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1.
Mycoses ; 67(3): e13706, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38438313

RESUMO

BACKGROUND: Fluconazole-resistant Candida parapsilosis is a matter of concern. OBJECTIVES: To describe fluconazole-resistant C. parapsilosis genotypes circulating across hospitals in Spain and Rome and to study their azole-resistance profile associated with ERG11p substitutions. PATIENTS/METHODS: We selected fluconazole-resistant C. parapsilosis isolates (n = 528 from 2019 to 2023; MIC ≥8 mg/L according to EUCAST) from patients admitted to 13 hospitals located in five Spanish cities and Rome. Additionally, we tested voriconazole, posaconazole, isavuconazole, amphotericin B, micafungin, anidulafungin and ibrexafungerp susceptibility. RESULTS: Of the 53 genotypes found, 49 harboured the Y132F substitution, five of which were dominating city-specific genotypes involving almost half the isolates. Another genotype involved isolates harbouring the G458S substitution. Finally, we found two genotypes with the wild-type ERG11 gene sequence and one with the R398I substitution. All isolates were fully susceptible/wild-type to amphotericin B, anidulafungin, micafungin and ibrexafungerp. The azole-resistance patterns found were: voriconazole-resistant (74.1%) or voriconazole-intermediate (25.2%), posaconazole-resistant (10%) and isavuconazole non-wild-type (47.5%). Fluconazole-resistant and voriconazole non-wild-type isolates were likely to harbour substitution Y132F if posaconazole was wild type; however, if posaconazole was non-wild type, substitution G458S was indicated if isavuconazole MIC was >0.125 mg/L or substitution Y132F if isavuconazole MIC was ≤0.125 mg/L. CONCLUSIONS: We detected a recent clonal spread of fluconazole-resistant C. parapsilosis across some cities in Spain, mostly driven by dominating city-specific genotypes, which involved a large number of isolates harbouring the Y132F ERG11p substitution. Isolates harbouring substitution Y132F can be suspected because they are non-susceptible to voriconazole and rarely posaconazole-resistant.


Assuntos
Azóis , Fluconazol , Glicosídeos , Nitrilas , Piridinas , Triazóis , Triterpenos , Humanos , Azóis/farmacologia , Fluconazol/farmacologia , Candida parapsilosis/genética , Cidades , Voriconazol/farmacologia , Anfotericina B , Anidulafungina , Micafungina , Itália , Hospitais , Genótipo
2.
Med Mycol ; 62(3)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38429972

RESUMO

Hyphal pellet formation by Aspergillus species in liquid cultures is one of the main obstacles to high-throughput anti-Aspergillus reagent screening. We previously constructed a hyphal dispersion mutant of Aspergillus fumigatus by disrupting the genes encoding the primary cell wall α-1,3-glucan synthase Ags1 and putative galactosaminogalactan synthase Gtb3 (Δags1Δgtb3). Mycelial growth of the mutant in liquid cultures monitored by optical density was reproducible, and the dose-response of hyphal growth to antifungal agents has been quantified by optical density. However, Δags1Δgtb3 still forms hyphal pellets in some rich growth media. Here, we constructed a disruptant lacking all three α-1,3-glucan synthases and galactosaminogalactan synthase (Δags1Δags2Δags3Δgtb3), and confirmed that its hyphae were dispersed in all the media tested. We established an automatic method to monitor hyphal growth of the mutant in a 24-well plate shaken with a real-time plate reader. Dose-dependent growth suppression and unique growth responses to antifungal agents (voriconazole, amphotericin B, and micafungin) were clearly observed. A 96-well plate was also found to be useful for the evaluation of mycelial growth by optical density. Our method is potentially applicable to high-throughput screening for anti-Aspergillus agents.


Assuntos
Antifúngicos , Aspergillus fumigatus , Animais , Aspergillus fumigatus/genética , Antifúngicos/farmacologia , Hifas/genética , Micélio , Anfotericina B
3.
J Infect Dev Ctries ; 18(2): 303-308, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38484360

