Review of treatment options for a multidrug-resistant fungus: Candida auris.

Candida auris is a widely distributed, highly lethal, multidrug-resistant fungal pathogen. It was first identified in 2009 when it was isolated from fluid drained from the external ear canal of a patient in Japan. Since then, it has caused infectious outbreaks in over 45 countries, with mortality rates approaching 60%. Drug resistance is common in this species, with a large proportion of isolates displaying fluconazole resistance and nearly half are resistant to two or more antifungal drugs. In this review, we describe the drug resistance mechanism of C. auris and potential small-molecule drugs for treating C. auris infection. Among these antifungal agents, rezafungin was approved by the US Food and Drug Administration (FDA) for the treatment of candidemia and invasive candidiasis on March 22, 2023. Ibrexafungerp and fosmanogepix have entered phase III clinical trials.

A novel model for predicting deep-seated candidiasis due to Candida glabrata among cancer patients: A 6-year study in a cancer center of China.

Followed by Candida albicans, Candida glabrata ranks as the second major species contributing to invasive candidiasis. Given the higher medical burden and lower susceptibility to azoles in C. glabrata infections, identifying these infections is critical. From 2016 to 2021, patients with deep-seated candidiasis due to C. glabrata and non-glabrata Candida met the criteria to be enrolled in the study. Clinical data were randomly divided into training and validation cohorts. A predictive model and nomogram were constructed using R software based on the stepwise algorithm and logistic regression. The performance of the model was assessed by the area under the receiver operating characteristic curve and decision curve analysis (DCA). A total of 197 patients were included in the study, 134 of them infected with non-glabrata Candida and 63 with C. glabrata. The predictive model for C. glabrata infection consisted of gastrointestinal cancer, co-infected with bacteria, diabetes mellitus, and kidney dysfunction. The specificity was 84.1% and the sensitivity was 61.5% in the validation cohort when the cutoff value was set to the same as the training cohort. Based on the model, treatment for patients with a high-risk threshold was better than 'treatment for all' in DCA, while opting low-risk patients out of treatment was also better than 'treatment for none' in opt-out DCA. The predictive model provides a rapid method for judging the probability of infections due to C. glabrata and will be of benefit to clinicians making decisions about therapy strategies.

Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study.

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34), and median birth weight was 1270 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%), and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines.

Our study describes neonates from low- and middle-income countries with neonatal invasive candidiasis (NIC). Most of them were outside the groups considered at high risk for NIC described in high-income countries. Candida spp. epidemiology was also different. The mortality was high (22%). Further research in these settings is required.

Serial (1-3)-beta-D-Glucan (BDG) monitoring shows high variability among premature neonates.

This study aimed to characterize the baseline values and dynamics of serum (1,3)-Beta-D-Glucan (BDG) in neonates at high risk of neonatal invasive candidiasis (NIC); as well as to determine the effect of various clinical variables on these levels. Single center prospective cohort study was performed including 20 high-risk neonates (gestational age < 29 weeks and/or birth weight ≤ 1000 gr). Samples for BDG (Fungitell® assay) were obtained twice weekly during 6 weeks. Nineteen neonates were enrolled with a median gestational age of 25 weeks (IQR 24-27), median birth weight of 730 gr (IQR 650-810). None of the neonates was diagnosed with NIC. 190 serum samples were included. The median BDG value was 59 pg/ml (IQR 30-148), mean was 119 pg/ml (SD ± 154). A total of 42.1% (80/190) samples showed values ≥80 pg/ml, with all the neonates presenting at least one test above this cut-off. Neonatal age did not show an association with BDG levels. Exposure to steroids and the use of a heel prick as sampling method were associated with statistically significant higher BDG levels. The BDG levels showed high variability and in a significant proportion of samples values were above the threshold for positivity (e.g., ≥80 pg/ml) in the absence of NIC. The exposure to postnatal steroids and the heel prick as the method of blood sampling were associated with higher BDG levels. LAY SUMMARY: Neonatal invasive candidiasis (NIC) presents high morbi-mortality. The diagnosis of NIC is often challenging. Blood cultures have limitations and better diagnostic tools are needed. Beta-D-glucan is a diagnostic marker which could be potentially used, although still more clinical data are required.

