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Therapeutic Advances in Infectious... 2024Invasive fungal infections are increasingly encountered with the expansion of iatrogenic immunosuppression, including not only solid organ and hematopoietic stem cell... (Review)
Review
Invasive fungal infections are increasingly encountered with the expansion of iatrogenic immunosuppression, including not only solid organ and hematopoietic stem cell transplant recipients but also patients with malignancies or autoimmune diseases receiving immunomodulatory therapies, such as Bruton Tyrosine Kinase (BTK) inhibitor. Their attributable mortality remains elevated, part of which is a contribution from globally emerging resistance in both molds and yeasts. Because antifungal susceptibility test results are often unavailable or delayed, empiric and tailored antifungal approaches including choice of agent(s) and use of combination therapy are heterogeneous and often based on clinician experience with knowledge of host's net state of immunosuppression, prior antifungal exposure, antifungal side effects and interaction profile, clinical severity of disease including site(s) of infection and local resistance data. In this review, we aim to summarize previous recommendations and most recent literature on treatment of invasive mold and yeast infections in adults to guide optimal evidence-based therapeutic approaches. We review the recent data that support use of available antifungal agents, including the different triazoles that have now been studied in comparison to previously preferred agents. We discuss management of complex infections with specific emerging fungi such as spp., spp., , and . We briefly explore newer antifungal agents or formulations that are now being investigated to overcome therapeutic pitfalls, including but not limited to olorofim, rezafungin, fosmanogepix, and encochleated Amphotericin B. We discuss the role of surgical resection or debridement, duration of treatment, follow-up modalities, and need for secondary prophylaxis, all of which remain challenging, especially in patients chronically immunocompromised or awaiting more immunosuppressive therapies.
PubMed: 38249542
DOI: 10.1177/20499361231224980 -
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 -
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 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 -
IScience Nov 2023Although severe cases of invasive mycoses of different hypoxic and anoxic body parts have been reported, growth and drug susceptibility of fungal pathogens under...
Although severe cases of invasive mycoses of different hypoxic and anoxic body parts have been reported, growth and drug susceptibility of fungal pathogens under anaerobic conditions remains understudied. The current study evaluated anaerobic growth potential and drug susceptibility of environmental isolates under aerobic and anaerobic conditions. All tested strains showed equivalent growth and higher sensitivity to tested antifungal drugs under anaerobic conditions with lower minimum inhibitory concentration (MIC) as compared to aerobic conditions. Antifungal azoles were effective against isolates under both aerobic and anaerobic conditions. Most strains were resistant to antifungal echinocandins and polyenes under aerobic conditions but exhibited sensitivity under anaerobic conditions. This study provides evidence that resistance of to antifungal drugs varies with oxygen concentration and availability and suggests re-evaluating clinical breakpoints for antifungal compounds to treat invasive fungal infections more effectively.
PubMed: 37965151
DOI: 10.1016/j.isci.2023.108304 -
Cureus Aug 2023sinusitis is an opportunistic fungal infection that is difficult to treat due to its inherent resistance to many antifungal agents. Infections may cause both localized...
sinusitis is an opportunistic fungal infection that is difficult to treat due to its inherent resistance to many antifungal agents. Infections may cause both localized or disseminated disease usually in skin and soft tissues. Immunocompetent persons are typically unaffected and disseminated disease occurs in immunocompromised hosts. is a common hyaline mold causing sinopulmonary disease in those with hematologic malignancies and neutropenia. A 38-year-old Caucasian male with a medical history significant for HIV with intermittent treatment compliance, high-grade diffuse large B cell lymphoma (DLBCL) on chemotherapy, and hemophagocytic lymphohistiocytosis (HLH) presented with right-sided facial pain and fever. Maxillofacial computed tomography (CT) showed thickening and opacification of the sphenoid and maxillary sinuses concerning for fungal sinusitis. Endoscopic transsphenoidal debridement showed fungal growth of and the patient's blood cultures were ultimately negative. The patient underwent debridement of fungal sinusitis as well as right medial maxillectomy and ethmoidectomy. A three-month course of voriconazole was started and completed with weekly liver enzyme tests to monitor medication side effects. He has since been observed well as an outpatient with his oncologist after three months loss to follow-up and his infection has resolved.
