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Objectives: This study aims to assess the urinary diffusion and clinical effectiveness of voriconazole in patients with fluconazole-resistant urinary candidiasis., Patients and Methods: In this prospective pilot study, we utilized a validated chromatography method to measure voriconazole in urine over a 12-hour period between two administrations of the drug and in plasma at trough., Results: Thirty-five patients, including five with fluconazole-resistant urinary candidiasis, were included. Urine and plasma voriconazole concentrations, mean 1.7 mg/L (range: 0.3-12.6) and mean 2.0 mg/L (range: 0.1-11.1) respectively, exhibited a strong correlation (R 2  = 0.88). None of the five patients treated for candidiasis experienced clinical or microbiological failure following treatment, with urine concentrations ranging from 0.5 to 2.7 mg/L., Conclusions: The urinary diffusion of voriconazole resulted in drug exposure above the target minimum inhibitory concentration (MIC) in the five patients treated for voriconazole-susceptible Candida strains in urine. Therapeutic drug monitoring may allow optimize in situ concentrations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [FL received research grants (paid to institution) from Astellas, Sandoz and Chiesi and fees to attend meetings from Viiv, MSD, Janssen-Cilag, Pfizer and Gilead. JPG received honoraria for scientificsymposia in congresses from Gilead, MundiPharma, Shionogi and Pfizer. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Phaeohyphomycosis is caused by dematiaceous (pigmented) fungi. Most phaeohyphomycosis is non-invasive infections, however, they can lead to invasive infections, including fungemia and disseminated disease, particularly in severely immunocompromised patients. Invasive phaeohyphomycosis has recently emerged, however, the treatment strategy was not determined because of the intrinsic resistance to antifungals and the lack of clinical experience. Here, we describe a novel case of echinocandin-breakthrough Coniochaeta hoffmannii (Lecythophora hoffmannii) fungemia after hematopoietic stem cell transplantation, which was identified using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and ribosomal RNA sequencing. The patient was a female in her 40s who had acute myeloid leukemia refractory to chemotherapy before progressing to cord blood transplantation. Before developing fungemia, the patient was administered multiple broad-spectrum antibiotics and micafungin for recurrent infections and prophylaxis. Clinical and microbiological responses to liposomal amphotericin B were poor but improved after replacement to voriconazole and engraftment. A literature review of the previously reported cases with C. hoffmannii human infections imply that disruption of the cutaneous/mucosal barrier and the use of antimicrobial agents, both antibiotics and antifungals, could incite C. hoffmannii invasive infections., Competing Interests: Declaration of Competing interest All authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the clinical characteristics and treatment outcomes of patients with chronic pulmonary aspergillosis (CPA) and to determine risk factors for disease recurrence., Methods: A total of 43 patients with CPA (mean ± SD age: 61.4 ± 10.5 years, 83.7% were males) were included in this retrospective study. Data on demographic, clinical and disease-related characteristics, galactomannan (GM) test positivity in bronchoalveolar lavage (BAL) samples, histopathological diagnosis, imaging (CT) findings and CPA forms, antifungal therapy, recurrence rate and time to recurrence were recorded., Results: Chronic obstructive pulmonary disease (COPD;76.7%) was the leading predisposing factor, and the aspergillus nodule (37.2%) was the most prevalent CPA form.GM test positivity was noted in 89.7% (35/39) of BAL samples. Median duration of voriconazole treatment was 180 days. CPA recurrence was noted in 14.0% of patients, while the comorbid tuberculosis sequela (66.7% vs. 16.2%, p = 0.02) and mild immunosuppressive disorder (100.0% vs. 51.4%, p = 0.032) were significantly more common in patients with recurrence vs. those without recurrence. Recurrence rate was 50.0% (3 of 6 patients) in patients with simple aspergilloma, and ranged from 0.0% to 25.0% in those with other CPA forms. Treatment duration and time to recurrence ranged 70-270 days and 1.1-37 months, respectively in simple aspergilloma, while they were ranged 150-180 days and 30-43.3 months, respectively in other CPA forms., Conclusions: Our findings indicate the importance of considering CPA in differential diagnosis in patients with predisposing conditions, and emphasize the tuberculosis sequela, immunosuppressive disorder and the certain CPA forms managed with shorter duration of antifungal therapy (i.e., simple aspergilloma) as the potential risk factors of CPA recurrence., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Summary: Invasive fungal infections are a significant cause of morbidity and mortality in children with immunodeficiencies. Current dosing recommendations for voriconazole often result in subtherapeutic exposure in pediatric patients. In this single-center retrospective study, we reviewed hospitalized pediatric patients receiving voriconazole with at least one inpatient serum trough concentration measured. Patient characteristics and voriconazole dosing courses with associated trough concentrations were summarized for all patients as well as grouped by age (0 to 1 y, 2 to 11 y, and 12 to 18 y). Of 106 included patients, the median age was 9 years (range, 29 d to 18 y). Five hundred ninety courses of voriconazole were administered with 365 associated troughs. Most troughs were subtherapeutic (49%) and 30% of patients never attained a therapeutic trough. The median oral daily dose associated with a therapeutic trough was higher in younger age groups: 21.6 mg/kg 0 to 1 year, 17.9 mg/kg 2 to 11, and 9.5 mg/kg 12 to 18 years ( P <0.001). Patients younger than 2 years had the largest proportion of subtherapeutic troughs and variability in dosing. Attainment of therapeutic voriconazole concentrations was challenging across all pediatric age groups. Higher starting doses for patients younger than 2 years are likely needed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients., Methods: A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (C ss-min ) in overall patients and in age subgroups was analyzed., Results: Voriconazole C ss-min correlated positively with age, and mean voriconazole C ss-min was significantly higher in the elderly group ( P  < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole C ss-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole C ss-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole C ss-min (>5.5 mg/l) was higher in the elderly patients. When the average C ss-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole C ss-min in the young group, while the influence of age on voriconazole C ss-min exceeded CYP2C19 genotypes in the elderly., Conclusion: CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Voriconazole is the first-line treatment for invasive aspergillosis. Its pharmacokinetics exhibit considerable inter- and intra-individual variability. The purpose of this study was to investigate the effects of CYP2C19, CYP2C9, CYP3A4, and FMO3 genetic polymorphisms and sex on the pharmacokinetics of voriconazole in healthy Chinese adults receiving single-dose and multiple-dose voriconazole, to provide a reference for its clinical individualized treatment. A total of 123 healthy adults were enrolled in the study, with 108 individuals and 15 individuals in the single-dose and multiple-dose doses, respectively. Plasma voriconazole concentrations were measured using a validated LC-MS/MS method, and pharmacokinetics parameters were calculated using the non-compartmental method with WinNonlin 8.2. CYP2C19, CYP2C9, CYP3A4, and FMO3 single-nucleotide polymorphisms were sequenced using the Illumina Hiseq X-Ten platform. The results suggested that CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of voriconazole at single doses of 4, 6, and 8 mg/kg and multiple doses of voriconazole. CYP3A4 rs2242480 had a significant effect on AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity) and MRT (mean residence time) of voriconazole at a single dose of 4 mg/kg in CYP2C19 extensive metabolizer. Regardless of the CYP2C19 genotype, CYP2C9 rs1057910 and FMO3 rs2266780 were not associated with the pharmacokinetics of voriconazole at three single-dose levels or multiple doses. No significant differences in most voriconazole pharmacokinetics parameters were noted between male and female participants after single and multiple dosing. For patients receiving voriconazole treatment, CYP2C19 genetic polymorphisms should be genotyped for its precision administration. In contrast, based on our study of healthy Chinese adults, it seems unnecessary to consider the effects of CYP2C9, CYP3A4, and FMO3 genetic polymorphisms on voriconazole pharmacokinetics., (© 2024, The American College of Clinical Pharmacology.)

