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Mycopathologia Jul 2024The genus Aspergillus consists of a vast number of medically and environmentally relevant species. Aspergillus species classified in series Versicolores are ubiquitous...
The genus Aspergillus consists of a vast number of medically and environmentally relevant species. Aspergillus species classified in series Versicolores are ubiquitous in the environment and include the opportunistic pathogen Aspergillus sydowii, which is associated with onychomycosis and superficial skin infections. Despite frequent clinical reports of A. sydowii and related series Versicolores species, antifungal susceptibility data are scarce, hampering optimal treatment choices and subsequent patient outcomes. Here, we employed antifungal susceptibility testing (AFST) based on microbroth dilution on a set of 155 series Versicolores strains using the common antifungals amphotericin B, itraconazole, voriconazole, posaconazole, isavuconazole and micafungin with the addition of luliconazole and olorofim. All strains were identified using partial calmodulin gene sequencing, with 145 being A. sydowii, seven A. creber and three A. versicolor, using the latest taxonomic insights. Overall, tested antifungals were potent against the entire strain collection. In comparison to A. fumigatus, azole and amphotericin B MICs were slightly elevated for some strains. AFST with luliconazole and olorofim, here reported for the first time, displayed the highest in vitro activity, making these antifungals interesting alternative drugs but clinical studies are warranted for future therapeutic use.
Topics: Antifungal Agents; Microbial Sensitivity Tests; Aspergillus; Humans; Aspergillosis; Environmental Microbiology; Calmodulin; Sequence Analysis, DNA; Acetamides; Piperazines; Pyrimidines; Pyrroles
PubMed: 38958798
DOI: 10.1007/s11046-024-00869-8 -
Antimicrobial Agents and Chemotherapy Jul 2024As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against spp. are lacking, we explored L-AMB pharmacodynamics against...
As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against spp. are lacking, we explored L-AMB pharmacodynamics against different species in an PK/PD dilution model. Eight , , and isolates (EUCAST/CLSI AMB MIC 0.125-1 mg/L) were studied in the PK/PD model simulating L-AMB = 0.25-64 mg/L and = 9 h. The model was validated with one susceptible and one resistant isolate. The /MIC-logCFU/mL reduction from the initial inoculum was analyzed with the model, and Monte Carlo analysis was performed for the standard (3 mg/kg with = 21.87 ± 12.47 mg/L) and higher (5 mg/kg with = 83 ± 35.2 mg/L) L-AMB dose. A ≥1.5 logCFU/mL reduction was found at L-AMB = 8 mg/L against , , and isolates (MIC 0.25-0.5 mg/L) whereas L-AMB ≥ 32 mg/L was required for isolates. The PK/PD relationship followed a sigmoidal pattern ( ≥ 0.85) with a mean /MIC required for stasis of 2.1 for (close to the stasis), 24/17 (EUCAST/CLSI) for , 8 for , and 10 for . The probability of target attainment was ≥99% for wild-type (WT) isolates with 3 mg/kg and for wild-type isolates of the other species with 5 mg/kg. L-AMB was four- to eightfold less active against the included non-. species than . A standard 3-mg/kg dose is pharmacodynamically sufficient for whereas our data suggest that 5 mg/kg may be recommendable for the included non-. species.
PubMed: 38958455
DOI: 10.1128/aac.00225-24 -
Brazilian Journal of Microbiology :... Jul 2024Fusarium oxysporum is a cross-kingdom pathogen that infects humans, animals, and plants. The primary concern regarding this genus revolves around its resistance profile...
Fusarium oxysporum is a cross-kingdom pathogen that infects humans, animals, and plants. The primary concern regarding this genus revolves around its resistance profile to multiple classes of antifungals, particularly azoles. However, the resistance mechanism employed by Fusarium spp. is not fully understood, thus necessitating further studies to enhance our understanding and to guide future research towards identifying new drug targets. Here, we employed an untargeted proteomic approach to assess the differentially expressed proteins in a soil isolate of Fusarium oxysporum URM7401 cultivated in the presence of amphotericin B and fluconazole. In response to antifungals, URM7401 activated diverse interconnected pathways, such as proteins involved in oxidative stress response, proteolysis, and lipid metabolism. Efflux proteins, antioxidative enzymes and M35 metallopeptidase were highly expressed under amphotericin B exposure. Antioxidant proteins acting on toxic lipids, along with proteins involved in lipid metabolism, were expressed during fluconazole exposure. In summary, this work describes the protein profile of a resistant Fusarium oxysporum soil isolate exposed to medical antifungals, paving the way for further targeted research and discovering new drug targets.
