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Trichosporon species are part of the normal microbiota of humans which can cause both superficial and invasive infections, primarily affecting immunocompetent and immunocompromised hosts, respectively. Giant ulcer caused by Trichosporon asahii is relatively uncommon in immunocompetent hosts. Increased drug resistance and biofilm-associated virulence makes the treatment of infectious ulcers challenging. Herein, we present a case of a massive ulcer caused by T. asahii which resulted in completed healing when treated with photodynamic therapy (PDT) and voriconazole. It provided the feasibility for PDT combined with antifungal drugs to treat similar refractory cases.

Purpureocillium lilacinum and Fusarium species are increasingly recognized as significant opportunistic fungal pathogens. We report a rare case of co-infection in a 63-year old heart transplant recipient presenting with nodular skin lesions, treated successfully with voriconazole. We highlight the importance of being vigilant about co-infection with moulds as it impacts on the selection of appropriate antifungal agents. 2012 Elsevier Ltd. All rights reserved.

This study reports a case of multidrug resistant Candida krusei as the cause of early neonatal sepsis in a term small-for-gestational age neonate weighing 1680 g that successfully responded to voriconazole therapy. Both blood culture and urine culture of the neonate sent on day 4 and day 8 respectively showed Gram positive oval budding yeast cells on Gram staining which was confirmed as C. krusei susceptible only to voriconazole by Vitek 2 Compact (Biomérieux, France) automated system. Voriconazole was given for fourteen days leading to good clinical response with microbiological clearance of fungus from blood and no side-effects.

In the current study, voriconazole (VCZ) augmented glycerosomes were optimized for topical otomycosis management according to a 23 factorial design, employing a thin film hydration method. By optimizing Glycerol volume, limonene: VCZ ratio and Span® 60: soybean phosphatidyl choline (PC) ratio, glycerosomes with maximum percentage entrapment efficiency (%EE) and zeta potential (ZP) and minimum vesicle size (VS) and polydispersity index (PDI) were to be obtained. An optimal augmented glycerosomal formula (OAG) that contained 10 mg VCZ, 150 mg PC, and 3 mL glycerol, comprising 2.5: and 0.92:1 ratios of the latter two independent variables, was proposed via numerical optimization. OAG exhibited high %EE and ZP values and acceptable low values for VS and PDI (84.3 ± 2.0 %, −38.8 ± 1.8 mV, 191.0 ± 1.1 nm, and 0.192 ± 0.01, respectively). Extensive in vitro testing of OAG revealed the entrapment of VCZ within OAG, biphasic in vitro release profile, stability for up to 3 months at 2–8 °C and spherical morphology of OAG with VS like that obtained via zetasizer. OAG demonstrated higher permeated amounts of VCZ and flux values than VCZ suspension, leading to an enhancement ratio of 2.56 in the ex vivo permeation study. The deeper penetration ability of OAG demonstrated by Confocal Laser Scanning Microscopy and its superior in vitro antifungal activity confirmed the validity of the ex vivo study. Also, the histopathological study confirmed the safety of OAG for topical use, suggesting that VCZ OAG was a promising topical antimycotic formula.

Aspergillus peritonitis is a rare but highly severe complication of peritoneal dialysis with a high mortality rate. We report a case of Aspergillus fumigatus peritonitis. Despite early removal of the catheter and oral voriconazole antifungal treatment for 3 weeks, the treatment effect was unsatisfactory, resulting in prolonged hospital stay and affecting the patient's quality of life. After switching to liposomalAmphotericin B, inflammation indicators rapidly decreased and infection was controlled. Liposomalamphotericin B provides an option for treatment of Aspergillus peritonitis.

Antifungal prophylaxis postheart transplant (HT) may include voriconazole or clotrimazole, which interact with tacrolimus. There is no guidance for tacrolimus adjustment when transitioning from voriconazole to clotrimazole; therefore, this study evaluates tacrolimus concentration/dose (C/D) ratio on voriconazole compared to clotrimazole. This retrospective, single-center analysis included HT recipients (February 2016-September 2021) who received tacrolimus and voriconazole followed by clotrimazole. Tacrolimus C/D ratio was compared on voriconazole vs clotrimazole, and on clotrimazole vs postantifungal discontinuation. Seventy-two patients were included. The median (interquartile range) tacrolimus C/D ratio was 41% (1.7-fold) lower after transition from voriconazole to clotrimazole [5.1 (3.5, 7.7) vs 3.0 (2.0, 4.6) (ng/ml)/(mg/day), p

Periosteal reaction may result from multiple causes including infection, trauma, medications, and neoplasms. One important etiology that must be considered in the differential diagnosis of symmetric periosteal reaction, especially in immunocompromised patients, is voriconazole use. We present a case of a 65-year-old man who underwent liver transplantation complicated by acute hypoxic respiratory failure and Aspergillus infection. Long term voriconazole therapy was initiated with resultant development of thoracic periosteal reaction which improved following discontinuation of the medication. Given the preferential upper body distribution of periosteal reaction induced by voriconazole, chest radiologists might be the first ones to recognize this adverse effect.

