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Invasive Candidiasis

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A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 21030

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Dr. Sofia Costa de Oliveira

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Division of Microbiology, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
Interests: medical microbiology; infectious diseases; invasive candidiasis; septicemia; antimicrobial resistance; biomarkers; flow cytometry; microbiological diagnostic; epidemiology; public health
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Dear Colleagues,

Invasive candidiasis is a very serious Candida spp. infection and includes candidemia (bloodstream and other sterile body site infections) and deep-seated infections, which may be localized or lead to secondary candidemia. Mortality rates associated with invasive candidiasis can range from 35 to 75%, and despite efforts to introduce new antifungal agents, candidiasis has not decreased in the past two decades, especially in intensive care units. The main factors contributing to this problem are the difficulty in diagnosis due to the nonspecific clinical symptoms of systemic fungal infections, delayed laboratory detection methods, and subsequent delays in the initiation of adequate antifungal therapy.

This Special Issue aims to highlight the importance of new diagnostic tools and antifungal drugs in the management of invasive candidiasis. Original research or reviews papers on host–pathogen interactions and antifungal resistance are also welcome.

Dr. Sofia Costa-de-Oliveira
Guest Editor

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Keywords

antifungal drugs
antifungal resistance
diagnostic tools
biofilms
candidemia
antifungal stewardship

Published Papers (10 papers)

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Research

13 pages, 644 KiB

Open AccessArticle

The Impact of COVID-19 on the Epidemiology and Outcomes of Candidemia: A Retrospective Study from a Tertiary Care Center in Lebanon

by Aline El Zakhem, Omar Mahmoud, Johnny Zakhour, Sarah B. Nahhal, Nour El Ghawi, Nadine Omran, Walaa G. El Sheikh, Hani Tamim and Souha S. Kanj

J. Fungi 2023, 9(7), 769; https://0-doi-org.brum.beds.ac.uk/10.3390/jof9070769 - 21 Jul 2023

Cited by 3 | Viewed by 1152

Abstract

Invasive fungal infections, notably candidemia, have been associated with COVID-19. The epidemiology of candidemia has significantly changed during the COVID-19 pandemic. We aim to identify the microbiological profile, resistance rates, and outcomes of COVID-19-associated candidemia (CAC) compared to patients with candidemia not associated with COVID-19. We retrospectively collected data on patients with candidemia admitted to the American University of Beirut Medical Center between 2004 and 2022. We compared the epidemiology of candidemia during and prior to the COVID-19 pandemic. Additionally, we compared the outcomes of critically ill patients with CAC to those with candidemia without COVID-19 from March 2020 till March 2022. Among 245 candidemia episodes, 156 occurred prior to the pandemic and 89 during the pandemic. Of the latter, 39 (43.8%) were CAC, most of which (82%) were reported from intensive care units (ICU). Non-albicans Candida (NAC) spp. were predominant throughout the study period (67.7%). Candida auris infection was the most common cause of NAC spp. in CAC. C. glabrata had decreased susceptibility rates to fluconazole and caspofungin during the pandemic period (46.1% and 38.4%, respectively). The mortality rate in the overall ICU population during the pandemic was 76.6%, much higher than the previously reported candidemia mortality rate observed in studies involving ICU patients. There was no significant difference in 30-day mortality between CAC and non-CAC (75.0% vs. 78.1%; p = 0.76). Performing ophthalmic examination (p = 0.002), CVC removal during the 48 h following the candidemia (p = 0.008) and speciation (p = 0.028) were significantly associated with a lower case-fatality rate. The epidemiology of candidemia has been significantly affected by the COVID-19 pandemic at our center. Rigorous infection control measures and proper antifungal stewardship are essential to combat highly resistant species such as C. auris. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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22 pages, 2811 KiB

