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Access Microbiology 2023, formerly , is an opportunistic yeast and emerging cause of human infections. The use of broth microdilution (BMD) methodologies for caspofungin (CSP) antifungal...
BACKGROUND
, formerly , is an opportunistic yeast and emerging cause of human infections. The use of broth microdilution (BMD) methodologies for caspofungin (CSP) antifungal susceptibility testing (AFST) against is reported to be prone to high inter-laboratory variation. We aimed to compare CSP MICs of isolates from our institution with those obtained by the Reference Laboratory for the same isolates.
METHODS
All clinically significant isolates from 2019 to 2021 inclusive were reviewed. AFST was performed locally using the VITEK2 system with the AST-YS08 card, while E-tests were performed at the Mycology Reference Laboratory (MRL), and agreement between these two methods was evaluated - categorical and essential.
RESULTS
Forty-one isolates were reviewed during the study period - 30 from blood cultures, seven from intra-operative theatre specimens and four from sterile site drain fluids. Despite an essential agreement of 100 % within ±2 log dilutions, marked discrepancies were noted in interpretative breakpoints between assays with 17 Minor and 16 Major category errors. Categorical agreement was 19.5 %, with the VITEK2 over-estimating resistance. A Mann-Whitney U-test assessed the relationship of MICs across the AFST modalities, and a statistically significant difference was noted, <0.01, with a higher mean rank for VITKEK2 outputs.
CONCLUSION
While the VITEK2 system is highly applicable, its performance for CSP AFST is unreliable and potentially results in the mis-classification of susceptible isolates as highlighted in our study. The use of VITEK2 AST-YS08 micafungin as a sentinel echinocandin should be explored and/or the evaluation of CSP-specific E-tests as utilized by the MRL. These methods appear more consistent and less prone to the variation seen with BMD for CSP.
PubMed: 37970072
DOI: 10.1099/acmi.0.000617.v4 -
International Journal of Medical... Nov 2023Candida glabrata is believed to be the underlying cause of many human ailments, including oral, gastrointestinal, and vaginal disorders. C. glabrata-caused deep-seated...
Candida glabrata is believed to be the underlying cause of many human ailments, including oral, gastrointestinal, and vaginal disorders. C. glabrata-caused deep-seated infections, coupled with its resistance to antifungal drugs, may contribute to a high mortality rate. Resveratrol is a polyphenol and can achieve better therapeutic effects when administered in combination with micafungin, but the underlying molecular mechanisms remain unknown. Here, we investigate the effects of varying doses of resveratrol on the proliferation, apoptosis, and activity of macrophages, which were co-cultured with micafungin-pretreated C. glabrata. Resveratrol can restore the decreased proliferative activity of macrophages caused by the phagocytosis of C. glabrata. Further investigations demonstrated that this restoration ability exhibited a dose-dependent manner, reaching the highest level at 200 µM of resveratrol. Resveratrol tended to be more effective in inhibiting macrophage apoptosis and reducing reactive oxygen species (ROS) levels with concentration increases. In addition, at medium concentrations, resveratrol may down-regulate the expression of most inflammatory cytokines, whereas at high concentrations, it started to exert pro-inflammatory functions by up-regulating their expressions. Macrophages may shift from an anti-inflammatory (M2) phenotype to an inflammatory (M1) phenotype by resveratrol at 200 µM, and from M1 to M2 at 400 µM. Our research shows that resveratrol with micafungin are effective in treating C. glabrata infections. The resveratrol-micafungin combination can reduce the production of ROS, and promote the proliferation, inhibit the apoptosis, and activate the polarization of macrophages in a dose-dependent manner. This study offers insights into how this combination works and may provide possible direction for further clinical application of the combination.
