Itraconazole Treatment Research Articles

Successful treatment of chronic pulmonary aspergillosis in a patient with early pulmonary tuberculosis and COVID-19: a case report.

Chronic pulmonary aspergillosis (CPA) often develops in residual lesions of pulmonary tuberculosis (PTB). Every year, 112,000 to 160,000 people worldwide will develop post-PTB CPA. The simultaneous occurrence of CPA with the first episode of PTB is rare. During the COVID-19 pandemic, COVID-19- associated invasive aspergillosis (CAPA) occurred in patients receiving high doses of corticosteroids and mechanical ventilation. However, CPA and COVID-19 are rarely reported simultaneously. This case study presents a patient with CPA in the first episode of PTB during hospitalization for COVID-19. The favorable evolution is highlighted, including the resolution of the cavitation and fungal ball with appropriate and early treatment. A 48-year-old female patient from the Central West of Brazil was admitted with a history of cough, yellow sputum, fever, and significant weight loss for two months. The respiratory symptoms worsened one week before admission. She tested positive for COVID-19 by RT-PCR. She had a history of hypertension and diabetes. Clinical examination revealed tachypnea, slurred speech, and hypoxia. She presented with hyperglycemia, obesity, hypertension, and an episode of hemoptysis. Chest CT revealed cavitation in the right upper lobe with a 45 mm aspergilloma, multifocal morning opacities, and nodular opacities. Laboratory tests confirmed the PTB with positive sputum for acid-fast bacilli and positive culture for Mycobacterium tuberculosis. The sputum culture also showed Aspergillus spp. She received early treatment for bacterial pneumonia with ceftriaxone, dexamethasone, enoxaparin, an anti-TB regimen, and itraconazole. There was a progressive clinical improvement and the patient was discharged after 15 days. She completed six months of anti-TB therapy and 13 months of itraconazole treatment for CPA, with complete resolution of the cavitation and aspergilloma. This case study presents a unique case of CPA that manifested as simple aspergilloma and was diagnosed concurrently with the initial episode of PTB in a COVID-19 patient with obesity, hypertension, and diabetes. Remarkably, the fungal ball and cavitation regressed spontaneously. The favorable clinical and radiological results highlight the importance of comprehensive treatment approaches for concurrent respiratory infections and emphasize the need to investigate CPA and PTB during COVID-19 hospitalization.

Aspergillus-mediated allergic airway inflammation is triggered by dendritic cell recognition of a defined spore morphotype.

BackgroundExposure to fungi, especially Aspergillus fumigatus (A.f.), can elicit potent allergic inflammation that triggers and worsens asthmatic disease. Dendritic cells (DCs), initiate allergic inflammatory responses to allergic stimuli. However, it is unclear if A.f. spores during isotropic growth (early spore swelling) can activate DCs to initiate allergic responses or if germination is required. This lack of basic understanding of how A.f. causes disease is a barrier to the development of new treatments. ObjectiveTo show that a precise A.f. morphotype stage during spore swelling can trigger DCs to mediate allergic inflammatory responses and ascertain if antifungal therapeutics can be effective at suppressing this process. MethodsWe employed an A.f. strain deficient in pyrimidine biosynthesis (ΔpyrG) to generate populations of A.f. spores arrested at different stages of isotropic growth (swelling) via temporal removal of uracil and uridine from growth media. These arrested spore stages were cultured with bone marrow derived DCs (BMDCs), and their activation measured via flow cytometry and ELISA to interrogate which growth stage was able to activate BMDCs. These BMDCs were then adoptively transferred into the airways, to assess if they were able to mediate allergic inflammation in naive recipient mice. Allergic airway inflammation in vivo was determined via flow cytometry, ELISA and qPCR. This system was also used to determine if antifungal drug (itraconazole) treatment could alter early stages of spore swelling and therefore BMDC activation and in vivo allergic inflammation upon adoptive transfer. ResultsWe found that A.f. isotropic growth is essential to trigger BMDC activation and mediate allergic airway inflammation. Furthermore, using time arrested A.f. stages, we found that least 3h in growth media enabled spores to swell sufficiently to activate BMDCs to elicit allergic airway inflammation in vivo. Incubation of germinating A.f. with itraconazole reduced spore swelling and partially reduced their ability to activate BMDCs to elicit in vivo allergic airway inflammation. ConclusionIn summary, our results have pinpointed the precise stage of A.f. development when germinating spores are able to activate DCs to mediate downstream allergic airway inflammation. Furthermore, we have identified that antifungal therapeutics partially reduced the potential of A.f. spores to stimulate allergic responses, highlighting a potential mechanism by which antifungal treatment might help to prevent the development of fungal allergy.

