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Infection and Drug Resistance 2023The emergence of resistance in to azoles and terbinafine has become increasingly evident in recent years, necessitating the development of novel antifungal drugs and...
INTRODUCTION
The emergence of resistance in to azoles and terbinafine has become increasingly evident in recent years, necessitating the development of novel antifungal drugs and the exploration of new indications for existing agents.
METHODS
In this study, we retrospectively evaluated the in vitro antifungal activity of 3 echinocandins (anidulafungin, caspofungin, and micafungin) against 73 clinical isolates of collected from a teaching hospital in Shanghai, China, using EUCAST E.DEF 9.3.1 with minor modification. We also reviewed the susceptibility of to echinocandins globally by literature searching.
RESULTS
Our findings revealed that micafungin exhibited the lowest modal minimum effective concentration (MEC) value (0.08 mg/L, n = 28) and the lowest geometric mean (GM) MEC value (0.014 mg/L) among the 73 isolates of tested, followed by anidulafungin with a modal MEC value of 0.016 mg/L (n = 67) and a GM of 0.018 mg/L. Caspofungin displayed a higher modal MEC value of 0.5 mg/L (n = 35) and a GM of 0.308 mg/L. Despite variations in methodologies, similar results were obtained from the review of five relevant studies included in our analysis.
DISCUSSION
Echinocandins exhibited excellent in vitro activity against isolates, with micafungin and anidulafungin demonstrating greater potency than caspofungin. These findings suggest that echinocandins could be considered as potential treatment options for managing recalcitrant dermatophytoses resulting from the emergence of resistance. However, it is important to note that the clinical efficacy of these in vitro findings has yet to be established and warrants further investigation.
PubMed: 37621698
DOI: 10.2147/IDR.S423735 -
The Journal of Infection Nov 2023The objectives of this study were to assess Candida spp. distribution and antifungal resistance of candidaemia across Europe. Isolates were collected as part of the...
The objectives of this study were to assess Candida spp. distribution and antifungal resistance of candidaemia across Europe. Isolates were collected as part of the third ECMM Candida European multicentre observational study, conducted from 01 to 07-07-2018 to 31-03-2022. Each centre (maximum number/country determined by population size) included ∼10 consecutive cases. Isolates were referred to central laboratories and identified by morphology and MALDI-TOF, supplemented by ITS-sequencing when needed. EUCAST MICs were determined for five antifungals. fks sequencing was performed for echinocandin resistant isolates. The 399 isolates from 41 centres in 17 countries included C. albicans (47.1%), C. glabrata (22.3%), C. parapsilosis (15.0%), C. tropicalis (6.3%), C. dubliniensis and C. krusei (2.3% each) and other species (4.8%). Austria had the highest C. albicans proportion (77%), Czech Republic, France and UK the highest C. glabrata proportions (25-33%) while Italy and Turkey had the highest C. parapsilosis proportions (24-26%). All isolates were amphotericin B susceptible. Fluconazole resistance was found in 4% C. tropicalis, 12% C. glabrata (from six countries across Europe), 17% C. parapsilosis (from Greece, Italy, and Turkey) and 20% other Candida spp. Four isolates were anidulafungin and micafungin resistant/non-wild-type and five resistant to micafungin only. Three/3 and 2/5 of these were sequenced and harboured fks-alterations including a novel L657W in C. parapsilosis. The epidemiology varied among centres and countries. Acquired echinocandin resistance was rare but included differential susceptibility to anidulafungin and micafungin, and resistant C. parapsilosis. Fluconazole and voriconazole cross-resistance was common in C. glabrata and C. parapsilosis but with different geographical prevalence.
PubMed: 37549695
DOI: 10.1016/j.jinf.2023.08.001 -
Clinical and Translational Science Oct 2023Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes...
Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (C ) was greater than three times higher than reported; moreover, midostaurin C , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.
Topics: Humans; Antifungal Agents; Micafungin; Prospective Studies; Leukemia, Myeloid, Acute; Neutropenia; fms-Like Tyrosine Kinase 3
PubMed: 37515369
DOI: 10.1111/cts.13595 -
Infection and Drug Resistance 2023Candidemia and antifungal resistance are major healthcare challenges. The aim of this study is to describe the frequency of candidemia cases, distribution of spp., and...
