COVID-19-Associated Candidiasis (CAC): An Underestimated Complication in the Absence of Immunological Predispositions?

The recent global pandemic of COVID-19 has predisposed a relatively high number of patients to acute respiratory distress syndrome (ARDS), which carries a risk of developing super-infections. Candida species are major constituents of the human mycobiome and the main cause of invasive fungal infections, with a high mortality rate. Invasive yeast infections (IYIs) are increasingly recognized as s complication of severe COVID-19. Despite the marked immune dysregulation in COVID-19, no prominent defects have been reported in immune cells that are critically required for immunity to Candida. This suggests that relevant clinical factors, including prolonged ICU stays, central venous catheters, and broad-spectrum antibiotic use, may be key factors causing COVID-19 patients to develop IYIs. Although data on the comparative performance of diagnostic tools are often lacking in COVID-19 patients, a combination of serological and molecular techniques may present a promising option for the identification of IYIs. Clinical awareness and screening are needed, as IYIs are difficult to diagnose, particularly in the setting of severe COVID-19. Echinocandins and azoles are the primary antifungal used to treat IYIs, yet the therapeutic failures exerted by multidrug-resistant Candida spp. such as C. auris and C. glabrata call for the development of new antifungal drugs with novel mechanisms of action.

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Opportunistic yeast pathogen Candida spp.: Secreted and membrane-bound virulence factors

Medical Mycology ◽

10.1093/mmy/myab053 ◽

2021 ◽

Author(s):

Si Jie Lim ◽

Mohd Shukuri Mohamad Ali ◽

Suriana Sabri ◽

Noor Dina Muhd Noor ◽

Abu Bakar Salleh ◽

...

Keyword(s):

Virulence Factors ◽

Drug Targets ◽

Fungal Infections ◽

Antifungal Drugs ◽

Host Immune System ◽

Structural Studies ◽

Candida Spp ◽

Structural Investigations ◽

Membrane Bound ◽

Aspartyl Proteinases

Abstract Candidiasis is a fungal infection caused by Candida spp. especially Candida albicans, C. glabrata, C. parapsilosis and C. tropicalis. Although the medicinal therapeutic strategies have rapidly improved, the mortality rate due to candidiasis has continuously increased. The secreted and membrane-bound virulence factors (VFs) are responsible for fungal invasion, damage and translocation through the host enterocytes besides the evasion from host immune system. VFs such as agglutinin-like sequences (Als), heat shock protein 70, phospholipases, secreted aspartyl proteinases (Sap), lipases, enolases and phytases are mostly hydrolases which degrade the enterocyte membrane components except for candidalysin, the VF acts as a peptide toxin to induce necrotic cell lysis. To date, structural studies of the VFs remain underexplored, hindering their functional analyses. Among the VFs, only secreted aspartyl proteinases and agglutinin-like sequences have their structures deposited in Protein Data Bank (PDB). Therefore, this review scrutinizes the mechanisms of these VFs by discussing the VF-deficient studies of several Candida spp. and their abilities to produce these VFs. Nonetheless, their latest reported sequential and structural analyses are discussed to impart a wider perception of the host-pathogen interactions and potential vaccine or antifungal drug targets. This review signifies that more VFs structural investigations and mining in the emerging Candida spp. are required to decipher their pathogenicity and virulence mechanisms compared to the prominent C. albicans. Lay Abstract Candida virulence factors (VFs) including mainly enzymes and proteins play vital roles in breaching the human intestinal barrier and causing deadly candidiasis. Limited VFs’ structural studies hinder deeper comprehension of their mechanisms and thus the design of vaccines and antifungal drugs against fungal infections.

