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BMC Microbiology Jan 2022This study was aimed to determine the potency of Minocycline (MIN) and azoles, including itraconazole (ITR), voriconazole (VOR) and posaconazole (POS) against...
BACKGROUND
This study was aimed to determine the potency of Minocycline (MIN) and azoles, including itraconazole (ITR), voriconazole (VOR) and posaconazole (POS) against Scedosporium and Lomentospora species.
RESULTS
This study revealed that MIN exhibited no significant antifungal activity against any of the tested strains, whereas in vitro combination of MIN with ITR, VOR or POS showed satisfactory synergistic effects against 8 (80%), 1 (10%), and 9 (90%) strains, respectively. Moreover, combined use of MIN with azoles decreased the minimum inhibitory concentration (MIC) range from 5.33-16 μg/ml to 1-16 μg/ml for ITR, from 0.42-16 μg/ml to 0.21-16 μg/ml for VOR, and from 1.33-16 μg/ml to 0.33-16 μg/ml for POS. Meanwhile, no antagonistic interactions were observed between the above combinations. The G. mellonella infection model demonstrated the in vivo synergistic antifungal effect of MIN and azoles.
CONCLUSIONS
The present study demonstrated that combinations between MIN and azoles lead to synergistic antimicrobial effects on Scedosporium and Lomentospora species, while showing a potential for overcoming and preventing azole resistance.
Topics: Animals; Antifungal Agents; Ascomycota; Azoles; Drug Resistance, Fungal; Drug Synergism; Humans; Larva; Microbial Sensitivity Tests; Minocycline; Moths; Scedosporium
PubMed: 35016611
DOI: 10.1186/s12866-021-02433-6 -
Memorias Do Instituto Oswaldo Cruz 2018BACKGROUND Scedosporium/Lomentospora species are opportunistic mould pathogens, presenting notable antifungal resistance. OBJECTIVES/METHODS We analysed the conidia and... (Comparative Study)
Comparative Study
Scedosporium apiospermum, Scedosporium aurantiacum, Scedosporium minutisporum and Lomentospora prolificans: a comparative study of surface molecules produced by conidial and germinated conidial cells.
BACKGROUND Scedosporium/Lomentospora species are opportunistic mould pathogens, presenting notable antifungal resistance. OBJECTIVES/METHODS We analysed the conidia and germinated conidia of S. apiospermum (Sap), S. aurantiacum (Sau), S. minutisporum (Smi) and L. prolificans (Lpr) by scanning electron microscopy and exposition of surface molecules by fluorescence microscopy. FINDINGS Conidia of Sap, Smi and Sau had oval, ellipsoidal and cylindrical shape, respectively, with several irregularities surrounding all surface areas, whereas Lpr conidia were rounded with a smooth surface. The germination of Sap occurred at the conidial bottom, while Smi and Sau germination primarily occurred at the centre of the conidial cell, and Lpr germination initiated at any part of the conidial surface. The staining of N-acetylglucosamine-containing molecules by fluorescein-labelled WGA primarily occurred during the germination of all studied fungi and in the conidial scars, which is the primary location of germination. Calcofluor white, which recognises the polysaccharide chitin, strongly stained the conidial cells and, to a lesser extent, the germination. Both mannose-rich glycoconjugates (evidenced by fluoresceinated-ConA) and cell wall externally located polypeptides presented distinct surface locations and expression according to both morphotypes and fungal species. In contrast, sialic acid and galactose-containing structures were not detected at fungal surfaces. MAIN CONCLUSIONS The present study demonstrated the differential production/exposition of surface molecules on distinct morphotypes of Scedosporium/Lomentospora species.
Topics: Cell Differentiation; Cell Membrane; Microscopy, Electron, Scanning; Microscopy, Fluorescence; Scedosporium; Spores, Fungal
PubMed: 29924142
DOI: 10.1590/0074-02760180102 -
Antimicrobial Agents and Chemotherapy Sep 2021Clinically relevant members of the / species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents , and...