Topics: Female; Humans; Micafungin; Candida glabrata; Echinocandins; Resveratrol; Reactive Oxygen Species; Antifungal Agents; Macrophages; Phagocytosis
PubMed: 37952279
DOI: 10.1016/j.ijmm.2023.151589 -
Microbial Biotechnology Jan 2024Invasive fungal infections have increased remarkably, which have become unprecedented concern to human health. However, the effectiveness of current antifungal drugs is... (Review)
Review
Invasive fungal infections have increased remarkably, which have become unprecedented concern to human health. However, the effectiveness of current antifungal drugs is limited due to drug resistance and toxic side-effects. It is urgently required to establish the effective biosynthetic strategy for developing novel and safe antifungal molecules economically. Echinocandins become a promising option as a mainstay family of antifungals, due to specifically targeting the fungal specific cell wall. To date, three kinds of echinocandins for caspofungin, anidulafungin, and micafungin, which derived from pneumocandin B , echinocandin B, and FR901379, are commercially available in clinic and have shown potential in managing invasive fungal infections in a cost-effective manner. However, current echinocandins-derived precursors all are produced by environmental fungal isolates with long fermentation cycle and low yields, which challenge the production efficacy of these precursors in industry. Therefore, understanding their biosynthetic machinery is of great importance for improving antifungal titres and creating new echinocandins-derived products. With the development of genome-wide sequencing and establishment of gene-editing technology, there are a growing number of reports on echinocandins-derived products and their biosynthetic gene clusters. This review briefly summarizes the discovery and development history of echinocandins, compares their structural characteristics and biosynthetic processes, and sums up existed strategies for improving their production. Moreover, the genomic analysis of related biosynthetic gene clusters of echinocandins is discussed, highlighting the similarities and differences among the clusters. Last, the biosynthetic processes of echinocandins are compared, focusing on the activation and attachment of side-chains and the formation of the hexapeptide core. This review aims to provide insights into the development and production of new echinocandin drugs by modifying the structure of echinocandin-derived precursors and/or optimizing the fermentation processes; and achieve a new microbial chassis for efficient production of echinocandins in heterologous hosts.
Topics: Humans; Antifungal Agents; Echinocandins; Fermentation; Invasive Fungal Infections; Microbial Sensitivity Tests; Lipopeptides
PubMed: 37885073
DOI: 10.1111/1751-7915.14359 -
Critical Care and Resuscitation :... Mar 2023To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate...
OBJECTIVE
To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity.
DESIGN SETTING AND PARTICIPANTS
This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected.
MAIN OUTCOME MEASURES
The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured.
RESULTS AND CONCLUSIONS
This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.
PubMed: 37876989
DOI: 10.1016/j.ccrj.2023.04.002 -
Virus Research Jan 2024Bat-borne emerging zoonotic viruses cause major outbreaks, such as the Ebola virus, Nipah virus, and/or beta coronavirus. Pteropine orthoreovirus (PRV), whose spillover...
Bat-borne emerging zoonotic viruses cause major outbreaks, such as the Ebola virus, Nipah virus, and/or beta coronavirus. Pteropine orthoreovirus (PRV), whose spillover event occurred from fruits bats to humans, causes respiratory syndrome in humans widely in South East Asia. Repurposing approved drugs against PRV is an effective tool to confront future PRV pandemics. We screened 2,943 compounds in an FDA-approved drug library and identified eight hit compounds that reduce viral cytopathic effects on cultured Vero cells. Real-time quantitative PCR analysis revealed that six of eight hit compounds significantly inhibited PRV replication. Among them, micafungin used clinically as an antifungal drug, displayed a prominent antiviral effect on PRV. Secondly, the antiviral effects of micafungin on PRV infected human cell lines (HEK293T and A549), and their transcriptome changes by PRV infection were investigated, compared to four different bat-derived cell lines (FBKT1 (Ryukyu flying fox), DEMKT1 (Leschenault's rousette), BKT1 (Greater horseshoe bat), YUBFKT1 (Eastern bent-wing bats)). In two human cell lines, unlike bat cells that induce an IFN-γ response pathway, an endoplasmic reticulum stress response pathway was commonly activated. Additionally, micafungin inhibits viral release rather than suppressing PRV genome replication in human cells, although it was disturbed in Vero cells. The target of micafungin's action may vary depending on the animal species, but it must be useful for human purposes as a first choice of medical care.
Topics: Animals; Chlorocebus aethiops; Humans; Orthoreovirus; Chiroptera; Reoviridae Infections; Micafungin; Vero Cells; HEK293 Cells; Viruses; Antiviral Agents
PubMed: 37858730
DOI: 10.1016/j.virusres.2023.199248 -
Frontiers in Immunology 2023CAR-T therapy has revolutionized the treatment of relapsed/refractory B-cell malignancies. Patients who are receiving such therapy are susceptible to an increased...