CaCO 3 nanoparticles (nano-CaCO 3 ) as nano-templates were prepared using CaCl 2 and Na 2 CO 3 solutions under controlled sonication (19.5 kHz). Using the same ultrasonic device, subsequently, hollow mesoporous silica nanoparticles (HMSNs) were obtained by the hard template of nano-CaCO 3 . HMSNs were selected as carriers for the antifungal drug voriconazole (VOR) loading to overcome poor water solubility. Three-dimensional CaCO 3 nanosheets HMSNs were obtained under gentle sonication. Three-dimensional CaCO 3 nanosheets of 24.5 nm (hydrodynamic diameter) were obtained under 17.6 W for 3 min. HMSNs were synthesized by double-template method with nano-CaCO 3 as the hard template. Transmission electron microscopy measurements showed that the prepared HMSNs possess hollow structures with particle size between 110 and 120 nm. Nitrogen physisorption at -196 °C revealed that the HMSNs had high surface area (401.57 m 2 /g), high pore volume (0.11 cm 3 /g), and uniform pore size (2.22 nm) that facilitated the effective encapsulation of VOR in the HMSNs. The loading capacity of VOR (wt%) on the HMSNs was 7.96%, and the total VOR release amount of VOR-HMSNs material was 71.40% at 480 min. The kinetic model confirmed that the release mechanism of HMSNs nanoparticles followed Fickian diffusion at pH = 7.4 and 37 °C. Moreover, the cumulative VOR release at 42 °C (86.05%) was higher than that at 37 °C (71.40%). The cumulative release amount of VOR from the VOR-HMSNs material was 92.37% at pH = 5.8 at the same temperature. Both nano-CaCO 3 templates and HMSNs were prepared by sonication at 19.5 kHz. The as-prepared HMSNs can effectively encapsulate VOR and released drug by Fickian diffusion., (© 2024. The Author(s).)

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

A 21-year-old retired polo Argentinian thoroughbred horse from a teaching herd was presented for a routine bronchoalveolar lavage demonstration, during which an incidental finding of a granulomatous mass on the dorsal aspect of the epiglottis was made. Rhinosporidium seeberi was suspected from a histological section obtained from an initial biopsy, and the mass was removed via laser surgery for cytology and PCR. Sequencing of the PCR amplicons confirmed the diagnosis of R. seeberi. A treatment protocol of nebulized voriconazole for 10 d postoperatively was used. Long-term follow-up required 2 more laser surgeries plus oral fluconazole to resolve the remaining fungal spores. However, 2.5 y later, there was no evidence of remaining fungal spores. Key clinical message: Horses from endemic regions can potentially be exposed to R. seeberi. Based on its travel history, this horse may have contracted the infection in South America, California, or Alberta. Treatments administered, including diode laser resection, voriconazole antifungal nebulization, and oral fluconazole administration, were successful but required repeated interventions., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Background: Fungus endophthalmitis is a rare and serious infection that is treated with systemic and topical antifungal drugs. There is no clear consensus on the treatment of fungal endophthalmitis with intravitreal injections (IVIs) of voriconazole. This systematic review aims to summarize the literature on IVIs of voriconazole for fungal endophthalmitis. Methods: We conducted a systematic review of the literature to determine the effectiveness and safety of IVIs of voriconazole in the treatment of fungal endophthalmitis. We searched databases such as PubMed and Embase using the following search terms "Endophthalmitis" AND "Intravitreal Injections" AND "Voriconazole" with date limits of January 1, 1900, to December 31, 2022. We included all reports on humans, which described clinical outcomes of IVIs of voriconazole in the treatment of fungal endophthalmitis, including randomized controlled trials (RCTs) and case series. A descriptive synthesis of the data was conducted with a pooling of data for interventions. Results: One RCT and 21 retrospective studies were analyzed in this review. In these reports, a wide range of heterogeneous treatment regimens was used, including IVI in combination with other drugs, systemic therapy in combination with other agents, and surgery. Combined with other treatments, intravitreal voriconazole results in a favorable anatomical and clinical cure that was well tolerated. Conclusions: Reports on IVIs of voriconazole for fungal endophthalmitis demonstrate a heterogeneous approach to treatment. Of these, IVIs of voriconazole in anatomical and clinical outcomes appeared to be highly effective, although more data on its safety are needed.

The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (C trough ) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of C trough , and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the C trough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target C trough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children., (© 2024. The Author(s).)

Background: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown., Methods: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole., Results: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily., Conclusions: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib., (© 2024 American Cancer Society.)