We presented two cases of Cryptococcus albidus fungemia in men who were identified with millary nodules by chest computed tomography (CT). They present cough and fever, with no other abnormal physical examination. The patients were treated successfully with a week-long course of voriconazole tablets. Accurate microbiological diagnosis of NGS and effective therapy as antifungal treatment of voriconazole tablet are critical for C albidus infection. Total of 18 cases of C albidus infection cases were identified from 2000 years to now, eight of which were invasive C albidus infection, and ten were noninvasive infection. None died cases were reported in noninvasive infection.

Aspergillosis is an infrequent infection in the Central Nervous System with a mortality rate higher than 95 %. Early diagnosis is challenging and crucial. In this report, we present the case of a six-year-old female with an intense headache accompanied by left hemiparesis, gaze deviation, horizontal nystagmus, and vomiting of mucous content on five occasions. After several approaches, a cerebrospinal fluid PCR resulted positive for Aspergillus spp., and then management started with amphotericin B at 2.6 mg/kg/day and was managed to have voriconazole. She survived, and two years after her first hospital admission, she suffered from cerebral aspergillosis sequelae. An area of improvement is the coordination between the request and delivery of studies outside the institution. In this case, the patient´s mother did not report the analysis results on time, delaying the diagnosis.

Scedosporium, a widespread filamentous fungus found in diverse environments, has experienced a rise in cases due to escalating malignancies and chronic immunosuppression. Clinical manifestations span mycetoma, airway involvement, and various infections, with osteomyelitis being a notable complication. We present a case of a 77-year-old female initially displaying cutaneous Scedosporium signs, which progressed to osteomyelitis. The patient, with a history of trauma, chronic low dose steroid use, and underlying conditions, presented with a foot injury caused by her dog. Despite initial management, worsening symptoms led to the identification of Scedosporium. A comprehensive approach involving debridement, antimicrobial therapy, and reduction of immunosuppression resulted in clinical improvement. The rarity of zoonotic transmission, diagnostic challenges, and antifungal efficacy are also discussed. The patient's positive trajectory emphasizes early diagnosis, targeted treatment, and vigilance in managing immunosuppression. An adaptable treatment protocol is proposed based on risk factors. Considering the rising opportunistic fungal infections and delayed culture results, initiating empirical antifungals based on clinical judgment and regional prevalence is vital for favorable outcomes.

Scedosporium apiospermum is a saprophytic filamentous fungus that is pathogenic to dogs. This report describes a case of S. apiospermum infection that caused multiple large peritoneal fungal granulomas in a dog with a history of jejunojejunostomy. The lesions were firmly attached to multiple organs and could not be surgically removed. In such cases, no precedent for the response to the treatment of this disease exists, and all affected dogs have died. This is the first report of an effective medical treatment for multiple intra-abdominal fungal granulomas using voriconazole.

Purpose: To describe a case of unilateral Acanthamoeba-associated retinitis in the absence of concomitant corneal infection in an immunocompetent host without risk factors. Observations: A 37-year-old woman presented with unilateral multifocal retinitis with minimal vitritis. Anterior segment was normal. Conventional diagnostics of bacterial, fungal, viral, Toxoplasma and Toxocara etiologies all returned negative. Empiric treatments were unsuccessful, including oral valacyclovir, oral fluconazole, as well as intravitreal injection of vancomycin and ceftazidime. Metagenomic deep sequencing (MDS) identified Acanthamoeba genomic fragments in the vitreous sample. Multiple intravitreal voriconazole injections were performed and achieved partial suppression of lesion growth. Subsequent dual therapy of oral voriconazole and trimethoprim-sulfamethoxazole led to resolution of the lesions and vision improvement without further injections. Conclusions and importance: This is an unusual case of unilateral Acanthamoeba-associated retinitis without concomitant corneal infection, diagnosed via unbiased DNA and RNA deep sequencing, with other etiologies ruled out by conventional approaches. Treatment with systemic and intravitreal therapy led to a successful resolution of retinitis and vision improvement. Our case demonstrates the potential of MDS as an unbiased diagnostic tool for rare ocular pathogens and the therapeutic effect of oral voriconazole with trimethoprim-sulfamethoxazole for Acanthamoeba intraocular infection.

Albeit invasive fusariosis is extremely rare in immunocompetent patients, we describe an immunocompetent patient suffering from a central line-associated blood stream infection (CLABSI) and the difficulties in distinguishing between blood culture contamination and clinical significance.