PubMed: 37711912
DOI: 10.7759/cureus.43475 -
Journal of Fungi (Basel, Switzerland) Jun 2023Rheumatoid arthritis (RA) patients deal with a higher risk of bacterial and fungal infections compared to the general population because of their dysregulated immune... (Review)
Review
Rheumatoid arthritis (RA) patients deal with a higher risk of bacterial and fungal infections compared to the general population because of their dysregulated immune system as well as the immunosuppressive therapy they usually receive. spp. is a fungal pathogen responsible for cutaneous, lung, central nervous system, and eye infections, mostly in immunocompromised patients, leading to death in disseminated cases. We report the case of an 81-year-old woman with rheumatoid arthritis treated with steroids and an IL-6 inhibitor who was diagnosed with scedosporiosis of the upper limb. She was treated with voriconazole for one month, which was discontinued due to adverse events, and when scedosporiosis relapsed, she switched to itraconazole. We also reviewed the current literature on RA patients presenting with infections. Early and accurate diagnosis of scedosporiosis has therapeutic and prognostic implications, as traditionally this fungus is resistant to commonly used antifungals. Clinical alertness regarding uncommon infections, including fungal, in patients with autoimmune diseases on immunomodulatory agents is essential for effective treatment.
PubMed: 37367619
DOI: 10.3390/jof9060683 -
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 -
BMC Infectious Diseases Aug 2023Fungal infections, other than candidiasis and aspergillosis, are an uncommon entity. Despite this, emerging pathogens are a growing threat. In the following case report,...
BACKGROUND
Fungal infections, other than candidiasis and aspergillosis, are an uncommon entity. Despite this, emerging pathogens are a growing threat. In the following case report, we present the case of an immunocompromised patient suffering from two serious opportunistic infections in the same episode: the first of these, Nocardia multilobar pneumonia; and the second, skin infection by Scedosporium apiospermum. These required prolonged antibacterial and antifungal treatment.
CASE PRESENTATION
This case is a 71-year-old oncological patient admitted for recurrent pneumonias that was diagnosed for Nocardia pulmonary infection. Nervous system involvement was discarded and cotrimoxazole was started. Haemorrhagic skin ulcers in the lower limbs appeared after two weeks of hospital admission. We collected samples which were positive for Scedosporium apiospermum and we added voriconazole to the treatment. As a local complication, the patient presented a deep bruise that needed debridement. We completed 4 weeks of intravenous treatment with slow improvement and continued with oral treatment until the disappearance of the lesions occurs.
CONCLUSIONS
Opportunistic infections are a rising entity as the number of immunocompromised patients is growing due to more use of immunosuppressive therapies and transplants. Clinicians must have a high suspicion to diagnose and treat them. A fluid collaboration with Microbiology is necessary as antimicrobial resistance is frequent.
Topics: Humans; Aged; Scedosporium; Nocardia; Antifungal Agents; Voriconazole; Skin Diseases; Pneumonia; Opportunistic Infections; Nocardia Infections; Immunocompromised Host
PubMed: 37559001
DOI: 10.1186/s12879-023-08484-6 -
Life (Basel, Switzerland) Jan 2024There has been a substantial increase in the number of cases of invasive fungal infections worldwide, which is associated with a growing number of immunosuppressed... (Review)
Review
There has been a substantial increase in the number of cases of invasive fungal infections worldwide, which is associated with a growing number of immunosuppressed patients and a rise in antifungal resistance. Some fungi that were previously considered harmless to humans have become emerging pathogens. One of them is , a ubiquitous filamentous fungus commonly found in the environment, especially in the air and soil. belongs to a bigger group of hyaline fungi that cause hyalohyphomycosis, a fungal infection caused by fungi with colorless hyphae. Although this is a heterogeneous group of fungi, there are similarities regarding their ubiquity, ways of transmission, affected patients, and difficulties in diagnostics and treatment. In hyalohyphomycosis, the skin is one of the most affected organs, which is why the involvement of dermatologists is crucial for the initial assessment, since the timely recognition and early diagnosis of this condition can prevent life-threatening infections and death. In this review, we covered cutaneous hyalohyphomycosis caused by and other fungi in the same group, including , , , , , and genera.
PubMed: 38276283
DOI: 10.3390/life14010154