Rare Case of Subcutaneous Phaeohyphomycosis Caused by Exophiala jeanselmei

Abstract Introduction/Objective Phaeohyphomycosis is a neglected tropical infection caused by dematiaceous fungi containing melanin in their cell wall. Currently, the prevalence of phaeohyphomycosis is very low in the United States compared to other mycotic agents. Trauma often precedes phaeohyphomycosis, and there are a limited number of cases associated with healthcare settings. This case report describes a nosocomial phaeohyphomycosis caused by Exophiala jeanselmei. Methods/Case Report A 60-year-old male with multiple myeloma, on immunosuppressive therapy, presented with a large fluctuant mass on the dorsum of his right hand. The mass had developed 6 months ago as a hematoma following a blown vein during a blood draw. Despite treatment with antibiotics, the mass continued to grow. The patient underwent surgical excision of the lesion, and the purulent aspirate was sent to the microbiology lab. Aerobic, anaerobic, mycobacterial, and fungal cultures, along with Gram and AFB stains, were performed. Direct microscopy of the aspirate revealed numerous leukocytes and few yeast cells. No sclerotic bodies were observed. Fungal growth with black pigmentation was observed during the second week of incubation. Colonies initially appeared smooth black and mucoid, later transforming into raised dome-shaped structures with a suede-like texture. Microscopic analysis revealed budding yeast cells and subglobose to broadly ellipsoidal germinating cells, which developed into short torulose hyphae before gradually transforming into unswollen hyphae. The isolate was further identified through D2 rDNA sequencing, revealing a 100% match for Exophiala jeanselmei. The patient was prescribed a one-month course of itraconazole treatment. The patient is progressing well during follow-up. Results (if a Case Study enter NA) NA Conclusion This case emphasizes the need for heightened clinical awareness in diagnosing phaeohyphomycosis, particularly in healthcare environments. Unique traumatic events like venepuncture should raise suspicion of phaeohyphomycosis. Culture and molecular diagnostics play a crucial role in confirming fungal causes and guiding treatment, leading to better patient outcomes.

Insights into Aspergillus fumigatus Colonization in Cystic Fibrosis and Cross-Transmission between Patients and Hospital Environments.

Approximately 60% of individuals with cystic fibrosis (CF) are affected by Aspergillus fumigatus infection. This condition is correlated with a decline in lung function and is identified as an independent risk factor contributing to hospital admissions among CF patients. This study investigates the dynamic interplay of A. fumigatus within the context of CF patients, tracing its evolution over time, with a specific emphasis on colonization dynamics. An analysis was conducted on 83 sequential A. fumigatus isolates derived from sputum samples of six patients receiving care at a renowned CF hospital in Brazil. Employing microsatellite genotyping techniques, alongside an investigation into cyp51A gene mutations, this research sheds light on the genetic variations, colonization, and resistance of A. fumigatus within the CF respiratory environment. Our research findings indicate that CF patients can harbor A. fumigatus strains from the same clonal complexes for prolonged periods. Additionally, we identified that clinical isolates have the potential to spread among patients in the same healthcare facility, evidencing hospital contamination. Two patients who underwent long-term Itraconazole treatment did not show phenotypic resistance. However, one of these patients exhibited mutations in the cyp51A gene, indicating the need to monitor resistance to azoles in these patients colonized for long periods by A. fumigatus. We also observed co-colonization or co-infection involving multiple genotypes in all patients over time. This comprehensive examination offers valuable insights into the pathogenesis of A. fumigatus infections in CF patients, potentially shaping future therapeutic strategies and management approaches. This enhanced understanding contributes to our knowledge of A. fumigatus impact on disease progression in individuals with cystic fibrosis. Additionally, the study provides evidence of cross-contamination among patients undergoing treatment at the same hospital.

Chronic Severe Laryngeal Inflammation Caused by Basidiobolomycosis

Basidiobolomycosis is an uncommon fungal infection primarily found in plants. In humans, it typically affects the skin and gastrointestinal tract on manifestation of the infection. A 29-year-old female presented to our clinic with complaints of shortness of breath and voice changes. On examination, she exhibited severe laryngeal edema. She was initially diagnosed with type 3 hereditary angioedema with a normal C1 inhibitor and later as a case of laryngeal sarcoidosis, treatment for both conditions proved ineffective. Ultimately, after further microbiological assessment, she was diagnosed with chronic granulomatous laryngeal fungal infection caused by the Basidiobolus species. Subsequently, she displayed significant improvement with itraconazole treatment. Chronic laryngeal edema can have various underlying causes. This case underscores the importance of considering fungal pathogens, especially rare ones when assessing such conditions. In cases where the diagnosis is uncertain or standard treatments are ineffective, patient reassessment and repeated laryngeal biopsies are essential.

