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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 -
Pharmaceutics Apr 2023is a multidrug-resistant pathogen against which echinocandins are the drug of choice. However, information on how the chitin synthase inhibitor nikkomycin Z influences...
is a multidrug-resistant pathogen against which echinocandins are the drug of choice. However, information on how the chitin synthase inhibitor nikkomycin Z influences the killing activities of echinocandins against is currently lacking. We determined the killing activities of anidulafungin and micafungin (0.25, 1, 8, 16 and 32 mg/L each) with and without nikkomycin Z (8 mg/L) against 15 isolates representing four clades (South Asian n = 5; East Asian n = 3; South African n = 3; South American n = 4, two of which were of environmental origin). Two and one isolates from the South Asian clade harbored mutations in the hot-spot 1 (S639Y and S639P) and 2 (R1354H) regions of the gene, respectively. The anidulafungin, micafungin and nikkomycin Z MIC ranges were 0.015-4, 0.03-4 and 2->16 mg/L, respectively. Anidulafungin and micafungin alone exerted weak fungistatic activity against wild-type isolates and the isolate with a mutation in the hot-spot 2 region of but was ineffective against the isolates with a mutation in the hot-spot 1 region. The nikkomycin Z killing curves were always similar to their respective controls. Twenty-two of sixty (36.7%) anidulafungin plus nikkomycin Z and twenty-four of sixty (40%) micafungin plus nikkomycin Z combinations produced at least 100-fold decreases in the CFUs (synergy), with a 41.7% and 20% fungicidal effect, respectively, against wild-type isolates. Antagonism was never observed. Similar results were found with the isolate with a mutation in hot-spot 2 of , but the combinations were ineffective against the two isolates with prominent mutations in hot-spot 1 of . The simultaneous inhibition of β-1,3 glucan and chitin synthases in wild-type isolates produced significantly greater killing rates than either drug alone. Further studies are warranted to verify the clinical efficacy of echinocandin plus nikkomycin Z combinations against echinocandin susceptible isolates.
PubMed: 37242607
DOI: 10.3390/pharmaceutics15051365 -
Mitochondrion Jul 2023The antifungal activity of the drug micafungin, a cyclic lipopeptide that interacts with membrane proteins, may involve inhibition of fungal mitochondria. In humans,...
The antifungal activity of the drug micafungin, a cyclic lipopeptide that interacts with membrane proteins, may involve inhibition of fungal mitochondria. In humans, mitochondria are spared by the inability of micafungin to cross the cytoplasmic membrane. Using isolated mitochondria, we find that micafungin initiates the uptake of salts, causing rapid swelling and rupture of mitochondria with release of cytochrome c. The inner membrane anion channel (IMAC) is altered by micafungin to transfer both cations and anions. We propose that binding of anionic micafungin to IMAC attracts cations into the ion pore for the rapid transfer of ion pairs.
Topics: Humans; Micafungin; Mitochondria; Mitochondrial Membranes; Anions; Ion Channels
PubMed: 37201620
DOI: 10.1016/j.mito.2023.05.004 -
Antimicrobial Agents and Chemotherapy Jun 2023We determined the echinocandin susceptibility and genotypes of 13 clinical isolates of Candida auris that were recovered from 4 patients at a tertiary care center in...
We determined the echinocandin susceptibility and genotypes of 13 clinical isolates of Candida auris that were recovered from 4 patients at a tertiary care center in Salvador, Brazil. Three isolates were categorized as echinocandin-resistant, and they harbored a novel mutation that led to an amino acid change W691L located downstream from hot spot 1. When introduced to echinocandin-susceptible C. auris strains by CRISPR/Cas9, Fks1 W691L induced elevated MIC values to all echinocandins (anidulafungin, 16 to 32×; caspofungin, >64×; micafungin, >64×).