Clinically relevant members of the / species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents , and infection due to these species is difficult to treat. We studied the efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-β-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.
Topics: Acetamides; Animals; Antifungal Agents; Invasive Fungal Infections; Mice; Piperazines; Pyrimidines; Pyrroles; Scedosporium
PubMed: 34252298
DOI: 10.1128/AAC.00434-21 -
Journal of Fungi (Basel, Switzerland) Feb 2023and are a group of filamentous fungi with some clinically relevant species causing either localized, invasive, or disseminated infections. Understanding how the host...
and are a group of filamentous fungi with some clinically relevant species causing either localized, invasive, or disseminated infections. Understanding how the host immune response is activated and how fungi interact with the host is crucial for a better management of the infection. In this context, an α-glucan has already been described in , which plays a role in the inflammatory response. In the present study, an α-glucan has been characterized in and was shown to be exposed on the fungal surface. The α-glucan is recognized by peritoneal macrophages and induces oxidative burst in activated phagocytes. Its recognition by macrophages is mediated by receptors that include Dectin-1 and Mincle, but not TLR2 and TLR4. These results contribute to the understanding of how 's and 's physiopathologies are developed in patients suffering with scedosporiosis and lomentosporiosis.
PubMed: 36983458
DOI: 10.3390/jof9030291 -
Infection and Drug Resistance 2017Antifungal resistance represents a major clinical challenge to clinicians responsible for treating invasive fungal infections due to the limited arsenal of systemically... (Review)
Review
Antifungal resistance represents a major clinical challenge to clinicians responsible for treating invasive fungal infections due to the limited arsenal of systemically available antifungal agents. In addition current drugs may be limited by drug-drug interactions and serious adverse effects/toxicities that prevent their prolonged use or dosage escalation. Fluconazole resistance is of particular concern in non- species due to the increased incidence of infections caused by these species in different geographic locations worldwide and the elevated prevalence of resistance to this commonly used azole in many institutions. resistance to the echinocandins has also been documented to be rising in several US institutions, and a higher percentage of these isolates may also be azole resistant. Azole resistance in due to clinical and environmental exposure to this class of agents has also been found worldwide, and these isolates can cause invasive infections with high mortality rates. In addition, several species of , and other molds, including and species, have reduced susceptibility or pan-resistance to clinically available antifungals. Various investigational antifungals are currently in preclinical or clinical development, including several of them that have the potential to overcome resistance observed against the azoles and the echinocandins. These include agents that also target ergosterol and b-glucan biosynthesis, as well as compounds with novel mechanisms of action that may also overcome the limitations of currently available antifungal classes, including both resistance and adverse effects/toxicity.
PubMed: 28919789
DOI: 10.2147/IDR.S124918 -
Current Research in Microbial Sciences 2023Dispersion is an essential step in the lifecycle of biofilms, since it enables the dissemination of microbial cells and, consequently, the potential colonization of new...
Dispersion is an essential step in the lifecycle of biofilms, since it enables the dissemination of microbial cells and, consequently, the potential colonization of new sites. Filamentous fungi belonging to the genera are opportunistic human pathogens able to form multidrug-resistant biofilms on surfaces of different chemical compositions, environments and nutritional conditions. Despite the rising understanding of how biofilms are formed by species, the cell dispersal step has not yet been explored. In the present study, the cell dispersion was investigated during biofilm formation by and cells. The results revealed that conidia were the major type of dispersed cells, which were detected throughout biofilm development (from 24 to 72 h). Dispersion was not influenced by increased glucose concentration (the main source for energetic metabolism) neither the presence of voriconazole (the most common antifungal used to treat scedosporiosis); however, the presence of mucin (a component of mucous, present in the lungs of cystic fibrosis patients, who are usually affected by these filamentous fungi) triggered cell dispersion. Contrarily, a poor nutritional environment (e.g., phosphate-buffered saline) inhibited this step. Overall, our study reveals new insights into the biofilm development of species.