Introduction: Voriconazole (VRZ) is the recommended standard treatment for life-threatening invasive aspergillosis. The plasma concentration of VRZ should be determined to optimise treatment results and reduce side effects. This study aimed to compare the correlation and concordance of ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) to determine VRZ plasma concentration in clinical practice. Methods: An isotopically labelled internal standard UPLC-MS/MS method was established, validated, and subsequently applied to determine VRZ concentration. The UPLC-MS/MS method was also compared with a commercial EMIT method regarding results correlation and concordance. Results: The calibration curve of UPLC-MS/MS was linear from 0.1 to 10 mg/L, the inter- and intra-day relative standard deviations (RSDs), and the stability of quality control samples were less than 15 %, satisfying the Bioanalytical Method Validation Guidelines. A total of 122 plasma samples were collected and analyzed using both methods. UPLC-MS/MS and EMIT showed a high correlation (r = 0.9534), and Bland-Altman analysis indicated a mean absolute bias of 1.035 mg/L and an average bias of 27.56 % between UPLC-MS/MS and EMIT. The paired Wilcoxon test and Bland-Altman analysis revealed poor consistency between the two methods. Furthermore, we compared the effects of different methods in clinical applications. Two threshold values for treatment efficacy (1.0 mg/L) and safety (5.5 mg/L) were established, and considerable discordance was observed between the original EMIT and UPLC-MS/MS results at both thresholds (p

Extracorporeal photopheresis is an established procedure for refractory graft-versus-host disease, a major complication associated with notable morbidity and mortality in patients with allogeneic hematopoietic stem cell transplant. Despite being implemented over a decade ago, there is scant information about potential interactions or analytical interferences with concomitant drugs in this polymedicated population. Here we report the case of a pediatric patient diagnosed with cutaneous steroid-refractory acute graft-versus-host disease after unrelated allogeneic hematopoietic stem cell transplant that was treated with photopheresis. Analytical quantification of voriconazole by HPLC-PDA the day following photopheresis treatment did not permit therapeutic drug monitoring (TDM) due to the presence of interference at the voriconazole retention time. Following investigations, it was demonstrated that the interference is likely attributable to a psoralen-based compound. The interference was not present when samples were obtained prior to photopheresis, enabling TDM. This case underscores the relevance of communication among the members of the treating team to perform reliable TDM, especially in routine clinical practice of pediatric patients with complex diseases undergoing innovative treatments. This finding is relevant to voriconazole quantification by HPLC-PDA, frequently used in laboratories based in middle-income countries.

Amphotericin B and itraconazole are the primary agents for treating histoplasmosis. Newer azoles are alternatives for patients refractory to or intolerant of standard therapy. We report an 83-year-old woman with rheumatoid arthritis complicated with pleuropulmonary histoplasmosis who responded to liposomal amphotericin B, but progressed under voriconazole and posaconazole maintenance therapy.

A two-year-old neutered male Coton de Tulear presented with lethargy, anorexia, and tachypnea. Cystic masses noticed at the cranial mediastinal region were diagnosed as granuloma containing hyphae of Aspergillus versicolor. Despite antifungal treatment using itraconazole, fluconazole, and voriconazole, the lesions spread to the lung. After euthanasia, Schizophyllum commune was identified in the lung and splenic lymph node. This is the first case of fungal infection caused by A. versicolor and S. commune in a dog.

We report a case of intractable Aspergillus otomycosis with multiple relapses despite conventional topical and systemic antifungal treatment, and adjunctive usage of hyperbaric oxygen therapy. Of note, otomycosis relapsed even after six months of continuous systemic antifungal treatment with therapeutic drug levels and without treatment interruption; and only resolved after application of topical voriconazole. (max. 75 words)

Chimeric antigen receptor (CAR-) T cell therapy is a relatively new form of immunotherapy for hematological malignancies. Although patients are at increased risk of infection following CAR-T cell therapy, reports of fungal infections are scarce. We report a case of Scedosporium apiospermum infection causing bursitis of the elbow in a lymphoma patient after treatment with CAR-T cells. The fungal bursitis relapsed under posaconazole treatment, but was cured after surgical extirpation of the bursa.