Open AccessArticle

The Effect of Sub-Lethal Successive Applications of Photodynamic Therapy on Candida albicans Biofilm Depends on the Photosensitizer

by Luana Mendonça Dias, Marlise Inêz Klein, Túlio Morandin Ferrisse, Karine Sousa Medeiros, Cláudia Carolina Jordão, Amanda Bellini and Ana Claudia Pavarina

J. Fungi 2023, 9(1), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/jof9010111 - 13 Jan 2023

Cited by 3 | Viewed by 1901

Abstract

This study aimed to evaluate the potential of successive applications of sub-lethal doses of the antimicrobial photodynamic therapy (aPDT) mediated by Photodithazine^® (PDZ) and curcumin (CUR) associated with LED in the viability, reactive oxygen species (ROS) production, and gene expression of Candida albicans. The microbial assays were performed using planktonic cultures and biofilms. Ten successive applications (Apl#) were performed: aPDT (P+L+; C+L+), photosensitizer (P+L−; C+L−), and LED (P−L+; C−L+). Control groups were used (P−L−; C−L−). The viability of C. albicans was determined by cultivating treated cultures on agar plates with or without fluconazole (FLU). In addition, the ROS detection and expression of SOD1, CAP1, and ERG11 genes were determined. For planktonic cultures, no viable colonies were observed after Apl#3 (without FLU) and Apl#2 (with FLU) for either photosensitizer. Biofilm treated with P+L+ resulted in the absence of cell viability after Apl#7, while C+L+ showed ~1.40 log₁₀ increase in cell viability after Apl#2, regardless of FLU. For both photosensitizers, after the last application with viable colonies, the production of ROS was higher in the biofilms than in the planktonic cultures, and SOD1 expression was the highest in P+L+. A reduction of CAP1 and ERG11 expression occurred after P+L+, regardless of FLU. C+L+ had a higher level of ROS, and the treatments were non-significant for gene expression. Sub-lethal doses of aPDT mediated by CUR could induce C. albicans resistance in biofilms, while C. albicans cells in biofilms were susceptible to aPDT mediated by PDZ. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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7 pages, 987 KiB

Open AccessCommunication

Impact of the Disk Diffusion Test on Fluconazole De-Escalation in Patients with Candidemia

by Suchavadee Tantasuwan, Piriyaporn Chongtrakool, Amiroh Waesamaae and Methee Chayakulkeeree

J. Fungi 2022, 8(11), 1185; https://0-doi-org.brum.beds.ac.uk/10.3390/jof8111185 - 10 Nov 2022

Viewed by 1406

Abstract

Disk diffusion (DD) is a simple antifungal susceptibility method for Candida. This study examined the impact of fluconazole DD testing on antifungal de-escalation. We enrolled patients with candidemia whose Candida isolates were tested for fluconazole susceptibility using DD between January 2019 and January 2020. The historical controls were patients with candidemia who underwent fluconazole susceptibility testing using the broth microdilution (BMD) method. Clinical data including antifungal therapy were analyzed. In total, 108 patients were enrolled. Most baseline characteristics were comparable between the groups. C. tropicalis was the predominant isolate (54.6%), followed by C. albicans (17.6%). The rates of antifungal de-escalation within 72 h were 25.9 and 9.3% in the DD and BMD groups, respectively (p = 0.023). The median time to de-escalation was 3 days in the DD group, versus 6 days in the BMD group (p = 0.037). The 14-day mortality rate and antifungal cost tended to be lower in the DD group. There were no differences in the length of hospital stay and treatment-related complications between the two groups. The agreement between the DD and BMD results was 90%. DD testing can be substituted for BMD to enhance antifungal de-escalation and antifungal stewardship. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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11 pages, 1074 KiB

Open AccessArticle

Assessment of Biofilm Formation by Candida albicans Strains Isolated from Hemocultures and Their Role in Pathogenesis in the Zebrafish Model

by Sabi Pokhrel, Nawarat Boonmee, Orawan Tulyaprawat, Sujiraphong Pharkjaksu, Iyarit Thaipisutikul, Phoom Chairatana, Popchai Ngamskulrungroj and Chalermchai Mitrpant