Aims: Although therapeutic drug monitoring (TDM) of voriconazole is performed in outpatients to prevent treatment failure and toxicity, whether TDM should be performed in all or only selected patients remains controversial. This study evaluated the association between voriconazole trough concentrations and clinical events., Methods: We investigated the aggravation of clinical symptoms, incidence of hepatotoxicity and visual disturbances, change in co-medications and interaction between voriconazole and co-medications in outpatients receiving voriconazole between 2017 and 2021 in three facilities. Abnormal trough concentrations were defined as <1.0 mg/L (low group) and >4.0 mg/L (high group)., Results: A total of 141 outpatients (578 concentration measurements) met the inclusion criteria (treatment, 37 patients, 131 values; prophylaxis, 104 patients, 447 values). The percentages of patients with abnormal concentrations were 29.0% and 31.5% in the treatment and prophylaxis groups, respectively. Abnormal concentrations showed 50% of the concentrations at the first measurement in both therapies. Aggravation of clinical symptoms was most frequently observed in the low treatment group (18.2%). Adverse events were most common in the high group for both therapies (treatment, hepatotoxicity 6.3%, visual disturbance 18.8%; prophylaxis, hepatotoxicity 27.9%). No differences were found in changes to co-medications and drug interactions. In the prophylaxis group, prescription duration in the presence of clinical events tended to be longer than in their absence (47.4 ± 23.4 days vs 39.7 ± 21.9 days, P = .1132)., Conclusions: We developed an algorithm based on clinical events for appropriate implementation of TDM in outpatients. However, future interventions based on this algorithm should be validated., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Aims: Voriconazole remains the mainstay for the treatment of invasive fungal infections in heart transplant patients and can significantly increase tacrolimus exposure because of drug-drug interaction (DDI). However, the magnitude of this DDI is highly variable and difficult to predict. The purpose of this study was to present the characteristics of the DDI between tacrolimus and voriconazole, and further identify the various predictors of tacrolimus dose modification., Methods: We retrospectively enrolled 69 heart transplant recipients who did not use voriconazole as the control and 68 patients received voriconazole treatment in voriconazole group. CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were thereafter genotyped by Sanger sequencing. The dose of tacrolimus required to achieve the therapeutic concentrations and tacrolimus dose-corrected trough concentration (C 0 /D) before and after VRC administration was evaluated., Results: The DDI between tacrolimus and voriconazole displayed a large interindividual variability with more than 10-fold changes in tacrolimus dose (range 1.28-13.00) and C 0 /D (range 1.43-13.75). In addition, the fold changes for the tacrolimus dose were associated with CYP2C19 genotype, which was found to be significantly lower in CYP2C19 extensive metabolizers than in CYP2C19 intermediate metabolizers or poor metabolizers (4.06 ± 1.85 vs 5.49 ± 2.47, P = .0031). However, no significant difference was found in both CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit acted as independent predicting factors for tacrolimus dose modification after voriconazole co-therapy., Conclusions: The findings of this study have identified the various important factors to adjust tacrolimus dosage when co-administrated with voriconazole in individual patients. CYP2C19 genotype and haematocrit should be considered when tailoring tacrolimus dose., (© 2022 British Pharmacological Society.)

Fungal keratitis is one of the leading causes of ophthalmic mycosis affecting the vision due to corneal scarring. Voriconazole (VRC) is the most preferred azole antifungal agent for treating ocular mycotic infections. Ocular drug delivery is challenging due to the shorter corneal residence time of the formulation requiring frequent administration, leading to poor patient compliance. The present study aimed at improving the solubility, transcorneal permeation, and efficacy of voriconazole via the formation of cyclodextrin-based ternary complexes and incorporation of the complex into mucoadhesive films. A phase solubility study suggested a ∼14-fold improvement in VRC solubility, whereas physicochemical characterization confirmed the inclusion of VRC in the cyclodextrin inner cavity. In silico docking studies were performed to predict the docking conformation and stability of the inclusion complex. Complex-loaded films showed sustained release of voriconazole from the films and improved transcorneal permeation by ∼4-fold with an improved flux of 8.36 μg/(cm 2 h) for ternary complex-loaded films compared to 1.86 μg/(cm 2 h) for the pure VRC film. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and hen's egg-chorioallantoic membrane test (HET-CAM) assays confirmed that the complexes and ocular films were nonirritant and safe for ocular administration. The antifungal study performed using Aspergillus fumigatus and Fusarium oxysporum suggested improved antifungal activity compared to the pure drug film. In conclusion, the supramolecular cyclodextrin ternary complex proved to be a promising strategy for enhancing the solubility and permeability and augmenting the antifungal activity of voriconazole in the management of fungal keratitis.

Background: Dermatophytosis is a worldwide public health problem, affecting > 25% of the world's population. There has been a rampant increase in the resistant, recurrent dermatophytosis in the past few years, especially in India. Azole resistance in dermatophytes has been reported to be as high as 19% worldwide, hence evaluating the efficacy and safety of a newer oral antifungal is important., Aim: To evaluate the efficacy and safety of oral voriconazole in the management of recalcitrant and recurrent dermatophytosis., Methods: Patients with extensive, recurring and resistant dermatophytosis. The clinical diagnosis was confirmed by potassium hydroxide staining. Patients were given a 2-week course of oral voriconazole, administered as 800 mg on Day 1, followed by two daily doses of 200 mg (total 400 mg/day) for the remaining 13 days. The patients were followed up in Week 2 to assess response and in Week 6 to assess recurrence. Patients were monitored for any adverse effects (AEs)., Results: In total, 40 patients completed the study. Complete clearance was seen in 90% and 75% at Weeks 2 and 6, respectively. By the end of Week 6, eight patients (20%) had partial improvement of disease without complete clearance and only 5% had recurrence. No AEs were recorded during the treatment course., Conclusion: Voriconazole, a novel oral antifungal that can be used for treatment of recurrent and resistant dermatophytosis, has a good efficacy and safety profile with a very low rate of recurrence., (© 2021 British Association of Dermatologists.)

Study Objectives: This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species., Design: Prospective pharmacokinetics study., Setting: The intensive care unit in a tertiary-care medical center., Patients: A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis., Methods: Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (C min ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC 24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC 24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients., Results: A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the C min target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma C min monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available., Conclusions: For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients., (© 2021 Pharmacotherapy Publications, Inc.)

Background: Antimicrobial stewardship programs promote the appropriate use of antimicrobial substances through the implementation of evidence-based, active and passive interventions. We analyzed the effect of a computer-assisted intervention on antimicrobial use in a tertiary care hospital., Methods: Between 2011 and 2016 we introduced an electronic alert for patients being prescribed meropenem, voriconazole and caspofungin. At prescription and at day 3 of treatment, physicians were informed about the risk related to these antimicrobial substances by an electronic alert in the medical records. Physicians were invited to revoke or confirm the prescription and to contact the infectious disease (ID) team. Using interrupted time series regression, the days of therapy (DOTs) and the number of prescriptions before and after the intervention were compared., Results: We counted 64,281 DOTs for 5549 prescriptions during 4100 hospital stays. Overall, the DOTs decreased continuously over time. An additional benefit of the alert could not be observed. Similarly, the number of prescriptions decreased over time, without significant effect of the intervention. When considering the three drugs separately, the alert impacted the duration (change in slope of DOTs/1000 bed days; P = 0.0017) as well as the number of prescriptions (change in slope of prescriptions/1000 bed days; P < 0.001) of voriconazole only., Conclusions: The introduction of the alert lowered prescriptions of voriconazole only. Thus, self-stewardship alone seems to have a limited impact on electronic prescriptions of anti-infective substances. Additional measures such as face-to-face prompting with ID physicians or audit and feedback are indispensable to optimize antimicrobial use., (© 2021. The Author(s).)