Background/Objective: Voriconazole treatment has been associated with diffuse periostitis, especially in immunocompromised patients who have had transplants or are on immunosuppressants. Here, we present a case of diffuse periostitis induced by prophylactic low-dose voriconazole for pulmonary aspergillosis. Case Report: A 66-year-old woman presented with 1 year of progressive, diffuse bone pain most prominent over the left shoulder and bilateral hips. She had a history of sarcoidosis requiring a single orthotopic lung transplant. Left phalangeal soft tissue swelling and painful nodules without clubbing were noted on examination. Prophylactic voriconazole 200 mg twice a day for pulmonary aspergillosis was prescribed for over 7 years. Elevated levels of alkaline phosphatase (469 units/L [reference range, 38-126]), bone-specific alkaline phosphatase (125 μg/L [0-20]), and parathyroid hormone (137 pg/mL [8-54]) and normal c-telopeptide level (842 pg/mL [34-1037]) were noted. Radiographs showed “multifocal periostitis” in both hip joints and bilateral proximal femurs, findings suggestive of voriconazole-induced periostitis deformans. Voriconazole was discontinued, and the patient improved symptomatically, despite persistent bone deformities on imaging. Discussion: Diffuse bone pain can be due to various pathologies, including metabolic or inflammatory diseases and bone tumors. Voriconazole-induced periostitis is caused by skeletal fluorosis, which can result in diffuse bone pain. It is a clinical diagnosis that is supported with radiologic findings, including focal, nodular, dense, and irregular periosteal reactions. Biochemical evaluation may reveal elevated alkaline phosphatase levels, but it is usually related to normal voriconazole trough levels. Periostitis is a benign condition, and discontinuation of the drug usually leads to clinical improvement. Conclusion: Voriconazole-induced periostitis should be considered as a diagnosis in elderly, immunosuppressed patients with diffuse bone pain on antifungal treatment. Early recognition of voriconazole-induced periostitis may result in both improved patient clinical outcomes and avoidance of unnecessary diagnostic testing.

Voriconazole is a broad-spectrum triazole antifungal used to treat invasive fungal infections. It is commonly used prophylactically in immunocompromized patient cohorts, including transplant recipients. Diffuse periostitis is a very rare complication of chronic voriconazole use. It is associated with diffuse bone pain, elevated serum alkaline phosphatase and fluorine levels. Characteristic imaging findings include periosteal thickening with a dense, nodular, irregular and often bilateral pattern. We describe the case of a 71-year-old female who presented with multifocal bone pain six years following double lung transplantation. Her post transplantation course had been complicated by a life threatening episode of sepsis secondary to Scedosporium apiospermum, a rare invasive fungal infection following which lifelong prophylaxis with oral Voriconazole was commenced. We discuss the characteristic clinical and imaging manifestations of this rare condition.

Cladophialophora and other dematiaceous or pigmented fungi are inhabitants of soil and decaying vegetation in tropical and sub-tropical environments. It usually causes subcutaneous phaeohyphomycosis post-inoculation by thorns or vegetable matter prick. It may be inhaled into paranasal sinuses and lungs with subsequent clearance by intact host immunity. In immunocompromised individuals, it can cause invasive sinusitis or pneumonitis followed by hematogenous dissemination to involve distant organs, particularly the brain. Disseminated disease with hematogenous brain abscess is found occasionally. We encountered such an interesting case and successfully treated it with surgical drainage followed by dual anti-fungal therapy.

We report a case of Talaromyces marneffei fungemia in a patient with HIV infection with a history of travelling to southern China. At first, Pneumocystis pneumonia was considered in this case because chest CT images showed typical ground-glass opacity and elevated β-D-glucan levels. However, PCR testing of sputum for Pneumocystis jirovecii was negative and a filamentous fungus was isolated from blood cultures. The cultured fungus was subsequently identified as T. marneffei, and the patient was considered to have pneumonia caused by this organism. However, skin disease and lymphadenopathy, which are common in T. marneffei infections, were not observed during the disease course. This patient was successfully treated with voriconazole and consequently the chest CT shadow disappeared. In the present case, T. marneffei infection required differentiation from pneumonia with Pneumocystis jirovecii infection.

Purpose: Pyrenochaeta unguis-hominis (syn. Neocucurbitaria unguis-hominis) is a rare fungal species belonging to the Coelomycetes group, mostly isolated from infected nails and skin.We present a case of contact lens-related fungal keratitis caused by Pyrenochaeta unguis-hominis. Observations: We present a case of a 69-year-old woman with multiple risk factors for a fungal keratitis including ophthalmological history of herpetic keratitis, contact lens wear and chronic steroid use. At presentation, the corneal ulcer resembled a recurrent herpetic keratitis but evolved into a more dense stromal infiltrate despite antiviral therapy. Microscopic examination, culture and staining of corneal tissue obtained by scraping showed mycelia. PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry confirmed the presence of Pyrenochaeta unguis-hominis. Topical antifungal treatment was able to dim the inflammation. Because of a persistent epithelial defect, an amniotic membrane transplantation was performed. Although corneal epithelium was restored, stromal scarring in the visual axis resulted in substantial vision loss. Conclusions: To our knowledge no other cases of fungal keratitis caused by Pyrenochaeta unguis-hominis have been described. Early diagnosis can allow prompt initiation of antifungal treatment, which should be guided by in vitro susceptibility testing.

