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Journal of Fungi (Basel, Switzerland) Oct 2020Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by and rare molds. Fosmanogepix... (Review)
Review
Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum in vitro activity against yeasts and molds, including difficult to treat pathogens. Because of its novel mechanism of action, manogepix retains potency against many resistant strains including echinocandin-resistant and azole-resistant Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as , and with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to and as well as pulmonary infection models of and Clinical trials demonstrated high oral bioavailability (>90%), enabling switching between fosmanogepix intravenous and oral formulations without compromising blood levels. Favorable drug-drug interaction, tolerability, and wide tissue distribution profiles are observed making fosmanogepix an attractive option for the treatment of invasive fungal infections. This systematic review summarizes the findings of published data on fosmanogepix.
PubMed: 33105672
DOI: 10.3390/jof6040239 -
Clinical Microbiology and Infection :... Apr 2014Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in...
Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium and Paecilomyces. Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first-line treatment of infections due to members of the genus Scedosporium. For Acremonium spp., Scopulariopsis spp., Purpureocillium spp. and Paecilomyces spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation.
Topics: Antifungal Agents; Fusarium; Humans; Hyalohyphomycosis; Scedosporium
PubMed: 24548001
DOI: 10.1111/1469-0691.12465 -
Open Forum Infectious Diseases Feb 2023Management of infections remains challenging. We described predisposing factors, clinical manifestations, and outcomes of these rare mold infections, including...
BACKGROUND
Management of infections remains challenging. We described predisposing factors, clinical manifestations, and outcomes of these rare mold infections, including predictors of early (1-month) and late (18-month) all-cause mortality and treatment failure.
METHODS
We conducted a retrospective Australian-based observational study of proven/probable infections from 2005 to 2021. Data on patient comorbidities, predisposing factors, clinical manifestations, treatment, and outcomes up to 18 months were collected. Treatment responses and death causality were adjudicated. Subgroup analyses, multivariable Cox regression, and logistic regression were performed.
RESULTS
Of 61 infection episodes, 37 (60.7%) were attributable to . Forty-five of 61 (73.8%) were proven invasive fungal diseases (IFDs), and 29 of 61 (47.5%) were disseminated. Prolonged neutropenia and receipt of immunosuppressant agents were documented in 27 of 61 (44.3%) and 49 of 61 (80.3%) episodes, respectively. Voriconazole/terbinafine was administered in 30 of 31 (96.8%) infections, and voriconazole alone was prescribed for 15 of 24 (62.5%) spp infections. Adjunctive surgery was performed in 27 of 61 (44.3%) episodes. Median time to death post-IFD diagnosis was 9.0 days, and only 22 of 61 (36.1%) attained treatment success at 18 months. Those who survived beyond 28 days of antifungal therapy were less immunosuppressed with fewer disseminated infections (both < .001). Disseminated infection and hematopoietic stem cell transplant were associated with increased early and late mortality rates. Adjunctive surgery was associated with lower early and late mortality rates by 84.0% and 72.0%, respectively, and decreased odds of 1-month treatment failure by 87.0%.
CONCLUSIONS
Outcomes associated with infections is poor, particularly with infections or in the highly immunosuppressed population.
PubMed: 36861090
DOI: 10.1093/ofid/ofad059 -
Emerging Infectious Diseases Jun 2024Scedosporium spp. and Lomentospora prolificans are emerging non-Aspergillus filamentous fungi. The Scedosporiosis/lomentosporiosis Observational Study we previously... (Observational Study)
Observational Study Review
Scedosporium spp. and Lomentospora prolificans are emerging non-Aspergillus filamentous fungi. The Scedosporiosis/lomentosporiosis Observational Study we previously conducted reported frequent fungal vascular involvement, including aortitis and peripheral arteritis. For this article, we reviewed 7 cases of Scedosporium spp. and L. prolificans arteritis from the Scedosporiosis/lomentosporiosis Observational Study and 13 cases from published literature. Underlying immunosuppression was reported in 70% (14/20) of case-patients, mainly those who had solid organ transplants (10/14). Osteoarticular localization of infection was observed in 50% (10/20) of cases; infections were frequently (7/10) contiguous with vascular infection sites. Scedosporium spp./Lomentospora prolificans infections were diagnosed in 9 of 20 patients ≈3 months after completing treatment for nonvascular scedosporiosis/lomentosporiosis. Aneurysms were found in 8/11 aortitis and 6/10 peripheral arteritis cases. Invasive fungal disease--related deaths were high (12/18 [67%]). The vascular tropism of Scedosporium spp. and L. prolificans indicates vascular imaging, such as computed tomography angiography, is needed to manage infections, especially for osteoarticular locations.