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

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 as 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 or interact with the enterocyte membrane components. Candidalysin, however, 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 Sap and Als 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 SUMMARY: Candida virulence factors (VFs) including mainly enzymes and proteins play vital roles in breaching the human intestinal barrier and causing deadly invasive candidiasis. Limited VFs' structural studies hinder deeper comprehension of their mechanisms and thus the design of vaccines and antifungal drugs against fungal infections.

Candida albicans-associated sepsis in a pre-term neonatal rhesus macaque (Macaca mulatta).

Invasive Candida infections (ICI) have been associated with neurodevelopmental impairment or death in human pre-term neonates. Candidiasis in nonhuman primates is seen mostly in immunosuppressed animals, and ICI is not commonly reported. Here, we report a case of Candida albicans-associated ICI in a pre-term neonatal rhesus macaque.

Disseminated Candidiasis in a Young, Previously Healthy, Dog and Review of Literature.

BACKGROUND: The reports on disseminated candidiasis in dogs so far describe at least one predisposing factor. This case report, however, highlights candidiasis in a dog without any known predisposition. PATIENT: A 1.5-year-old intact female Hovawart dog was presented with subcutaneous nodules and polyuria/polydipsia. An excisional biopsy revealed a chronic pyogranulomatous and necrotizing inflammation with mycotic structures. The patient became febrile and lethargic, and developed lameness. METHODS: A physical examination, blood tests, urinalysis, thoracic radiographs, abdominal ultrasonography of the abdomen, fine-needle aspiration biopsies, and a culture of a subcutaneous nodule aspirate were obtained. Selected sections of multiple organs were collected for routine histology postmortem. The isolate and a subcutaneous mass were subjected to molecular identification and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis. RESULTS: Clinical, laboratory, and radiological findings were consistent with a granulomatous chronic systemic inflammation. Cytology and histology showed a pyogranulomatous and necrotizing inflammation with myriads of intra- and extra-cellular yeasts and extracellular hyphae. Culture yielded numerous yeast colonies, which appeared Candida albicans-like, but showed a negative serum test and a low identification in API 20 C AUX. Nucleic acid sequences showed homology with the C. albicans-type strain CBS 562. Multilocus sequence typing (MLST) resulted in a new type with designation DST121. The identification of the isolates was confirmed by MALDI-TOF-MS analysis. CONCLUSION AND CLINICAL IMPORTANCE: Future MLST typing and investigation of virulence can provide further evidence whether this MLST-type is associated with clinical cases of disseminated candidiasis without an apparent predisposing condition.

Candida species isolated from urban bats of Londrina-Paraná, Brazil and their potential virulence.

The aim of this study was to isolate yeasts from the faeces of urban bats inhabiting the city of Londrina, Paraná, Brazil and to determine their potential virulence attributes. Seven (12.3%) of 57 bats screened in this study showed yeasts in their faeces. Five species of the genus Candida were isolated: C. guilliermondii, C. krusei, C. lusitaniae, C. parapsilosis, and C. pelliculosa. No phospholipase activity was detected in the egg yolk plate assay; however, all isolates demonstrated protease secretion in skim milk agar. Yeasts isolated from bats produced biofilm on the surface of polystyrene plates and all were classified as intermediate biofilm producers. Minimal inhibitory concentration (MIC) values for fluconazole in the yeasts varied according to the species. Only one isolate (M34 - C. lusitaniae) was considered susceptible dose-dependent to fluconazole. The yeasts were injected intravenously into Swiss mice, and at 15 days post-infection, the animals were killed and portions of their kidneys cultured on Sabouraud dextrose agar medium. All tissues analysed showed positive cultures of Candida spp. This is the first study evaluating the presence of fungi in the faeces of bats in an urban region, where the yeast species found were shown to be potentially pathogenic. As bats are commonly found in cities, these findings indicate the need for continuous surveillance concerning environmental contamination by their excreta.