According to the ICH M9 Guideline, the triazole antifungal voriconazole is a Biopharmaceutics Classification System (BCS) class II drug, being highly soluble at the highest dose strength but not at the highest single dose. Although the ICH M9 allows for consideration of BCS-based biowaivers in such cases, voriconazole does not meet the additional requirement of dose proportional pharmacokinetics (PK) over the therapeutic dose range. By contrast, if the classification were based on the FDA solubility criteria that were in place prior to ICH M9 (based on the highest dose strength), voriconazole would belong to BCS class I and thus qualify for the BCS-based biowaiver. Since the highest oral dose strength of voriconazole dissolves very rapidly under all BCS conditions, and comparative in vitro dissolution of different tablet formulations aligns with the demonstration of BE in clinical studies, it seems that the ICH Guideline may be unnecessarily restrictive in the case of voriconazole. Therefore, this review discusses potential revisions of eligibility criteria and the extension of biowaiver approvals to encompass a wider range of appropriate drugs. Specifically, a classification system that is more relevant to in vivo conditions, the refined Developability Classification System (rDCS), coupled with biorelevant dissolution testing, may be more applicable to compounds like voriconazole., Competing Interests: Declaration of competing interests The 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. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Journal name] and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024. Published by Elsevier Inc.)

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum, caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase general control of amino-acid synthesis 5-like 2. Impairment of general control of amino-acid synthesis 5-like 2 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors, rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Trichosporon species are part of the normal microbiota of humans which can cause both superficial and invasive infections, primarily affecting immunocompetent and immunocompromised hosts, respectively. Giant ulcer caused by Trichosporon asahii is relatively uncommon in immunocompetent hosts. Increased drug resistance and biofilm-associated virulence makes the treatment of infectious ulcers challenging. Herein, we present a case of a massive ulcer caused by T. asahii which resulted in completed healing when treated with photodynamic therapy (PDT) and voriconazole. It provided the feasibility for PDT combined with antifungal drugs to treat similar refractory cases., Competing Interests: Declaration of competing interest All authors declare no potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. 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.)

We report an atypical presentation of Beauveria bassiana keratitis which unusually presented in a 85-year-old patient with a corneal ulcer with an anterior segment inflammation and hypopyon. Despite negative culture and unspecific results from panfungal PCR-based sequencing, the patient was treated for a presumed fungal infection. Following clinical deterioration an emergency surgical intervention with apposition of a corneal patch was performed. Infection resolution was achieved following the introduction of systemic voriconazole to the topical one.

Background/purpose: Invasive Trichosporon infections are emerging, but association of different therapeutic management of Trichosporon fungemia and clinical outcomes were rarely reported. This study investigates the epidemiology, species distribution and genotypes of trichosporonosis in Taiwan, and identified the predictors of clinical outcomes in patients with Trichosporon fungemia. Methods: Strains collected from four medical centers in Taiwan, during 2010–2018. Species identification was confirmed by sequencing of IGS1 region, and antifungal susceptibility was performed using Sensititre YeastOne panel. Results: Among 115 isolates, Trichosporon asahii was the leading species (73.0%), followed by Trichosporon dermatis (11.3%), Trichosporon faecales (6.1%), and Trichosporon montevideense (5.2%). Of the 84 T. asahii isolates, genotype 1 was the predominant (41.7%). High fluconazole minimal inhibitory concentration (MICs,≧8 μg/mL) were observed for 70.2% T. asahii isolates and 16.1% non-asahii Trichosporon isolates. Posaconazole and voriconazole possess the most potent antifungal activity against all Trichosporon isolates, with geometric mean values of 0.251 μg/mL and 0.111 μg/mL, respectively. Fifty-three isolates collected from blood cultures, and 42 patients with fungemia enrolled for the Kaplan–Meier plot which revealed that voriconazole treatment had a significantly better survival rate compared with those without (p = 0.042). In multivariate analysis, source control (odds ratio [OR]: 0.13 95%CI [confidence interval]: 0.02–0.83, p = 0.031) and voriconazole use (OR: 0.11 95%CI: 0.02–0.74, p = 0.023) are independent predictors of 14-day mortality. Conclusion: This is the largest series of Trichosporon fungemia up till the present moment. Voriconazole therapy and source control play important roles in 14-day mortality.

We present a case of Kluyveromyces marxianus keratitis nine months after Descemet's membrane endothelial keratoplasty (DMEK) in a patient with Fuchs endothelial disease. Endothelial scraping revealed this rare yeast infection at the interface between graft and host cornea. Immediate antifungal treatment with intracameral and corneal intrastromal injections of voriconazole and amphotericin B remained unsuccessful, requiring penetrating keratoplasty. This case highlights the challenging management of keratomycosis in patients with endothelial grafts.