J. Fungi 2022, 8(10), 1014; https://0-doi-org.brum.beds.ac.uk/10.3390/jof8101014 - 27 Sep 2022

Cited by 10 | Viewed by 1819

Abstract

Candida albicans, an opportunistic pathogen, has the ability to form biofilms in the host or within medical devices in the body. Biofilms have been associated with disseminated/invasive disease with increased severity of infection by disrupting the host immune response and prolonging antifungal treatment. In this study, the in vivo virulence of three strains with different biofilm formation strengths, that is, non-, weak-, and strong biofilm formers, was evaluated using the zebrafish model. The survival assay and fungal tissue burden were measured. Biofilm-related gene expressions were also investigated. The survival of zebrafish, inoculated with strong biofilms forming C. albicans,, was significantly shorter than strains without biofilms forming C. albicans. However, there were no statistical differences in the burden of viable colonogenic cell number between the groups of the three strains tested. We observed that the stronger the biofilm formation, the higher up-regulation of biofilm-associated genes. The biofilm-forming strain (140 and 57), injected into zebrafish larvae, possessed a higher level of expression of genes associated with adhesion, attachment, filamentation, and cell proliferation, including eap1, als3, hwp1, bcr1, and mkc1 at 8 h. The results suggested that, despite the difference in genetic background, biofilm formation is an important virulence factor for the pathogenesis of C. albicans. However, the association between biofilm formation strength and in vivo virulence is controversial and needs to be further studied. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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16 pages, 1202 KiB

Open AccessArticle

Nationwide Surveillance of Antifungal Resistance of Candida Bloodstream Isolates in South Korean Hospitals: Two Year Report from Kor-GLASS

by Eun Jeong Won, Min Ji Choi, Seok Hoon Jeong, Dokyun Kim, Kyeong Seob Shin, Jeong Hwan Shin, Young Ree Kim, Hyun Soo Kim, Young Ah Kim, Young Uh, Namhee Ryoo, Jeong Su Park, Kyoung Un Park, Seung A. Byun, Ga Yeong Lee, Soo Hyun Kim and Jong Hee Shin

J. Fungi 2022, 8(10), 996; https://0-doi-org.brum.beds.ac.uk/10.3390/jof8100996 - 22 Sep 2022

Cited by 7 | Viewed by 2000

Abstract

We incorporated nationwide Candida antifungal surveillance into the Korea Global Antimicrobial Resistance Surveillance System (Kor-GLASS) for bacterial pathogens. We prospectively collected and analyzed complete non-duplicate blood isolates and information from nine sentinel hospitals during 2020–2021, based on GLASS early implementation protocol for the inclusion of Candida species. Candida species ranked fourth among 10,758 target blood pathogens and second among 4050 hospital-origin blood pathogens. Among 766 Candida blood isolates, 87.6% were of hospital origin, and 41.3% occurred in intensive care unit patients. Adults > 60 years of age accounted for 75.7% of cases. Based on species-specific clinical breakpoints, non-susceptibility to fluconazole, voriconazole, caspofungin, micafungin, and anidulafungin was found in 21.1% (154/729), 4.0% (24/596), 0.1% (1/741), 0.0% (0/741), and 0.1% (1/741) of the isolates, respectively. Fluconazole resistance was determined in 0% (0/348), 2.2% (3/135, 1 Erg11 mutant), 5.3% (7/133, 6 Pdr1 mutants), and 5.6% (6/108, 4 Erg11 and 1 Cdr1 mutants) of C. albicans, C. tropicalis, C. glabrata, and C. parapsilosis isolates, respectively. An echinocandin-resistant C. glabrata isolate harbored an F659Y mutation in Fks2p. The inclusion of Candida species in the Kor-GLASS system generated well-curated surveillance data and may encourage global Candida surveillance efforts using a harmonized GLASS system. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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9 pages, 762 KiB

