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Pharmacy (Basel, Switzerland) Oct 2015Posaconazole (PCZ) is a relatively new addition to the azole antifungals. It has fungicidal activities against , , selected species, , and . PCZ also has fungistatic... (Review)
Review
Posaconazole (PCZ) is a relatively new addition to the azole antifungals. It has fungicidal activities against , , selected species, , and . PCZ also has fungistatic activities against , , selected spp., , and In addition, combining the drug with caspofungin or amphotericin B results in a synergistic interaction against , and . The absorption of PCZ suspension is enhanced when given with food, nutritional supplements, and carbonated beverages. Oral administration of PCZ in divided doses also increases its bioavailability. PCZ has a large volume of distribution and is highly protein bound (>95%). The main elimination route of PCZ is fecal. PCZ is an inhibitor of the CYP3A4 enzyme; therefore, monitoring for drug-drug interactions is warranted with other CYP3A4 substrates/inhibitors/inducers. The most common adverse effects include headache, fatigue, nausea, vomiting and elevated hepatic enzymes. PCZ, with its unique antifungal activities, expands the azole class of antifungal agents. Because of its limit in formulation, PCZ oral suspension is recommended in immunocompromised patients with functional gastrointestinaltracts who fail conventional antifungal therapies or who are suspected to have a breakthrough fungal infection. However, a delayed-release tablet formulation and intravenous (IV) injection became available in 2014, expanding the use of PCZ in other patient populations, including individuals who are unable to take oral formulations.
PubMed: 28975914
DOI: 10.3390/pharmacy3040210 -
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 -
Frontiers in Cellular and Infection... 2021and species are filamentous fungi responsible for a wide range of infections in humans and are frequently associated with cystic fibrosis and immunocompromising...
and species are filamentous fungi responsible for a wide range of infections in humans and are frequently associated with cystic fibrosis and immunocompromising conditions. Because they are usually resistant to many antifungal drugs available in clinical settings, studies of alternative targets in fungal cells and therapeutic approaches are necessary. In the present work, we evaluated the antifungal activity of miltefosine against and species and how this phospholipid analogue affects the fungal cell. Miltefosine inhibited different and species at 2-4 µg/ml and reduced biofilm formation. The loss of membrane integrity in caused by miltefosine was demonstrated by leakage of intracellular components and lipid raft disorganisation. The exogenous addition of glucosylceramide decreased the inhibitory activity of miltefosine. Reactive oxygen species production and mitochondrial activity were also affected by miltefosine, as well as the susceptibility to fluconazole, caspofungin and myoricin. The data obtained in the present study contribute to clarify the dynamics of the interaction between miltefosine and and cells, highlighting its potential use as new antifungal drug in the future.
Topics: Antifungal Agents; Ascomycota; Humans; Microbial Sensitivity Tests; Phosphorylcholine; Scedosporium
PubMed: 34368017
DOI: 10.3389/fcimb.2021.698662 -
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 -
American Journal of Transplantation :... Feb 2018
Topics: Humans; Mycoses; Salvage Therapy; Scedosporium; Transplant Recipients; Triazoles
PubMed: 29206346
DOI: 10.1111/ajt.14616 -
European Respiratory Review : An... Dec 2022Non- filamentous fungi causing invasive mould infections have increased over the last years due to the widespread use of anti- prophylaxis and increased complexity and...
Non- filamentous fungi causing invasive mould infections have increased over the last years due to the widespread use of anti- prophylaxis and increased complexity and survival of immunosuppressed patients. In the few studies that have reported on invasive mould infection epidemiology, Mucorales are the most frequently isolated group, followed by either spp. or spp. The overall incidence is low, but related mortality is exceedingly high. Patients with haematological malignancies and haematopoietic stem cell transplant recipients comprise the classical groups at risk of infection for non- moulds due to profound immunosuppression and the vast use of anti- prophylaxis. Solid organ transplant recipients also face a high risk, especially those receiving lung transplants, due to direct exposure of the graft to mould spores with altered mechanical and immunological elimination, and intense, associated immunosuppression. Diagnosing non- moulds is challenging due to unspecific symptoms and radiological findings, lack of specific biomarkers, and low sensitivity of cultures. However, the advent of molecular techniques may prove helpful. Mucormycosis, fusariosis and scedosporiosis hold some differences regarding clinical paradigmatic presentations and preferred antifungal therapy. Surgery might be an option, especially in mucormycosis. Finally, various promising strategies to restore or enhance the host immune response are under current evaluation.
