Explore the vast range of titles available.

Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice–web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of −1·0% (95% CI −7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. Astellas Pharma Global Development, Basilea Pharmaceutica International.

Voriconazole, an antifungal drug, is metabolized by a cytochrome P450 isozyme. Increased adverse effects are observed in Asians because of the high rate of poor metabolizers. In this therapeutic drug monitoring (TDM) guideline, recommendations were made according to ethnic group. Five clinical questions were used. For the preparation of the guideline, the performance of TDM in multicenter studies was surveyed (study 1). We also conducted a systematic review and meta-analysis (study 2) to establish recommendations for non-Asians and Asians. In study 1, 401 patients were surveyed. A risk of supratherapeutic concentrations was found in Japanese patients who adhered to the recommended dose. Target trough levels were achieved in 87% of patients with dose reductions. Although the trough level measured at the onset of adverse effects (AEs) was significantly associated with hepatotoxicity, no significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by the trough-guided dosing. In study 2, 22 studies (11 Asian locations and 11 non-Asian locations) were included in meta-analysis for the relationship between trough cutoff level (3, 4, 5, 5.5, and 6 µg/mL) and AEs. Significant differences were found for all cutoff levels, with the highest odds ratio for 4.0 µg/mL in Asian locations. In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL, at which level a significant increase in AEs was found. These findings indicate that TDM is strongly recommended to prevent AEs in Asians, and TDM is generally recommended for non-Asians to address subtherapeutic concentrations. TDM on day 3 is recommended to assess pharmacokinetic properties, including loading and maintenance doses. If the patient condition permits, delaying until day 5 is suggested for Asians because of the prolonged t½ in poor metabolizers. A trough level ≥1.0 µg/mL is strongly recommended to improve efficacy. Trough levels ≥2.0 µg/mL are suggested for invasive aspergillosis. To decrease adverse effects, trough levels <4.0 µg/mL are strongly recommended in Asians, whereas trough levels <5.5 µg/mL are generally recommended in non-Asians. Maintenance doses of 4 and 3 mg/kg twice daily are recommended in non-Asians and Asians, respectively. Different indications, timings, and target trough levels for TDM and different regimens are suggested for Asians and non-Asians.

To compare the efficacy of topical caspofungin 0.5% with topical voriconazole 1% in patients with fungal keratitis. In this pilot clinical trial, thirty-four eyes from 34 patients diagnosed with fungal keratitis, confirmed by positive smear or culture results or in vivo confocal microscopy (IVCM), were included in the study. Patients were randomized to receive either topical caspofungin 0.5% or voriconazole 1%. The primary outcome measure was best spectacle-corrected visual acuity (BSCVA) at 3 months of follow-up. Secondary outcomes were the percentage of healed ulcers, time to healing, and scar size. After 3 months of treatment, the mean BSCVA was1.17 ± 0.85 logarithm of minimum angle of resolution (LogMAR) units in the caspofungin group and 0.49 ± 0.56 LogMAR units in the voriconazole group and the difference between two groups was 0.18 LogMAR (95% CI, -0.14 to 0.51 P = 0.276). The final mean scar size was similar between the caspofungin group (2.47 ± 2.1) and the voriconazole group (3.09 ± 1.11) (P = 0.254, 95% CI, -1.88 to 0.50 mm). The percentage of cases healed was 70.6% (12/17) in the caspofungin group and 100% (17/17) in the voriconazole group (P = 0.060, Hazard ratio ,2.06 95% CI,0.97 to 4.37). Fusarium species were the most common species (9/34; 26.5% cases). Complete stromal healing occurred in all 5 patients infected with Fusarium species who were treated with voriconazole 1%. one out of 4 patients in the caspofungin group showed complete healing (P = 0.048). The patients in caspofungin group had large mean infiltration size 4.81± 1.60 mm, (P = 0.255) than 2.90± 1.60 mm in voriconazole group and deeper infiltration depth 25 ±13% than 15± 9%voriconazole group (P = 0.120). This study indicates that topical caspofungin 0.5% may be effective as topical voriconazole 1%, making caspofungin 0.5% a viable primary treatment option for patients with fungal keratitis.