Vulvovaginal candidiasis is a pervasive gynecological condition among women worldwide due to infection recurrence and resistance to conventional drugs. This calls for a novel formulation of alternative medication and with enhanced efficacy. This study aimed to fabricate mixed-lipid nanoconstructs (MLNCs) of voriconazole (VCZ) with a low concentration of lipids applying high shear homogenization and ultrasonication to form a semisolid formulation. Tefose 63 and Gelot 64 were employed as emulsifiers that are specified for vaginal preparations; as per their mucoadhesive properties and their texture enhancing characters, although usually used as lipids in different lipid carriers. A 2 4 factorial design was established and the optimized formulation was prepared using 10% total lipids, in which solid lipids (Sterotex NF: Glyceryl monostearate) ratio was 1.92:1 and the oils percentage was 30% (Maisine: Glyceryl monooleate, in the ratio of 1:1), and the emulsifiers mixture (Tefose 63: Gelot 64) ratio was 1:1, as 10% of total formulation weight. The optimized formulation with a viscosity of 964.49 ± 57.99 cp showed spherical nanoparticles (322.72 ± 15.11 nm) that entrapped 67.16 ± 3.45% of VCZ and exhibited release of 70.08 ± 2.87% in 8 h. The optimized formulation with high bioadhesive potentials significantly reduced the fungal burden in female Wistar rats infected with vaginal candidiasis, compared to the aqueous VCZ suspension ( p  < .05). Furthermore, in vivo histopathological findings proved the effectiveness and the safety of the optimized MLNCs formulation after vaginal application. Inclusively, MLNCs formulation could be a promising vaginal delivery system of VCZ for the treatment of vulvovaginal candidiasis.

Fungal infections of the paranasal cavity are among the most widely spread illnesses nowadays. The aim of the current study was to estimate the effectiveness of an in situ gel loaded with voriconazole‒clove oil nano-transferosomes (VRC-CO-NT) in enhancing the activity of voriconazole against Aspergillus flavus , which causes rhinosinusitis. The nephrotoxic side effects of voriconazole may be reduced through the incorporation of the clove oil, which has antioxidant activity that protects tissue. The Box‒Behnken design was applied to formulate the VRC-CO-NT. The particle size, entrapment efficiency, antifungal inhibition zone, and serum creatinine concentration were considered dependent variables, and the soybean lecithin, VRC, and CO concentrations were considered independent ones. The final optimized formulation was loaded into a deacetylated gellan gum base and evaluated for its gelation, rheological properties, drug release profile, permeation capabilities, and in vivo nephrotoxicity. The optimum formulation was determined to be composed of 50 mg/mL lecithin, 18 mg/mL VRC, and 75 mg/mL CO, with a minimum particle size of 102.96 nm, an entrapment efficiency of 71.70%, an inhibition zone of 21.76 mm, and a serum creatinine level of 0.119 mmol/L. The optimized loaded in situ gel released 82.5% VRC after 12 hours and resulted in a 5.4-fold increase in drug permeation. The in vivo results obtained using rabbits resulted in a nonsignificant differentiation among the renal function parameters compared with the negative control group. In conclusion, nasal in situ gel loaded with VRC-CO-NT is considered an efficient novel carrier with enhanced antifungal properties with no signs of nephrotoxicity.

Voriconazole (VCZ) is a well-known broad spectrum triazole antifungal, mainly used orally and intravenously. The study aimed to formulate VCZ into ultradeformable elastosomes for the topical treatment of ocular fungal keratitis. Different formulae were prepared using a modified ethanol injection method, employing a 3 3 Box-Behnken design. They were characterized by measuring their entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP). The optimized formula was subjected to further in vitro investigations and in vivo evaluation studies. The prepared vesicles had satisfactory EE%, PS, PDI and ZP values. The numerical optimization process suggested an optimal elastosomal formula (OE) composed of phosphatidyl choline and brij S100 at the weight ratio of 3.62: 1, 0.25%w/v hyaluronic acid and 5% (percentage from phosphatidyl choline/brij mixture) polyvinyl alcohol. It had high EE (72.6%), acceptable PS and PDI (362.4 nm and 0.25, respectively) and highly negative ZP of -41.7 mV. OE exhibited higher elasticity than conventional liposomes, with acceptable stability for three months. Transmission electron microscopy demonstrated the spherical morphology of vesicles with an external transparent coat of Hyaluronic acid. OE was expected to cause no ocular irritation or blurring in vision as reflected by pH and refractive index measurements. The histopathological study revealed the safety of OE for ocular use. The fungal susceptibility testing using Candida albicans demonstrated the superiority of OE to VCZ suspension, with greater and more durable growth inhibition. Therefore, OE can be regarded as a promising formula, achieving both safety and efficacy.

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment., Competing Interests: The authors have declared that no competing interests exist.