Topics: Humans; Mucormycosis; Antifungal Agents; Fungi; Biomarkers; Lung
PubMed: 36261156
DOI: 10.1183/16000617.0104-2022 -
IMA Fungus Dec 2023Emerging fungal pathogens are a global challenge for humankind. Many efforts have been made to understand the mechanisms underlying pathogenicity in bacteria, and OMICs...
Emerging fungal pathogens are a global challenge for humankind. Many efforts have been made to understand the mechanisms underlying pathogenicity in bacteria, and OMICs techniques are largely responsible for those advancements. By contrast, our limited understanding of opportunism and antifungal resistance is preventing us from identifying, limiting and interpreting the emergence of fungal pathogens. The genus Scedosporium (Microascaceae) includes fungi with high tolerance to environmental pollution, whilst some species can be considered major human pathogens, such as Scedosporium apiospermum and Scedosporium boydii. However, unlike other fungal pathogens, little is known about the genome evolution of these organisms. We sequenced two novel genomes of Scedosporium aurantiacum and Scedosporium minutisporum isolated from extreme, strongly anthropized environments. We compared all the available Scedosporium and Microascaceae genomes, that we systematically annotated and characterized ex novo in most cases. The genomes in this family were integrated in a Phylum-level comparison to infer the presence of putative, shared genomic traits in filamentous ascomycetes with pathogenic potential. The analysis included the genomes of 100 environmental and clinical fungi, revealing poor evolutionary convergence of putative pathogenicity traits. By contrast, several features in Microascaceae and Scedosporium were detected that might have a dual role in responding to environmental challenges and allowing colonization of the human body, including chitin, melanin and other cell wall related genes, proteases, glutaredoxins and magnesium transporters. We found these gene families to be impacted by expansions, orthologous transposon insertions, and point mutations. With RNA-seq, we demonstrated that most of these anciently impacted genomic features responded to the stress imposed by an antifungal compound (voriconazole) in the two environmental strains S. aurantiacum MUT6114 and S. minutisporum MUT6113. Therefore, the present genomics and transcriptomics investigation stands on the edge between stress resistance and pathogenic potential, to elucidate whether fungi were pre-adapted to infect humans. We highlight the strengths and limitations of genomics applied to opportunistic human pathogens, the multifactoriality of pathogenicity and resistance to drugs, and suggest a scenario where pressures other than anthropic contributed to forge filamentous human pathogens.
PubMed: 38049914
DOI: 10.1186/s43008-023-00128-3 -
Journal of Fungi (Basel, Switzerland) Jan 2023species are usually soil saprophytes but some members of the genus such as and have been regularly reported as causing human respiratory infections, particularly in...
species are usually soil saprophytes but some members of the genus such as and have been regularly reported as causing human respiratory infections, particularly in patients with cystic fibrosis (CF). Because of their low sensitivity to almost all available antifungal drugs, a better understanding of the pathogenic mechanisms of these fungi is mandatory. Likewise, identification of the origin of the contamination of patients with CF may be helpful to propose prophylactic measures. In this aim, environmental studies were conducted demonstrating that species are abundant in human-made environments and associated with nutrient-rich substrates. Although their natural habitat remains unknown, there is accumulated evidence to consider them as wood-decaying fungi. This study aimed to demonstrate the ability of these fungi to utilize lignocellulose compounds, especially lignin, as a carbon source. First, the lignolytic properties of species were confirmed by cultural methods, and biochemical assays suggested the involvement of peroxidases and oxidases as lignin-modifying enzymes. genomes were then screened using tBLASTn searches. Fifteen candidate genes were identified, including four peroxidase and seven oxidase genes, and some of them were shown, by real-time PCR experiments, to be overexpressed in lignin-containing medium, thus confirming their involvement in lignin degradation.
PubMed: 36675925
DOI: 10.3390/jof9010105 -
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 -
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