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Phaeohyphomycosis

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0039-3400957 ◽

2020 ◽

Vol 41 (01) ◽

pp. 131-140 ◽

Cited By ~ 3

Author(s):

Jonathan T. Arcobello ◽

Sanjay G. Revankar

Keyword(s):

Fungal Infections ◽

Case Reports ◽

Invasive Disease ◽

Molecular Techniques ◽

Diagnostic Tools ◽

Dematiaceous Fungi ◽

Serious Disease ◽

Cerebral Infection ◽

Disseminated Disease ◽

Immunocompromised Hosts

AbstractPhaeohyphomycosis refers to infections due to a large group of heterogenous organisms called “dematiaceous” or “melanized” fungi. These fungi are distinguished by the predominance of melanin in their cell walls, which likely acts as a virulence factor. Virtually, everyone is exposed to dematiaceous fungi through inhalation, as they are ubiquitous in the environment, although the development of infection is extremely uncommon. Invasive disease is rare but remains important due to the ability to cause serious disease in immunocompetent and immunocompromised hosts, unlike other fungal infections such as aspergillosis. A large variety of invasive manifestations can be caused by these organisms, including deep local infections, pulmonary infection, cerebral infection, and disseminated disease, which is associated with high mortality. While advances in molecular techniques are promising, they have still not replaced histology and culture as the primary diagnostic tools. Therapy is not standardized and is based primarily on clinical experience from descriptive case reports.

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Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens

Journal of Fungi ◽

10.3390/jof5030067 ◽

2019 ◽

Vol 5 (3) ◽

pp. 67 ◽

Cited By ~ 36

Author(s):

Friedman ◽

Schwartz

Keyword(s):

North America ◽

Fungal Pathogens ◽

Fungal Infections ◽

Trichophyton Mentagrophytes ◽

Invasive Fungal Disease ◽

Multidrug Resistant ◽

Antifungal Prophylaxis ◽

Candida Spp ◽

Sporothrix Brasiliensis ◽

Emerging Fungal Infections

: The landscape of clinical mycology is constantly changing. New therapies for malignant and autoimmune diseases have led to new risk factors for unusual mycoses. Invasive candidiasis is increasingly caused by non-albicans Candida spp., including C. auris, a multidrug-resistant yeast with the potential for nosocomial transmission that has rapidly spread globally. The use of mould-active antifungal prophylaxis in patients with cancer or transplantation has decreased the incidence of invasive fungal disease, but shifted the balance of mould disease in these patients to those from non-fumigatus Aspergillus species, Mucorales, and Scedosporium/Lomentospora spp. The agricultural application of triazole pesticides has driven an emergence of azole-resistant A. fumigatus in environmental and clinical isolates. The widespread use of topical antifungals with corticosteroids in India has resulted in Trichophyton mentagrophytes causing recalcitrant dermatophytosis. New dimorphic fungal pathogens have emerged, including Emergomyces, which cause disseminated mycoses globally, primarily in HIV infected patients, and Blastomyces helicus and B. percursus, causes of atypical blastomycosis in western parts of North America and in Africa, respectively. In North America, regions of geographic risk for coccidioidomycosis, histoplasmosis, and blastomycosis have expanded, possibly related to climate change. In Brazil, zoonotic sporotrichosis caused by Sporothrix brasiliensis has emerged as an important disease of felines and people.

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Autopsy Analysis On Epidemiology and Site of Involvement Of Invasive Fungal Infections (IFI) In Hematological Malignancies : A Retrospective Study at Hematologic Tertiary Care Department

Blood ◽

10.1182/blood.v122.21.5589.5589 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5589-5589

Author(s):

Anna Chierichini ◽

Francesca Monardo ◽

Barbara Anaclerico ◽

Paola Anticoli Borza ◽

Velia Bongarzoni ◽

...

Keyword(s):