PubMed: 37229517
DOI: 10.1016/j.crmicr.2023.100191 -
Antimicrobial Agents and Chemotherapy Oct 2015N-Chlorotaurine (NCT), a well-tolerated endogenous long-lived oxidant that can be applied topically as an antiseptic, was tested on its fungicidal activity against...
N-Chlorotaurine (NCT), a well-tolerated endogenous long-lived oxidant that can be applied topically as an antiseptic, was tested on its fungicidal activity against Scedosporium and Lomentospora, opportunistic fungi that cause severe infections with limited treatment options, mainly in immunocompromised patients. In quantitative killing assays, both hyphae and conidia of Scedosporium apiospermum, Scedosporium boydii, and Lomentospora prolificans (formerly Scedosporium prolificans) were killed by 55 mM (1.0%) NCT at pH 7.1 and 37°C, with a 1- to 4-log10 reduction in CFU after 4 h and a 4- to >6-log10 reduction after 24 h. The addition of ammonium chloride to NCT markedly increased this activity. LIVE/DEAD staining of conidia treated with 1.0% NCT for 0.5 to 3 h increased the permeability of the cell wall and membrane. Preincubation of the test fungi in 1.0% NCT for 10 to 60 min delayed the time to germination of conidia by 2 h to >12 h and reduced their germination rate by 10.0 to 100.0%. Larvae of Galleria mellonella infected with 1.0 × 10(7) conidia of S. apiospermum and S. boydii died at a rate of 90.0 to 100% after 8 to 12 days. The mortality rate was reduced to 20 to 50.0% if conidia were preincubated in 1.0% NCT for 0.5 h or if heat-inactivated conidia were used. Our study demonstrates the fungicidal activity of NCT against different Scedosporium and Lomentospora species. A postantifungal effect connected with a loss of virulence occurs after sublethal incubation times. The augmenting effect of ammonium chloride can be explained by the formation of monochloramine.
Topics: Ammonium Chloride; Animals; Anti-Infective Agents, Local; Antifungal Agents; Cell Membrane; Cell Membrane Permeability; Cell Wall; Chloramines; Hyphae; Larva; Microbial Sensitivity Tests; Moths; Scedosporium; Spores, Fungal; Taurine
PubMed: 26239996
DOI: 10.1128/AAC.00957-15 -
Journal of Fungi (Basel, Switzerland) Feb 2023The incidence of invasive sino-pulmonary diseases due to non- hyaline molds is increasing due to an enlarging and evolving population of immunosuppressed hosts as well... (Review)
Review
The incidence of invasive sino-pulmonary diseases due to non- hyaline molds is increasing due to an enlarging and evolving population of immunosuppressed hosts as well as improvements in the capabilities of molecular-based diagnostics. Herein, we review the following opportunistic pathogens known to cause sinopulmonary disease, the most common manifestation of hyalohyphomycosis: spp., spp., , spp., spp., spp., , , species complex, , and species. To facilitate an understanding of the epidemiology and clinical features of sino-pulmonary hyalohyphomycoses in the context of host immune impairment, we utilized a host-based approach encompassing the following underlying conditions: neutropenia, hematologic malignancy, hematopoietic and solid organ transplantation, chronic granulomatous disease, acquired immunodeficiency syndrome, cystic fibrosis, and healthy individuals who sustain burns, trauma, or iatrogenic exposures. We further summarize the pre-clinical and clinical data informing antifungal management for each pathogen and consider the role of adjunctive surgery and/or immunomodulatory treatments to optimize patient outcome.