Hormographiella aspergillata is a rare cause of invasive mold infection, mostly described in patients with hematological malignancies. We describe two cases of invasive H. aspergillata infections in patients with acute myeloid leukemia, successfully managed with complete surgical resection of the lesions and antifungal therapy of voriconazole alone or liposomal amphotericin B, followed by voriconazole, highlighting the key role of a multidisciplinary approach for the treatment of this rare and severe invasive mold infection.

Invasive pulmonary aspergillosis is a complication in critically ill patients with acute respiratory distress syndrome, especially those with severe coronavirus disease-associated pneumonia. In this study, five cases of presumed invasive pulmonary aspergillosis in one immunocompromised and four immunocompetent patients with COVID-19 in Buenos Aires are described. In all cases, the underlying conditions, clinical presentation, fungal diagnostic tests used and their results, features of the chest scan images, antifungals used and clinical outcomes are detailed.

Background and objectives: Aspergillus keratitis are in the increasing trend and reported as the second most common cause of mycotic keratitis in developing countries. The present study was designed to isolate, identify Aspergillus spp. from the keratits/corneal ulcer patients attending a tertiary care eye hospital, Coimbatore, South India and to assess the minimum inhibitory concentrations (MICs) against ten clinically used first-line antifungal drugs. Methods: A total of seventy-three Aspergillus strains isolated from corneal scrapings were included and assessed for a period of one year. All isolates were identified up to the species level by morphological observations. Antifungal drug susceptibilities were determined against a standard panel of antifungal agents. Conclusions: Five different species of aspergilli, A. flavus (n=53), A. fumigatus (n=14), A. terreus (n=9), A. tamarii (n=6) and A. niger (n=3) were identified based on morphological features. Minimum inhibitory concentration analyses indicated that, voriconazole, natamycin, itraconazole, clotrimazole, econazole followed by ketoconazole shall be the order of choices for the effective treatment for Aspergillus keratitis.

Background: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity., Methods: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination., Results: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of V max inhibition [V max, inh ] = 100 %; V max  = 0). The estimated parameters of V max,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher., Conclusion: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect V max,inh of voriconazole in children with malignancy or inborn errors of immunity., Competing Interests: Declaration of competing interest KS received honoraria for lectures from Viatris, Inc. IM and MK received honoraria from Pfizer for lectures. All the other authors have indicated they have no potential conflicts of interest to disclose., (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.)

Objectives: Voriconazole serum concentration, which is affected by several factors, is associated with treatment response and toxicity. There is paucity of data on voriconazole therapeutic drug monitoring (TDM) among Southeast Asians, who exhibit a higher prevalence of CYP2C19-poor metabolisers compared with Caucasians and East Asians. Hence, there are concerns for higher risk of voriconazole accumulation and toxicity.We aim to determine the utility of voriconazole TDM through establishing: (1) proportion of patients achieving therapeutic troughs without dose adjustments; (2) characterisation of patients with sub-therapeutic, therapeutic and supra-therapeutic levels; (3) appropriate dose titrations/dose required for therapeutic troughs; (4) correlation between troughs and adverse events, treatment response/fungal breakthrough. Patients and methods: A single-centre retrospective analysis of data from adults (≥21 years old) with ≥1 voriconazole trough measured at Singapore General Hospital from 2015 to 2017 was performed. Results: Thirty-two patients (45.7%) among 70 patients achieved therapeutic troughs (defined as 2.0–5.5 mg/L) without dose adjustments. Eleven patients (15.7%) experienced hepatotoxicity (troughs 0.5 to >7.5 mg/L). Neurotoxicity occurred in three patients (4.3%) (troughs ≥6.7 mg/L) and all patients had symptom resolution upon dose reduction. Treatment failure of invasive fungal infection appeared less in patients with therapeutic troughs compared with sub-therapeutic troughs (11.4% vs. 14.2%). Two patients experienced treatment failure despite supra-therapeutic voriconazole troughs. Conclusions: TDM should be implemented due to significant unpredictability in dose exposure. TDM can reduce unnecessary switches to alternatives due to intolerability and rule in the possibility of resistant organisms in the event of treatment failure despite therapeutic troughs, alerting clinicians to switch to alternatives promptly.

Sternal Osteomyelitis from Aspergillus fumigatus in immunocompetent patients is extremely rare with limited number of cases reported so far. Here we discuss the case of a 65-year-old female with osteomyelitis of the sternum caused by Aspergillus fumigatus after undergoing coronary artery bypass graft surgery. Patient was treated with surgical debridement and prolonged antifungal therapy; however, the course was complicated due to poor adherence to antifungal therapy.

Sphenoid sinus aspergilloma (SSA) with visual loss has rarely been reported. Timely recognition and prompt surgical intervention are crucial to avoid permanent neurological consequences.