Topics: Humans; Scedosporium; France; Male; Middle Aged; Aged; Female; Mycoses; Adult; Antifungal Agents; Aged, 80 and over; Invasive Fungal Infections
PubMed: 38781681
DOI: 10.3201/eid3006.231409 -
Microbiology Spectrum Feb 2023spp. and are an emerging group of fungi refractory to current antifungal treatments. These species largely affect immunocompromised individuals but can also be lung...
spp. and are an emerging group of fungi refractory to current antifungal treatments. These species largely affect immunocompromised individuals but can also be lung colonizers in cystic fibrosis patients. Although Scedosporium apiospermum is thought to be the predominant species, the group has been expanded to a species complex. The distribution of species within the S. apiospermum species complex and other closely related species in the United States is largely unknown. Here, we used β-tubulin and ITS sequences to identify 37 isolates to the species level. These isolates as well as 13 isolates were tested against a panel of nine antifungal drugs, including the first in novel class orotimide, olorofim. and infections are notoriously hard to treat as these organisms can be resistant to numerous antifungals. The manuscript contributes to our knowledge of the activity of the new antifungal agent olorofim and comparator agents against and against isolates that have been molecularly identified to the species level. The efficacy of olorofim against all species of and was confirmed.
Topics: Humans; Antifungal Agents; Scedosporium; Piperazines; Pyrimidines; Ascomycota; Microbial Sensitivity Tests
PubMed: 36629417
DOI: 10.1128/spectrum.02789-22 -
Internal Medicine (Tokyo, Japan) 2016Scedosporium prolificans, a hyaline filamentous fungus, is widely distributed in the environment and is currently an emerging human pathogen, especially among... (Review)
Review
Scedosporium prolificans, a hyaline filamentous fungus, is widely distributed in the environment and is currently an emerging human pathogen, especially among immunocompromised patients. However, S. prolificans endocarditis is rare. We herein report a case of S. prolificans endocarditis in a 64-year-old patient with breast cancer in complete remission for 30 years after chemotherapy and radiation treatment who was not cured. Susceptibility testing showed resistance to all antifungal drugs, except echinocandin. A review of the literature revealed 10 cases of S. prolificans endocarditis; of these, only one involved an immunocompetent host with no risk factors and only two patients survived. In order to improve the mortality rate, it is necessary to establish rapid diagnostic methods and efficient therapeutic approaches.
Topics: Antifungal Agents; Breast Neoplasms; Echinocandins; Endocarditis; Fatal Outcome; Female; Humans; Immunocompromised Host; Middle Aged; Mycoses; Scedosporium
PubMed: 26726091
DOI: 10.2169/internalmedicine.55.5592 -
Microbiology Spectrum Jun 2023Infections with spp. and Lomentospora prolificans have become a serious threat in clinical settings. The high mortality rates associated with these infections can be...
Infections with spp. and Lomentospora prolificans have become a serious threat in clinical settings. The high mortality rates associated with these infections can be correlated with their multidrug resistance. The development of alternative treatment strategies has become crucial. Here, we investigate the and activity of luliconazole (LLCZ) against Scedosporium apiospermum (including its teleomorph Pseudallescheria boydii) and . The LLCZ MICs were determined for a total of 37 isolates (31 isolates, 6 Scedosporium apiospermum/ strains) according to EUCAST. Furthermore, the LLCZ antifungal activity was tested , using an XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt] growth kinetics assay and biofilm assays (crystal violet and XTT assay). In addition, a Galleria mellonella infection model was used for treatment assays. The MIC of LLCZ was determined to be 0.25 mg/L for all tested pathogens. Growth was inhibited within 6 to 48 h of the start of incubation. LLCZ inhibited biofilm formation in both preadhesion stages and late-stage adhesion. , a single dose of LLCZ increased the survival rate of the larvae by 40% and 20% for and spp., respectively. This is the first study demonstrating LLCZ activity against and and the first study showing the antibiofilm effect of LLCZ in spp. and S. apiospermum are opportunistic, multidrug-resistant pathogens causing invasive infections in immunosuppressed patients and sometimes in healthy persons. is panresistant against the currently available antifungals, and both species are associated with high mortality rates. Thus, the discovery of novel antifungal drugs exhibiting an effect against these resistant fungi is crucial. Our study shows the effect of luliconazole (LLCZ) against and spp. , as well as in an infection model. These data reveal the previously unknown inhibitory effect of LLCZ against and its antibiofilm effect in spp. It represents an extension of the literature regarding azole-resistant fungi and could potentially lead to the development of future treatment strategies against these opportunistic fungal pathogens.
