Evaluation of nikkomycin Z with frequent oral administration in an experimental model of central nervous system coccidioidomycosis.

We evaluated the in vivo activity of nikkomycin Z against central nervous system coccidioidomycosis. Mice were inoculated intracranially with arthroconidia of Coccidoides immitis, and treatment with nikkomycin Z (50, 100, or 300 mg/kg orally TID) or fluconazole (25 mg/kg orally BID) began 2 days later. Each dose of nikkomycin Z and fluconazole significantly improved survival and reduced brain fungal burden compared with vehicle control. Further studies of nikkomycin Z against coccidioidomycosis are warranted. IMPORTANCE: Coccidioides species are endemic fungi that are capable of causing disease in patients with various comorbidities, as well as in otherwise healthy individuals. Treatment options for coccidioidomycosis are suboptimal, as azole antifungals may be limited by drug interactions and adverse effects due to interactions with enzymes found in humans and other mammals. Nikkomycin Z is an investigational agent that works against a target specific to the fungal cell wall (chitin), which is not present in the cells of humans or other mammals. In this study, we show that frequent oral administration of nikkomycin Z is effective in an experimental model of central nervous system coccidioidomycosis. Further studies of nikkomycin Z against coccidioidomycosis may be warranted.

Universal digital high-resolution melting for the detection of pulmonary mold infections.

Invasive mold infections (IMIs) are associated with high morbidity, particularly in immunocompromised patients, with mortality rates between 40% and 80%. Early initiation of appropriate antifungal therapy can substantially improve outcomes, yet early diagnosis remains difficult to establish and often requires multidisciplinary teams evaluating clinical and radiological findings plus supportive mycological findings. Universal digital high-resolution melting (U-dHRM) analysis may enable rapid and robust diagnoses of IMI. A universal fungal assay was developed for U-dHRM and used to generate a database of melt curve signatures for 19 clinically relevant fungal pathogens. A machine learning algorithm (ML) was trained to automatically classify these pathogen curves and detect novel melt curves. Performance was assessed on 73 clinical bronchoalveolar lavage samples from patients suspected of IMI. Novel curves were identified by micropipetting U-dHRM reactions and Sanger sequencing amplicons. U-dHRM achieved 97% overall fungal organism identification accuracy and a turnaround time of ~4 hrs. U-dHRM detected pathogenic molds (Aspergillus, Mucorales, Lomentospora, and Fusarium) in 73% of 30 samples classified as IMI, including mixed infections. Specificity was optimized by requiring the number of pathogenic mold curves detected in a sample to be >8 and a sample volume to be 1 mL, which resulted in 100% specificity in 21 at-risk patients without IMI. U-dHRM showed promise as a separate or combination diagnostic approach to standard mycological tests. U-dHRM's speed, ability to simultaneously identify and quantify clinically relevant mold pathogens in polymicrobial samples, and detect emerging opportunistic pathogens may aid treatment decisions, improving patient outcomes. IMPORTANCE: Improvements in diagnostics for invasive mold infections are urgently needed. This work presents a new molecular detection approach that addresses technical and workflow challenges to provide fast pathogen detection, identification, and quantification that could inform treatment to improve patient outcomes.

A Mini-Review of In Vitro Data for Candida Species, Including C. auris, Isolated during Clinical Trials of Three New Antifungals: Fosmanogepix, Ibrexafungerp, and Rezafungin.

This mini-review summarizes the clinical outcomes and antifungal susceptibility results, where available, for three new antifungals, including fosmanogepix, ibrexafungerp, and rezafungin, against Candida isolates cultured from patients in clinical trials. When reported, most of the data were generated by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method or by both the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodologies. For fosmanogepix, we summarize the in vitro data for C. auris isolates from 9 patients and for Candida spp. cultured from 20 patients in two clinical trials. Ibrexafungerp has also been evaluated in several clinical trials. From conference proceedings, a total of 176 Candida isolates were evaluated in the FURI and CARES studies, including 18 C. auris isolates (CARES study). However, MIC data are not available for all clinical isolates. Results from the ReSTORE rezafungin phase 3 clinical study also included in vitro results against Candida spp., but no patients with C. auris infections were included. In conclusion, this mini-review summarizes insights regarding clinical outcomes and the in vitro activity of three new antifungals against Candida spp. cultured from patients in clinical trials.

Choanephora infundibulifera Rhinosinusitis in Man with Acute Lymphoblastic Leukemia, Tennessee, USA.

Choanephora infundibulifera is a member of the Mucorales order of fungi. The species is associated with plants as a saprophyte or parasite and may be responsible for spoilage or disease but is an uncommon cause of human infection. We describe C. infundibulifera rhinosinusitis in a young man with leukemia in Tennessee, USA.

Cutaneous Lagenidium deciduum infection in a patient with relapsed acute myeloid leukemia.

