BACKGROUND: Echinocandins belong to the fourth generation of antifungals, and there are no systematic studies on their risk in coagulation dysfunction; this study will predict the risk of coagulation dysfunction of echinocandins using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.
METHODS: Data from January 2004 to March 2024 were obtained from FAERS. We examined the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare echinocandins with the full database.
RESULTS: There were 313 reports of coagulation dysfunction related to echinocandins as the primary suspect (PS) drug. The median time to incident for coagulation dysfunction was 3 (interquartile range [IQR] 1-9) days. Compared to triazoles and polyenes, echinocandins have a stronger signal (ROR 3.18, 95%CI 2.81-3.51, p < 0.01) of coagulation dysfunction. Compared to caspofungin and micafungin, anidulafungin has a stronger signal (ROR 6.84, 95%CI 4.83-9.70, p < 0.01). The strongest signal corresponding to disseminated intravascular coagulation (DIC), platelet count decreased, thrombocytopenia, gastrointestinal haemorrhage, cerebral haemorrhage, pulmonary haemorrhage and thrombotic thrombocytopenic purpura (TTP) is micafungin (ROR 27.19, 95%CI 18.49-39.98), micafungin (ROR 3.50, 95%CI 2.36-5.19), anidulafungin (ROR 9.75, 95%CI 5.22-18.19), micafungin (ROR 3.17, 95%CI 2.02-4.97), micafungin (ROR 4.95, 95%CI 2.81-8.72), caspofungin (ROR 20.76, 95%CI 11.77-36.59), micafungin (ROR 20.43, 95%CI 8.49-49.14), respectively.
CONCLUSIONS: For coagulation dysfunction, we found stronger signals for echinocandins than triazoles and polyenes, and stronger signals for anidulafungin than micafungin and caspofungin. Coagulation parameters should be closely monitored while using the respective drugs.

OBJECTIVE: Literature is limited regarding ideal micafungin dosing in pediatric patients with hematologic malignancies receiving chemotherapy or hematopoietic stem cell transplantation. Micafungin is an intravenous echinocandin with activity against Candida and Aspergillus species and has a favorable safety profile compared with other antifungal classes. Our objective was to evaluate the breakthrough invasive fungal infection (IFI) rate in pediatric patients who received a prophylactic micafungin course at our institution.
METHODS: A single-center, retrospective study was conducted between January 1, 2011, and July 31, 2017, to determine the IFI rate in patients receiving micafungin prophylaxis. Patients with suspected IFI were evaluated for probable or proven infection based on European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group invasive fungal disease definitions. Statistical analyses were descriptive.
RESULTS: A total of 170 prophylactic micafungin courses from 129 unique patients ages <12 years at a median dose of 3 mg/kg daily were identified. The rate of probable or proven breakthrough IFIs was 2.4% as determined by clinical, radiologic, microbiologic, and histopathologic criteria.
CONCLUSIONS: A low rate of breakthrough IFI was seen with micafungin prophylaxis that is consistent with prior published adult hematopoietic stem cell transplantation studies. Micafungin was well tolerated, with liver function test elevations being transient in most cases and thought to be related to alternative factors.

Invasive fungal infections including invasive pulmonary aspergillosis (IPA) generally have a poor prognosis, because the fungi spread throughout various organs. Therefore, it is important to accurately identify the fungal species for treatment. In this article, we present the results of pathological and molecular morphological analyses that were performed to elucidate the cause of respiratory failure in a patient who died despite suspicion of IPA and treatment with micafungin (MCFG). Pathological analysis revealed the existence of cystic and linear fungi in lung tissue. The fungi were identified as Aspergillus fumigatus (A. fumigatus) by partial sequencing of genomic DNA. Correlative light microscopy and electron microscopy (CLEM) analysis confirmed that fungi observed with light microscopy can also be observed with scanning electron microscopy (SEM) using formalin-fixed paraffin-embedded tissue sections. SEM revealed an atypical ultrastructure of the fungi including inhomogeneous widths, rough surfaces, and numerous cyst-like structures of various sizes. The fungi showed several morphological changes of cultured A. fumigatus treated with MCFG that were previously reported. Our results indicate that integrated analysis of ultrastructural observation by SEM and DNA sequencing may be an effective tool for analyzing fungi that are difficult to identify by conventional pathological analysis.

BACKGROUND: Although combination therapy of echinocandins with trimethoprim-sulfamethoxazole (TMP-SMX) has been reported for patients with Pneumocystis jirovecii pneumonia (PCP), the effectiveness of this combination therapy in patients with PCP without human immunodeficiency virus (HIV) infection remains unknown.
METHODS: Data from the Japanese Diagnosis Procedure Combination inpatient database was used to identify non-HIV patients who underwent their first hospitalisation for PCP between April 2012 and March 2022. The patients were divided into those treated with TMP-SMX alone and those treated with TMP-SMX combined with echinocandins. We performed propensity-score overlap-weighting analysis to estimate in-hospital mortality.
RESULTS: Among the 1324 eligible patients, 122 received TMP-SMX plus echinocandins, while 1202 received TMP-SMX alone. The propensity-score overlap-weighting analysis showed that the combination therapy was not associated with reduced in-hospital mortality in comparison with TMP-SMX alone (22.2 % vs. 26.9 %; risk difference, 4.6 %; 95 % confidence interval, -6.1 %-15.3 %; P = 0.398).
CONCLUSIONS: Echinocandins combined with TMP-SMX may not improve in-hospital mortality due to PCP in patients without HIV infection.

Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 μM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 μM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity.

Candida auris is an emerging, multidrug-resistant yeast that causes systemic infections, mainly in hospitalized or immunosuppressed patients. This pathogen has a high mortality and morbidity rate. This study aims to evaluate the antifungal potential of micafungin (MICA) encapsulated in a nanoemulsion (NEM) against four clades of C. auris and other non-C. auris species. The antifungal potential of MICA and NEM was evaluated by determining mature biofilm inhibition (0.78-50 µg/mL). The antifungal activities of MICA and NEM (5.92 mg/Kg) were evaluated using an in vivo model of Galleria mellonella. The results showed that NEM intensified the antibiofilm action of MICA, especially in 48 h mature biofilms. In vivo results displayed a higher effectiveness of NEM against all clades of C. auris tested, inhibiting the fungal load in the hemolymph and tissues of G. mellonella with a difference of 3 log10. In addition, C. auris infection caused granulomas surrounded by hemocytes, mainly at the lower and upper ends. Conversely, C. albicans developed pseudohyphae, biofilms, filaments, and chlamydospores. In conclusion, encapsulation of MICA in a nanoemulsion enhances its antifungal activity against mature biofilms of C. auris. This strategy may be considered a therapeutic approach for the control of infections and the dissemination of this new global health threat.

Candida glabrata (also called Nakaseomyces glabratus) is an opportunistic pathogen that can resist common antifungals and rapidly acquire multidrug resistance. A large amount of genetic variation exists between isolates, which complicates generalizations. Portable transposon-sequencing (Tn-seq) methods can efficiently provide genome-wide information on strain differences and genetic mechanisms. Using the Hermes transposon, the CBS138 reference strain and a commonly studied derivative termed 2001 were subjected to Tn-seq in control conditions and after exposure to varying doses of the clinical antifungal micafungin. The approach revealed large differences between these strains, including a 131-kb tandem duplication and a variety of fitness differences. Additionally, both strains exhibited up to 1,000-fold increased transposon accessibility in subtelomeric regions relative to the BG2 strain, indicative of open subtelomeric chromatin in these isolates and large epigenetic variation within the species. Unexpectedly, the Pdr1 transcription factor conferred resistance to micafungin through targets other than CDR1. Other micafungin resistance pathways were also revealed including mannosyltransferase activity and biosynthesis of the lipid precursor sphingosine, the inhibition of which by SDZ 90-215 and myriocin enhanced the potency of micafungin in vitro. These findings provide insights into the complexity of the C. glabrata species as well as strategies for improving antifungal efficacy.

Though echinocandins are the first line of therapy for C. auris candidemia, there is little clinical data to guide the choice of therapy within this class. This was the first study to compare the three echinocandins in terms of efficacy and outcomes for C. auris candidemia. This was a retrospective analysis of 82 episodes of candidemia caused by C. auris comparing outcomes across the three echinocandins. Majority patients in our study were treated with micafungin. Susceptibility rates were the lowest for caspofungin (35.36% resistance), with no resistance reported for the other two echinocandins. When a susceptible echinocandin was chosen, caspofungin resistance was not a factor significantly associated with mortality. Also, when a susceptible echinocandin was used for therapy, the choice within the class did not affect clinical cure, microbiological cure, or mortality (P > 0.05 for all). Failure to achieve microbiological cure (P = 0.018) and receipt of immune-modulatory therapy (P = 0.01) were significantly associated with increased mortality. Significant cost variation was noted among the echinocandins. Considering the significant cost variation, comparable efficacies can be reassuring for the prescribing physician.
This is the first study comparing efficacy of the three echinocandins in C. auris candidemia. The clinical efficacy of the three echinocandins was found to be comparable. Micafungin and anidulafungin had lower minimum inhibitory concentrations. A significant cost variation was noted.

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HRS9432(A) is a long-acting echinocandin antifungal medication primarily used to treat invasive fungal infections, particularly invasive candidiasis. The safety, tolerability, and pharmacokinetic characteristics of HRS9432(A) injection were investigated in a randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose Phase I study involving 56 healthy adult subjects. Doses ranging from 200 to 1200 mg were administered. Safety was continually monitored, including adverse events, clinical laboratory examinations, vital signs, 12-lead electrocardiograms, and physical examinations, while the pharmacokinetic profile within the body was evaluated. The results indicated that concentrations of HRS9432 peaked immediately after infusion, demonstrating essentially linear pharmacokinetic characteristics within the dosage range of 200-1,200 mg. It exhibited a low clearance rate and an extended half-life, with a clearance of approximately 0.2 L/h, a volume of distribution of around 40 L, and a half-life of approximately 140h following a single dose. The accumulation index for AUC0-τ after multiple doses ranged from 1.41 to 1.75. No severe adverse events occurred during the study, and the severity of all adverse events was mild or moderate. Therefore, the intravenous administration of HRS9432(A) in healthy Chinese adult subjects, either as multiple infusions of 200 to 600 mg (once a week, four doses) or as a single infusion of 900-1,200 mg, demonstrated overall good safety and tolerability. The pharmacokinetic exhibited essentially linear characteristics in the body, supporting a weekly dosing frequency for clinical applications and providing additional options for the treatment or prevention of invasive fungal infections.
RESULTS: This study is registered with the International Clinical Trials Registry Platform as ChiCTR2300073525.