Purpureocillium lilacinum and Fusarium species are increasingly recognized as significant opportunistic fungal pathogens. We report a rare case of co-infection in a 63-year old heart transplant recipient presenting with nodular skin lesions, treated successfully with voriconazole. We highlight the importance of being vigilant about co-infection with moulds as it impacts on the selection of appropriate antifungal agents. 2012 Elsevier Ltd. All rights reserved., (© 2024 The Authors.)

This study reports a case of multidrug resistant Candida krusei as the cause of early neonatal sepsis in a term small-for-gestational age neonate weighing 1680 g that successfully responded to voriconazole therapy. Both blood culture and urine culture of the neonate sent on day 4 and day 8 respectively showed Gram positive oval budding yeast cells on Gram staining which was confirmed as C. krusei susceptible only to voriconazole by Vitek 2 Compact (Biomérieux, France) automated system. Voriconazole was given for fourteen days leading to good clinical response with microbiological clearance of fungus from blood and no side-effects., (© 2024 The Authors.)

Recognizing that metal ions play an important role in modifying the pharmacological properties of known organic-based drugs, the present manuscript addresses the complexation of the antifungal agent voriconazole (vcz) with the biologically relevant silver(I) ion as a strategy for the development of new antimycotics. The synthesized silver(I) complexes with vcz were characterized by mass spectrometry, IR, UV-Vis and NMR spectroscopy and single-crystal X-ray diffraction analysis. The crystallographic results showed that complexes {[Ag(vcz)(H 2 O)]CH 3 SO 3 } n (1), {[Ag(vcz) 2 ]BF 4 } n (2) and {[Ag(vcz) 2 ]PF 6 } n (3) have polymeric structures in the solid state, in which silver(I) ions have a distorted tetrahedral geometry. On the other hand, DFT calculations revealed that the investigated silver(I) complexes 1-3 in DMSO exist as linear [Ag(vcz-N2)(vcz-N19)] + (1a), [Ag(vcz-N2)(vcz-N4)] + (2a) and [Ag(vcz-N4) 2 ] + (3a) species, respectively. The evaluated complexes showed an enhanced anti-Candida activity compared to the parent drug with minimal inhibitory concentration (MIC) values in the range of 0.02-1.05 μM. In comparison with vcz, the corresponding silver(I) complexes showed better activity in prevention hyphae and biofilm formation of C. albicans, indicating that they could be considered as promising agents against Candida that significantly inhibit its virulence. Also, these complexes are much better inhibitors of ergosterol synthesis in the cell membrane of C. albicans at the concentration of 0.5 × MIC. This is also confirmed by a molecular docking, which revealed that complexes 1a - 3a showed better inhibitory activity than vcz against the sterol 14α-demethylase enzyme cytochrome P450 (CYP51B), which plays a crucial role in the formation of ergosterol., Competing Interests: Declaration of competing interest The 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. Published by Elsevier Inc.)

Background: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert., Methods: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms., Results: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 μg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group., Conclusions: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy., Competing Interests: Declaration of Competing interest Y. M. received travel funding and lecture fee from Pfizer Japan Inc. H. M. received honorarium from Pfizer R&D Japan G.K. The other authors declare no conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (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.)

With the evolving COVID-19 pandemic, increasing concerns about invasive fungal infections have been reported particularly with the use of potent immunosuppressant medications to treat the immunological storms in patients with severe COVID-19 illnesses. Trichosporon asahii (T. asahii) is an emerging highly resistant pathogen with considerable mortality particularly in critically ill patients and immunocompromised individuals. We describe a case of a 58-year-old patient who developed T. asahii fungemia after using immunosuppressant agents for his severe COVID-19 related cytokines release syndrome. Pseudohyphae, arthroconidia, and lateral blastoconidia were seen in the stain, and later confirmed to be T. asahii. Voriconazole successfully treated this multi-drug-resistant fungal infection. The clinical presentation, assessment, and management are reviewed to raise awareness of the circumstances leading to coinfection with this emerging resistant yeast.

Antifungal prophylaxis is crucial for successful hematopoietic stem cell transplantation (HSCT). Maintenance therapy with fluconazole (FLCZ) is generally prescribed as secondary prophylaxis in patients with human immunodeficiency virus infection and non-immunocompromised hosts. However, previous reports have revealed that FLCZ is insufficient as a secondary prophylaxis for cryptococcal infection in HSCT cases. There is no well-established evidence of effective secondary prophylaxis against cryptococcal infection in conditions of severe immunosuppression, such as in HSCT. Herein, we report a case of atypical chronic myeloid leukemia (aCML) presenting with cryptococcal meningitis. A 58-year-old man with progressive leukocytosis and headache was referred to our hospital. Bone marrow biopsy revealed aCML. Because the estimated overall survival was limited, HSCT was indicated. Furthermore, enhanced magnetic resonance imaging and lumbar puncture aided in diagnosing cryptococcal meningitis, which was treated with a combination therapy comprising liposomal amphotericin B and 5-fluorocystine for 28 days. Given the high recurrence rate of cryptococcal meningitis, voriconazole (VRCZ) dose was calculated using the trough concentration of VRCZ in the cerebrospinal fluid. Eventually, HSCT was successfully performed at an appropriate therapeutic range of VRCZ. To the best of our knowledge, there is no case report on HSCT with secondary prophylaxis against cryptococcal meningitis. Our report thus emphasizes the efficacy of VRCZ maintenance therapy as secondary prophylaxis for cryptococcal infection.