BACKGROUND: Lagenidium deciduum is an oomycete that can cause infections in mammals that present similarly to pythiosis and mucormycosis. Most of the existing case reports have occurred in canines and have been fatal. In animals, medical therapy has not been successful, so surgical excision is the mainstay of treatment. Lagenidium sp. infections in humans are rare. There is only one case of a human Lagenidium sp. infection in the literature, and it presented as an ocular infection. The human ocular infection was resistant to medical therapy and required a penetrating keratoplasty for cure. Additional reports of effective therapy are needed to guide management of this emerging pathogen. We present the first case of a cutaneous Lagenidium deciduum infection in a human patient, which is also the first documented case of a Lagenidium deciduum infection in an immunocompromised host of any species. CASE PRESENTATION: An 18-year-old female with relapsed acute myeloid leukemia, awaiting a haploidentical stem cell transplant, presented with erythematous cutaneous lesions on her left hip and bilateral buttocks that enlarged and blackened over several days. About 1 week later, boil-like lesions appeared on her bilateral buttocks. The skin lesions were initially presumed to be bacterial in origin, so the patient was treated with clindamycin and cefepime with little improvement. Upon further investigation, fungal cultures and skin biopsies revealed aseptate hyphae, so the patient was switched to isavuconazole and amphotericin B due to concern for mucormycosis. Phenotypic characterization and DNA sequencing were performed by the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, which identified the causal fungal organism as Lagenidium deciduum. All of her cutaneous lesions were surgically excised, and the patient was treated with micafungin, terbinafine, doxycycline, and azithromycin. Micafungin and terbinafine were continued until she achieved engraftment post-transplant. CONCLUSIONS: We report the first successful treatment of a human Lagenidium infection in an immunocompromised host through a combination of aggressive surgical excision and prolonged antifungal therapy during the prolonged neutropenia associated with allogeneic stem cell transplant. Prompt diagnosis and management may prevent disseminated oomycosis.

Ibrexafungerp is efficacious in a neutropenic murine model of pulmonary mucormycosis as monotherapy and combined with liposomal amphotericin B.

Ibrexafungerp (formerly SCY-078) is the first member of the triterpenoid class that prevents the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan by inhibiting the enzyme glucan synthase. We evaluated the in vivo efficacy of ibrexafungerp against pulmonary mucormycosis using an established murine model. Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with placebo (diluent control), ibrexafungerp (30 mg/kg, PO BID), liposomal amphotericin B (LAMB 10 mg/kg IV QD), posaconazole (PSC 30 mg/kg PO QD), or a combination of ibrexafungerp plus LAMB or ibrexafungerp plus PSC began 16 h post-infection and continued for 7 days for ibrexafungerp or PSC and through day 4 for LAMB. Ibrexafungerp was as effective as LAMB or PSC in prolonging median survival (range: 15 days to >21 days) and enhancing overall survival (30%-65%) vs placebo (9 days and 0%; P < 0.001) in mice infected with R. delemar. Furthermore, median survival and overall percent survival resulting from the combination of ibrexafungerp plus LAMB were significantly greater compared to all monotherapies (P ≤ 0.03). Similar survival results were observed in mice infected with M. circinelloides. Monotherapies also reduce the lung and brain fungal burden by ~0.5-1.0log10 conidial equivalents (CE)/g of tissue vs placebo in mice infected with R. delemar (P < 0.05), while a combination of ibrexafungerp plus LAMB lowered the fungal burden by ~0.5-1.5log10 CE/g compared to placebo or any of the monotherapy groups (P < 0.03). These results are promising and warrant continued investigation of ibrexafungerp as a novel treatment option against mucormycosis.

Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease.

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

Disseminated Aspergillus citrinoterreus and concurrent localized dermal phaeohyphomycosis in an immunosuppressed dog.

Key Clinical message: We report on a dog with immune-mediated hemolytic anemia (IMHA) treated with immunomodulatory therapy that developed phaeohyphomycosis and Aspergillus citrinoterreus infections. This is the first reported case of A. citrinoterreus in dogs. It details cytological and microbiological findings leading to diagnosis and highlights the importance of investigating new lesions in immunocompromised patients. Abstract: A 5-year-old Staffordshire terrier mix treated with immunosuppressive therapy for IMHA was diagnosed with concurrent disseminated A. citrinoterreus and localized Curvularia lunata infections. This case highlights the potential development of multiple concurrent opportunistic fungal infections and is the first reported case of A. citrinoterreus infection in a dog.

A Recombinant Multivalent Vaccine (rCpa1) Induces Protection for C57BL/6 and HLA Transgenic Mice against Pulmonary Infection with Both Species of Coccidioides.

Coccidioidomycosis is caused by Coccidioides posadasii (Cp) and Coccidioides immitis (Ci), which have a 4-5% difference in their genomic sequences. There is an urgent need to develop a human vaccine against both species. A previously created recombinant antigen (rCpa1) that contains multiple peptides derived from Cp isolate C735 is protective against the autologous isolate. The focus of this study is to evaluate cross-protective efficacy and immune correlates by the rCpa1-based vaccine against both species of Coccidioides. DNA sequence analyses of the homologous genes for the rCpa1 antigen were conducted for 39 and 17 clinical isolates of Cp and Ci, respectively. Protective efficacy and vaccine-induced immunity were evaluated for both C57BL/6 and human HLA-DR4 transgenic mice against five highly virulent isolates of Cp and Ci. There are total of seven amino acid substitutions in the rCpa1 antigen between Cp and Ci. Both C57BL/6 and HLA-DR4 mice that were vaccinated with an rCpa1 vaccine had a significant reduction of fungal burden and increased numbers of IFN-γ- and IL-17-producing CD4+ T cells in the first 2 weeks post challenge. These data suggest that rCpa1 has cross-protection activity against Cp and Ci pulmonary infection through activation of early Th1 and Th17 responses.