The aim of the present study is to examine the possibility of nephrotoxicity following the intravitreal injection of the antifungal agents voriconazole and micafungin. Μale and female New Zealand white rabbits were divided into the control group C that received no medication and the study groups that underwent either one or two intravitreal injections of voriconazole or micafungin solution, respectively, or one co-administration of the two agents. Euthanasia was performed ten days after the last intravitreal administration, and kidney tissue samples were obtained and prepared for electron microscopy study, as well as immunohistochemical study for EGFR and IL-6 markers. Ultrastructural alterations of the renal tissue were found in places of limited extent, more evident at the level of the proximal tubules. The expression of the two markers was positive, especially in the double and the combined administration of the two drugs, both in the renal corpuscle and the tubules. The finding of the aforementioned histological lesions triggers the need for an additional study of the effect of the specific drugs on the kidney to establish whether these alterations are reversible or not. Redesigning the dosage regimen during intravitreal administration of these agents could be a future therapeutic goal to prevent potential nephrotoxicity. The intravitreal concentrations used in rabbits, particularly for voriconazole, closely approximate those used in humans, supporting the clinical relevance of the findings.

Despite implementation of therapeutic drug monitoring (TDM) for voriconazole, the incidence of hepatotoxicity remains high. The albumin-bilirubin (ALBI) score may be useful for estimating voriconazole-induced hepatotoxicity. This pilot study aimed to investigate whether the ALBI score could estimate voriconazole-induced hepatotoxicity during TDM implementation. This single-center, retrospective cohort study included 134 patients. The primary outcome was voriconazole-induced hepatotoxicity. The cutoff value of the ALBI score was determined using a receiver operating characteristic curve. The cumulative risk of hepatotoxicity was evaluated using Kaplan–Meier curve analysis with a log-rank test for the cutoff value and ALBI grade. Moreover, the group of patients with the trough concentration of voriconazole 1−4 μg/mL was also investigated. The incidence of hepatotoxicity was 13.4% (18/134). The cutoff value of the ALBI score was -1.91 (sensitivity, 0.611; specificity, 0.655; area under the curve, 0.615). The cumulative risk of hepatotoxicity was significantly higher in the ALBI score ≥-1.91 group than in the ALBI score <-1.91 group (P = 0.024) and patients with higher ALBI grades tended to be at higher risk (P = 0.080). The cumulative risk tended to be higher with ALBI ≥-1.91 in the trough concentration 1−4 μg/mL group; however, no significant difference was found (P = 0.134). The pilot study indicated that the ALBI score ≥-1.91 may be an indicator for voriconazole-induced hepatotoxicity even when TDM is conducted. Because this study was a single-center and small cohort design, further studies should be conducted using a large datasets and translational research.

Background Isavuconazole has been used to treat invasive fungal infections, however, it is unclear whether the efficacy of isavuconazole is superior to that of voriconazole. The purpose of this meta-analysis was to assess the efficacy and safety of isavuconazole compared to voriconazole in treating invasive fungal infections. Methods Electronic databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, were searched to identify relevant studies. Studies evaluating the effect of isavuconazole in the treatment of patients with invasive fungal infections were included. Pooled rates of overall response, all-cause mortality, drug-related adverse events (AEs), and discontinuation due to drug-related AEs were calculated. Results Seven studies involving 890 patients were included. Meta-analysis showed that there was no significant difference between isavuconazole and voriconazole in overall response (risk ratio [RR]: 1.02, 95% confidence interval [CI]: 0.83 to 1.25, p  = 0.86) and all-cause mortality (RR: 0.95, 95% CI: 0.78 to 1.16, p  = 0.61). However, isavuconazole had a significantly lower incidence of drug-related AEs (RR: 0.70, 95% CI: 0.61 to 0.81, p  < 0.001) and discontinuation due to drug-related AEs (RR: 0.56, 95% CI: 0.39 to 0.82, p  = 0.003) compared with voriconazole. Trial sequential analysis (TSA) confirmed that the difference between isavuconazole and voriconazole in discontinuation due to drug-related AEs need further valiadation, but the results of other outcomes were conclusive.  < 0.001) and discontinuation due to drug-related AEs (RR: 0.56, 95% CI: 0.39 to 0.82, p  = 0.003) compared with voriconazole. Trial sequential analysis (TSA) confirmed that the difference between isavuconazole and voriconazole in discontinuation due to drug-related AEs needs further validation, but the results of other outcomes were conclusive. Conclusions Our findings support the use of isavuconazole as the primary therapy for invasive fungal infections. More research is needed to compare the discontinuation rates of isavuconazole and voriconazole.