Acute Leukemia ◽

Hematological Malignancies ◽

Conflicts Of Interest ◽

Fungal Infections ◽

Tertiary Care ◽

Diagnostic Methods ◽

Diagnostic Tools ◽

P Value ◽

Candida Spp ◽

Acute Leukemias

Abstract Background Clinical diagnosis of IFI is difficult ,due to lack of sensitive and specific diagnostic tools. An assessment of trends concerning the prevalence of IFI is a challenge and postmortem data may be useful to monitor the local epidemiology ,the frequency and the disease patterns. Aim The aim of this retrospective analysis is to determinate the local epidemiology and the prevalence at autopsy of IFI, occurring in hematological malignancies at a single center over a eleven years period. Methods We have retrospectively reviewed 161 patients – median age 62,5 yrs, range 22 -83 - with hematological malignancies, who underwent autopsy between 2002 -2012. Acute Myeloid Leukemia (AML) were 77, Acute Lymphoid Leukemia (ALL) 11, Lymphoproliferative disorders (LPD) 56 and other disorders 17. Acute leukemia pts received systemic antifungal prophilaxis, whereas the others not absorbable prophilaxis. None patients received transplant procedures. An experienced pathologist evaluated the organ involvement and the IFI pathologic pattern. Fisher’s Exact test was used to recognize the IFI prevalence, the main occurring pathogens and the involved site; a p-value of <0.05 was considered statistically significant. Results The analysis of 161 consecutive autopsies identified 40 pts.(25%)resulting to have IFI; of these, 22 were AML (55%) ,6 ALL (15%),11LPD (28%) and 1 other. Aspergillus spp. infection was detected in 20 cases (50%), Mucor spp in 8 (20%) and Candida spp. in 12 (30%). Moulds were prevalent in acute leukemia pts. and Aspergillus spp. is the leading pathogen with respect to Candida and Mucor spp. (p 0,0396),with a statistically significant prevalence in ALL (p 0,0186).The site more involved resulted lung (p 0.0002). Whereas the standardized EORTC/MSG criteria applied in vivo were conclusive for IFI in 6 pts ( 15%) only, the postmortem findings revealed fungal infections in further 34 pts (85%). Conclusion This analysis confirms that the IFI diagnosis is still an unresolved issue in hematological malignancies. Acute leukemias remain the subset with the higher prevalence of mould infections. As in other largest studies, in our experience Aspergillus spp and lung proved to be the most recurrent pathogen and site of involvement. At now, the diagnostic methods are not still completely able to identify the underlying IFI, thus the autopsy rate should be increased to achieve a better knowledge of epidemiology and to critically review previous misdiagnosis. Disclosures: No relevant conflicts of interest to declare.

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Prevalence and Fluconazole Susceptibility Profile of Candida spp. Clinical Isolates in a Brazilian Tertiary Hospital in Minas Gerais, Brazil

Anais da Academia Brasileira de Ciências ◽

10.1590/0001-3765201520140717 ◽

2015 ◽

Vol 87 (2 suppl) ◽

pp. 1349-1359 ◽

Cited By ~ 10

Author(s):

Athayde Neves-Junior ◽

Ana Carolina Cartágenes-Pinto ◽

Débora A.S. Rocha ◽

Leandro F. Reis de Sá ◽

Maria de Lourdes Junqueira ◽

...

Keyword(s):

Opportunistic Infections ◽

Fungal Infections ◽

Tertiary Hospital ◽

Antifungal Drugs ◽

Control Measures ◽

Clinical Isolates ◽

University Hospital ◽

Effective Control ◽

Candida Spp ◽

Resistance Phenotype

Candidiasis has become an important concern for clinical practice, especially with the increasing incidence of immunocompromised patients. In this scenario, the development resistance to fluconazole presents a challenge for treating these opportunistic infections. The aim of this study was to evaluate some epidemiology features of Candidainfections in a Brazilian University Hospital using data, previously unavailable. We observed that 44% of the 93 clinical isolates tested, belonged to Candida albicansspecies and 56% belonged to non-Candida albicansspecies (mainly Candida tropicalis and Candida glabrata). Most strains were isolated from urine samples where C. albicans was predominantly detected. 29 strains presented a fluconazole resistance phenotype and of these, 22 were chemosensitised by FK506, a classical inhibitor of ABC transporters related to azoles resistance. These data suggest the probable role of efflux pumps in this resistance phenotype. Our study highlights the need for developing effective control measures for fungal infections, rational use of antifungal drugs and development of new molecules able to abrogate the active transport of antifungals.

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A Study on Prevalence and Characterization of Candida Species in Immunocompromised Patients

Journal of Pure and Applied Microbiology ◽

10.22207/jpam.15.4.29 ◽

2021 ◽

Author(s):

Dhanapal Nandini ◽

J. Manonmoney ◽

J. Lavanya ◽

K.V. Leela ◽

Sujith

Keyword(s):

Risk Factors ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Predisposing Factors ◽