Spinal epidural abscess caused by Aspergillus spp is a debilitating form of invasive aspergillosis that can easily be misdiagnosed as spinal tuberculosis due to shared risk factors and clinical features. In this Grand Round, we describe a case of thoracic aspergillus spinal epidural abscess in a patient with underlying HIV infection. The initial diagnostic consideration was that of spinal tuberculosis. Consequently, despite positive microbiological cultures of Aspergillus fumigatus, antifungal therapy was delayed until histopathological evaluation of the affected tissue confirmed the presence of fungal hyphae. The patient showed an initial favourable response after surgical removal of the infected focus, but unfortunately never returned to premorbid functioning. This case highlights the importance of early diagnosis, urgent surgery, and prompt antifungal therapy for the management of aspergillus spinal epidural abscesses. Associated morbidity and mortality can be substantially increased if physicians fail to recognise this condition and do not institute appropriate and timely surgical and medical treatment., Competing Interests: Declaration of interests NPG reports grants from the US National Institutes of Health, US Centers for Disease Control and Prevention, Bill & Melinda Gates Foundation, UK Research and Innovation Medical Research Council, and South African National Health Laboratory Service Research Trust and non-financial support from Gilead, outside the submitted work. The other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Limited data are available on antimicrobials exposure and microbiology evolution in pediatric acute myeloid leukemia (AML) patients underwent antimicrobials prophylaxis. To assess the effectiveness of antimicrobials prophylaxis, antibiotic susceptibilities of bacteria, and exposure of antimicrobials during intensive chemotherapy for AML patients, 90 consecutive de novo AML patients aged 0-18 years between January 1, 1997 and March 31, 2018 were enrolled. Vancomycin, ciprofloxacin and voriconazole prophylaxis was administered from January 1, 2010. During the preprophylaxis period, January 1997 to December 2009, 62 patients experienced a total of 87 episodes of bloodstream infection (BSI) and 17 episodes of invasive fungal infection (IFI) among 502 courses of chemotherapy. In contrast, 16 episodes of BSI occurred and no IFIs were reported to occur in 28 patients who received 247 courses of chemotherapy in the prophylaxis period. Patients who received antimicrobial prophylaxis had a significant reduction of BSI, IFI, and febrile neutropenia in comparison with patients without prophylaxis. Exposure to amikacin, carbapenem, amphotericin B was reduced in the prophylaxis period. Imipenem susceptibility of Enterobacter cloacae as well as vancomycin susceptibility of Enterococcus species were reduced in the prophylaxis period. At the time of the last follow up, patients with prophylaxis had a better subsequent 5-year overall survival rate than those without prophylaxis. Prophylactic antimicrobials administration in children with AML who undergo chemotherapy can significantly reduce the rates of life-threatening infection, exposure to antimicrobials, and might result in a better outcome., (© 2021. The Author(s).)

Posaconazole has been used anecdotally to treat aspergillosis in falcons resistant to voriconazole. In human medicine, it is used prophylactically in immunosuppressed human subjects with invasive pulmonary aspergillosis. So far, no studies have been performed in birds. The aim of this study was to evaluate the in-vivo pharmacokinetic behavior of oral posaconazole after a single administration in six large falcons (i.e gyrfalcons, saker falcons). Posaconazole oral suspension (Noxafil, 40 mg/ml, Schering-Plough) was administered per os without meal in a single dosage of 12.5 mg/kg in 3 falcons. A comparison was done in two more falcons, one with a natural fatty meal at the same single dose, and one with a natural fatty meal and a higher dosage (20 mg/kg). Finally, six falcons received posaconazole pre-dissolved in corn oil with a natural low-fat meal in the higher single dose (20 mg/kg). No side effects were observed in the falcons in any of the experiments. In starved state posaconazole was poorly absorbed, more so than in other species. As expected, absorption of posaconazole was higher with the administration of meal or in the presence of plant (corn) oil, with a fourfold increase in apparent bioavailability. Despite the preferential absorption in the presence of fat, for both dosing schemes the AUC24 : MIC ratio was lower than described in human medicine to achieve a therapeutic effect. The AUCinf : MIC which is an indicator of efficacy after steady-state, while variable, did indicate that the drug is worth trying when susceptibility testing shows to be the only effective drug., Lay Abstract: The focus of this work is to determine the pharmacokinetic parameters of oral posaconazole in large falcons for the first time after a single dose. Posaconazole has higher bioavailability when administered with meal and fatty components. No adverse reactions have been observed. The ratio of the area under the curve (AUC24) to minimum inhibitory concentration was lower compared to the therapeutic level in human., (© The Author(s) 2021. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Purpose: To describe a surgical technique for the diagnosis and treatment of post-Descemet stripping automated endothelial keratoplasty (DSAEK) infectious interface keratitis presenting as a cold abscess., Methods: This study included 2 eyes of 2 patients that developed delayed-onset interface infections after DSAEK. Through an anterior keratotomy, diagnostic samples for microbial culture and histopathology examination were collected, and empiric antibiotic therapy was delivered directly to the site of the infection at the graft-host interface., Results: In both cases, microbiological examinations confirmed a fungal etiology consistent with Candida. Resolution of infection was achieved, and no signs of posterior segment involvement or recurrence of infection were observed. Both corneas remained clear with final visual acuity of 20/25 and 20/32. No case required additional surgical intervention or repeat keratoplasty after more than 15 months of follow-up., Conclusions: Interface drainage with antimicrobial irrigation may be considered for the management of post-DSAEK interface infections presenting as a peripheral cold abscess. By avoiding intraocular seeding of infectious pathogens, the anterior approach can achieve clinical resolution of infection, maintain visual function, and preserve the DSAEK graft, thereby obviating the need for a therapeutic keratoplasty., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The purpose of this manuscript is to develop sustained release molecularly imprinted voriconazole (VOR) that were loaded into collagen shield (CS) for ocular treatment of fungal keratitis. Various molecularly imprinted polymer (MIP) formulae were prepared by a precipitation polymerization technique. Different monomers and crosslinkers were tested to obtain better binding capacity. Two promising formulae; (F1: VOR: Acrylamide: ethylene glycol dimethacrylate (EGDMA): benzoyl peroxide (BPO) in the molar ratio of 1:5:15:1.6 mM, respectively) and (F3: VOR: Acrylamide: methyl methacrylic acid (MMA): EGDMA: BPO in the molar ratio 1:2.5:2.5:15:1.6 mM, respectively) were selected according to their binding capacities (82.79% ± 0.86, and 94.90% ± 1.25 respectively), and their release profiles over 48 h in simulated tears fluid (STF) (41.64 ± 1.92, and 85.39 ± 1.64 respectively). Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscope (SEM) were carried out. The selected CS (F1 CS and F3 CS) showed sustained release profiles (57.38%± 0.72, and 98.51%±0.49 respectively) over 72 h in STF. Results of trans-corneal permeation and antifungal activity were enhanced for the optimized formula (F3 CS) compared to (F1 CS) and drug solution. Furthermore, in vivo pharmacokinetic studies were conducted showing significant increase in C max , delayed T max and promoted relative bioavailability. After ocular insertion of F3 CS in male albino rabbits, histopathological studies were attained to assure the safety of the formula. Finally, optimized VOR-MIP-CS could provide promising ocular drug delivery systems (DDS)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Invasive pulmonary aspergillosis (IPA) after liver transplantation (LT) is most often fatal. We analyzed the outcomes of IPA in a single center., Methods: We reviewed, retrospectively, the medical records of recipients of living donor LT (LDLT) or deceased donor LT (DDLT) performed between 1995 and 2019 at our institute. We analyzed the incidence of IPA and assessed the treatment courses of patients treated successfully and those not treatment successfully., Results: Among 326 recipients, IPA was diagnosed in 6 (1.8%). The incidence of IPA was significantly higher in patients with acute liver failure (ALF, 9.8%) than in those without ALF (0.4%), after DDLT (8.8%) than after LDLT (1.0%), and in recipients who received preoperative steroid pulse therapy (16.0%) than in those who did not (0.7%). Complete cure of IPA was achieved in the most recent three patients, by administering voriconazole immediately after the diagnosis of IPA and performing lung resection, while the IPA lesion was single and localized., Conclusions: Patients with risk factors for IPA must be monitored closely. Our three successfully treated cases demonstrate that initiating immediate voriconazole treatment and making a calculated decision about lung resection can contribute to a favorable outcome., (© 2021. Springer Nature Singapore Pte Ltd.)