Open AccessArticle

The Risk Factors and Mechanisms of Azole Resistance of Candida tropicalis Blood Isolates in Thailand: A Retrospective Cohort Study

by Teera Leepattarakit, Orawan Tulyaprawat and Popchai Ngamskulrungroj

J. Fungi 2022, 8(10), 983; https://0-doi-org.brum.beds.ac.uk/10.3390/jof8100983 - 20 Sep 2022

Cited by 2 | Viewed by 1611

Abstract

In recent decades, an epidemiological shift has been observed from Candida infections to non-albicans species and resistance to azoles. We investigated the associated factors and molecular mechanisms of azole-resistant blood isolates of C. tropicalis. Full-length sequencing of the ERG11 gene and quantitative real-time RT-PCR for the ERG11, MDR1, and CDR1 genes were performed. Male sex (odds ratio, 0.38), leukemia (odds ratio 3.15), and recent administration of azole (odds ratio 10.56) were associated with isolates resistant to azole. ERG11 mutations were found in 83% of resistant isolates, with A395T as the most common mutation (53%). There were no statistically significant differences in the expression of the ERG11, MDR1, and CDR1 genes between the groups resistant and susceptible to azole. The prevalence of azole-resistant isolates was higher than the usage of antifungal drugs, suggesting the possibility of environmental transmission in the healthcare setting. The unknown mechanism of the other 17% of the resistant isolates remains to be further investigated. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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17 pages, 17701 KiB

Open AccessArticle

Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in Candida albicans Causing Ergosterol Biosynthesis Inhibition

by Irfan A. Rather, Jamal S. M. Sabir, Amer H. Asseri, Mohmmad Younus Wani and Aijaz Ahmad

J. Fungi 2022, 8(7), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/jof8070688 - 29 Jun 2022

Cited by 4 | Viewed by 1933

Abstract

Candida albicans is the most dominant and prevalent cause of fungal infections in humans. Azoles are considered as first-line drugs for the treatment of these infections. However, their prolonged and insistent use has led to multidrug resistance and treatment failures. To overcome this, modification or derivatization of the azole ring has led to the development of new and effective antifungal molecules. In a previous study, we reported on the development of new triazole-based molecules as potential antifungal agents against Candida auris. In this study, the most potent molecules from the previous study were docked and simulated with lanosterol 14-alpha demethylase enzyme. These compounds were further evaluated for in vitro susceptibility testing against C. albicans. In silico results revealed favorable structural dynamics of the compounds, implying that the compounds would be able to effectively bind to the target enzyme, which was further manifested by the strong interaction of the test compounds with the amino acid residues of the target enzyme. In vitro studies targeting quantification of ergosterol content revealed that pta1 was the most active compound and inhibited ergosterol production by >90% in both drug-susceptible and resistant C. albicans isolates. Furthermore, RT-qPCR results revealed downregulation of ERG11 gene when C. albicans cells were treated with the test compound, which aligns with the decreased ergosterol content. In addition, the active triazole derivatives were also found to be potent inhibitors of biofilm formation. Both in silico and in vitro results indicate that these triazole derivatives have the potential to be taken to the next level of antifungal drug development. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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11 pages, 317 KiB

Open AccessArticle

International Multicentre Study of Candida auris Infections

by Nirav Pandya, Yasemin Cag, Nenad Pandak, Abdullah Umut Pekok, Aruna Poojary, Folusakin Ayoade, Teresa Fasciana, Anna Giammanco, Hulya Caskurlu, Dhanji P. Rajani, Yogesh Kumar Gupta, Ilker Inanc Balkan, Ejaz Ahmed Khan and Hakan Erdem

