Spectrum of infection and outcomes in individuals with Candida auris infection in Qatar.

BACKGROUND: We investigated the spectrum of infection and risk factors for invasive fungal disease due to Candida auris (CA) in Qatar. METHODS: We performed structured chart reviews on individuals with any positive CA culture between May 2019 and December 2022 at three tertiary care hospitals in Qatar. Invasive CA disease (ICAD) was defined as a positive sterile site culture, or any positive culture for CA with appropriate antifungal prescription. Main outcomes included proportion of individuals who developed ICAD among those with positive cultures, and 30-day/in-hospital mortality. RESULTS: Among 331 eligible individuals, median age was 56 years, 83.1% were male, 70.7% were non-Qataris, and 37.5% had ≥ 3 comorbidities at baseline. Overall, 86.4% were deemed to have colonization and 13.6% developed ICAD. Those with ICAD were more likely to have invasive central venous or urinary catheterization and mechanical ventilation. Individuals with ICAD had longer prior ICU stay (16 vs 26 days, P = 0.002), and longer hospital length of stay (63 vs. 43 days; P = 0.003), and higher 30-day mortality (38% vs. 14%; P<0.001). In multivariable regression analysis, only mechanical ventilation was associated with a higher risk of ICAD (OR 3.33, 95% CI 1.09-10.17). CONCLUSION: Invasive Candida auris Disease is associated with longer hospital stay and higher mortality. Severely ill persons on mechanical ventilation should be especially monitored for development of ICAD.

Candida albicans cDNA library screening reveals novel potential diagnostic targets for invasive candidiasis.

The detection of patterns associated with the invasive form of Candida albicans, such as Candida albicans germ tube antibodies (CAGTA), is a useful complement to blood culture for Invasive Candidiasis (IC) diagnosis. As CAGTA are detected by a non-standardisable and non-automatable technique, a Candida albicans cDNA expression library was screened with CAGTA isolated from serum of an animal model of invasive candidiasis, and five protein targets were identified: hyphally regulated cell wall protein 1 (Hyr1), enolase 1 (Eno1), coatomer subunit gamma (Sec21), a metallo-aminopeptidase (Ape2) and cystathionine gamma-lyase (Cys3). Homology with proteins from other organisms rules out Cys3 as a good biomarker while Sec21 results suggest that it is not in the germ tubes surface but secreted to the external environment. Our analysis propose Ape2, Sec21 and a region of Hyr1 different from the one currently being studied for immunoprotection as potential biomarker candidates for the diagnosis of IC.

Outcomes by Candida spp. in the ReSTORE Phase 3 trial of rezafungin versus caspofungin for candidemia and/or invasive candidiasis.

Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline Candida species distribution was similar in the two treatment groups; C. albicans (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), C. glabrata (25.8% and 26.6%), and C. tropicalis (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by Candida species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of Candida species.

Pathobiology of Candida auris infection analyzed by multiplexed imaging and single cell analysis.

Fungal organisms contribute to significant human morbidity and mortality and Candida auris (C. auris) infections are of utmost concern due to multi-drug resistant strains and persistence in critical care and hospital settings. Pathogenesis and pathology of C. auris is still poorly understood and in this study, we demonstrate how the use of multiplex immunofluorescent imaging (MxIF) and single-cell analysis can contribute to a deeper understanding of fungal infections within organs. We used two different neutrophil depletion murine models (treated with either 1A8-an anti-Ly6G antibody, or RB6-8C5-an anti-Ly6G/Ly6C antibody; both 1A8 and RB6-8C5 antibodies have been shown to deplete neutrophils) and compared to wildtype, non-neutropenic mice. Following pathologist assessment, fixed samples underwent MxIF imaging using a C. albicans antibody (shown to be cross-reactive to C. auris) and immune cell biomarkers-CD3 (T cells), CD68 (macrophages), B220 (B cells), CD45 (monocytes), and Ly6G (neutrophils) to quantify organ specific immune niches. MxIF analysis highlighted the heterogenous distribution of C. auris infection within heart, kidney, and brain 7 days post-infection. Size and number of fungal abscesses was greatest in the heart and lowest in brain. Infected mice had an increased count of CD3+, CD68+, B220+, and CD45+ immune cells, concentrated around C. auris abscesses. CD68+ cells were predominant in wildtype (non-neutropenic mice) and CD3+/CD45+ cells were predominant in neutropenic mice, with B cells being the least abundant. These findings suggest a Th2 driven immune response in neutropenic C. auris infection mice models. This study demonstrates the value of MxIF to broaden understanding of C. auris pathobiology, and mechanistic understanding of fungal infections.