Objective: To present an interesting case of left opaque hemithorax in an adult female and discuss its assessment and management., Methods: Design: Case Report., Setting: Tertiary care hospital., Patient: One., Results: 44yrs retropositive female admitted with complaints of acute onset dry cough since 15-20 days, sudden breathlesness since 5 days which was progressive in nature, left sided heaviness in chest since 5 days. CECT Thorax showed complete collapse of left lung with cut off of left main bronchus while video bronchoscopy showed left main bronchus completely blocked with very thick necrotic mass and was difficult to dislodge. Debulking with cryo probe was done and left main bronchus was completely cleared off. Allergen panel showed very high serum IgE, high S.IgE against aspergillus and high specific S.IgG against aspergillus. Patient and her Chest X-ray showed significant improvement post cryo debulking and was discharged satisfactorily on oral voriconazole therapy., Conclusion: Endobronchial aspergillosis is characterized by massive intrabronchial overgrowth of the aspergillus species, mainly aspergillus fumigatus. Most patients with chronic pulmonary aspergillosis, including those with simple aspergillomas and Aspergillus nodules, have positive Aspergillus IgG antibodies in the blood. We hereby present a case of 44 yrs female presenting with complaints of dry cough and dyspnea and was diagnosed with endobronchial aspergillosis with complete obliteration of left main bronchus by fungal debris in which cryo debulking was done which relieved the symptoms significantly and was discharged in satisfactory condition on oral voriconazole therapy., Competing Interests: Conflicts of interest Dr. Chawla has nothing to disclose., (Copyright © 2020. Published by Elsevier B.V.)

Letermovir has been approved for the prevention of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HCT). Letermovir is a cytochrome P450 (CYP) 2C19 inducer. Voriconazole, which is a broad-spectrum triazole antifungal agent, is mainly metabolized by CYP2C19. Thus, voriconazole trough concentration may decrease due to the drug interaction between voriconazole and letermovir. This study aimed to clarify the effects of letermovir on voriconazole trough concentration in allogeneic HCT recipients. We retrospectively examined voriconazole trough concentration in 24 allogeneic HCT recipients who had letermovir for prevention of CMV infection. The median voriconazole C/D ratios significantly decreased after starting letermovir from 0.25 L/kg to 0.11 L/kg (p < 0.01), and increased after discontinuing letermovir from 0.15 L/kg to 0.24 L/kg (p = 0.02). The median fold change of voriconazole trough concentration during letermovir administration was 0.40. Our results suggest that voriconazole trough concentration decreases when voriconazole is combined with letermovir in allogeneic HCT recipients. Therefore, close therapeutic drug monitoring of voriconazole trough concentration is warranted in allogeneic HCT recipients after starting or discontinuing letermovir.

What Is Known and Objective: While bioavailability of oral voriconazole is known to be >90%, several reports have observed much lower oral bioavailability. The aim of the present study was to assess the oral bioavailability of voriconazole in clinical use by evaluating the change in serum voriconazole concentration in patients who received intravenous-to-oral switch therapy with the same dose of voriconazole., Methods: A single-centre, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous-to-oral switch therapy with the same dose of voriconazole between 1 January 2011 and 31 December 2018 were enrolled in the present study. We evaluated changes in serum voriconazole concentration before and after switch therapy., Results: Voriconazole trough concentrations significantly decreased following oral compared to intravenous treatment (2.5 ± 1.5 µg/mL vs 3.3 ± 2.0 µg/mL, p = 0.021). The median change rate of serum concentration by switching the route of administration was 82.7%, with wide inter-individual variability (range 27.2-333.3%). Further, concomitant glucocorticoid administration was a significant protective factor for reducing serum concentration (OR 0.16, 95% CI 0.03-0.79, p = 0.025)., What Is New and Conclusion: Switching from intravenous to oral treatment resulted in a significant decline in voriconazole trough concentrations with wide inter-individual variability. Therefore, measurement of serum concentration for dose adjustment should be performed after switching to the oral form., (© 2021 John Wiley & Sons Ltd.)

The aim of this study is to compare the curative effect of empirical with diagnostic-driven (pre-emptive) therapy of voriconazole in severe aplastic anaemia patients (SAAs) with invasive fungal disease (IFD) after intensive immunosuppressive therapy (IST). Patients undergoing voriconazole antifungal therapy were randomized to empirical therapy group and diagnostic-driven therapy group. Empirical therapy group accounted for 48.5% of all cases, and diagnostic-driven therapy group accounted for 51.5%. The morbidity of IFD (probable and proven cases) was slightly increased in diagnostic-driven therapy group compared with empirical therapy group (P > 0.05). The total effective rate was 62.1%. The effective rate in empirical therapy group was 78.1%, which was significantly increased compared with diagnostic-driven therapy group (47.1%) (P < 0.05). This value was especially significant in possible IFD cases (P < 0.05). The efficacy of possible IFD cases in empirical therapy group was the best (84%) followed by the probable and proven cases in empirical therapy group (57.1%). In diagnostic-driven therapy group, the efficacy of possible IFD cases was 50%, and the efficacy of probable and proven cases was only 37.5%. The difference was statistically significant (P < 0.05). Absolute neutrophil count (ANC) is the key anti-infection factor. The efficacy of patients whose ANC ˂ 0.1 × 10 9 /L was 39.28%, which was significantly reduced compared with that of patients whose ANC ≥ 0.1 × 10 9 /L (78.95%) (P < 0.05). This finding was especially obvious in diagnostic-driven therapy group. As empirical therapy is superior to diagnostic-driven therapy, we recommend that empirical therapy should be started for high-risk patients, and efforts should be made to definitively diagnose the disease.