PubMed: 38954219
DOI: 10.1007/s42770-024-01417-8 -
Indian Journal of Medical Microbiology Jun 2024Rhino-orbital-cerebral mucormycosis (ROCM) is linked to uncontrolled diabetes, diabetic ketoacidosis, iron overload, corticosteroid therapy, and neutropenia. This study...
Rhino-orbital-cerebral mucormycosis (ROCM) is linked to uncontrolled diabetes, diabetic ketoacidosis, iron overload, corticosteroid therapy, and neutropenia. This study evaluated a commercial real-time PCR system's effectiveness in detecting Mucorales from nasal swabs in 50 high-risk patients. Nasal swab PCR showed 30% positivity, compared to 8% with KOH microscopy. Despite its improved sensitivity, nasal swab PCR has limitations, highlighting the importance of established sampling methods in mucormycosis diagnosis. Participants were predominantly male (64%), with diabetes (78%) and amphotericin B use (96%). Prior COVID-19 was 42%, with 30% positive for Mucorales by PCR, compared to 8% with KOH microscopy.
PubMed: 38950657
DOI: 10.1016/j.ijmmb.2024.100661 -
BioRxiv : the Preprint Server For... Jun 2024The global epidemic of drug-resistant continues unabated. We do not know what caused the unprecedented appearance of pan-drug resistant (PDR) strains in a hospitalized...
What makes pan-drug resistant? Integrative insights from genomic, transcriptomic, and phenomic analysis of clinical strains resistant to all four major classes of antifungal drugs.
The global epidemic of drug-resistant continues unabated. We do not know what caused the unprecedented appearance of pan-drug resistant (PDR) strains in a hospitalized patient in New York; the initial report highlighted both known and unique mutations in the prominent gene targets of azoles, amphotericin B, echinocandins, and flucytosine antifungal drugs. However, the factors that allow to acquire multi-drug resistance and pan-drug resistance are not known. Therefore, we conducted a comprehensive genomic, transcriptomic, and phenomic analysis to better understand PDR . Among 1,570 genetic variants in drug-resistant , 299 were unique to PDR strains. The whole genome sequencing results suggested perturbations in genes associated with nucleotide biosynthesis, mRNA processing, and nuclear export of mRNA. Whole transcriptome sequencing of PDR revealed two genes to be significantly differentially expressed - a DNA repair protein and DNA replication-dependent chromatin assembly factor 1. Of 59 novel transcripts, 12 candidate transcripts had no known homology among expressed transcripts found in other organisms. We observed no fitness defects among multi-drug resistant (MDR) and PDR strains grown in nutrient-deficient or - enriched media at different temperatures. Phenotypic profiling revealed wider adaptability to nitrogenous nutrients with an uptick in the utilization of substrates critical in upper glycolysis and tricarboxylic acid cycle. Structural modelling of 33-amino acid deletion in the gene for uracil phosphoribosyl transferase suggested an alternate route in to generate uracil monophosphate that does not accommodate 5-fluorouracil as a substrate. Overall, we find evidence of metabolic adaptations in MDR and PDR in response to antifungal drug lethality without deleterious fitness costs.
PubMed: 38948750
DOI: 10.1101/2024.06.18.599548 -
Mycobiology 2024ranks as among the most frequently encountered fungal infections that associated with high morbidity and mortality. Quinoxaline derivatives are a group of small...