Misdiagnosis of cutaneous facial sporotrichosis: An analysis of five cases.

Facial cutaneous sporotrichosis presents with diverse clinical manifestations, often leading to misdiagnosis. This study aims to present the clinical characteristics of five misdiagnosed cases of facial cutaneous sporotrichosis, aiming to enhance understanding of this disease and prevent misdiagnosis and mistreatment. Clinical data, histopathology, and fungal culture results of these five cases were comprehensively analyzed. Among these five patients, three presented with lymphocutaneous sporotrichosis, while two had the fixed cutaneous type. Due to misdiagnosis, initial treatments were ineffective for all patients. Upon histopathological examination and fungal culture confirming sporotrichosis, treatment with itraconazole for 3 months led to complete resolution of lesions. While one patient experienced a relapse due to noncompliance with the prescribed medication. Facial sporotrichosis, with its diverse clinical manifestations and obscure trauma history, is prone to misdiagnosis. Timely and thorough examinations are crucial for precise diagnosis and management. Itraconazole treatment demonstrated notable efficacy, and patient compliance is also essential for favorable outcomes.

When cat rescue fails — Part 1. Lion-clip shaving, enilconazole bathing and oral itraconazole treatment failed to control an iatrogenic Microsporum canis outbreak in a shelter: but a novel ophytrium-chlorhexidine shampoo and mousse treatment succeeded in the home

OBJECTIVE: To identify the reason(s) for failure to prevent repeated nosocomial dermatophyte infection of shelter cats and to present alternative strategies which are less stressful to the cats and humans involved. ANIMALS: The Dorset branch of the Royal Society for the Prevention of Cruelty to Animals (RSPCA) seized 30 of 32 Persian cats from a cat breeder on the 2nd of August 2019 and put them into Ashley Heath RSPCA shelter. Two cats and three dogs were left at home. All 30 cats were returned to their guardian in July 2020. Three cats died between 2020 and 2022, leaving 29 cats which were seized on the 8th of March 2022 and put into two RSPCA shelters. The dogs were not seized. Four cats were later euthanased. METHODS: RSPCA Animal Treatment Reports along with photographs used for evidence in the court case against the breeder and the veterinary records of their primary veterinary surgeon were retrospectively reviewed. RESULTS: Clinical signs of dermatophytosis occurred on the index_ _case one week after dematting with clippers in August 2019. _Microsporum canis_ (_M. canis) _was cultured from 27 of 30 (90%)_ _cats on the 39th day of the Ashley Heath shelter stay in 2019. _M. canis_ infection could only have been acquired while in RSPCA care because the incubation period from infection to development of clinical signs for _M. canis_ is one to three weeks, and there was no history of ringworm in their home. Efforts to control the ringworm outbreak in the shelter included lion clipping, weekly enilconazole bathing and oral itraconazole (EI treatment) for five or seven weeks until culture negative. Six cats became culture positive again in 2020. Cats were housed in pairs in 2019 to 2020 and singly in 2022, therefore transmission was indirect (i.e. via fomites). Two cats remained positive when the cats were returned to their guardian in 2020, all 30 were treated with a single ophytrium-chlorhexidine (Douxo S3 Pyo) shampoo followed by ophytrium-chlorhexidine mousse rubbed into their fur for three weeks. It was reasonable to conclude that the ophytrium-chlorhexidine treatment had cleared the _M. canis_ infection for the following six reasons: first no cat developed clinical signs of dermatophytosis during the 20 months in their home. Second, no obvious ringworm lesions were seen on the photographs taken for evidence and third, no veterinary surgeon noted in the records any lesions suspicious of dermatophytosis during the examination of the cats within days of them being seized again in March 2022. Fourth: no positive dermatophyte results were produced as evidence during the trial (ringworm charges against the owner were dropped). Fifth: three of four dermatophyte tests performed on EI untreated cats were negative and samples from the positive cat were after three months in the shelter. Sixth: no EI treatment was administered until the cats had been in the shelters again for two and a half months. Nevertheless, shelter staff assumed ringworm infection from the arrival of the cats in 2022 and again subjected them to the stressful shaving/bathing/itraconazole protocol. CLINICAL RELEVANCE AND CONCLUSIONS: This is the first report of ophytrium-chlorhexidine for treatment and prevention of _M. canis _in cats. We recommend shelter staff be trained in basic barrier nursing and be educated regarding the difference between true dermatophyte infection versus fomite carriage.