J. Fungi 2021, 7(10), 878; https://0-doi-org.brum.beds.ac.uk/10.3390/jof7100878 - 19 Oct 2021

Cited by 17 | Viewed by 3145

Abstract

Background:Candida auris has emerged globally as a multi-drug resistant yeast and is commonly associated with nosocomial outbreaks in ICUs. Methods: We conducted a retrospective observational multicentre study to determine the epidemiology of C. auris infections, its management strategies, patient outcomes, and infection prevention and control practices across 10 centres from five countries. Results: Significant risk factors for C. auris infection include the age group of 61–70 years (39%), recent history of ICU admission (63%), diabetes (63%), renal failure (52%), presence of CVC (91%) and previous history of antibiotic treatment (96%). C. auris was commonly isolated from blood (76%). Echinocandins were the most sensitive drugs. Most common antifungals used for treatment were caspofungin (40%), anidulafungin (28%) and micafungin (15%). The median duration of treatment was 20 days. Source removal was conductedin 74% patients. All-cause crude mortality rate after 30 days was 37%. Antifungal therapy was associated with a reduction in mortality (OR:0.27) and so was source removal (OR:0.74). Contact isolation precautions were followed in 87% patients. Conclusions:C. auris infection carries a high risk for associated mortality. The organism is mainly resistant to most azoles and even amphotericin-B. Targeted antifungal therapy, mainly an echinocandin, and source control are the prominent therapeutic approaches. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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11 pages, 1002 KiB

Open AccessArticle

The Prediction and Prognosis of Fungal Infection in Lung Transplant Recipients—A Retrospective Cohort Study in South Korea

by Yae-Jee Baek, Yun-Suk Cho, Moo-Hyun Kim, Jong-Hoon Hyun, Yu-Jin Sohn, Song-Yee Kim, Su-Jin Jeong, Moo-Suk Park, Jin-Gu Lee and Hyo-Chae Paik

J. Fungi 2021, 7(8), 639; https://0-doi-org.brum.beds.ac.uk/10.3390/jof7080639 - 06 Aug 2021

Cited by 5 | Viewed by 2055

Abstract

(1) Background: Lung transplant recipients (LTRs) are at substantial risk of invasive fungal disease (IFD), although no consensus has been reached on the use of antifungal agents (AFAs) after lung transplantation (LTx). This study aimed to assess the risk factors and prognosis of fungal infection after LTx in a single tertiary center in South Korea. (2) Methods: The study population included all patients who underwent LTx between January 2012 and July 2019 at a tertiary hospital. It was a retrospective cohort study. Culture, bronchoscopy, and laboratory findings were reviewed during episodes of infection. (3) Results: Fungus-positive respiratory samples were predominant in the first 90 days and the overall cumulative incidence of Candida spp. was approximately three times higher than that of Aspergillus spp. In the setting of itraconazole administration for 6 months post-LTx, C. glabrata accounted for 36.5% of all Candida-positive respiratory samples. Underlying connective tissue disease-associated interstitial lung disease, use of AFAs before LTx, a longer length of hospital stay after LTx, and old age were associated with developing a fungal infection after LTx. IFD and fungal infection treatment failure significantly increased overall mortality. Host factors, antifungal drug resistance, and misdiagnosis of non-Aspergillus molds could attribute to the breakthrough fungal infections. (4) Conclusions: Careful bronchoscopy, prompt fungus culture, and appropriate use of antifungal therapies are recommended during the first year after LTx. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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12 pages, 1750 KiB

Open AccessArticle

CD137 Signaling Is Critical in Fungal Clearance during Systemic Candida albicans Infection

by Vuvi G. Tran, Na N. Z. Nguyen and Byungsuk Kwon

J. Fungi 2021, 7(5), 382; https://0-doi-org.brum.beds.ac.uk/10.3390/jof7050382 - 14 May 2021

Cited by 8 | Viewed by 2382

Abstract

Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance during systemic C. albican infection, yet little has been known regarding which surface receptor controls neutrophils’ antifungal activities. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of neutrophil CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9^−/− mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9^−/− mice that received wild-type (WT) neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance. Full article

(This article belongs to the Special Issue Invasive Candidiasis)

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