A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence.

Candida auris is an emerging fungal pathogen responsible for health care-associated outbreaks that arise from persistent surface and skin colonization. We characterized the arsenal of adhesins used by C. auris and discovered an uncharacterized adhesin, Surface Colonization Factor (Scf1), and a conserved adhesin, Iff4109, that are essential for the colonization of inert surfaces and mammalian hosts. SCF1 is apparently specific to C. auris, and its expression mediates adhesion to inert and biological surfaces across isolates from all five clades. Unlike canonical fungal adhesins, which function through hydrophobic interactions, Scf1 relies on exposed cationic residues for surface association. SCF1 is required for C. auris biofilm formation, skin colonization, virulence in systemic infection, and colonization of inserted medical devices.

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.

A study on candiduria in neonates and infants from a tertiary care center, North India.

PURPOSE: Candida albicans is the major cause of fungal UTI in neonates and infants but nowadays non albicans Candida is also increasing and these are mostly multidrug resistant. So it's important to know the species of candidal UTI for the proper management. This study was undertaken to determine the Candida species distribution in UTI along with their susceptibility pattern and outcome in infants and neonates admitted in different wards and ICU of our hospital. We also assess the incidence rate of candiduria in ICUs. METHOD: Urine samples were collected from infants and neonates presented in pediatrics and neonatal ICU (intensive care units) and clinical wards with a clinical suspicion of candiduria and infants at risk of invasive candidiasis were also included in the study. Identification of Candida sp. was done by Gram's staining, germ tube test, chlamydospore formation on corn meal agar, color appearance on CHROM agar and also confirmed by MALDI-TOF Assay. Antifungal susceptibility was performed by using broth microdilution method as per the CLSI M27-A3/M27-S4. RESULT: Urine samples were received from 219 infants, and Candida was isolated from samples from 52 infants (isolation rate 23.75%), of which 30 were admitted in pediatric or neonatal ICU and 22 in the wards. The incidence rate of candiduria in ICU was 3.25%. Candida albicans was the most frequently isolated species from the samples of infants in the wards (13/22 i.e. 59%), while Candida tropicalis was most frequently isolated from samples of infants in the ICUs (13/30 i.e. 43.34%). Candida glabrata was the least commonly isolated species and was only encopuntered in the ICU. There was no discrepancy between the results of conventional methods of identification and MALDI-TOF. Antifungal susceptibility was performed for 18 randomly selected isolates. All were found to be susceptible to caspofungin, micafungin, itraconazole, voriconazole, fluconazole, amphotericin B. CONCLUSION: High suspicion of candiduria is needed especially in ICU admitted infants and identification of candida at species level along with the susceptibility pattern is important for the better management of patients.

Development and Validation of TaqMan Chemistry Probe-Based Rapid Assay for the Detection of Echinocandin-Resistance in Candida auris.