Abstract 5286: M2 to M1 repolarization of tumor-associated macrophages via the lysosomal effect of itraconazole

Abstract Objective: Itraconazole (ITZ), an antifungal agent, has been reported to have tumor agnostic anticancer effects. Previous reports have shown prolonged survival in patients with lung and ovarian cancer who received ITZ. The anticancer mechanisms vary depending on the cancer type and stromal cells. Based on our previous studies, we focused on tumor-associated macrophages (TAMs). Methods: Anti-tumorigenic M1 and pro-tumorigenic M2 macrophages were established from THP-1 cells and their phenotypes were determined based on morphology, cell surface antigens by Western blotting, and secreted proteins by ELISA. Bulk proteomic analysis of cell proteins was conducted using liquid chromatography-tandem mass spectrometry. The viability of CaSki cervical cancer cells was evaluated both in culture with the supernatant and co-culture with M2 macrophages after treatment with ITZ (10-5 M). Single-cell RNA sequencing (scRNA-seq) with surface labeling of M2 macrophages with and without the ITZ was performed. Using LoupeBrowser (10x Genomics, Inc.), ITZ-treated M2 macrophages were divided into two groups, one with newly emerged clusters after ITZ treatment (group 1) and the other (group 2). Differentially expressed genes between group 1 and group 2 were identified based on a two-fold and a 0.05 adjusted p value and were subjected to Reactome pathway analysis. Significant pathways were identified based on both p value < 0.05 and FDR <0.3. A triple-labeling immunofluorescence study was conducted to detect cholesterol, IL-1β, and organelles (the endoplasmic reticulum, phagosome, and lysosome). Results: ITZ changed M2 macrophages to M1-like morphology and protein expression. While co-culture with M2 macrophages promoted cancer cell proliferation, both culture with the supernatant and co-culture with ITZ-treated M2 macrophages significantly inhibited CaSki cell growth. scRNA-seq identified newly emerged clusters (group 1) among M2 macrophages following ITZ treatment. Group 1 had elevated mRNA expression of M1 markers, including IL1β, IL6, CD86, TL4, GAPDH, and RKM, compared to group 2. Group 1 expressed the CD86 and TLR4 surface antigen proteins. Pathway analysis identified 176 significant pathways including lysosome vesicle biogenesis. Immunofluorescence analysis showed that M1-like macrophages in ITZ-treated M2 macrophages had enlarged lysosomes containing cholesterol. Conclusion: ITZ repolarized THP-1 derived M2 macrophage to an M1-like phenotype. The mechanism of repolarization involves intracellular cholesterol accumulation via lysosomal dysfunction. Citation Format: Yumi Takimoto, Hiroshi Tsubamoto, Kazuko Sakata, Roze Isono-Taniguchi, Tomoko Ueda, Hiroaki Shibahara. M2 to M1 repolarization of tumor-associated macrophages via the lysosomal effect of itraconazole [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5286.

Efficacy and Safety of Combination Treatment of Oral Terbinafine and Itraconazole in Patients with Extensive Superficial Dermatophytes

Background: Dermatophytosis, a prevalent fungal infection, is instigated by species like Trichophyton, Epidermophytonand Microsporum. The current approach for treating dermatophytosis involves a blend of systemic and topical antifungal therapies, applicable to all patients except those with localized, untreated Tinea. Notably, there is a growing incidence of inadequate response to the standard treatment regimen in recent times. Objective: To evaluate the efficacy andsafety of combination treatment of oralterbinafine anditraconazole in patients with extensive superficial dermatophytes. Materials and Methods: This research comprised a randomized clinical trial involving 50 individuals diagnosed with extensive superficial dermatophytosis. Study conducted at the Department of Dermatology and Venereology, Combined Military HospitalCumilla, the study spanned from July 2022 to June 2023. During the six-week duration, patients underwent treatment with terbinafine and itraconazole, with follow-up examinations every two weeks, including relevant investigations. Evaluation of treatment outcomes occurred at both four and six weeks. Statistical analysis was performed using version 25 of the Statistical Package for the Social Sciences (SPSS). Results: This study shows the majority of the participants within the age range of 16-30 years (56.0%) and the average age of the participants is 31.74±11.77 years. In terms of gender, the majority are male (78.0%). The most prevalent diagnosis is Tinea corporis (68.0%), followed by Tinea cruris (36.0%), Tinea faciei (28.0%), and Tinea incognito (12.0%). The majority of participants (85.0%) have had the disease for 12 months or less. The most common sites are the trunk (35.0%), whole body (26.0%), and crural area (24.0%). The majority of participants experience severe itching (56.0%), followed by moderate itching (34.0%), and a smaller percentage report mild itching (10.0%). The majority of participants showed improvement, with percentages increasing from 66.0% after 2 weeks to 84.0% after 4 weeks.The percentage of cured individuals also increased over time, reaching a substantial 90.0% after 6 weeks. Conclusion: The amalgamation of terbinafine and itraconazole demonstrates a superior clinical cure rate compared to use of single systemic antifungals. However, the observed clinical cure rate percentage is lower when juxtaposed with findings from previous studies. Notably, neither combination of systemic antifungals has exhibited efficacy against tinea infections previously treated with formulations containing topical steroids