ranks as among the most frequently encountered fungal infections that associated with high morbidity and mortality. Quinoxaline derivatives are a group of small molecules that showed a promising antimicrobial activity. This study aimed to investigate the fungicidal effects of 3-hydrazinoquinoxaline-2-thiol against in comparison with Amphotericin B as a reference. Also, we aim to assess the efficacy of 3-hydrazinoquinoxaline-2-thiol using mice oral candidiasis model. Fifty-six isolates were subjected to susceptibility testing by broth microdilution method for 3-hydrazinoquinoxaline-2-thiol and Amphotericin B. Therefore, Minimal inhibitory concentrations (MIC) were assessed and compared. The oral candidiasis mice model was used to evaluate the activity of 3-hydrazinoquinoxaline-2-thiol . Microbiological evaluation of progression and ELISA were used in this study. 3-hydrazinoquinoxaline-2-thiol was more effective than Amphotericin B against most clinical isolates of . Higher effectiveness was seen against and isolates. However, the efficiency against isolates varies. 3-hydrazinoquinoxaline-2-thiol was also effective against and . 3-hydrazinoquinoxaline-2-thiol showed a good efficacy in mice model against cells ATCC 10231. 3-hydrazinoquinoxaline-2-thiol has shown promising antifungal and anti-inflammatory activity against different species. More tests and experiments are needed.
PubMed: 38948451
DOI: 10.1080/12298093.2024.2362497 -
Frontiers in Microbiology 2024This study aimed to explore the anti-oxidative and anti-inflammatory properties of . HFY14 (LLSLHFY14) and investigate its effects on the intestinal barrier, cranial...
INTRODUCTION
This study aimed to explore the anti-oxidative and anti-inflammatory properties of . HFY14 (LLSLHFY14) and investigate its effects on the intestinal barrier, cranial nerve, and motor function in mice treated with antibiotics.
METHODS
Mice were administered an antibiotic mixture (neomycin 5 mg/mL, vancomycin 25 mg/mL, amphotericin B 0.1 mg/mL, ampicillin 10 mg/mL, metronidazole file 5 mg/mL, and lipopolysaccharide 1.5 μg/mL) intraperitoneally, and oxidative stress and inflammatory markers in the serum and brain tissues, and liver index were measured. H&E staining was performed to detect pathological alterations in brain tissues. The expression of intestinal-barrier-related genes and that of genes involved in inflammatory pathways in the brain were detected using polymerase chain reaction (PCR).
RESULTS
LLSLHFY14 administration extended the weight-loaded swimming and running times of mice and decreased the liver index. Moreover, the levels of malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the serum and brain tissue were reduced, whereas those of superoxide dismutase (SOD), glutathione (GSH), and interleukin-10 (IL-10) were elevated. Elevated brain expression of the protein kinase B ()/cAMP-response element binding protein ()/brain-derived neurotrophic factor ()/extracellular signal-regulated kinase 1 () pathway, decreased brain expression of the gene, and elevated cecum expression of , and genes were noted. LLSLHFY14 supplementation significantly increased expression but decreased expression, thus increasing the ratio.
DISCUSSION
Overall, LLSLHFY14 supplementation ameliorated antibiotic-induced oxidative stress and inflammation in the mouse central nervous system, intestinal barrier dysfunction, and increased motor function, thus confirming its potential application as probiotics.
PubMed: 38946910
DOI: 10.3389/fmicb.2024.1418556 -
Hemodialysis International.... Jun 2024A 61-year-old female with diabetes and stage 5 chronic kidney disease on hemodialysis since 3 years via left brachiocephalic arteriovenous fistula presented with...
A 61-year-old female with diabetes and stage 5 chronic kidney disease on hemodialysis since 3 years via left brachiocephalic arteriovenous fistula presented with uncontrolled sugars, weight loss, and dysphagia. On evaluation, she was found to have an oral thrush with leucocytosis. Initial blood and urine cultures were sterile, and ultrasonography revealed hypoechoic lesions in the left lobe of the liver. She had high-grade fever followed by seizures on postadmission Day 10. Brain imaging and serum electrolytes were normal. Cerebrospinal fluid analysis was noncontributory, and urine culture revealed Candida non-albicans with elevated white blood cell counts. She was started on fluconazole; however, her clinical condition deteriorated, with hemodynamic instability. Repeat abdominal computerized tomography revealed increasing hypodense lesions in the left lobe of the liver with elevated beta D glucan levels. Percutaneous drainage of the abscess revealed no fungal elements. In view of clinical deterioration, amphotericin B was started, which resulted in clinical improvement. Clinician should have high index of suspicion for fungal etiology in hemodialysis patients presenting with liver abscess.