Candida auris is a multidrug-resistant yeast pathogen causing outbreaks in health care facilities worldwide, and the emergence of echinocandin-resistant C. auris is a concern. Currently used Clinical and Laboratory Standards Institute (CLSI) and commercial antifungal susceptibility tests (AFST) are phenotype-based, slow, and not scalable, limiting their effectiveness in the surveillance of echinocandin-resistant C. auris. The urgent need for accurate and rapid methods of assessment of echinocandin resistance cannot be overstated, as this class of antifungal drugs is preferred for patient management. We report the development and validation of a TaqMan chemistry probe-based fluorescence melt curve analysis (FMCA) following asymmetric polymerase chain reaction (PCR) to assess mutations within the hot spot one (HS1) region of FKS1, the gene responsible for encoding 1,3-ß-d-glucan synthase that is a target for echinocandins. The assay correctly identified F635C, F635Y, F635del, F635S, S639F or S639Y, S639P, and D642H/R645T mutations. Of these mutations, F635S and D642H/R645T were not involved in echinocandin resistance, while the rest were, as confirmed by AFST. Of 31 clinical cases, the predominant mutation conferring echinocandin resistance was S639F/Y (20 cases) followed by S639P (4 cases), F635del (4 cases), F635Y (2 cases), and F635C (1 case). The FMCA assay was highly specific and did not cross-react with closely and distantly related Candida and other yeast and mold species. Structural modeling of the Fks1 protein, its mutants, and docked conformations of three echinocandin drugs suggest a plausible Fks1 binding orientation for echinocandins. These findings lay the groundwork for future evaluations of additional FKS1 mutations and their impact on the development of drug resistance. The TaqMan chemistry probe-based FMCA would allow rapid, high throughput, and accurate detection of FKS1 mutations conferring echinocandin resistance in C. auris.

An overview of micafungin as a treatment option for invasive candidiasis in pediatric patients younger than 4 months old.

INTRODUCTION: Invasive candidiasis remains a leading cause of morbidity and mortality in various categories of patients at risk. AREAS COVERED: Structure and mechanism of action, pharmacokinetics and pharmacodynamics, clinical studies, safety, and regulatory status of micafungin are explored in the present review, focusing on pediatric patients younger than 4 months old. EXPERT OPINION: Although limited, the available data on the efficacy and safety of micafungin in pediatric patients younger than 4 months old support its use for the treatment of invasive candidiasis in this particular population, in line with the most updated recommendations from the European Medicines Agency and the US Food and Drug Administration. Additional study, especially of high-dose micafungin, could further optimize the use of this drug in pediatric patients younger than 4 months old with Candida meningoencephalitis. The recent worrisome worldwide diffusion of Candida auris, more frequently resistant to polyenes than to echinocandins and showing high rates of resistance to azoles, could render micafungin even more crucial for guaranteeing an efficacious antifungal treatment for invasive candidiasis in pediatric patients younger than 4 months old.

Performance of existing clinical scores and laboratory tests for the diagnosis of invasive candidiasis in critically ill, nonneutropenic, adult patients: A systematic review with qualitative evidence synthesis.

BACKGROUND: The Fungal Infections Definitions in Intensive Care Unit (ICU) patients (FUNDICU) project aims to provide standard sets of definitions for invasive fungal diseases in critically ill, adult patients. OBJECTIVES: To summarise the available evidence on the diagnostic performance of clinical scores and laboratory tests for invasive candidiasis (IC) in nonneutropenic, adult critically ill patients. METHODS: A systematic review was performed to evaluate studies assessing the diagnostic performance for IC of clinical scores and/or laboratory tests vs. a reference standard or a reference definition in critically ill, nonneutropenic, adult patients in ICU. RESULTS: Clinical scores, despite the heterogeneity of study populations and IC prevalences, constantly showed a high negative predictive value (NPV) and a low positive predictive value (PPV) for the diagnosis of IC in the target population. Fungal antigen-based biomarkers (with most studies assessing serum beta-D-glucan) retained a high NPV similar to that of clinical scores, with a higher PPV, although the latter showed important heterogeneity across studies, possibly reflecting the targeted or untargeted use of these tests in patients with a consistent clinical picture and risk factors for IC. CONCLUSIONS: Both clinical scores and laboratory tests showed high NPV for the diagnosis of IC in nonneutropenic critically ill patients. The PPV of laboratory tests varies significantly according to the baseline patients' risk of IC. This qualitative synthesis will provide the FUNDICU panel with baseline evidence to be considered during the development of definitions of IC in critically ill, nonneutropenic adult patients in ICU.