The efficacy of oral itraconazole in the treatment of otomycosis accompanied by a perforated tympanic membrane

: Managing otomycosis in patients with an existing tympanic membrane perforation can pose challenges. However, this study underscores the efficacy of oral itraconazole as a viable treatment option for such instances.The research encompassed 34 individuals experiencing both otomycosis and a perforated tympanic membrane. These participants received a combination of oral itraconazole and antibiotic ear drops as treatment. Over a period of six weeks, their progress was monitored to assess the treatment's effectiveness and to observe any potential instances of recurrence.Out of the total 34 subjects examined in the study, 25 individuals achieved complete recovery after just one week of oral itraconazole treatment. Among the remaining 9 patients, 6 experienced a successful resolution of the condition following two weeks of therapy. For 3 patients, an extended treatment duration was required, and in a singular case, a recurrence of the condition was observed at the six-week mark.Oral itraconazole treatment presents as an efficacious substitute for conventional approaches in addressing otomycosis accompanied by tympanic membrane perforation.

Efficacy and Safety of Combination Treatment of Oral Terbinafine and Itraconazole in Patients with Extensive Superficial Dermatophytes

Efficacy and Safety of Combination Treatment of Oral Terbinafine and Itraconazole in Patients with Extensive Superficial Dermatophytes

MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses-A Multicenter, Open-Label, Randomized Comparative Trial.

Invasive fungal disease caused by dimorphic fungi is associated with significant morbidity and mortality. Super-bioavailability itraconazole (SUBA-itra) is a novel antifungal agent with pharmacokinetic advantages over currently available formulations. In this prospective comparative study, we report the outcomes of patients with endemic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). This open-label randomized trial evaluated the efficacy, safety, and pharmacokinetics SUBA-itra compared with conventional itraconazole (c-itra) treatment for endemic fungal infections. An independent data review committee determined responses on treatment days 42 and 180. Eighty-eight patients were enrolled for IFD (SUBA-itra, n = 42; c-itra, n = 46) caused by Histoplasma (n = 51), Blastomyces (n = 18), Coccidioides (n = 13), or Sporothrix (n = 6). On day 42, clinical success was observed with SUBA-itra and c-itra on day 42 (in 69% and 67%, respectively, and on day 180 (in 60% and 65%). Patients treated with SUBA-itra exhibited less drug-level variability at days 7 (P = .03) and 14 (P = .06) of randomized treatment. The concentrations of itraconazole and hydroxyitraconazole were comparable between the 2 medications (P = .77 and P = .80, respectively). There was a trend for fewer adverse events (AEs; 74% vs 87%, respectively; P = .18) and serious AEs (10% vs 26%; P = .06) in the SUBA-itra-treated patients than in those receiving c-itra. Serious treatment-emergent AEs were less common in SUBA-itra-treated patients (12% vs 50%, respectively; P < .001). SUBA-itra was bioequivalent, well tolerated, and efficacious in treating endemic fungi, with a more favorable safety profile than c-itra. NCT03572049.

Itraconazole inhibits tumor growth via CEBPB-mediated glycolysis in colorectal cancer.