PURPOSE
Candidemia and antifungal resistance are major healthcare challenges. The aim of this study is to describe the frequency of candidemia cases, distribution of spp., and the associated risk factors for mortality in an academic institution in Saudi Arabia over an 18-month period. We also evaluated the susceptibility patterns of blood isolates.
METHODS
Candidemia cases were collected from King Fahad Hospital of the University over the period between July 1st, 2020 through December 31st, 2021. They were prospectively reviewed for the preceding risk factors and antifungal (AF) susceptibility, testing results to fluconazole (FL), voriconazole (VO), itraconazole (IT), posaconazole (PO), caspofungin (CASP), anidulafungin (AND), micafungin (MYC), flucytosine (FLC) and amphotericin B (AMPB) using a broth microdilution kit (Sensititre™ YeastOne).
RESULTS
A total of 48 candidemia isolates were included that were isolated from 43 patients. The median age of cases was 62 ± 23.3 years (60.4% males and 83% ICU patients). Independent risk factors for mortality at 30 days in candidemia patients were age, COVID-19 co-infection, and use of tocilizumab. The most commonly isolated species were and (22.9% each) followed by (18.75%). AF resistance for ≥1 antifungal was detected in 39.3% of 33 cases tested, with no cross-resistance identified. Resistance rates for each AF were as follows: FL (18%), VO (6%), IT (6%), PO (9%) and AMPB (3%). No resistance was seen for echinocandins apart from one strain showing an intermediate result for CASP.
CONCLUSION
The study showed an overall high rate of non-, with the predominance of and , representing a therapeutic challenge. AF resistance rate was high which emphasizes the importance of continuing surveillance and providing accurate and reliable tools in the laboratories for rapid speciation and susceptibility testing.
PubMed: 37457797
DOI: 10.2147/IDR.S411865 -
Journal of Family Medicine and Primary... May 2023In the past few decades, candidemia has escalated to worrisome levels, leading to substantial morbidity and mortality in neonates. The rise in anti-fungal drug...
PURPOSE
In the past few decades, candidemia has escalated to worrisome levels, leading to substantial morbidity and mortality in neonates. The rise in anti-fungal drug resistance demands prompt diagnosis and treatment. This study aimed to determine the speciation and susceptibility pattern of recovered from special care new-born units and identify risk factors for developing candidemia in neonates.
METHOD
A total of 580 blood samples from clinically suspected septicemic neonates were collected and subjected to culture. Cultures positive for yeasts were sub-cultured on Sabouraud dextrose agar. Identification of a suspected purified colony of was confirmed to the species level by both conventional and automated techniques matrix-assisted laser desorption and ionization time-of-flight mass spectrometry. Anti-fungal susceptibility of isolates was performed by an automated method (VITEK 2 system) using VITEK 2 cards. Multi-variate logistic regression analysis was used to identify risk factors associated with candidemia.
RESULT
A total of 56 (9.66%) isolates of were recovered from 580 blood cultures. Non-albicans species predominated with 82.14% of cases, whereas 17.86% of cases were caused by . (46.42%) was the most common isolate recovered, followed by (17.8%). Risk factor analyses identified a very low birth weight [odds ratio (OR) =4.05, 95% confidence interval (CI) =2.03-8.08] and prolonged antibiotic therapy (OR = 3.79, 95% CI = 1.7-8.7) among others as significant predictors of candidemia. All the Candida isolates showed 100% sensitivity to voriconazole and micafungin, whereas the overall sensitivities for fluconazole, amphotericin B, caspofungin, and flucytosine were 85.71%, 96.43%, 96.43%, and 91.07%, respectively.
CONCLUSION
Candidemia is a life-threatening condition in neonates. Identification of and routine anti-fungal susceptibility is a must to select a suitable and effective anti-fungal therapy to revoke emerging resistance to anti-fungals.