A 52-year-old woman with overlap syndrome and interstitial pneumonia underwent immunosuppressive therapy and she was suspected to suffer from pulmonary aspergillosis. Oral voriconazole was initiated, and a rapid elevation of alkaline phosphatase (ALP) occurred after 4 weeks. After 2 months, the patient presented diffuse pain in bilateral skeletal regions, and bone scintigraphy revealed bilateral multiple areas of increased radiotracer uptake. We suspected the skeletal involvement as voriconazole-induced periostitis. Actually, the plasma fluoride level was increased. Voriconazole was replaced with itraconazole, and after 3 weeks, the patient stopped complaining of bone pain concomitant with the decrease in ALP. Voriconazole-induced periostitis is a rare condition but had previously been reported in solid organ or patients with bone marrow transplant who received a long-term voriconazole therapy. Our present case is distinctive of previous ones, because it occurred in a patient with connective tissue disease which had its rapid progression.

Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson’s disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587–42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421–7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.

Chronic pulmonary aspergillosis (CPA) requires prolonged treatment with itraconazole or voriconazole. However, adverse events (AEs) are common with the use of these agents, with the need to discontinue the offending drug in a significant proportion of the patients. The aim of this study was to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of CPA. We searched Embase and Medline to select clinical studies providing information on AEs to itraconazole or voriconazole for the treatment of CPA from inception to May 2020. Reviews, single case reports, and case series reporting less than 10 patients were excluded. Random effect meta-analysis was performed using STATA 16.0. We included 9 eligible studies with an overall total of 534 CPA patients enrolled. Of these, 69% (n = 366) were treated with voriconazole and 31% (n = 168) with itraconazole. The median daily dose of both itraconazole and voriconazole used was 400mg. In a pooled analysis, AEs were observed in 36% (95% CI: 20-52%, N = 366) of patients on voriconazole and 25% (95% CI: 18 to 31%, N = 168) in those treated with itraconazole. Discontinuation rate due to AEs was the same for both drugs; 35% (47/366) and 35% (15/168) for voriconazole and itraconazole, respectively. There were 70 AEs reported with itraconazole use, the commonest being cardiotoxicity (29%). Skin AEs (28%) were the most frequent among the 204 AEs reported with voriconazole use. None of the studies compared the tolerability of itraconazole head-to-head with voriconazole. AEs due itraconazole and voriconazole are common and may lead to discontinuation of treatment in a significant proportion of patients. This information can be used to educate patients prior to commencement of these antifungal therapies. CRD42020191627.

Though triazole antifungals are the first choice for preventing and treating invasive fungal infections, periostitis caused by voriconazole has been described in emerging case reports; however, no studies exist on this association in real-world clinical settings. Our study aimed to identify the association between periostitis and triazole antifungals by analyzing data from the FDA Adverse Event Reporting System (FAERS). We extracted and analyzed reports on the association between periostitis and triazole antifungals in FAERS from the first quarter of 2004 to the second quarter of 2022 using OpenVigil 2.1. Disproportionality analysis was performed to evaluate the association between periostitis and triazole antifungals, and chi-squared (χ 2 ), relative reporting ratio (RRR), reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural networks (BCPNN) of information components (IC) were reported. In total, 143 patients experienced periostitis while using voriconazole. Disproportionality analysis identified an association between periostitis and voriconazole (χ 2  = 82,689.0, RRR = 583.6, 95%CI [472.4, 721.1], PRR = 1808.9, 95%CI [1356.0, 2412.9], ROR = 1831.7, 95%CI [1371.6, 2446.3], IC = 9.2, 95%CI [8.6, 9.8]). However, no safety signals were observed between periostitis and other triazole antifungals. When stratified by sex and age, disproportionality analysis identified positive signals between periostitis and voriconazole. The possible association between periostitis and voriconazole should attract sufficient attention in clinical practice. Alternative treatment with other triazole antifungals can be considered, and causality needs to be verified in further prospective studies.