Immunocompromised Patients ◽

Candida Spp ◽

Gram Staining ◽

Number Of Patients ◽

Candida Infections ◽

Associated Risk Factors

Candida spp. is one among the major causes of nosocomial infection, with candidemia gaining increasing prevalence worldwide in parallel with mortality rates ranging from 10-49%. Epidemiology and predisposing factors of candidemia have changed since the number of patients receiving transplants and immunosuppressive therapy, the use of broadspectrum antimicrobials, and the number of AIDS patients have increased. Candidemia is more common among patients with subcutaneous and cutaneous candida infections, through percutaneous inoculation. Major predisposing factors for invasive candidiasis includes neutropenia, haematological malignancies, bone marrow transplantation, total parenteral nutrition, chemotherapy, invasive procedures, and immune-suppressive agents. This study analyses the risk factors of immunocompromised patients with candidemia and antibiogram of Candida spp. isolated from ICU patients. To evaluate the prevalence, distribution and antibiogram of Candida spp., associated risk factors, and outcome in candidemia patients. Blood samples received from patients with clinically suspected fungal infections were subjected to gram staining, culture, sugar assimilation & fermentation, Candida Chrome agar (CCA) & Corn meal agar for identification and speciation. Antifungal susceptibility tests were performed by disk-diffusion tests. Among a total of 337 samples received, 22 (6.5%) samples were positive for candida infections, of which Candida tropicalis 9 (41%) was the predominant isolate followed by C. albicans 5 (23%), Candida glabrata 4 (18%), Candida parapsilosis 2 (9%) and Candida krusei 2 (9%). Male patients had a higher prevalence of candidemia 15 (68.2%). Among the age group of 51-70 years, uncontrolled DM(Diabetes mellitus) and CKD (chronic kidney disease) were found to be the predominant co-morbidities with candidemia.

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Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00924-20 ◽

2020 ◽

Vol 64 (9) ◽

Cited By ~ 2

Author(s):

Gina Wall ◽

Jose L. Lopez-Ribot

Keyword(s):

Antifungal Activity ◽

Antifungal Agents ◽

Fungal Infections ◽

Alternative Pathway ◽

Drug Repurposing ◽

Pathogenic Fungi ◽

Multidrug Resistant ◽

Modern Medicine ◽

Antifungal Drugs ◽

Promising Alternative

ABSTRACT Fungal organisms are ubiquitous in nature, and progress of modern medicine is creating an expanding number of severely compromised patients susceptible to a variety of opportunistic fungal infections. These infections are difficult to diagnose and treat, leading to high mortality rates. The limited antifungal arsenal, the toxicity of current antifungal drugs, the development of resistance, and the emergence of new multidrug-resistant fungi, all highlight the urgent need for new antifungal agents. Unfortunately, the development of a novel antifungal is a rather long and expensive proposition, and no new classes of antifungal agents have reached the market in the last 2 decades. Drug repurposing, or finding new indications for old drugs, represents a promising alternative pathway to drug development that is particularly appealing within the academic environment. In the last few years, there has been a growing interest in repurposing approaches in the antifungal arena, with multiple groups of investigators having performed screenings of different repurposing libraries against different pathogenic fungi in search for drugs with previously unrecognized antifungal effects. Overall, these repurposing efforts may lead to the fast deployment of drugs with novel antifungal activity, which can rapidly bring benefits to patients, while at the same time reducing health care costs.

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In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01124-20 ◽

2020 ◽

Vol 64 (11) ◽

Cited By ~ 1

Author(s):

YanChun Zhu ◽

Shannon Kilburn ◽

Mili Kapoor ◽

Sudha Chaturvedi ◽

Karen Joy Shaw ◽

...

Keyword(s):

New York ◽

Fungal Infections ◽

Geometric Mean ◽

Multidrug Resistant ◽

Antifungal Drugs ◽

New Drugs ◽

Wild Type ◽

Candida Auris ◽

Content Type

ABSTRACT An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are panresistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug fosmanogepix is currently in phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50 and MIC90, 0.03 mg/liter; range, 0.004 to 0.06 mg/liter). The local epidemiological cutoff value (ECV) for MGX indicated all C. auris isolates were within the population of wild-type (WT) strains; 0.06 mg/liter defines the upper limit of wild type (UL-WT). MGX was 8- to 32-fold more active than the echinocandins, 16- to 64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators’ MIC50, MIC90, or geometric mean (GM) values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris panresistant isolates was 0.008 to 0.015 mg/liter, and the median and mode MIC values were 0.015 mg/liter, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