PubMed: 37448944
DOI: 10.4103/jfmpc.jfmpc_2104_22 -
Frontiers in Cellular and Infection... 2023The aim of this study is to identify the pathogen causing ocular infection in a Chinese patient and to describe its morphological characteristics.
OBJECTIVE
The aim of this study is to identify the pathogen causing ocular infection in a Chinese patient and to describe its morphological characteristics.
METHODS
Samples from the patient's intraoperative pus were collected for microscopic examination and culture. Morphology and drug sensitivities of the isolated fungus were analyzed. Ribosomal DNA (rDNA) sequencing was performed and blasted in GenBank.
RESULTS
A strain of fungi was repeatedly isolated from pus samples in different types of medium. No conidia were shown when the isolate cultured on normal PDA medium, whereas pseudoseptate thick-walled conidia were shown when cultured on medium containing leaf leachate. The results of BLAST and phylogenetic trees based on internal transcribed spacer, beta-tubulin, translation elongation factor 1-alpha, and RNA polymerase II gene demonstrated that the isolated fungus was . Minimum inhibitory concentration results of this organism were as follows: anidulafungin, 0.06 μg/ml; amphotericin B, 0.12 μg/ml; micafungin, 0.06 μg/ml; caspofungin, 0.5 μg/ml; 5-fluorocytosine, >64 μg/ml; posaconazole, 2 μg/ml; voriconazole, 0.25 μg/ml; itraconazole, 0.5 μg/ml; fluconazole, 64 μg/ml.
CONCLUSION
The case was infected with and led to eye suppurative endophthalmitis and blindness. Combined applications of morphological and molecular biology techniques facilitate accurate diagnosis of fungal infections.
Topics: Humans; Phylogeny; Ascomycota; Amphotericin B; Eye Infections
PubMed: 37448776
DOI: 10.3389/fcimb.2023.1160831 -
Antimicrobial Agents and Chemotherapy Aug 2023Candida (Clavispora) lusitaniae is a rare, emerging non- species that can cause life-threatening invasive infections, spread within hospital settings, and rapidly...
Candida (Clavispora) lusitaniae is a rare, emerging non- species that can cause life-threatening invasive infections, spread within hospital settings, and rapidly acquire antifungal drug resistance, including multidrug resistance. The frequency and spectrum of mutations causing antifungal drug resistance in C. lusitaniae are poorly understood. Analyses of serial clinical isolates of any Candida species are uncommon and often analyze a limited number of samples collected over months of antifungal therapy with multiple drug classes, limiting the ability to understand relationships between drug classes and specific mutations. Here, we performed comparative genomic and phenotypic analysis of 20 serial C. lusitaniae bloodstream isolates collected daily from an individual patient treated with micafungin monotherapy during a single 11-day hospital admission. We identified isolates with decreased micafungin susceptibility 4 days after initiation of antifungal therapy and a single isolate with increased cross-resistance to micafungin and fluconazole, despite no history of azole therapy in this patient. Only 14 unique single nucleotide polymorphisms (SNPs) were identified between all 20 samples, including three different alleles among isolates with decreased micafungin susceptibility and an missense mutation found only in the isolate with increased cross-resistance to both micafungin and fluconazole. This is the first clinical evidence of an mutation in C. lusitaniae that occurred during echinocandin monotherapy and is associated with cross-resistance to multiple drug classes. Overall, the evolution of multidrug resistance in C. lusitaniae is rapid and can emerge during treatment with only first-line antifungal therapy.
Topics: Humans; Micafungin; Antifungal Agents; Fluconazole; Candidiasis; Candida; Echinocandins; Drug Resistance, Fungal; Drug Resistance, Multiple; Microbial Sensitivity Tests
PubMed: 37428075
DOI: 10.1128/aac.00543-23 -
Biofilm Dec 2023species cause life-threatening infections with high morbidity and mortality rates and their resistance to conventional therapy is closely linked to biofilm formation....