RESUMO

INTRODUCTION: Invasive Candida infections have recently shown a significant increase in prevalence and are associated with high mortality rates. Initiating early antifungal treatment in patients with candidemia is vital. The aim of our study was to compare the antifungal susceptibility results of a new method called Flat Plate Method modified from reference "Clinical and Laboratory Standards Institute (CLSI) microdilution method by us with Sensitititre Yeast One colorimetric method and the reference CLSI method. METHODOLOGY: We tested 100 Candida isolates from blood cultures. We followed the CLSI M27-A3 (reference method for broth dilution antifungal susceptibility testing of yeasts; third edition) guidelines for testing in vitro susceptibility to amphotericin B. In the Flat Plate method, 96-well plates were used for evaluation with an inverted microscope. Minimum inhibitory concentration (MIC) values in the SYO method were measured following the manufacturer's instructions. The MIC values obtained by all three methods were considered compatible if they were within ± 2 dilution limits. RESULTS: The SYO method detected C. albicans and C. glabrata with 100% essential agreement, whereas there was 96.29% essential agreement in the case of C. parapsilosis. In the Flat Plate method, the essential agreement with amphotericin B was 91.42%, for C. albicans isolates and 89.47%.for C. glabrata strains. CONCLUSIONS: When determining early antifungal susceptibility using the Flat Plate method, the results are obtained quickly, with high accuracy, and without incurring additional costs. However, there is a need for comprehensive studies comparing different antifungals.


Assuntos
Candidemia , Candidíase Invasiva , Humanos , Antifúngicos/farmacologia , Anfotericina B/farmacologia , Candida , Candidemia/epidemiologia , Testes de Sensibilidade Microbiana , Candida albicans , Fluconazol/farmacologia
4.
Taiwan J Obstet Gynecol ; 63(2): 242-244, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38485323

RESUMO

OBJECTIVE: Recurrent disseminated coccidioidal meningitis in two subsequent pregnancies is rare and can pose a challenge in ensuring the health of both mother and baby. In this unique case we highlight this rare occurrence and subsequent treatment. CASE REPORT: A 29-year-old G4P1021 with a history of disseminated coccidioidomycosis in a previous pregnancy presented at 8 weeks gestation with nausea, headache, and neck pain. Cerebrospinal fluid analysis was positive for recurrent coccidioidal infection. She was started on Amphotericin and discharged. She re-presented at 30 week's gestation with phonophobia and photophobia, emesis, neck pain and swelling. MRI showed evidence of ventriculomegaly with communicating hydrocephalus. She was treated with therapeutic lumbar punctures throughout her pregnancy and a ventriculoperitoneal shunt following delivery. She had a spontaneous vaginal delivery at 38 weeks and 3 days with no complications. CONCLUSION: This unique case highlights the susceptibility of recurrent disseminated coccidioidomycosis in subsequent pregnancies and treatment thereof.


Assuntos
Coccidioidomicose , Hidrocefalia , Meningite Fúngica , Humanos , Lactente , Feminino , Gravidez , Adulto , Coccidioidomicose/diagnóstico , Coccidioidomicose/tratamento farmacológico , Cervicalgia/complicações , Cervicalgia/tratamento farmacológico , Meningite Fúngica/diagnóstico , Meningite Fúngica/tratamento farmacológico , Meningite Fúngica/complicações , Anfotericina B/uso terapêutico , Hidrocefalia/etiologia
5.
Emerg Microbes Infect ; 13(1): 2322649, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38431850

RESUMO

Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.


Assuntos
Anfotericina B , Antifúngicos , Candidíase , Animais , Camundongos , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Candida auris , Lansoprazol/farmacologia , Respiração , Citocromos
6.
Zhonghua Nei Ke Za Zhi ; 63(3): 230-257, 2024 Mar 01.
Artigo em Chinês | MEDLINE | ID: mdl-38448188

RESUMO

Amphotericin B (AmB) is a broad-spectrum and potent polyene antifungal drug for the treatment of invasive fungal diseases (IFDs). Currently, amphotericin B deoxycholate (AmB-D) and three AmB lipid formulations, namely liposomal amphotericin B (L-AmB), amphotericin B colloidal dispersion (ABCD), and amphotericin B lipid complex (ABLC) are available for clinical use. In view of clinical concerns and misperceptions in the selection of different formulations of AmB, the present consensus summarized their pharmaceutical characteristics, antifungal mechanism, pharmacokinetics/phamacodynamics, drug interactions, indications, dosage, local administration, and adverse reactions based on the latest clinical research evidence, guidelines, and clinical experience. This consensus also recommends formulation selection and dosage adjustment for the treatment of target IFDs and in special populations, thereby providing expert consensus for clinical decision-making and standardized application of AmB.