Advanced colorectal cancer (CRC) is characterized by a high recurrence and metastasis rate, which is the primary cause of patient mortality. Unfortunately, effective anti-cancer drugs for CRC are still lacking in clinical practice. We screened FDA-approved drugs by utilizing targeted organoid sequencing data and found that the antifungal drug itraconazole had a potential therapeutic effect on CRC tumors. However, the effect and mechanism of itraconazole on CRC tumors have not been investigated. A cell line-derived xenograft model in tumor-bearing mice was established and single-cell RNA sequencing was performed on tumor samples from four mice with or without itraconazole treatment. The proportion of cell populations and gene expression profiles was significantly different between the two groups. We found that itraconazole could inhibit tumor growth and glycolysis. We revealed that CEBPB was a new target for itraconazole, and that silencing CEBPB could repress CRC glycolysis and tumor growth by inhibiting ENO1 expression. Clinical analysis showed that CEBPB expression was obviously elevated in CRC patients, and was associated with poor survival. In summary, itraconazole treatment remodeled cell composition and gene expression profiles. Itraconazole inhibited cell glycolysis and tumor growth via the CEBPB-ENO1 axis. In this study, we illustrate a new energy metabolism mechanism for itraconazole on tumor growth in CRC that will provide a theoretical basis for CRC targeting/combination therapy.

Abstract A029: Re-purposing non-oncology agent itraconazole to target the dynamic cellular ecosystem of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of only 10% and persists as the third most common cause of cancer-related death in Western societies. Precision medicine is a likely future for all cancer treatment, but may have its greatest impact in less common, high-mortality and molecularly heterogeneous cancers, including pancreatic cancer. Fortunately, in the era of Big Data, bioinformatic analyses of genomic datasets have helped us gain new insights of how novel molecular-guided therapies can modulate signalling within tumors and their ecosystem (Vennin et al. 2017; Waddell, N, Pajic, M, Patch, AM. et al. 2015; Chou A. et al. 2018; Lau, MT. et al 2020). In this study, we delineate, at single-cell resolution, the complex stromal mechanisms by which a clinically-used, orally available anti-fungal agent itraconazole improves the overall anti-tumor response in PDAC. Single-cell RNAseq analysis of the genetically-engineered KPC model (LSL- KrasG12D;LSL-Trp53 R172H/+) revealed significant downregulation of the pro-tumorigenic CD105+ cancer-associated fibroblast (CAF) signature post-itraconazole therapy in vivo. Moreover, single-cell trajectory inference of CAFs subsets revealed a marked effect of treatment on myofibroblasts (myCAFs), which produce the fibrotic PDAC desmoplasia. In support of these findings, immunofluorescence analyses further demonstrated decreased deposition of collagen and altered matrix remodelling within itraconazole-treated tumors. Within the antigen-presenting apCAF and inflammatory iCAF populations, itraconazole treatment led to decreased pro-tumorigenic Igf1-Itga6:Itgb4 signalling to specific tumor cell subsets, which was functionally associated with reduced metastatic colonisation in vivo. apCAFs also showed decreased expression of H2-Aa and CD74, major antigens expressed by apCAFs which act as decoys for corresponding receptors on CD4+/CD8+ T cells, thus leading to their impaired activation (Lakins et al, 2018). These potentially promising effects on the immune environment of PDAC were supported by significant positive changes within macrophage populations, including enrichment of M1-like pro-inflammatory macrophage signatures (confirmed via immunofluorescence), and further associated with positive signalling via Cxcl9-Cxcr3 and Tnf1rs-1a/1b ligand-receptors. scRNAseq revealed dampening of regulatory T cell homing and functional potency signals within the pancreatic tumor microenvironment was associated with increased CD8+ T-cell infiltration post-itraconazole treatment, and importantly, significantly improved response to immune checkpoint blockade in an advanced in vivo model of pancreatic cancer. In summary, these integrated bioinformatic and molecular studies provide scientific rationale for the development of itraconazole and immunotherapy combination in pancreatic cancer. Citation Format: Diego Chacon-Fajardo, Sean Porazinski, Jennifer Man, Howard Yim, Emad El-Omar, Anthony Joshua, Marina Pajic. Re-purposing non-oncology agent itraconazole to target the dynamic cellular ecosystem of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A029.