species cause life-threatening infections with high morbidity and mortality rates and their resistance to conventional therapy is closely linked to biofilm formation. Thus, the development of new approaches to study biofilms and the identification of novel therapeutic strategies could yield improved clinical outcomes. In the current study, we have set up an impedance-based system to study spp biofilms in real-time and to evaluate their sensitivity to two conventional antifungal groups used in clinical practice - azoles and echinocandins. Both fluconazole and voriconazole were unable to inhibit biofilm formation in most strains tested, while echinocandins showed biofilm inhibitory capacity at relatively low concentrations (starting from 0.625 mg/L). However, assays performed on 24 h and biofilms revealed that micafungin and caspofungin failed to eradicate mature biofilms at all tested concentrations, evidencing that once formed, spp. biofilms are extremely difficult to eliminate using currently available antifungals. We then evaluated the antifungal and anti-biofilm effect of andrographolide, a natural compound isolated from the plant with known antibiofilm activity on Gram-positive and Gram-negative bacteria Optical density measures, impedance evaluation, CFU counts, and electron microscopy data showed that andrographolide strongly inhibits planktonic spp. growth and halts spp. biofilm formation in a dose-dependent manner in all tested strains. Moreover, andrographolide was capable of eliminating mature biofilms and viable cell numbers by up to 99.9% in the and strains tested, suggesting its potential as a new approach to treat multi-resistant spp. biofilm-related infections.
PubMed: 37396463
DOI: 10.1016/j.bioflm.2023.100134 -
Microorganisms Jun 2023Respiratory Syncytial Virus (RSV) is the top cause of infant hospitalization globally, with no effective treatments available. Researchers have sought small molecules to...
Respiratory Syncytial Virus (RSV) is the top cause of infant hospitalization globally, with no effective treatments available. Researchers have sought small molecules to target the RNA-dependent RNA Polymerase (RdRP) of RSV, which is essential for replication and transcription. Based on the cryo-EM structure of the RSV polymerase, in silico computational analysis including molecular docking and the protein-ligand simulation of a database, including 6554 molecules, is currently undergoing phases 1-4 of clinical trials and has resulted in the top ten repurposed compound candidates against the RSV polymerase, including Micafungin, Totrombopag, and Verubecestat. We performed the same procedure to evaluate 18 small molecules from previous studies and chose the top four compounds for comparison. Among the top identified repurposed compounds, Micafungin, an antifungal medication, showed significant inhibition and binding affinity improvements over current inhibitors such as ALS-8112 and Ribavirin. We also validated Micafungin's inhibition of the RSV RdRP using an in vitro transcription assay. These findings contribute to RSV drug development and hold promise for broad-spectrum antivirals targeting the non-segmented negative-sense (NNS) RNA viral polymerases, including those of rabies (RABV) and Ebola (EBOV).
PubMed: 37375110
DOI: 10.3390/microorganisms11061608 -
Mycopathologia Dec 2023We performed a retrospective survey of non-Candida albicans candidemia in patients with cancer, including those with solid tumors and those with hematological...
We performed a retrospective survey of non-Candida albicans candidemia in patients with cancer, including those with solid tumors and those with hematological malignancies as well as transplants patients both, solid-organ transplant recipients and hematopoietic stem cell transplant recipients. The study was performed at two healthcare centers in New York City and covered the years 2018-2022. A total of 292 patients (318 isolates) were included in the study. In order of frequency, C. glabrata (38%) was the most common species recovered, followed by C. parapsilosis (19.2%), C. tropicalis (12.6%), C. krusei (10.7%), C. lusitaniae (5.7%), and C. guilliermondii (4.4%). Micafungin was the most common antifungal treatment and 18.5% of patients were on antifungal prophylaxis. The 30-day crude mortality was 40%. 4.5% of patients had more than one non-albicans species detected. In conclusion, this study represents one of the largest surveys of non-albicans species in cancer and transplant patients and provides data on the current epidemiology of these Candida species in this patient population.
Topics: Humans; Antifungal Agents; Transplant Recipients; Retrospective Studies; Microbial Sensitivity Tests; Candida; Candidemia; Candida glabrata; Candida parapsilosis; Candida tropicalis; Neoplasms
PubMed: 37365379
DOI: 10.1007/s11046-023-00765-7