CAR-T therapy has revolutionized the treatment of relapsed/refractory B-cell malignancies. Patients who are receiving such therapy are susceptible to an increased incidence of infections due to post-treatment immunosuppression. The need for antifungal prophylaxis during the period of neutropenia remains to be determined. The clinical outcome of a 55-year-old patient with relapsed/refractory DLBCL who received axicabtagene ciloleucel is described here. The patient developed CRS grade II and ICANS grade IV requiring tocilizumab, prolonged use of steroids and anakinra. An invasive pulmonary aspergillosis arose after 1 month from CAR-T reinfusion, resolved with tracheal sleeve pneumonectomy. The patient is now in Complete Remission. This case suggests that antifungal prophylaxis should be considered. We have now included micafungin as a standard prophylaxis in our institution.
Topics: Humans; Middle Aged; Receptors, Chimeric Antigen; Antifungal Agents; Neoplasm Recurrence, Local; Antigens, CD19; Invasive Fungal Infections; Cell- and Tissue-Based Therapy
PubMed: 37841271
DOI: 10.3389/fimmu.2023.1272798 -
Medicine Sep 2023Streptococcal toxic shock syndrome (STSS) rapidly leads to refractory shock and multiple organ failure. The mortality rate among patients with STSS is 40%; however, most... (Review)
Review
RATIONALE
Streptococcal toxic shock syndrome (STSS) rapidly leads to refractory shock and multiple organ failure. The mortality rate among patients with STSS is 40%; however, most deaths occur within a few days of onset. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) may help avoid acute death in adult patients with STSS. However, the effectiveness of VA-ECMO is unclear. In this study, we report a case of group B STSS, which was successfully treated with VA-ECMO despite cardiopulmonary arrest (CPA) owing to rapidly progressive refractory shock.
PATIENT CONCERNS
A 60-year-old woman was hospitalized because of diarrhea and electrolyte abnormalities owing to chemoradiation therapy for rectal cancer. A sudden deterioration of her condition led to CPA. Conventional cardiopulmonary resuscitation was immediately performed but was ineffective. Therefore, VA-ECMO was initiated. Contrast-enhanced computed tomography revealed duodenal perforation. Hence, septic shock owing to peritonitis was diagnosed, and emergency surgery was performed under VA-ECMO. However, the patient had progressive multiple organ failure and required organ support therapy in the intensive care unit (ICU).
DIAGNOSES
On day 2 in the ICU, blood and ascites fluid culture tests revealed beta-hemolytic streptococci, and the patient was finally diagnosed as having STSS caused by Streptococcus agalactiae.
INTERVENTIONS
Clindamycin was added to meropenem, vancomycin, and micafungin, which had been administered since the sudden deterioration. In addition, VA-ECMO, mechanical ventilation, blood purification therapy, and treatment for disseminated intravascular coagulation were continued.
OUTCOMES
Thereafter, hemodynamics improved rapidly, and the patient was weaned off VA-ECMO on day 5 of ICU admission. She was transferred to a general ward on day 22 in the ICU.
LESSONS
In patients with fatal STSS and rapid progressive refractory shock or CPA, VA-ECMO may help to avoid acute death and improve prognosis by ameliorating tissue oxygenation and providing extra time to treat invasive streptococcal infection.
Topics: Humans; Adult; Female; Middle Aged; Shock, Septic; Extracorporeal Membrane Oxygenation; Multiple Organ Failure; Streptococcal Infections; Clindamycin
PubMed: 37713845
DOI: 10.1097/MD.0000000000034680 -
Methodist DeBakey Cardiovascular Journal 2023A 53-year-old male presented with worsening fever, chest pain, and dyspnea during the past 2 weeks. He was hypoxic, tachycardic, and hypotensive on admission. Labs were...
A 53-year-old male presented with worsening fever, chest pain, and dyspnea during the past 2 weeks. He was hypoxic, tachycardic, and hypotensive on admission. Labs were notable for high-sensitivity troponin of 657 pg/mL and B-type natriuretic peptide of 1,648 pg/mL. Chest imaging was consistent with acute respiratory distress syndrome. Transthoracic echocardiography revealed an ejection fraction of 30% to 35% and a mobile 1.5 cm x 1.6 cm hyperechoic mass on the ventricular surface of the aortic valve (AV) with left ventricular outflow obstruction and mean pressure gradient of 38.7 mm Hg and maximum velocity of 3.64 m/s. The patient was initiated on empiric antibiotic and antifungal therapy. Cardiothoracic surgery was consulted for urgent AV repair. Blood cultures were positive for , and intravenous fluconazole and micafungin were initiated. Despite aggressive and prompt medical management, the patient sustained cerebral embolic events in the middle cerebral artery territory and passed away.