Development of the invasive candidiasis discharge [I Can discharge] model: a mixed methods analysis.

Patients with invasive candidiasis (IC) have complex medical and infectious disease problems that often require continued care after discharge. This study aimed to assess echinocandin use at hospital discharge and develop a transition of care (TOC) model to facilitate discharge for patients with IC. This was a mixed method study design that used epidemiologic assessment to better understand echinocandin use at hospital discharge TOC. Using grounded theory methodology focused on patients given echinocandins during their last day of hospitalization, a TOC model for patients with IC, the invasive candidiasis [I Can] discharge model was developed to better understand discharge barriers. A total of 33% (1405/4211) echinocandin courses were continued until the last day of hospitalization. Of 536 patients chosen for in-depth review, 220 (41%) were discharged home, 109 (20%) were transferred, and 207 (39%) died prior to discharge. Almost half (46%, 151/329) of patients discharged alive received outpatient echinocandin therapy. Independent predictors for outpatient echinocandin use were osteomyelitis (OR, 4.1; 95% CI, 1.1-15.7; p = 0.04), other deep-seated infection (OR, 4.4; 95% CI, 1.7-12.0; p = 0.003), and non-home discharge location (OR, 3.9, 95% CI, 2.0-7.7; p < 0.001). The I Can discharge model was developed encompassing four distinct themes which was used to identify potential barriers to discharge. Significant echinocadin use occurs at hospital discharge TOC. The I Can discharge model may help clinical, policy, and research decision-making processes to facilitate smoother and earlier hospital discharges.

Prediction of Prognostic Risk Factors in Patients with Invasive Candidiasis and Cancer: A Single-Centre Retrospective Study.

Background: Invasive candidiasis is a common cancer-related complication with a high fatality rate. If patients with a high risk of dying in the hospital are identified early and accurately, physicians can make better clinical judgments. However, epidemiological analyses and mortality prediction models of cancer patients with invasive candidiasis remain limited. Method: A set of 40 potential risk factors was acquired in a sample of 258 patients with both invasive candidiasis and cancer. To begin, risk factors for Candida albicans vs. non-Candida albicans infections and persistent vs. nonpersistent Candida infections were analysed using classic statistical methods. Then, we applied three machine learning models (random forest, logistic regression, and support vector machine) to identify prognostic indicators related to mortality. Prediction performance of different models was assessed by precision, recall, F1 score, accuracy, and AUC. Results: Of the 258 patients both with invasive candidiasis and cancer included in the analysis. The median age of patients was 62 years, and 95 (36.82%) patients were older than 65 years, of which 178 (66.28%) were male. And 186 (72.1%) patients underwent surgery 2 weeks before data collection, 100 (39.1%) patients stayed in ICU during hospitalisation, 99 (38.4%) patients had bacterial blood infection, 85 (32.9%) patients had persistent invasive candidiasis, and 41 (15.9%) patients died within 30 days. The usage of drainage catheter and prolonged length of hospitalisation are the dominant risk factors for non-Candida albicans infections and persistent Candida infections, respectively. Risk factors, such as septic shock, history of surgery within the past 2 weeks, usage of drainage tubes, length of stay in ICU, total parenteral nutrition, serum creatinine level, fungal antigen, stay in ICU during hospitalisation, and total bilirubin level, were significant predictors of death. The RF model outperformed the LR and SVM models. Precision, recall, F1 score, accuracy, and AUC for RF were 64.29%, 75.63%, 69.23%, 89.61%, and 91.28%. Conclusions: In this study, the machine learning-based models accurately predicted the prognosis of cancer and invasive candidiasis patients. The algorithm could be used to help clinicians in high-risk patients' early intervention.

In Vitro Antifungal Activity of Ibrexafungerp (SCY-078) Against Contemporary Blood Isolates From Medically Relevant Species of Candida: A European Study.