The aim of this study was to formulate and optimize by statistical means mucoadhesive and biodegradable sponge-like inserts loaded with voriconazole (VCZ) which increases the contact time of the drug with the eye and sustain its release from the formula in a controlled manner. This avoids the pulsed effect reported for the drug suspension and results in reducing the number of drug instillations in the eye with the result of enhancing the patient compliance. Also, the sponge like nature of the insert reduces the foreign body sensation caused by other ocular solid dosage forms. They were prepared using casting/freeze-drying technique using five polymers namely high molecular weight chitosan (CH), sodium alginate (AL), sodium carboxy methyl cellulose (CMC), gellan gum (GG) and xanthan gum (XG). The prepared inserts were subjected to evaluations of their visual appearance, weight variation, drug content, surface pH, in-vitro release (percent drug released after 1h (Q1 (%)), mean dissolution time (MDT) and dissolution efficiency (DE)) in addition to kinetic analysis of the release data, water uptake, mucoadhesion and rheology of the forming plain polymer solution at the maximum rate of shear. The independent variables of the D-optimal factorial design were the polymer type and concentration while Q1 (%), MDT, DE, % water uptake after 15 minutes and rheology at the maximum rate of shear were chosen as dependant variables. The performed optimization process using design expert software showed an optimum formula consisting of 2 % GG. It showed slow release behavior compared to the drug suspension. FTIR and DSC studies showed that there is no interaction between VCZ and GG. The optimum formula has good in-vitro mucoadhesive properties and pH in the safe ocular range. Moreover, it showed promising in-vivo results of rapid hydration and gelling in addition to good mucoadhesive behavior when instilled in the eye, high ocular safety and biocompatibility, sustained antifungal activity in comparison to the drug suspension and finally biodegradation. So, it may be taken into consideration as an outstanding carrier for the ocular delivery of VCZ., Competing Interests: Declaration of Competing Interest The 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 © 2023. Published by Elsevier Inc.)

Purpose: Only recently Tintelnotia was described as a new genus in the Phaeosphaeriaceae family of fungi containing two species, T. opuntiae and T. destructans. Until now, T. destructans keratitis was associated with contact lens wear and ocular trauma. We present the first case of T. destructans keratomycosis presenting as a superinfection in herpetic keratitis. Observations: We present a case of a 53-year-old woman who presented with a unilateral keratitis since 3 weeks without history of trauma or contact lens wear, not responding to topical ofloxacin. Polymerase Chain Reaction (PCR) of the corneal ulcer was positive for Herpes Simplex Virus type 1 (HSV-1). Signs and symptoms progressively improved after starting topical and systemic antiviral therapy. Six weeks later however, our patient presented with a new white infiltrate in the previous herpetic epithelial defect. In vivo confocal microscopy showed fungal hyphae and culture from corneal scrapings identified a hyphomycete. Intensive antimycotic therapy could not prevent a corneal perforation 1 week later. Penetrating keratoplasty was performed with intracameral injection of amphotericin B. Culture of the corneal button and PCR and sequence analysis on the fungal isolate confirmed the diagnosis of T. destructans keratomycosis. Six months after penetrating keratoplasty, biomicroscopy showed a clear graft without recurrence of fungal activity. Conclusions and importance: T. destructans is an emerging opportunistic pathogen causing severe keratomycosis. Despite intensive antimycotic therapy, rapid progression to corneal perforation can be seen. Early diagnosis using confocal microscopy, fungal culture and PCR can allow prompt initiation of treatment, which should be guided by in vitro susceptibility testing.

Infections caused by Aspergillus species are often life-threatening. Drugs effective for Aspergillus infection are limited. Voriconazole is one of the most important drugs, however, considerable portion of patients experience liver toxicity and have to stop the drug administration. We frequently experience liver toxicity even though the serum concentration of voriconazole is within the target range. Historically, in some life-threatening situations like tuberculosis, where a suitable alternative is unavailable, rechallenge has been attempted. However, there have been no report on the rechallenge of voriconazole. We report cases of successful re-administration of voriconazole after liver toxicity.