Abstract C017: The anti-fungal itraconazole improves immunotherapy efficacy in pancreatic ductal adenocarcinoma by reversing the immune-suppressive tumor microenvironment

Abstract Pancreatic cancer (PC) has 5-year survival rates of 11% and is projected to become the second leading cause of cancer-related deaths by 2030. Poor outcomes result from early metastasis and a lack of effectual therapies for advanced disease. Our previous large-scale genomics studies revealed PC is molecularly highly varied (1). This heterogeneity, lack of effective therapies and high mortality rate make PC a prime arena to advance personalised medicine strategies, where individual cancers are selected for optimal therapy depending on molecular subtype. Utilising our significant experience of molecular-guided anti-cancer therapies (2-6) and stromal biology expertise (2,6,7), we are taking drug-repurposing approaches to test agents with effects on stromal biology in combination with standard-of-care chemotherapies and immunotherapy, to improve clinical outcomes. Itraconazole is an FDA-approved anti-fungal with potential anti-cancer effects, although its efficacy in PC remains relatively unexplored. Preliminary in vivo findings indicate that itraconazole, in combination with standard-of-care chemotherapy gemcitabine/nab-paclitaxel, significantly delays disease progression in both mouse and patient-derived xenograft models of PC. Single cell RNA-seq analyses of tumors from the KPC orthotopic model of PC suggest itraconazole treatment can inhibit immunosuppressive aspects of the stroma and pro-tumorigenic, pro-metastatic signalling. Excitingly, combining itraconazole with anti-PD1/-CTLA4 immunotherapy provides significant survival advantages in the KPC orthotopic model of PC. Finally, using a model of metastatic PC, we show that itraconazole hinders metastatic colonisation in the liver. This work aims to identify subtypes of PC responsive to itraconazole allowing optimisation and translation of tailored therapies combining itraconazole and the latest clinically-utilised chemotherapies and immunotherapies.

A case of chromoblastomycosis caused by Fonsecaea pedrosoi: challenge in diagnosis

Link of Video Abstract: https://youtu.be/9CxOCuDn4f4 Background: Chromoblastomycosis (CBM) is a chronic, granulomatous mycosis of the skin and subcutaneous tissue produced by the traumatic inoculation of various dematiaceous fungi. CBM lesions are clinically polymorphic and often misdiagnosed as multiple infectious and noninfectious diseases. Early diagnosis and prompt treatment of CBM are important to prevent further complications. This case study aims to evaluate the chromoblastomycosis caused by Fonsecaea pedrosoi as a challenge in diagnosis. Case Presentation: A male, 47 years old, came to the dermatovenereology clinic with a chief complaint of a wound on his right leg 17 years ago. The skin appeared thicker and scaly and felt rough. He also complained of pain and itch on the wound. Dermatological examination revealed multiple verrucous erythematous plaques, sized 10x20 cm, irregular with a well-defined and elevated border and black punctum. Results of potassium hydroxide, culture, and histopathology examination confirmed CBM with F. pedrosoi as the etiological agent. The patient was treated with a favorable outcome with oral itraconazole, local thermotherapy, and CO2 laser. Conclusion: The diagnosis of Chromoblastomycosis remains a challenge because lesions are clinically polymorphic and often misdiagnosed as various infectious and noninfectious diseases. Physicians should raise awareness of CBM as one of the differential diagnoses for chronic wounds. This case also showed that the combination treatment of itraconazole with adjuvant thermotherapy and CO2 laser had a favorable outcome.

Paracoccidioidomycosis and pregnancy: A 40-year single-center cohort study in the endemic area of Rio de Janeiro, Brazil.

The occurrence of acute paracoccidioidomycosis (PCM) in urban areas of the Rio de Janeiro state, Brazil, has emerged in recent years. Therefore, young populations, including pregnant women, are at a higher risk of infection. Furthermore, young women undergoing itraconazole treatment for PCM have increased chances to get pregnant because this medication may reduce the effectiveness of contraceptives. Acute PCM is invasive, reaching abdominal organs, posing a maternal-fetal risk. PCM treatment in pregnant women is also challenging due to the teratogenicity associated with the currently available oral drugs. There are scarce studies on PCM and pregnancy, mainly consisting of case reports and experimental murine models that highlight the severity of this association. We conducted a database research at a PCM reference center in Rio de Janeiro state from 1980 to 2020. We included patients diagnosed with PCM who were pregnant shortly before, at admission, or at any moment of their PCM follow-up care. Data related to pregnancy, childbirth, and the newborn were obtained from the Brazilian official public databases. We also reviewed the epidemiological and clinical features of these patients. During the study period, we identified 18 pregnant patients, with a median age of 26 years (range: 16-38). Among these cases, six (33.3%) were detected in the last 5 years, and 14 (77.8%) presented acute PCM, supporting the recent shift in the epidemiological profile towards acute PCM. Most pregnancies occurred during PCM treatment (n = 11, 61.1%), which led to challenges in the therapeutic management. Maternal-fetal complications occurred in some of these cases, including vaginal bleeding (n = 1), preeclampsia (n = 1), prematurity (n = 2), low birth weight (n = 4), and fetal deaths (n = 2). PCM during pregnancy presents a significant public health concern in the context of the emergence of acute PCM in urban areas.