PubMed: 36836326
DOI: 10.3390/jof9020212 -
Contemporary Oncology (Poznan, Poland) 2016Despite greater knowledge and possibilities in pharmacotherapy, fungal infections remain a challenge for clinicians. As the population of immunocompromised patients and... (Review)
Review
Despite greater knowledge and possibilities in pharmacotherapy, fungal infections remain a challenge for clinicians. As the population of immunocompromised patients and those treated for their hematologic ailments increases, the number of fungal infections grows too. This is why there is still a quest for new antifungal drugs as well as for optimization of pharmacotherapy with already registered pharmaceutics. Voriconazole and posaconazole are broad-spectrum, new generation, triazole antifungal agents. The drugs are used in the pharmacotherapy of invasive aspergillosis, and infections. Voriconazole is also used in infections caused by . Posaconazole is used in the treatment of coccidioidomycosis and chromoblastomycosis. Besides some similarities, the two mentioned drugs also show differences in therapeutic indications, pharmacokinetics (mainly absorption and metabolism), frequency and severity of adverse drug reactions, drug-drug interactions and dosage. As both of the drugs are used in the treatment of invasive fungal infections in adults and children, detailed knowledge of the clinical pharmacology of antifungal agents is the main factor in pharmacotherapy optimization in treatment of fungal infections. The goal of the article is to present and compare the clinical pharmacology of voriconazole and posaconazole as well as to point out the indications and contraindications of using the drugs, determine factors influencing their pharmacotherapy, and provide information that might be helpful in the treatment of fungal infections.
PubMed: 28373817
DOI: 10.5114/wo.2016.64594 -
Frontiers in Cellular and Infection... 2022and infections in humans are generally chronic and stubborn. The use of azoles alone cannot usually inhibit the growth of these fungi. To further explore the combined...
and infections in humans are generally chronic and stubborn. The use of azoles alone cannot usually inhibit the growth of these fungi. To further explore the combined effect of multiple drugs and potential mechanisms of action, we tested the antifungal effects of tacrolimus (FK506) and everolimus in combination with azoles and on 15 clinical strains of / species and detected the level of Rhodamine 6G, ROS activity, and apoptosis. The results showed that the combinations of tacrolimus with itraconazole, voriconazole, and posaconazole showed synergistic effects on 9 strains (60%), 10 strains (73%), and 7 strains (47%), respectively, and the combinations of everolimus with itraconazole, voriconazole, and posaconazole showed synergistic effects on 8 strains (53%), 8 strains (53%), and 7 strains (47%), respectively. The synergistic effects might correspond to the elevated ROS activity (the tacrolimus + itraconazole group compared to the itraconazole group, ( < 0.05)), early apoptosis (itraconazole ( < 0.05) and voriconazole ( < 0.05) combined with everolimus), and late apoptosis (the tacrolimus + itraconazole group compared to the itraconazole group, ( < 0.01); the tacrolimus + posaconazole group compared to the posaconazole group, ( < 0.05)), but not inhibition of efflux pump activity. Our results suggested that a combination of tacrolimus or everolimus and azoles have a synergistic effect against . The synergistic mechanisms of action might be triggering excessive ROS activity and apoptosis, the survival rate of (sixth instar larvae) was significantly improved by tacrolimus alone, everolimus alone, azoles alone, and tacrolimus and everolimus combined with azoles separately ( < 0.05 for the tacrolimus group; < 0.01 for the everolimus group and the itraconazole group; = 0.0001 for the tacrolimus and posaconazole group; < 0.0001 for other groups except the everolimus and itraconazole group, everolimus and posaconazole group, and tacrolimus and itraconazole group). From the results, we infer that the combination of tacrolimus or everolimus with azoles has obvious synergistic effect on , and might enhance the level of apoptosis and necrosis. However, the synergistic effects were not related to the efflux pump. In conclusion, from our and study, tacrolimus and everolimus combined with azoles may have a synergistic effect in the treatment against , improving the drug activity of azoles and promoting a better prognosis for patients.
Topics: Ascomycota; Azoles; Everolimus; Humans; Itraconazole; Microbial Sensitivity Tests; Reactive Oxygen Species; Scedosporium; Tacrolimus; Voriconazole
PubMed: 35493742
DOI: 10.3389/fcimb.2022.864912