Topics: Male; Humans; Middle Aged; Ventricular Outflow Obstruction, Left; Heart Valve Diseases; Endocarditis; Administration, Intravenous; Anti-Bacterial Agents
PubMed: 37636317
DOI: 10.14797/mdcvj.1241 -
Journal of Fungi (Basel, Switzerland) Aug 2023Echinocandins, used for the prevention and treatment of invasive fungal infections, have led to a rise in breakthrough infections caused by resistant species. Among...
Echinocandins, used for the prevention and treatment of invasive fungal infections, have led to a rise in breakthrough infections caused by resistant species. Among these species, those belonging to the complex are rare multidrug-resistant (MDR) yeasts that are frequently misidentified but have emerged as significant healthcare-associated pathogens causing invasive infections. The objectives of this study were to investigate the evolutionary pathways of echinocandin resistance in by identifying mutations in the gene and evaluating the impact of resistance on fitness. After subjecting a MDR clinical isolate of (named Ch4) to direct selection using increasing caspofungin concentrations, we successfully obtained an isolate (designated ) that exhibited a high level of resistance, with MIC values exceeding 16 mg/L for all tested echinocandin drugs (caspofungin, micafungin, and anidulafungin). Sequence analysis revealed a specific mutation in the resistant strain, leading to an arginine-histidine amino acid substitution (R1354H), occurring at the G4061A position of the HS2 region of the gene. Compared to the wild-type strain, exhibited significantly reduced growth proliferation, biofilm formation capability, and phagocytosis ratio, indicating a decrease in fitness. Transmission electron microscopy analysis revealed alterations in cell wall components, with a notable increase in cell wall thickness. The resistant strain also exhibited higher amounts (2.5-fold) of chitin, a cell wall-located molecule, compared to the wild-type strain. Furthermore, the resistant strain demonstrated attenuated virulence in the larval model. The evolved strain maintained its resistance profile in vivo since the treatment with either caspofungin or micafungin did not improve larval survival or reduce the fungal load. Taken together, our findings suggest that the acquisition of pan-echinocandin resistance occurred rapidly after drug exposure and was associated with a significant fitness cost in . This is particularly concerning as echinocandins are often the first-line treatment option for MDR species.
PubMed: 37623630
DOI: 10.3390/jof9080859 -
The Journal of International Medical... Aug 2023Vinca alkaloid (VA)-induced ileus, a rare but severe autonomic neuropathy, can be enhanced by concomitant use of antifungal triazole agents. We herein present a case of... (Review)
Review
Vinca alkaloid (VA)-induced ileus, a rare but severe autonomic neuropathy, can be enhanced by concomitant use of antifungal triazole agents. We herein present a case of VA-induced ileus in a 17-year-old girl who was diagnosed with B-cell acute lymphoblastic leukemia. On day 1, the patient received cyclophosphamide, vincristine, and methylprednisolone. On day 2, she began treatment with posaconazole oral suspension at 200 mg three times daily for prophylaxis against invasive fungal infection. On day 5, she began induction therapy consisting of vindesine, methylprednisolone, daunorubicin, and cyclophosphamide. The patient developed severe abdominal pain with marked constipation on day 11 and was diagnosed with incomplete ileus. After switching the antifungal agent to micafungin, performing gastrointestinal decompression, administering parenteral nutrition, and omitting the fourth dose of vindesine, the ileus symptoms were relieved. This case emphasizes the potential interaction between VAs and posaconazole. We also herein present a review of the literature on ileus caused by the combination of VAs and antifungal triazole agents. In clinical practice, physicians and pharmacists should be aware of the possibility of ileus caused by the use of VAs in combination with posaconazole. It is important to reduce complications during chemotherapy to improve patients' prognosis.
Topics: Female; Humans; Adolescent; Vinca Alkaloids; Vindesine; Antifungal Agents; Ileus; Intestinal Obstruction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Triazoles; Cyclophosphamide
PubMed: 37622457
DOI: 10.1177/03000605231193823