Topics: Animals; Humans; Scedosporium; Antifungal Agents; Imidazoles
PubMed: 37017567
DOI: 10.1128/spectrum.05130-22 -
Virulence Dec 2021The slowing-down drug-discovery emphasized the importance of repurposing old drugs. This is particularly true when combating infections caused by therapy-refractory...
The slowing-down drug-discovery emphasized the importance of repurposing old drugs. This is particularly true when combating infections caused by therapy-refractory microorganisms, such as species and . Recent studies on responses to oxidative stress underscored the importance of targeting the underlying mechanisms. Auranofin, ebselen, PX-12, honokiol, and to a lesser extent, conoidin A are known to disturb redox-homeostasis systems in many organisms. Their antifungal activity was assessed against 27 isolates belonging to the major species: , and . Auranofin and honokiol were the most active against all species (mean MIC values of 2.875 and 6.143 μg/ml, respectively) and against isolates (mean MIC values of 4.0 and 3.563μg/ml respectively). Combinations of auranofin with voriconazole or honokiol revealed additive effects against 9/27 and 18/27 isolates, respectively. Synergistic interaction between auranofin and honokiol was only found against one isolate of . The effects of auranofin upon exposure to oxidative stress were also investigated. For all species except , the maximal growth in the presence of auranofin significantly decreased when adding a sublethal dose of menadione. The analysis of the expression of genes encoding oxidoreductase enzymes upon exposure of to honokiol unveiled the upregulation of many genes, especially those coding peroxiredoxins, thioredoxin reductases, and glutaredoxins. Altogether, these data suggest that auranofin and honokiol act via dampening the redox balance and support their repurposing as antifungals against species and .
Topics: Antifungal Agents; Auranofin; Biphenyl Compounds; Drug Repositioning; Lignans; Scedosporium
PubMed: 33825667
DOI: 10.1080/21505594.2021.1909266 -
International Journal of Infectious... Mar 2020Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups,...
OBJECTIVES
Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups, clinical manifestation and treatment strategies of these infections.
METHODS
Pediatric patients (age ≤18 years) with proven/probable Scedosporium spp. or L. prolificans infection were identified in PubMed and the FungiScope® registry. Data on diagnosis, treatment and outcome were collected.
RESULTS
Fifty-five children (median age 9 years [IQR: 5-14]) with invasive Scedosporium spp. (n = 33) or L. prolificans (n = 22) infection were identified between 1990 and 2019. Malignancy, trauma and near drowning were the most common risk factors. Infections were frequently disseminated. Most patients received systemic antifungal therapy, mainly voriconazole and amphotericin B, plus surgical treatment. Overall, day 42 mortality was 31%, higher for L. prolificans (50%) compared to Scedosporium spp. (18%). L. prolificans infection was associated with a shorter median survival time compared to Scedosporium spp. (6 days [IQR: 3-28] versus 61 days [IQR: 16-148]). Treatment for malignancy and severe disseminated infection were associated with particularly poor outcome (HR 8.33 [95% CI 1.35-51.40] and HR 6.12 [95% CI 1.52-24.66], respectively). Voriconazole use at any time and surgery for antifungal treatment were associated with improved clinical outcome (HR 0.33 [95% CI 0.11-0.99] and HR 0.09 [95% CI 0.02-0.40], respectively).
CONCLUSIONS
Scedosporium spp. and L. prolificans infections in children are associated with high mortality despite comprehensive antifungal therapy. Voriconazole usage and surgical intervention are associated with successful outcome.
Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Humans; Infant; Male; Mycoses; Risk Factors; Scedosporium; Voriconazole
PubMed: 31863876
DOI: 10.1016/j.ijid.2019.12.017 -
Cureus Sep 2023() is an increasingly prevalent and treatment-resistant opportunistic fungus. The pathogen is known to cause a variety of clinical manifestations ranging from localized...
() is an increasingly prevalent and treatment-resistant opportunistic fungus. The pathogen is known to cause a variety of clinical manifestations ranging from localized cutaneous disease to disseminated systemic infection. Herein we present an otherwise healthy 41-year-old male with biopsy-proven cutaneous infection. The patient experienced drastic clinical improvement on two months of a combination of oral itraconazole and oral minocycline. exhibits resistance to many antifungal agents, thus, single-agent antifungal therapy has a high failure rate and often results in the need for surgical excision or debridement. Recent accounts suggest that minocycline in combination with azole antifungals has a synergistic effect in treating . This case highlights the excellent response to combination oral therapies with minocycline and itraconazole. Prompt and efficacious treatment reduces the risk of destructive or disseminated disease and may avoid the need for surgical intervention.
PubMed: 37809133
DOI: 10.7759/cureus.44738