Topics: Humans; Antifungal Agents; Candida auris; Fungal Proteins; Echinocandins; Caspofungin; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 37222585
DOI: 10.1128/aac.00423-23 -
Clinical Laboratory Aug 2023The aim was to discover the infectivity characteristics of recurrent vulvovaginal candidiasis (RVVC) in Chengdu, Sichuan Province, and provide a reference for RVVC...
BACKGROUND
The aim was to discover the infectivity characteristics of recurrent vulvovaginal candidiasis (RVVC) in Chengdu, Sichuan Province, and provide a reference for RVVC clinical diagnosis and treatment.
METHODS
The clinical data of 500 patients with RVVC were retrospectively analyzed, including life history, clinical symptoms, combined gynecological diseases, age, and distribution of pathogenic fungi, and the in vitro drug sensitivity of isolated fungi to antifungal drugs was assessed.
RESULTS
Among the 500 patients with RVVC, 486 (97.20%) had a sexual history, and the main clinical symptoms were vulva pruritus (394, 78.80%) and abnormal discharge (232, 46.40%). Common gynecological diseases were cervicitis (156 patients, 31.20%), human papillomavirus infection (130 patients, 26.00%), and coinfection with oth-er pathogens (127 patients, 25.40%). The high-incidence population was mainly concentrated in the 31 to 40-year-old age group, followed by the 20 to 30- and 41 to 50-year-old age groups. The number of patients gradually increased with time. Fungal culture was dominated by Candida albicans (69.80%), followed by Candida glabrata (28.40%), and Candida cerevisiae (0.60%). In vitro susceptibility testing showed that the highest drug resistance rate to antifungal drugs was to terbinafine (96.40%), followed by voriconazole (32.00%), fluconazole (26.40%), and itraconazole (17.40%), whereas the drug resistance rates to 5-fluorocytosine, caspofungin, amphotericin B, and micafungin were relatively low (1.80%, 0.60%, 0.40%, and 0.00%, respectively); the drug resistance rate to azoles gradually increased with age.
CONCLUSIONS
The occurrence of RVVC is closely related to sexual history. The most common cases are in women of childbearing age aged 20 - 50. The main pathogen is C. albicans, and the resistance rate to common azole antifungal drugs is increasing over time.
Topics: Humans; Female; Antifungal Agents; Candidiasis, Vulvovaginal; Retrospective Studies; Microbial Sensitivity Tests; Drug Resistance, Fungal; Candida albicans; Communicable Diseases
PubMed: 37560852
DOI: 10.7754/Clin.Lab.2023.230304 -
European Journal of Pharmacology Jul 2023The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in...
The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.
Topics: Animals; Rats; Ferroptosis; Ischemia; Micafungin; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Myocardial Reperfusion Injury; NF-E2-Related Factor 2; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury
PubMed: 37146710
DOI: 10.1016/j.ejphar.2023.175774 -
Antimicrobial Agents and Chemotherapy Aug 2019Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal... (Review)
Review
Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the and clinical efficacy of echinocandins against spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host's response. Moreover, spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other β-1,3-glucan synthase inhibitors (ibrexafungerp).
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Echinocandins; HSP90 Heat-Shock Proteins; Host-Pathogen Interactions; Humans; Invasive Fungal Infections
PubMed: 31138565
DOI: 10.1128/AAC.00399-19 -
Oral Surgery, Oral Medicine, Oral... Nov 2020Oral candidiasis is a common opportunistic infection that requires knowledge of the various clinical presentations and management strategies for successful treatment.... (Review)
Review
Oral candidiasis is a common opportunistic infection that requires knowledge of the various clinical presentations and management strategies for successful treatment. Numerous local and systemic factors contribute to the development of candidiasis, and the infections can range from superficial mucocutaneous overgrowths to invasive bloodstream infections with a high mortality rate. In addition to Candida albicans, various fungal strains have been isolated from the oral cavity, including C. tropicalis, C. glabrata, C. krusei, and many others. Antifungal agents are available in various forms, each with differing indications, dosing regimens, adverse effects, and drug interactions. Some antifungal agents are available as oral suspensions, pastilles, or creams, whereas others are administered systemically in capsule or intravenous form. This review describes the various presentations of oral candidiasis and the diagnostic methods and treatment alternatives, with a specific focus on pharmacologic management. Spectra of activity, mechanisms of action, adverse reactions, drug interactions, and dosing regimens are explored in the context of both topical and systemic pharmacotherapy used to treat candidiasis. Polyenes (nystatin, amphotericin B); azoles (ketoconazole, miconazole, clotrimazole, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole); and echinocandins (caspofungin, micafungin, anidulafungin) are discussed. Novel approaches in antifungal therapy with the use of probiotics are also reviewed.