Retrospective Analysis of Liver Enzyme Abnormalities in Patients Prescribed Terbinafine and Itraconazole for Onychomycosis.

Introduction Onychomycosis (OM) is defined as a nail fungal infection. Its prevalence increases with advancing age. Human-to-human transmission makes it a serious public health risk. Although OM is not a life-threatening disease, it has a detrimental effect on patients' quality of life. Due to the long therapy duration and potential side effects of systemic antifungal medicines, physicians may be reluctant to treat OM orally. In this study, we aimed to evaluate the effect of terbinafine and itraconazole on liver transaminases, the side effects of these treatments, and patients' adherence to systemic treatment of OM. Methods This is a retrospective study conducted in our dermatology department (Ordu University, Ordu) between June 2020 and October 2021. Hospital records were analyzed, and patients with the diagnosis of tinea unguium (ICD code B35.1) were investigated. Patients who were prescribed terbinafine or itraconazole were included in the study. Following a clinical diagnosis of OM, the researchers first tried to confirm it through direct microscopic examination with potassium hydroxide (KOH). If the direct microscopic examination was negative but the suspicion about OM continued, confirmation was done through a fungal culture. Results This study included 735 patients, of whom 409 (55.6%) were female and 326 (44.4%) were male. The research covered all of the patients who were given one of these two medications. To find patients who could apply to other hospitals, the Turkish National Healthcare System was checked in addition to hospital information. To identify patients who could apply to other healthcare institutions, all hospitals share their data with this national healthcare system. Terbinafine was used by 433 patients (76.4%), 75 patients (13.2%), and 37 patients (6.5%), respectively, for one, two, and three months. A total of 119 patients (70.8%) took itraconazole for a month, 32 patients (19%) took it for two months, and four patients (2.33%) took it for three months. At the end of the first month, the proportion of the patients with elevated aspartate transaminase (AST) levels was 5.2% for terbinafine and 0% for itraconazole. Eighteen (8.4%) patients with terbinafine had elevated alanine aminotransferase (ALT) levels, and four patients (7.5%) who were on itraconazole treatment had high ALT levels. None of the patients reported cutaneous adverse drug reactions, gastrointestinal disturbances, or headaches due to OM treatment. Also, no patients discontinued treatment because of hepatotoxicity. Conclusion In this study, none of the patients discontinued the treatment because of hepatotoxicity. According to the results of this study, oral terbinafine and itraconazole can be used with close follow-up. Baseline and regular laboratory monitoring for AST and ALT should be done to monitor liver toxicity with terbinafine and itraconazole. Besides, we did not observe other side effects like cutaneous or cardiac side effects or drug-drug interactions.

Comparison of Efficacy and Safety between Super-bioavailable Itraconazole and Conventional Itraconazole in the Treatment of Tinea Infection of Glabrous Skin – A Randomised Observer-blinded Pilot Study

Itraconazole is now being used as the first line drug for dermatophytosis. Complete clinical and mycological cure are not achieved in some cases. The Super Bioavailable (SB) formulation is being marketed as a better formulation of drug in terms of bioavailability. To compare the efficacy and safety of SB and conventional Itraconazole in treatment of dermatophytosis. We compared the efficacy and safety of conventional itraconazole 100 mg twice daily with SB itraconazole 50 mg twice daily in dermatophytosis for two weeks. A convenient sample size of 30 was taken in each group. There was no significant difference in clinical parameters like erythema, scaling, number of papules between the two groups. Change in mean haemoglobin, total leucocyte count, platelet count, liver enzymes SGOT and SGPT and ALP did not differ significantly between the groups. There was no significant difference in the change in KOH status between the groups. There was no significant difference in clinical and mycological clearance between the conventional and the Super Bioavailable itraconazole at the end of two weeks in case of dermatophytosis of glabrous skin.

Antifungal Therapeutic Drug Monitoring Practices: Results of an Emerging Infections Network Survey.

In a survey of 523 infectious disease specialists, a moderate to high percentage reported using any antifungal therapeutic drug monitoring (TDM) during itraconazole (72%), posaconazole (72%), and voriconazole (90%) treatment, and a low to moderate percentage reported using any antifungal TDM during prophylaxis (32%, 55%, and 65%, respectively). Long turnaround times for send-out TDM testing and logistical difficulties were frequent barriers.