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Clinical Microbiology Reviews Jun 2024SUMMARYAlthough species and are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a... (Review)
Review
SUMMARYAlthough species and are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a limited armamentarium of antifungal drugs. In light of recent advances, including in the area of new antifungals, the present review provides a timely and updated overview of these IFDs, with a focus on the taxonomy, clinical epidemiology, pathogenesis and host immune response, disease manifestations, diagnosis, antifungal susceptibility, and treatment. An expansion of hosts at risk for these difficult-to-treat infections has emerged over the last two decades given the increased use of, and broader population treated with, immunomodulatory and targeted molecular agents as well as wider adoption of antifungal prophylaxis. Clinical presentations differ not only between genera but also across the different species. is intrinsically resistant to most currently available antifungal agents, and the prognosis of immunocompromised patients with lomentosporiosis is poor. Development of, and improved access to, diagnostic modalities for early detection of these rare mold infections is paramount for timely targeted antifungal therapy and surgery if indicated. New antifungal agents (e.g., olorofim, fosmanogepix) with novel mechanisms of action and less cross-resistance to existing classes, availability of formulations for oral administration, and fewer drug-drug interactions are now in late-stage clinical trials, and soon, could extend options to treat scedosporiosis/lomentosporiosis. Much work remains to increase our understanding of these infections, especially in the pediatric setting. Knowledge gaps for future research are highlighted in the review.
Topics: Humans; Antifungal Agents; Scedosporium; Drug Resistance, Fungal; Mycoses; Invasive Fungal Infections; Ascomycota
PubMed: 38551323
DOI: 10.1128/cmr.00004-23 -
Molecular Aspects of Medicine Dec 2023Infection by non-Aspergillus molds has been increasingly reported. The management of such infections is challenging both for diagnosis and treatment, including the need... (Review)
Review
Infection by non-Aspergillus molds has been increasingly reported. The management of such infections is challenging both for diagnosis and treatment, including the need of well-trained mycologists to properly identify rare fungi, difficulties in distinguishing between contamination, colonization and infection, the lack of randomized studies comparing different drugs or regimens, poor activity of available antifungal agents, lack of correlation between in vitro antifungal susceptibility tests and clinical outcome, and poor prognosis. Mucormycosis and fusariosis are the most frequent non-Aspergillus mold infections. Mucormycosis occurs more frequently in four major groups of patients: solid organ transplant recipients, patients with hematologic malignancies receiving chemotherapy or hematopoietic cell transplantation, diabetic patients, and immunocompetent individuals who suffer various types of skin and soft tissue trauma. Invasive fusariosis occurs almost exclusively in patients with hematologic malignancies. In this review we discuss practical issues related to the management of these and other non-Aspergillus mold infections.
Topics: Humans; Mucormycosis; Fungi; Antifungal Agents; Fusariosis; Hematologic Neoplasms
PubMed: 38011770
DOI: 10.1016/j.mam.2023.101230 -
Expert Review of Respiratory Medicine Mar 2020: Considered for a long time to be exclusively responsible for chronic localized infections, fungi of the genus have recently received a renewed interest because of... (Review)
Review
: Considered for a long time to be exclusively responsible for chronic localized infections, fungi of the genus have recently received a renewed interest because of their recognition as common colonizing agents of the respiratory tract of patients with cystic fibrosis, and of the description of severe disseminated infections in patients undergoing lung transplantation. Recently, several studies have been carried out on these opportunistic pathogens, which led to some advances in the understanding of their pathogenic mechanisms and in the biological diagnosis of the airway colonization/respiratory infections caused by these fungi.: From a bibliographic search on the Pubmed database, we summarize the current knowledge about the taxonomy of species, the epidemiology of these fungi and their pathogenic mechanisms, and present the improvements in the detection of the airway colonization and diagnosis of respiratory infections, the difficulties in their therapeutic management, and the antifungal drugs in development.: As described in this review, many advances have been made regarding the taxonomy and ecology of species or the molecular determinants of their pathogenicity, but also in the management of infections, particularly by improving the biological diagnostic and publishing evidence for the efficacy of combined therapy.