Objectives: To examine current knowledge on the clinical utility of therapeutic drug monitoring (TDM) in voriconazole therapy, the impact of CYP2C19 genotype on voriconazole plasma concentrations, and the role of CYP2C19 genotyping in voriconazole therapy., Data Sources: Three literature searches were conducted for original reports on (1) TDM and voriconazole outcomes and (2) voriconazole and CYP2C19 polymorphisms. Searches were conducted through EMBASE, MEDLINE/PubMed, Scopus, and Cochrane Central Register of Controlled Trials from inception to June 2020., Study Selection and Data Extraction: Randomized controlled trials, cohort studies, and case series with ≥10 patients were included. Only full-text references in English were eligible., Data Synthesis: A total of 63 studies were reviewed. TDM was recommended because of established concentration and efficacy/toxicity relationships. Voriconazole trough concentrations ≥1.0 mg/L were associated with treatment success; supratherapeutic concentrations were associated with increased neurotoxicity; and hepatotoxicity associations were more prevalent in Asian populations. CYP2C19 polymorphisms significantly affect voriconazole metabolism, but no relationship with efficacy/safety were found. Genotype-guided dosing with TDM was reported to increase chances of achieving therapeutic range., Relevance to Patient Care and Clinical Practice: Genotype-guided dosing with TDM is a potential solution to optimizing voriconazole efficacy while avoiding treatment failures and common toxicities., Conclusions: Voriconazole plasma concentrations and TDM are treatment outcome predictors, but research is needed to form a consensus target therapeutic range and dosage adjustment guidelines based on plasma concentrations. CYP2C19 polymorphisms are a predictor of voriconazole concentrations and metabolism, but clinical implications are not established. Large-scale, high-methodological-quality trials are required to investigate the role for prospective genotyping and establish CYP2C19 -guided voriconazole dosing recommendations.

Background: Crazy-paving patterns are rarely reported as radiological manifestations of pulmonary cryptococcosis., Case Presentation: Herein, we presented a very rare case of a crazy-paving pattern as a radiological manifestation of pulmonary cryptococcosis in a patient with primary ciliary dyskinesia. The diagnosis of pulmonary cryptococcosis and primary ciliary dyskinesia was ultimately confirmed by bronchoscopic biopsy, fungus culture, whole exome sequencing of blood, etc. The patient received flucytosine (PO, 5 g per day) and amphotericin B (IV, 70 mg per day) during hospitalization and sequential therapy with voriconazole (PO, 200 mg twice a day) after discharge. He recovered during follow-up., Conclusions: We concluded that pulmonary cryptococcosis should be considered a possible cause of crazy-paving patterns in chest CT scans.

Acanthamoeba keratitis is a serious infection of the eye that can result in permanent visual impairment or blindness, caused by free-living amoebae of the genus Acanthamoeba. Early diagnosis is necessary for effective treatment of Acanthamoeba keratitis. Acanthamoeba is abundant in nature and can be found in water, soil, and air. Acanthamoeba keratitis is usually diagnosed by culture from a scraping of the eye or by confocal microscopy. In this paper, two complicated Acanthamoeba keratitis cases are reported.

We describe a 6-week-old male-term infant with a pulmonary aspergilloma diagnosed following lobectomy for suspected pleuropulmonary blastoma, with characteristic histopathologic findings and Aspergillus detected by polymerase chain reaction. Intensive testing did not reveal primary or secondary immunodeficiency. During 5 weeks treatment with voriconazole including regular therapeutic drug monitoring and dose adjustment, a level in the target range was never achieved. When the patient developed photosensitivity, treatment was stopped without relapse over 12 months follow-up. Voriconazole dosing is notoriously challenging in children. We review the cumulative published experience with voriconazole use in infants to highlight even greater difficulty in infants. Pulmonary aspergillosis is typically a disease affecting immunocompromised or critically ill patients. In children, it is well described in those with chronic granulomatous disease (CGD) as a complication of immunosuppressive antineoplastic chemotherapy and rarely in extremely- or very-low birthweight premature neonatal intensive care patients. The diagnosis is extremely rare in children without underlying risk factors. To our knowledge, this is the first report of a pulmonary aspergilloma in an immunocompetent infant., Competing Interests: The authors have no funding or conflicts of interest to disclose. A.G. attended an MSD Asia Pacific Forum., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Coccidioidal meningitis remains difficult to treat. The newer triazole, isavuconazole, has demonstrated efficacy in invasive fungal disease with less side effects than other azoles. We describe a case of refractory pediatric coccidioidal meningitis with disease stabilization and improvement on isavuconazole after failing treatment with other antifungal agents., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R 2  = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Voriconazole has been recommended as primary treatment for patients with invasive aspergillosis. Intravenous and tablet formulations of posaconazole that have improved systemic absorption could be an effective alternative to voriconazole. We aimed to assess non-inferiority of posaconazole to voriconazole for the primary treatment of invasive aspergillosis., Methods: We did a randomised, prospective, double-blind, double-dummy, controlled trial comparing posaconazole (intravenous or oral posaconazole 300 mg twice on day 1, followed by 300 mg once a day for days 2-84) with voriconazole (6 mg/kg intravenous or 300 mg oral twice on day 1 followed by 4 mg/kg intravenously or 200 mg orally twice a day for days 2-84) for 12 weeks or less in the primary treatment of invasive aspergillosis. Participants were from 91 study sites in 26 countries, were aged 13 years or older, weighed at least 40 kg, and met criteria for proven, probable, or possible fungal disease. Participants were randomly assigned (1:1) via a computer-generated randomisation schedule with stratification by risk status. The primary endpoint was cumulative all-cause mortality up until day 42 in the intention-to-treat (ITT) population (defined as randomly assigned participants who received ≥1 dose of study drug), with a 10% non-inferiority margin. The ITT population was also evaluated for safety. This study is registered with ClinicalTrials.gov, NCT01782131, and EudraCT, 2011-003938-14., Findings: Between Oct 25, 2013, and Sept 10, 2019, of 653 individuals assessed for eligibility, 575 ITT participants were randomly assigned and received one or more doses of study drug (n=288 [50%] posaconazole, n=287 [50%] voriconazole). Mortality up until day 42 was 15% (44 of 288) in the posaconazole group and 21% (59 of 287) in the voriconazole group (treatment difference -5·3% [95% CI -11·6 to 1·0]; p<0·0001). Mortality up until day 42 in the full-analysis-set subpopulation (ITT participants with proven or probable invasive aspergillosis) supported this conclusion: 31 (19%) of 163 participants in the posaconazole group and 32 (19%) of 171 participants in the voriconazole group (treatment difference 0·3% [95% CI -8·2 to 8·8]). The most frequently reported treatment-related adverse events (incidence >3%) were increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT), nausea, hypokalaemia, and vomiting in the posaconazole group and increased ALT, AST, or alkaline phosphatase, hallucination, increased γ-glutamyltransferase peptidase, nausea, and blurred vision in the voriconazole group. The overall incidence of treatment-related adverse event rates in the ITT population was 30% for posaconazole and 40% for voriconazole (treatment difference -10·2% [95% CI -17·9 to -2·4])., Interpretation: Posaconazole was non-inferior to voriconazole for all-cause mortality up until day 42 in participants with invasive aspergillosis. Posaconazole was well tolerated, and participants had fewer treatment-related adverse events than in the voriconazole group. This study supports the use of posaconazole as a first-line treatment for the condition., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics, and optimal regimens of voriconazole are currently not well defined in cirrhotic patients., Design: Retrospective pharmacokinetics study., Setting: Two large, academic, tertiary-care medical center., Patients: Two hundred nineteen plasma trough concentrations (C min ) from 120 cirrhotic patients and 83 plasma concentrations from 11 non-cirrhotic patients were included., Methods: Data pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model-based simulation was used to optimize voriconazole dosage regimens., Results: Voriconazole-related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold C min for AE was 5.12 mg/L. A two-compartment model with first-order elimination adequately described the data. The Child-Pugh class and body weight were the significant covariates in the final model. Voriconazole clearance in non-cirrhotic, Child-Pugh class A and B cirrhotic (CP-A/B) and Child-Pugh class C cirrhotic (CP-C) patients was 7.59, 1.86, and 0.93 L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model-based simulations showed that a loading dose regimen of 200 mg/12 hours intravenously or orally led to 65.0-75.7% of voriconazole C min in therapeutic range on day 1, and the appropriate maintenance dosage regimens were 75 mg/12 hours and 150 mg/24 hours intravenously or orally for CP-A/B patients, and 50 mg/12 hours and 100 mg/24 hours intravenously or orally for CP-C patients. The predicted probability of achieving the therapeutic target concentration for optimized regimens at steady-state was 66.8-72.3% for CP-A/B patients and 70.3-74.0% for CP-C patients., Conclusions: These results recommended that the halved loading dose regimens should be used, and voriconazole maintenance doses in cirrhotic patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/B patients compared to that for patients with normal liver function., (© 2020 Pharmacotherapy Publications, Inc.)