Background: Ibrexafungerp (SCY-078) is the newest oral and intravenous antifungal drug with broad activity, currently undergoing clinical trials for invasive candidiasis. Objective: The aim of this study was to assess the in vitro activity of ibrexafungerp and comparators against a collection of 434 European blood isolates of Candida. Methods: Ibrexafungerp, caspofungin, fluconazole, and micafungin minimum inhibitory concentrations (MICs) were collected from 12 European laboratories for 434 blood isolates, including 163 Candida albicans, 108 Candida parapsilosis, 60 Candida glabrata, 40 Candida tropicalis, 29 Candida krusei, 20 Candida orthopsilosis, 6 Candida guilliermondii, 2 Candida famata, 2 Candida lusitaniae, and 1 isolate each of Candida bracarensis, Candida catenulata, Candida dubliniensis, and Candida kefyr. MICs were determined by the EUCAST broth microdilution method, and isolates were classified according to recommended clinical breakpoints and epidemiological cutoffs. Additionally, 22 Candida auris from different clinical specimens were evaluated. Results: Ibrexafungerp MICs ranged from 0.016 to ≥8 mg/L. The lowest ibrexafungerp MICs were observed for C. albicans (geometric MIC 0.062 mg/L, MIC range 0.016-0.5 mg/L) and the highest ibrexafungerp MICs were observed for C. tropicalis (geometric MIC 0.517 mg/L, MIC range 0.06-≥8 mg/L). Modal MICs/MIC50s (mg/L) against Candida spp. were 0.125/0.06 for C. albicans, 0.5/0.5 for C. parapsilosis, 0.25/0.25 for C. glabrata, 0.5/0.5 for C. tropicalis, 1/1 for C. krusei, 4/2 for C. orthopsilosis, and 0.5/0.5 for C. auris. Ibrexafungerp showed activity against fluconazole- and echinocandin-resistant isolates. If adopting wild-type upper limits, a non-wild-type phenotype for ibrexafungerp was only observed for 16/434 (3.7%) isolates: 11 (4.6%) C. parapsilosis, 4 (5%) C. glabrata, and 1 (2.5%) C. tropicalis. Conclusion: Ibrexafungerp showed a potent in vitro activity against Candida.

Invasive candidiasis: investigational drugs in the clinical development pipeline and mechanisms of action.

INTRODUCTION: The epidemiology of invasive Candida infections is evolving. Infections caused by non-albicans Candida spp. are increasing; however, the antifungal pipeline is more promising than ever and is enriched with repurposed drugs and agents that have new mechanisms of action. Despite progress, unmet needs in the treatment of invasive candidiasis remain, and there are still too few antifungals that can be administered orally or that have CNS penetration. AREAS COVERED: The authors shed light on those antifungal agents active against Candida that are in early- and late-stage clinical development. Mechanisms of action and key pharmacokinetic and pharmacodynamic properties are discussed. Insights are offered on the potential future roles of the investigational agents MAT-2203, oteseconazole, ATI-2307, VL-2397, NP-339, and the repurposed drug miltefosine. EXPERT OPINION: Ibrexafungerp and fosmanogepix have novel mechanisms of action and will provide effective options for the treatment of Candida infections (including those caused by multiresistant Candida spp). Rezafungin, an echinocandin with an extended half-life allowing for once weekly administration, will be particularly valuable for outpatient treatment and prophylaxis. Despite this, there is an urgent need to garner clinical data on investigational drugs, especially in the current rise of azole-resistant and multidrug-resistant Candida spp.

Surveillance Study of Epidemiology, Antifungal Susceptibility and Risk Factors of Invasive Candidiasis in Critically ill Patients.