Topics: Antifungal Agents; Cystic Fibrosis; Disease Management; Humans; Invasive Fungal Infections; Lung Transplantation; Phylogeny; Respiratory Tract Infections; Scedosporium
PubMed: 31868041
DOI: 10.1080/17476348.2020.1705787 -
The Journal of Antimicrobial... Dec 2020To evaluate the in vitro activity of olorofim, a new broad-spectrum antifungal with a novel mechanism of action, against a collection of 123 Spanish clinical isolates...
OBJECTIVES
To evaluate the in vitro activity of olorofim, a new broad-spectrum antifungal with a novel mechanism of action, against a collection of 123 Spanish clinical isolates belonging to five Scedosporium species and Lomentospora prolificans.
METHODS
The activity of olorofim against Scedosporium apiospermum (n = 30), Scedosporium boydii (n = 30), Scedosporium ellipsoideum (n = 10), Scedosporium aurantiacum (n = 20), Scedosporium dehoogii (n = 3) and Lomentospora prolificans (n = 30) was compared with that of amphotericin B, voriconazole, isavuconazole and micafungin by performing EUCAST and CLSI reference methods for antifungal susceptibility testing.
RESULTS
Amphotericin B and isavuconazole showed MICs ≥2 mg/L for all the species evaluated and voriconazole was moderately active (GM, MIC50 and MIC90 values ≤2 mg/L) against all of them except L. prolificans. Micafungin was effective against S. apiospermum complex strains, but exhibited elevated MECs for S. dehoogii and S. aurantiacum. Olorofim showed low MICs for all the Scedosporium strains tested (GM values were lower than 0.130 and 0.339 by the EUCAST method and the CLSI method, respectively, for all of the species), including those belonging to the MDR species L. prolificans, for which GM values were 0.115 and 0.225 mg/L by the EUCAST method and the CLSI method, respectively, while the GMs for the rest of the antifungals evaluated were higher than 3.732 mg/L using both methodologies.
CONCLUSIONS
Olorofim displayed promising in vitro activity against the Scedosporium and L. prolificans strains tested, some of which have reduced susceptibility to the antifungals that are currently in use.
Topics: Acetamides; Antifungal Agents; Microbial Sensitivity Tests; Piperazines; Pyrimidines; Pyrroles; Scedosporium
PubMed: 32856079
DOI: 10.1093/jac/dkaa351 -
Antimicrobial Agents and Chemotherapy Nov 2019While spp. remain the major cause of invasive mold infections in hematologic cancer patients and transplant recipients, other opportunistic molds, such as , , and spp.... (Review)
Review
While spp. remain the major cause of invasive mold infections in hematologic cancer patients and transplant recipients, other opportunistic molds, such as , , and spp. are increasingly encountered in an expanding population of patients with severe and prolonged immunosuppression. High potential for tissue invasion and dissemination, resistance to multiple antifungals and high mortality rates are hallmarks of these non- invasive mold infections (NAIMIs). Assessment of drug efficacy is particularly difficult in the complex treatment scenarios of NAIMIs. Specifically, correlation between susceptibility and responses to antifungals is hard to assess, in view of the multiple, frequently interrelated factors influencing outcomes, such as pharmacokinetic/pharmacodynamic parameters determining drug availability at the site of infection, the net state of immune suppression, delay in diagnosis, or surgical debulking of infectious foci. Our current therapeutic approach of NAIMIs should evolve toward a better integration of the dynamic interactions between the pathogen, the drug and the host. Innovative concepts of experimental research may consist in manipulating the host immune system to induce a specific antifungal response or targeted drug delivery. In this review, we discuss the challenges in the management of NAIMIs and provide an update about the latest advances in diagnostic and therapeutic approaches.
