target attainment and the cumulative fraction of response analyses were performed for dose optimization. Results The developed PBPK model was successfully validated in different populations. Most predicted concentration–time points aligned with the observed data, with acceptable predictive errors for the critical parameters. We predicted the PK profiles and parameters of ISA in a population with severe hepatic impairment (HI), a population with obesity and paediatric patients aged 1 to less than 6 years old. The probability of target attainment and cumulative fraction of response analyses indicated that the population with severe HI should have half the maintenance dose. The population with obesity and population with severe HI should have a loading dose of 300 mg every 8 h for 2 days. For paediatric patients aged 1 to less than 6 years old, a weight-based dosing regimen (5.38 mg/kg) of ISA was suggested. Conclusion The predicted value aligns with observations, suggesting ISA's potential predictability in PK profiles for other populations. The recommended dosing regimens increase our understanding of the use of ISA in special populations. [ABSTRACT FROM AUTHOR]

BackgroundTo explore and analyze post-marketing adverse drug event (ADE) signals for voriconazole, posaconazole, and isavuconazole, and to compare the safety differences among the three drugs, aiming to provide insights for rational clinical use.MethodsUsing the Open Vigil 2.1 online tool, extract adverse drug event (ADE) report data for voriconazole, posaconazole, and isavuconazole from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) database from the time the drugs were marketed up to the third quarter of 2023. Employ the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods for data mining. Filter out ADE signals detected by both the ROR and PRR methods, and categorize these ADE signals by System Organ Class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA 26.0).ResultsA total of 8,898 ADE reports with voriconazole as the primary suspect drug were retrieved, 1,948 for posaconazole, and 944 for isavuconazole. From the basic analysis of the adverse event reports, male patients (50.31%) outnumber female patients (32.11%). In terms of age, the majority of patients are over 45 years old (52.72%). The reports primarily come from the United States, Japan, France, China, and other countries. A total of 607 ADE signals were identified, with 402 for voriconazole, 159 for posaconazole, and 46 for isavuconazole. Voriconazole ADEs primarily involved the following SOCs: Investigations (9.45%), Eye Disorders (8.46%), and Nervous System Disorders (7.21%); Posaconazole ADEs primarily involved the following SOCs: Investigations (13.84%), General Disorders and Administration Site Conditions (11.95%), and Nervous System Disorders (6.29%); Isavuconazole ADEs primarily involved the following SOCs: General Disorders and Administration Site Conditions (15.22%), Hepatobiliary Disorders (10.87%), and Blood and Lymphatic System Disorders (10.87%).ConclusionVoriconazole, posaconazole, and isavuconazole all potentially pose safety risks related to hepatobiliary disorders and cardiac disorders. Additionally, voriconazole carries a higher safety risk for eye disorders and nervous system disorders. Newly discovered ADE signals not mentioned in the drug package inserts include voriconazole-induced rhabdomyolysis, posaconazole-induced peripheral neuropathy, and isavuconazole-induced visual impairment and mental confusion. These findings are significant for guiding rational clinical use of these medications.

BackgroundVoriconazole, isavuconazole, and amphotericin (AmB) formulations are currently recommended to treat invasive pulmonary aspergillosis (IPA). We aimed to estimate the efficacy of different antifungal drugs in the initial treatment of IPA.MethodsWe included all available randomized controlled trials (RCTs) evaluating first-line treatments for IPA by searching PubMed, Medline, EMBASE, the Cochrane Library, and the ClinicalTrials.gov database. We performed a network meta-analysis to compare the relative efficacy of different drugs in treating IPA. The primary outcomes were the overall response and all-cause mortality (ACM).ResultsEight studies were identified that compared different drugs including voriconazole, isavuconazole, posaconazole, anidulafungin, liposomal AmB (L-AmB) at standard, high and low doses (3-5 mg/kg/d; 10 mg/kg/d; 1 mg/kg/d), AmB deoxycholate (dAmB) and amphotericin B colloidal dispersion (ABCD). We found that second-generation triazole antifungal drugs containing voriconazole, isavuconazole, and posaconazole exhibited significantly superior overall response to dAmB and ABCD. Voriconazole was ranked as the best drug on network rank analysis. We found no difference in efficacy between triazole antifungals and L-AmB. A combination of voriconazole with anidulafungin, isavuconazole and voriconazole showed significantly better safety than dAmB.ConclusionThe efficacy of second-generation triazole antifungal drugs for the first-line treatment of IPA is comparable with L-AmB and is better than both dAmB and ABCD. Isavuconazole may show better safety than voriconazole and posaconazole. Combination therapy with voriconazole and anidulafungin may serve as an alternative option for IPA patients with limited drug tolerance.Systematic review registrationhttps://inplasy.com/.