Background: Incidence of pulmonary aspergillosis is rising worldwide, owing to an increased population of immunocompromised patients. Notable potential of the pulmonary route has been witnessed in antifungal delivery due to distinct advantages of direct lung targeting and first-pass evasion. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization., Results: The developed nanosystem exhibited a particle size in the range of 228-255 nm and drug entrapment of 45-54.8%. Nebulized microdroplet characterization of NPs dispersion revealed a mean diameter of  ≤ 5 μm, corroborating its deep lung deposition potential as determined by next-generation impactor studies. Biophysical interaction of LPH NPs with lipid-monolayers indicated their surface-active potential and ease of intercalation into the pulmonary surfactant membrane at the air-lung interface. Cellular viability and uptake studies demonstrated their cytocompatibility and time-and concentration-dependent uptake in lung-epithelial A549 and Calu-3 cells with clathrin-mediated internalization. Transepithelial electrical resistance experiments established their ability to penetrate tight airway Calu-3 monolayers. Antifungal studies on laboratory strains and clinical isolates depicted their superior efficacy against Aspergillus species. Pharmacokinetic studies revealed nearly 5-, 4- and threefolds enhancement in lung AUC, T max , and MRT values, construing significant drug access and retention in lungs., Conclusions: Nebulized LPH NPs were observed as a promising solution to provide effective and safe therapy for the management of pulmonary aspergillosis infection with improved patient compliance and avoidance of systemic side-effects.

Background: The present limitations related to the ocular administration of antifungal drugs for the treatment of fungal keratitis include poor ocular bioavailability, limited retention time, and low ocular tissue penetration., Methods: This study aimed to prepare a novel ophthalmic voriconazole-loaded nanosuspension based on Eudragit RS 100. Pharmasolve® was explored as a corneal permeation enhancer in voriconazole ophthalmic formulation using in vitro and in vivo experiments. Briefly, 1% voriconazole-loaded nanosuspension was prepared using the quasi-emulsion solvent evaporation process., Results: Characterizations of the voriconazole-loaded nanosuspension by Zetasizer Nano ZS and Transmission Electron Microscope (TEM) showed a uniform spherical shape without any agglomeration. The well-discreted nanoparticle with a size of 138 ± 1.3 nm was achieved with high entrapment efficiency (98.6 ± 2.5%) and positive zeta potential in the range of 22.5-31.2mV, indicating excellent physical stability., Discussion: Voriconazole-loaded nanosuspension containing the penetration enhancer displayed good permeability both in vitro and in vivo compared with the commercial voriconazole injection. The voriconazole-loaded nanosuspension exhibited good antifungal activity, significantly inhibiting the growth of Candida albicans at a lower concentration of voriconazole (2.5μg/mL, p < 0.05)., Conclusion: In conclusion, the voriconazole-loaded nanosuspension containing Pharmasolve® can be used as an effective ophthalmic formulation for the topical ocular delivery of voriconazole., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

For intensive care unit (ICU) patients, injectable voriconazole (VRCZ) is difficult to use because the patients often develop acute kidney injury. Since many ICU patients have consciousness disturbance, oral ingestion of tablet formulation is also difficult, and administration of a suspension via enteral feeding tube is required when using VRCZ. In this study, we investigated the in vitro adsorption property of oral VRCZ to feeding tube and performed pharmacokinetic analysis of VRCZ prepared by powdering and simple suspension for ICU patients. VRCZ was tube-administered to five ICU patients at a loading dose of 300 mg and plasma VRCZ concentrations before and at 1, 2, 4, 8, 12 h after the first dose were measured using HPLC. Pharmacokinetic parameters were calculated by non-compartmental model analysis. The recovery rate of VRCZ after infusion of the suspension through feeding tube was 89.8 ± 8.3%, but the cumulative rates after the first and second re-infusion were 102.7 ± 20.7 and 99.3 ± 10.3%, respectively, suggesting almost no residual drug in the tube after re-infusion. Metabolic phenotype was extensive metabolizer (EM) in two patients and intermediate metabolizer (IM) in three patients. The values of total clearance (CL tot /F) calculated by moment analysis were 0.51 and 0.55 L/h/kg in two EM patients, and 0.09, 0.29 and 0.31 L/h/kg in three IM patients. The CL tot /F was apparently lower in IM patients compared to EM. In conclusion, powdered and suspended VRCZ administered via enteral feeding tube showed pharmacokinetics depending on CYP2C19 gene polymorphism, similar to that observed in usual oral administration.