Topics: Antifungal Agents; Drug Resistance, Fungal; Humans; Immunocompromised Host; Invasive Fungal Infections
PubMed: 31481441
DOI: 10.1128/AAC.01244-19 -
Journal of the American Podiatric... Mar 2023Recently, an increasing number of resistant-to-terbinafine dermatophytosis cases have been reported. Thus, identifying an alternative antifungal agent that possesses a...
Antifungal Activity of Efinaconazole Compared to Fluconazole, Itraconazole, and Terbinafine against Terbinafine- and Itraconazole-Resistant and -Susceptible Clinical Isolates of Dermatophytes, Candida, and Mold.
BACKGROUND
Recently, an increasing number of resistant-to-terbinafine dermatophytosis cases have been reported. Thus, identifying an alternative antifungal agent that possesses a broad-spectrum activity, including against resistant strains, is needed.
METHODS
In this study, we compared the antifungal activity of efinaconazole to fluconazole, itraconazole, and terbinafine against clinical isolates of dermatophyte, Candida, and molds using in vitro assays. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of each antifungal was quantified and compared. Both susceptible and resistant clinical isolates of Trichophyton mentagrophytes (n=16), T. rubrum (n=43), T. tonsurans (n=18), T. violaceum (n=4), Candida albicans (n=55), C. auris (n=30), Fusarium sp., Scedosporium sp., and Scopulariopsis sp. (n=15 for each) were tested.
RESULTS
Our data shows that efinaconazole was the most active antifungal, compared to the other agents tested, against dermatophytes with MIC50 and MIC90 (Concentration that inhibited 50% and 90% of strains tested, respectively) values of 0.002 and 0.03 μg/ml, respectively. Fluconazole, itraconazole and terbinafine showed MIC50 and MIC90 values of 1 and 8 μg/ml, 0.03 and 0.25 μg/ml, and 0.031 and 16 μg/ml, respectively. Against Candida isolates, efinaconazole MIC50 and MIC90 values were 0.016 and 0.25 μg/ml, respectively, whereas fluconazole, itraconazole and terbinafine had MIC50 and the MIC90 values of 1 and 16 μg/ml, 0.25 and 0.5 μg/ml, and 2 and 8 μg/ml, respectively. Against various mold species, efinaconazole MIC values ranged from 0.016 and 2 μg/ml, compared to 0.5 to greater than 64 μg/ml for the comparators.
CONCLUSIONS
efinaconazole showed superior potent activity against a broad panel of susceptible and resistant dermatophyte, Candida, and mold isolates.
PubMed: 37040333
DOI: 10.7547/22-132 -
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 -
Cytokine Dec 2023Fungal infections caused by Scedosporium species are rising among immunocompromised and immunocompetent patients. Within the immunocompetent group, patients with cystic...
Fungal infections caused by Scedosporium species are rising among immunocompromised and immunocompetent patients. Within the immunocompetent group, patients with cystic fibrosis (pwCF) are at high risk of developing a chronic airway colonization by these molds. While S. apiospermum is one of the major species encountered in the lungs of pwCF, S. dehoogii has rarely been reported. The innate immune response is believed to be critical for host defense against fungal infections. However, its role has only recently been elucidated and the immune mechanisms against Scedosporium species are currently unknown. In this context, we undertook a comparative investigation of macrophage-mediated immune responses toward S. apiospermum and S. dehoogii conidia. Our data showed that S. apiospermum and S. dehoogii conidia strongly stimulated the expression of a set of pro-inflammatory cytokines and chemokines such as IL-1β, IL-8, IL-6 and TNFα. We demonstrated that S. dehoogii was more potent in stimulating the early release of pro-inflammatory cytokines and chemokines while S. apiospermum induced a late inflammatory response at a higher level. Flow cytometry analysis showed that M1-like macrophages were able to internalize both S. apiospermum and S. dehoogii conidia, with a similar intracellular killing rate for both species. In conclusion, these results suggest that M1-like macrophages can rapidly initiate a strong immune response against both S. apiospermum and S. dehoogii. This response is characterized by a similar killing of internalized conidia, but a different time course of cytokine production.