Isavuconazole is used to treat fungal infections. This study aims to describe isavuconazole pharmacokinetics in critically ill patients and evaluate their relationship with clinical efficacy and patient safety. We conducted a prospective, observational study in patients treated with intravenous isavuconazole. Samples were collected at predose (Cmin), 1 h (Cmax) and 12 h (C50) after the last dose. The plasma concentration was determined by high-performance liquid chromatography. The relationship between plasma concentration and clinical and microbiological outcomes and safety was evaluated. The influence of covariates (age, sex, weight, SAPS3, creatinine, liver enzymes and extracorporeal devices: continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO)) was analysed. Population pharmacokinetic modelling was performed using NONMEN®. A total of 71 isavuconazole samples from 24 patients were analysed. The mean Cmin was 1.76 (1.02) mg/L; 87.5% reached the optimal therapeutic target and 12.5% were below 1 mg/L. Population pharmacokinetics were best described by a one-compartment model with first-order elimination. No factor had a significant impact on the plasma concentration or pharmacokinetic parameters. Thus, isavuconazole could be safely used in a critically ill population, even in those treated with CRRT and ECMO, from a pharmacokinetic standpoint. Therefore, routine therapeutic drug monitoring may not be strictly necessary in daily clinical practice. [ABSTRACT FROM AUTHOR]

Patients with burn injury and inhalation injury are highly susceptible to infectious complications, including opportunistic pathogens, due to the loss of skin cover and mucosal damage of respiratory tract as well as the disruption of homeostasis. This case report, a 34-year-old man suffered critical burns, provides the first literature description of triple-impact immunoparalysis (critical burns, inhalation injury, and SARS-CoV-2 infection), leading to a lethal multifocal infection caused by several fungi including very rare environmental representatives Metschnikowia pulcherrima and Wickerhamomyces anomalus. The co-infection by these common environmental yeasts in a human is unique and has not yet been described in the literature. Importantly, our patient developed refractory septic shock and died despite targeted antifungal therapy including the most potent current antifungal agent—isavuconazole. It can be assumed that besides immunoparalysis, effectiveness of therapy by isavuconazole was impaired by the large distribution volume in this case. As this is a common situation in intensive care patients, routine monitoring of plasmatic concentration of isavuconazole can be helpful in personalization of the treatment and dose optimization. Whatmore, many fungal species often remain underdiagnosed during infectious complications, which could be prevented by implementation of new methods, such as next-generation sequencing, into clinical practice. [ABSTRACT FROM AUTHOR]

Background: Invasive fungal infections (IFI) are associated with significant morbidity and mortality. The objective of this work was to compare the costs per adult patient, associated with intravenous isavuconazole (ISAV) followed by oral ISAV versus the regimen of liposomal amphotericin B followed by posaconazole (L-AMB→POSA) in the treatment of IFI. The comparison was conducted from the perspective of the Spanish National Health System (SNS). Methods: As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration, hospitalization, laboratory tests and adverse events costs were evaluated from SNS perspective. Deterministic and probabilistic sensitivity analyzes were performed. Results: Total costs per-patient were €24,715.54 with ISAV versus €29,753.53 with L-AMB→POSA, resulting in cost-savings per patient treated with ISAV of €5,037.99 (−16.9%). Treatment costs of IFI remained lower for ISAV than for L-AMB→POSA across all sensitivity analyses (−7,968.89€ to −326.59€), being treatment duration the most influential parameter. Conclusion: According to the present model, the treatment of IFIs with ISAV would generate savings for the SNS compared to L-AMB→POSA. These savings are attributed to the shorter duration of IV treatment, reduced use of healthcare resources and lower costs associated with managing adverse effects when ISAV was employed. [ABSTRACT FROM AUTHOR]

The increasing incidence of invasive fungal infections, coupled with the growing population of immunocompromised patients, has led to an increased need for antifungal agents. The newest azole, isavuconazole, plays an important role in the treatment of invasive aspergillosis in adults due to its broad spectrum, tolerability, and no need for therapeutic drug monitoring. This agent, which has not yet been approved for use in children, has significant problems with drug supply in Türkiye. We present the treatment response to isavuconazole combination therapy used in salvage treatment in a patient with breakthrough invasive aspergillosis, who had treatment failure with different antifungal combination treatment options and surgical resection. [ABSTRACT FROM AUTHOR]