Topics: Amphotericin B; Antifungal Agents; Dentistry; Drug Resistance, Fungal; Echinocandins; Fluconazole; Microbial Sensitivity Tests
PubMed: 32907786
DOI: 10.1016/j.oooo.2020.08.011 -
Brazilian Journal of Microbiology :... Dec 2022Meyerozyma guilliermondii has been accepted as a complex composed of Meyerozyma guilliermondii, Meyerozyma carpophila, and Meyerozyma caribbica. M. guilliermondii is a... (Review)
Review
Meyerozyma guilliermondii has been accepted as a complex composed of Meyerozyma guilliermondii, Meyerozyma carpophila, and Meyerozyma caribbica. M. guilliermondii is a saprophyte detected on human mucosa and skin. It can lead to serious infections in patients with risk factors like chemotherapy, immunodeficiency, gastrointestinal or cardiovascular surgery, and oncology disorders. Most deaths related to M. guilliermondii infections occur in individuals with malignancy. In recent decades, incidence of M. guilliermondii infections is increased. Sensitivity of this microorganism to conventional antifungals (e.g., amphotericin B, fluconazole, micafungin and anidulafungin) was reduced. Prophylactic and empirical uses of these drugs are linked to elevated minimal inhibitory concentrations (MICs) of M. guilliermondii. Drug resistance has concerned many researchers across the world. They are attempting to discover appropriate solution to combat this challenge. This study reviews the most important mechanisms of resistance to antifungals developed by in M. guilliermondii species complex.
Topics: Humans; Antifungal Agents; Drug Resistance, Fungal; Fluconazole; Amphotericin B; Microbial Sensitivity Tests
PubMed: 36306113
DOI: 10.1007/s42770-022-00813-2 -
Tropical Medicine and Infectious Disease Feb 2022Micafungin is the empiric antifungal agent of choice for the treatment of invasive candidiasis (IC). Pathophysiologic changes that occur in obese and/or critically ill...
Micafungin is the empiric antifungal agent of choice for the treatment of invasive candidiasis (IC). Pathophysiologic changes that occur in obese and/or critically ill patients can alter micafungin serum concentrations and the probability of target attainment. Although high doses of micafungin have been shown to be safe, clinical outcomes have not been widely evaluated. We conducted a single-center, retrospective observational study evaluating safety and clinical outcomes among adult patients treated with ≥200 mg of micafungin for ≥3 days for proven IC from 1 September 2013 through 1 September 2021. Twenty-three unique encounters for 21 patients were evaluated. The median BMI and APACHE II scores were 37.1 (IQR 28.8-48.9) and 24 (IQR 17.7-31), respectively. The median average daily dose of micafungin was 300 mg (IQR 275-400). Patients were treated with high-dose (HD) micafungin for the entirety of their echinocandin course in 15 encounters (65.2%). Transaminases remained stable, while a trend towards increased alkaline phosphatase was observed. A total of four deaths occurred (17.4%). Patients that died were predominantly young, Hispanic males who were obese and/or critically ill. Future studies are needed to determine the necessity and appropriate placement of HD micafungin in obese and/or critically ill patients.
PubMed: 35202218
DOI: 10.3390/tropicalmed7020023