PubMed: 38945692
DOI: 10.1111/hdi.13172 -
Clinical Infectious Diseases : An... Jun 2024Limited data exist on the antifungal activity of daily liposomal amphotericin B with flucytosine induction regimens for cryptococcal meningitis, which are recommended in...
Comparison of early fungicidal activity and mortality between daily liposomal amphotericin B and daily amphotericin B deoxycholate among patients with HIV-associated cryptococcal meningitis.
BACKGROUND
Limited data exist on the antifungal activity of daily liposomal amphotericin B with flucytosine induction regimens for cryptococcal meningitis, which are recommended in high-income countries. Liposomal amphotericin B monotherapy at 3 mg/kg previously failed to meet non-inferiority criteria compared to amphotericin B deoxycholate in its registrational clinical trial. We aimed to compare the quantitative antifungal activity and mortality between daily amphotericin B deoxycholate and daily liposomal amphotericin among persons with HIV-related cryptococcal meningitis receiving adjunctive flucytosine 100 mg/kg/day.
METHODS
We analyzed data from three clinical studies involving participants with HIV-associated cryptococcal meningitis receiving either daily liposomal amphotericin B at 3 mg/kg/day with flucytosine (N = 94) or amphotericin B deoxycholate at 0.7-1.0 mg/kg/day with flucytosine (N = 404) as induction therapy. We compared participant baseline characteristics, CSF early fungicidal activity (EFA), and 10-week mortality.
RESULTS
We included 498 participants in this analysis, of whom 201 had available EFA data (N = 46 liposomal amphotericin; N = 155 amphotericin deoxycholate). Overall, there is no statistical evidence that the antifungal activity of liposomal amphotericin B (mean EFA = 0.495 log10 CFU/mL/day; 95%CI, 0.355-0.634) differ from amphotericin B deoxycholate (mean EFA = 0.402 log10 CFU/mL; 95%CI, 0.360-0.445) (P = 0.13). Mortality at 10 weeks trended lower for liposomal amphotericin (28.2%) vs amphotericin B deoxycholate (34.6%) but was not statistically different when adjusting for baseline characteristics (adjusted Hazard Ratio = 0.74; 95%CI, 0.44-1.25; P = 0.26).
CONCLUSIONS
Daily liposomal amphotericin B induction demonstrated a similar rate of CSF fungal clearance and 10-week mortality as amphotericin B deoxycholate when combined with flucytosine for the treatment of HIV-associated cryptococcal meningitis.
PubMed: 38943665
DOI: 10.1093/cid/ciae326 -
Mycopathologia Jun 2024Candidemia, a bloodstream infection predominantly affecting critically ill patients, poses a significant global health threat especially with the emergence of... (Review)
Review
INTRODUCTION
Candidemia, a bloodstream infection predominantly affecting critically ill patients, poses a significant global health threat especially with the emergence of non-albicans Candida species, including drug-resistant strains. In Brazil, limited access to advanced diagnostic tools and trained microbiologists hampers accurate identification of Candida species and susceptibility to antifungals testing hindering surveillance efforts.
METHODS
We conducted a systematic review spanning publications from 2017 to 2023 addressing Candida species distribution and antifungal susceptibility among Brazilian patients with candidemia.
RESULTS
Despite initially identifying 7075 records, only 16 met inclusion criteria providing accurate information of 2305 episodes of candidemia. The predominant species were C. albicans, C. parapsilosis, and C. tropicalis, followed by notable proportions of Nakaseomyces glabratus. Limited access to diagnostic tests was evident as only 5 out of 16 studies on candidemia were able to report antifungal susceptibility testing results. In vitro resistance to echinocandins was rare (only 6/396 isolates, 1,5%). In counterpart, fluconazole exhibited resistance rates ranging from 0 to 43%, with great heterogeneity among different studies and species of Candida considered.
CONCLUSION
Our review underscores the critical need for enhanced surveillance and research efforts to address the evolving landscape of candidemia and antifungal resistance in Brazil. Despite some limitations, available data suggest that while resistance to echinocandins and amphotericin B remains rare, there is a growing concern regarding resistance to fluconazole among Candida species.
Topics: Candidemia; Brazil; Humans; Antifungal Agents; Candida; Drug Resistance, Fungal; Microbial Sensitivity Tests
PubMed: 38940953
DOI: 10.1007/s11046-024-00867-w