BACKGROUND: The aim of the study was to investigate the Candida species distribution and their antifungal sensitivities, clinical characteristics, and risk factors of the critically ill patients with invasive Candida infections in a tertiary hospital. METHODS: Candida strains from critically ill patients were isolated in a tertiary hospital of Anhui Province from June 2019 to June 2020 through fungal cultures and identified with MALDI-TOF MS system. The antifungal susceptibility was measured by ATB Fungus-3 method. Demographic information and laboratory data were retrieved from the computerized hospital data system. RESULTS: Candida albicans (C. albicans, 41.49%) was the predominant species in sterile body sites of critically ill patients developing invasive candidiasis, followed by C. glabrata (24.47%) and C. tropicalis (20.21%). The specimen sources were mainly urine (47.87%), then bronchoalveolar lavage fluid (18.09%) and blood (14.89%). In vitro, common Candida species were observed to be highly sensitive to amphotericin B and 5-fluorocytosine. All C. albicans exhibited susceptibility to both fluconazole and voriconazole, as did C. glabrata and C. parapsilosis. However, some C. tropicalis identified were frequently resistant to fluconazole, itraconazole, and voriconazole. The rate of Candida infection was positively correlated with certain risk factors including invasive interventions, age, length of stay in hospital, etc. Conclusions: C. albicans was the main species of invasive Candida infections in critically ill patients, followed by C. glabrata and C. tropicalis. Candida spp. showed the highest rate (10.60%) of resistance to fluconazole, followed by itraconazole (5.30%), voriconazole (5.30%), and 5-fluorocytosine (1.10%). All invasive Candida isolates were sensitive to amphotericin B. In addition, several C. tropicalis were tested and exhibited a high-level resistance to azoles. Notably, a variety of specific risk factors for candidiasis were identified in critically ill patients which need to be taken into consideration.

Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria.

Antibiotics are a modifiable iatrogenic risk factor for the most common human nosocomial fungal infection, invasive candidiasis, yet the underlying mechanisms remain elusive. We found that antibiotics enhanced the susceptibility to murine invasive candidiasis due to impaired lymphocyte-dependent IL-17A- and GM-CSF-mediated antifungal immunity within the gut. This led to non-inflammatory bacterial escape and systemic bacterial co-infection, which could be ameliorated by IL-17A or GM-CSF immunotherapy. Vancomycin alone similarly enhanced the susceptibility to invasive fungal infection and systemic bacterial co-infection. Mechanistically, vancomycin reduced the frequency of gut Th17 cells associated with impaired proliferation and RORγt expression. Vancomycin's effects on Th17 cells were indirect, manifesting only in vivo in the presence of dysbiosis. In humans, antibiotics were associated with an increased risk of invasive candidiasis and death after invasive candidiasis. Our work highlights the importance of antibiotic stewardship in protecting vulnerable patients from life-threatening infections and provides mechanistic insights into a controllable iatrogenic risk factor for invasive candidiasis.

Evaluation of Rezafungin Provisional CLSI Clinical Breakpoints and Epidemiological Cutoff Values Tested against a Worldwide Collection of Contemporaneous Invasive Fungal Isolates (2019 to 2020).

Rezafungin is a new echinocandin under development for the treatment of candidemia and invasive candidiasis. CLSI recently approved provisional susceptible-only breakpoints and epidemiological cutoff values for Candida spp. and rezafungin. The activities of rezafungin and comparators against 2019 to 2020 invasive fungal isolates was evaluated by applying the new CLSI breakpoints. Rezafungin demonstrated potent activity against Candida albicans (MIC50/MIC90, 0.03/0.06 mg/L; 100.0% susceptible), Candida tropicalis (MIC50/MIC90, 0.03/0.06 mg/L; 100% susceptible), Candida glabrata (MIC50/MIC90, 0.06/0.06 mg/L; 98.3% susceptible), Candida krusei (MIC50/MIC90, 0.03/0.03 mg/L; 100% susceptible), and Candida dubliniensis (MIC50/MIC90, 0.06/0.12 mg/L; 100% susceptible) when tested by the CLSI broth microdilution method. Rezafungin inhibited 99.6% of Candida parapsilosis isolates (MIC50/MIC90, 1/2 mg/L) at the susceptible breakpoint of ≤2 mg/L. All C. albicans, C. tropicalis, and C. krusei isolates, as well as most C. glabrata (96.2% to 97.9%) and C. parapsilosis (86.2% to 100%) isolates, were susceptible to comparator echinocandins. Fluconazole resistance was detected among 0.5%, 4.5%, 10.5%, and 1.2% of C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis isolates, respectively. All echinocandins displayed limited activity against Cryptococcus neoformans. Rezafungin and other echinocandins were active against Aspergillus fumigatus (minimum effective concentration for 90% of isolates tested [MEC90] range, 0.015 to 0.06 mg/L) and Aspergillus section Flavi (MEC90 range, 0.015 to 0.03 mg/L). All but 16 (8.6%) A. fumigatus isolates were susceptible to voriconazole, and 100% of Aspergillus section Flavi isolates were WT to mold-active azoles. When applying the CLSI clinical breakpoints, rezafungin displayed high susceptibility rates (>98.0%) against Candida isolates from invasive fungal infections and showed potent activity against Aspergillus isolates.