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Anticapsular and Antifungal Activity of α-Cyperone

Antibiotics ◽

10.3390/antibiotics10010051 ◽

2021 ◽

Vol 10 (1) ◽

pp. 51

Author(s):

Connor Horn ◽

Govindsamy Vediyappan

Keyword(s):

Antifungal Activity ◽

Fungal Pathogens ◽

Fungal Infections ◽

Antifungal Drugs ◽

Cyperus Rotundus ◽

Drug Resistant ◽

Fungal Virulence ◽

Medical Needs ◽

Number Of Patients ◽

Immunosuppressed Patients

Fungal infections affect 300 million people and cause 1.5 million deaths globally per year. With the number of immunosuppressed patients increasing steadily, there is an increasing number of patients infected with opportunistic fungal infections such as infections caused by the species of Candida and Cryptococcus. In fact, the drug-resistant Can. krusei and the emerging pan-antifungal resistant Can. auris pose a serious threat to human health as the existing limited antifungals are futile. To further complicate therapy, fungi produce capsules and spores that are resistant to most antifungal drugs/host defenses. Novel antifungal drugs are urgently needed to fill unmet medical needs. From screening a collection of medicinal plant sources for antifungal activity, we have identified an active fraction from the rhizome of Cyperus rotundus, the nut grass plant. The fraction contained α-Cyperone, an essential oil that showed fungicidal activity against different species of Candida. Interestingly, the minimal inhibitory concentration of α-Cyperone was reduced 8-fold when combined with a clinical antifungal drug, fluconazole, indicating its antifungal synergistic potential and could be useful for combination therapy. Furthermore, α-Cyperone affected the synthesis of the capsule in Cryp. neoformans, a causative agent of fungal meningitis in humans. Further work on mechanistic understanding of α-Cyperone against fungal virulence could help develop a novel antifungal agent for drug-resistant fungal pathogens.

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DectiSomes: Glycan Targeting of Liposomal Drugs Improves the Treatment of Disseminated Candidiasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01467-21 ◽

2021 ◽

Author(s):

Suresh Ambati ◽

Tuyetnhu Pham ◽

Zachary A. Lewis ◽

Xiaorong Lin ◽

Richard B. Meagher

Keyword(s):

Fungal Infections ◽

Drug Efficacy ◽

Antifungal Drugs ◽

Outer Cell ◽

Candida Spp ◽

Fungal Burden ◽

Disseminated Candidiasis ◽

Binding Domains ◽

One Year

Candida albicans causes life-threatening disseminated candidiasis. Individuals at greatest risk have weakened immune systems. An outer cell wall, exopolysaccharide matrix, and biofilm rich in oligoglucans and oligomannans help Candida spp. evade host defenses. Even after antifungal treatment, the one-year mortality rate exceeds 25%. Undoubtedly, there is room to improve drug performance. The mammalian C-type lectin pathogen receptors Dectin-1 and Dectin-2 bind to fungal oligoglucans and oligomannans, respectively. We previously coated amphotericin B-loaded liposomes, AmB-LLs, pegylated analogs of AmBisome, with the ligand binding domains of these two Dectins. DectiSomes, DEC1-AmB-LLs and DEC2-AmB-LLs, showed two distinct patterns of binding to the exopolysaccharide matrix surrounding C. albicans hyphae grown in vitro. Here we showed that DectiSomes were preferentially associated with fungal colonies in the kidneys. In a neutropenic mouse model of candidiasis, DEC1-AmB-LLs and DEC2-AmB-LLs delivering only one dose of 0.2 mg/kg AmB reduced the kidney fungal burden several fold relative to AmB-LLs. DEC1-AmB-LLs and DEC2-AmB-LLs increased the percent of surviving mice 2.5-fold and 8.3-fold, respectively, relative to AmB-LLs. Dectin-2 targeting of anidulafungin loaded liposomes, DEC2-AFG-LLs, and of commercial AmBisome, DEC2-AmBisome, reduced fungal burden in the kidneys several fold over their untargeted counterparts. The data herein suggest that targeting of a variety of antifungal drugs to fungal glycans may achieve lower safer effective doses and improve drug efficacy against a variety of invasive fungal infections.

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