Topics: Humans; Scedosporium; Macrophages; Mycoses; Cytokines; Cystic Fibrosis; Chemokines
PubMed: 37832161
DOI: 10.1016/j.cyto.2023.156384 -
Medical Mycology May 2021The genus Scedosporium is composed of clinically relevant fungal species, such as Scedosporium aurantiacum, Scedosporium apiospermum, and Scedosporium boydii. Surface...
The genus Scedosporium is composed of clinically relevant fungal species, such as Scedosporium aurantiacum, Scedosporium apiospermum, and Scedosporium boydii. Surface molecules have been described that play crucial roles in fungi-macrophage interaction, and many of them are pathogen-associated molecular patterns (PAMPs). The present study aims to characterize peptidoglycans obtained from Scedosporium aurantiacum and Scedosporium minutisporum, a clinical and an environmental isolate, respectively, and compare their roles in pathogen-host interaction. Both molecules were characterized as peptidorhamnomannans (PRMs), similar to what has been already described for other Scedosporium species. Rabbit immune sera obtained by injecting whole cells from each species recognized both fungal cells and purified PRMs, suggesting that a cross-reaction occur between both fungi. Immunofluorescent microscopy revealed that PRMs are exposed on fungal surface. Prior incubation of purified molecules with immune sera before adding to cells led to loss of fluorescent, indicating that PRM is a major molecule recognized by immune sera. Fungi-macrophage interaction revealed that S. aurantiacum is able to survive more inside phagocytic cells than S. minutisporum, and PRM from both fungi plays a role in phagocytosis when the purified molecule is pre-incubated with macrophage. In addition, PRM induce nitric oxide release by macrophages. Our data indicate that PRM is an important PAMP exposed on fungal surface with the potential of immune modulation.
Topics: Animals; Antibodies, Fungal; Female; Glycoproteins; Host Microbial Interactions; Humans; Invasive Fungal Infections; Macrophages; Mice; Mice, Inbred BALB C; Nitric Oxide; Pathogen-Associated Molecular Pattern Molecules; Phagocytosis; Rabbits; Scedosporium
PubMed: 32766889
DOI: 10.1093/mmy/myaa065 -
Medical Mycology Jul 2023The (1→3)-β-D-glucan (BDG) is a component of the fungal cell wall that can be detected in serum and used as an adjunctive tool for the diagnosis of invasive mold... (Meta-Analysis)
Meta-Analysis
The (1→3)-β-D-glucan (BDG) is a component of the fungal cell wall that can be detected in serum and used as an adjunctive tool for the diagnosis of invasive mold infections (IMI) in patients with hematologic cancer or other immunosuppressive conditions. However, its use is limited by modest sensitivity/specificity, inability to differentiate between fungal pathogens, and lack of detection of mucormycosis. Data about BDG performance for other relevant IMI, such as invasive fusariosis (IF) and invasive scedosporiosis/lomentosporiosis (IS) are scarce. The objective of this study was to assess the sensitivity of BDG for the diagnosis of IF and IS through systematic literature review and meta-analysis. Immunosuppressed patients diagnosed with proven or probable IF and IS, with interpretable BDG data were eligible. A total of 73 IF and 27 IS cases were included. The sensitivity of BDG for IF and IS diagnosis was 76.7% and 81.5%, respectively. In comparison, the sensitivity of serum galactomannan for IF was 27%. Importantly, BDG positivity preceded the diagnosis by conventional methods (culture or histopathology) in 73% and 94% of IF and IS cases, respectively. Specificity was not assessed because of lacking data. In conclusion, BDG testing may be useful in patients with suspected IF or IS. Combining BDG and galactomannan testing may also help differentiating between the different types of IMI.
Topics: Animals; Fusariosis; beta-Glucans; Invasive Fungal Infections; Sensitivity and Specificity
PubMed: 37381179
DOI: 10.1093/mmy/myad061