Invasive candidiasis in a neonatal intensive care unit in Fukuoka.

BACKGROUND: Invasive candidiasis (IC) is a leading cause of morbidity and mortality in preterm infants. The objective of this study was to determine the prevalence of IC infection in newborns in the neonatal intensive care unit (NICU) of a tertiary hospital in Japan, and to identify specific predisposing factors for IC. METHODS: We retrospectively collected data on demographics, clinical characteristics, and outcomes of infants with IC, who were discharged from a tertiary NICU in Japan between January 2009 and December 2020. We compared predisposing factors associated with the occurrence of early-onset IC (EOIC < 72 h) and late-onset IC (LOIC ≥ 72 h) with those of early-onset and late-onset bacterial sepsis. RESULTS: Between January 2009 and December 2020, 3,549 infants were admitted to the NICU, including 344 extremely-low birthweight (ELBW) infants. Eleven infants (including nine ELBW infants) had IC (incidence 0.31%), and the mortality rate of IC was 0%. Four (36%) infants had EOIC and seven (64%) had LOIC. All those with EOIC presented with skin lesions and 86% with LOIC had thrombocytopenia. Maternal vaginal Candida colonization was a more specific predisposing factor for EOIC, while gestational age <26 weeks, broad-spectrum antibiotic use, prior bacterial infection, prior gastrointestinal (GI) surgery, and GI diseases were more specific predisposing factors for LOIC. CONCLUSIONS: The findings suggest that maternal vaginal Candida colonization and skin lesions in ELBW infants may contribute to early recognition of EOIC. LOIC should be suspected if ELBW infants with several predisposing factors of LOIC have thrombocytopenia.

Candida Isolates From Blood and Other Normally Sterile Foci From ICU Patients: Determination of Epidemiology, Antifungal Susceptibility Profile and Evaluation of Associated Risk Factors.

Background: The clinical diagnosis and therapy for ICU patients with invasive candidiasis are challenged by the changes of Candida community composition and antimicrobial resistance. The epidemiology and drug sensitivity of candidiasis in ICU as well as its risk factors and drug resistance mechanism were investigated. Methods: In the present study, 115 patients in ICU were recruited from June 2019 through July 2020. Among them, 83 Candida isolates were identified with MALDI-TOF mass spectrometry. The susceptibility to antifungals was measured by microdilution method. The molecular mechanisms of azole-resistant Candida tropicalis were explored by sequencing, and their outcomes were explicitly documented. Results:Candida glabrata and C. tropicalis were the predominant non-C. albicans Candida. The specimen sources were mainly urine, bronchoalveolar lavage fluid and blood. The age, length of hospitalization, tracheotomy, diabetes and concomitant bacterial infection were the main risk factors for candidiasis. The majority of Candida species exhibited susceptibility to antifungals. However, certain C. tropicalis were frequently resistant to azoles. The polymorphism of the ERG11 in C. tropicalis was likely associated with azole resistance. Conclusion: The multiple risk factors for candidiasis in ICU patients need to be considered. Certain C. tropicalis exhibit resistance to azoles likely due to the ERG11 gene polymorphism.