Assuntos
Anfotericina B , Infecções Fúngicas Invasivas , Humanos , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Consenso , Infecções Fúngicas Invasivas/tratamento farmacológico
7.
Front Cell Infect Microbiol ; 14: 1366472, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38500502

RESUMO

Pulmonary Mucormycosis is a fatal infectious disease with high mortality rate. The occurrence of Mucormycosis is commonly related to the fungal virulence and the host's immunological defenses against pathogens. Mucormycosis infection and granulation tissue formation occurred in the upper airway was rarely reported. This patient was a 60-year-old male with diabetes mellitus, who was admitted to hospital due to progressive cough, sputum and dyspnea. High-resolution computed tomography (HRCT) and bronchoscopy revealed extensive tracheal mucosal necrosis, granulation tissue proliferation, and severe airway stenosis. The mucosal necrotic tissue was induced by the infection of Rhizopus Oryzae, confirmed by metagenomic next-generation sequencing (mNGS) in tissue biopsy. This patient was treated with the placement of a covered stent and local instillation of amphotericin B via bronchoscope. The tracheal mucosal necrosis was markedly alleviated, the symptoms of cough, shortness of breath, as well as exercise tolerance were significantly improved. The placement of airway stent and transbronchial microtube drip of amphotericin B could conduce to rapidly relieve the severe airway obstruction due to Mucormycosis infection.


Assuntos
Obstrução das Vias Respiratórias , Mucormicose , Masculino , Humanos , Pessoa de Meia-Idade , Anfotericina B/uso terapêutico , Mucormicose/diagnóstico , Mucormicose/microbiologia , Mucormicose/patologia , Rhizopus oryzae , Necrose/patologia , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/patologia , Tecido de Granulação/patologia , Tosse/patologia
8.
mSphere ; 9(2): e0057723, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38299868

RESUMO

Since 2016, in Colombia, ongoing transmission of Candida auris has been reported in multiple cities. Here, we provide an updated description of C. auris genomic epidemiology and the dynamics of antifungal resistance in Colombia. We sequenced 99 isolates from C. auris cases with collection dates ranging from June 2016 to January 2021; the resulting sequences coupled with 103 previously generated sequences from C. auris cases were described in a phylogenetic analysis. All C. auris cases were clade IV. Of the 182 isolates with antifungal susceptibility data, 67 (37%) were resistant to fluconazole, and 39 (21%) were resistant to amphotericin B. Isolates predominately clustered by country except for 16 isolates from Bogotá, Colombia, which grouped with isolates from Venezuela. The largest cluster (N = 166 isolates) contained two subgroups. The first subgroup contained 26 isolates, mainly from César; of these, 85% (N = 22) were resistant to fluconazole. The second subgroup consisted of 47 isolates from the north coast; of these, 81% (N = 38) were resistant to amphotericin B. Mutations in the ERG11 and TAC1B genes were identified in fluconazole-resistant isolates. This work describes molecular mechanisms associated with C. auris antifungal resistance in Colombia. Overall, C. auris cases from different geographic locations in Colombia exhibited high genetic relatedness, suggesting continued transmission between cities since 2016. These findings also suggest a lack of or minimal introductions of different clades of C. auris into Colombia. IMPORTANCE: Candida auris is an emerging fungus that presents a serious global health threat and has caused multiple outbreaks in Colombia. This work discusses the likelihood of introductions and local transmission of C. auris and provides an updated description of the molecular mechanisms associated with antifungal resistance in Colombia. Efforts like this provide information about the evolving C. auris burden that could help guide public health strategies to control C. auris spread.


Assuntos
Antifúngicos , Candidíase , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Anfotericina B , Candida auris , Fluconazol , Colômbia/epidemiologia , Candida/genética , Candidíase/microbiologia , Filogenia , Genômica
9.
Medicine (Baltimore) ; 103(6): e37160, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38335438

RESUMO

RATIONALE: Children with haematological malignancies have a higher risk of developing aggressive pulmonary aspergillosis and a higher mortality rate. The most common site of extrapulmonary aspergillosis in children is the central nervous system (CNS), and the death rate is higher when CNS is affected. Therefore, early diagnosis and treatment of invasive aspergillosis are essential for reducing mortality. PATIENT CONCERNS: We report a case of an 8-year-old girl with acute lymphoblastic leukaemia who developed invasive pulmonary aspergillosis complicated by CNS aspergillosis. Aspergillus was confirmed by metagenomic sequencing of pathogenic microorganisms. DIAGNOSES: Invasive pulmonary and central nervous system aspergillosis. INTERVENTIONS: The patient was treated with combined systemic antifungal agents (voriconazole and liposomal amphotericin B) and intrathecal injection of amphotericin B. OUTCOMES: The treatment was well tolerated and resulted in remarkable clinical and radiological head improvements. LESSONS: Invasive aspergillosis has a high mortality rate and requires early diagnosis and treatment. Pathogenic microbial metagenomic sequencing is a convenient method to assist in the early diagnosis of aspergillosis. Voriconazole is the drug of choice for the treatment of invasive aspergillosis. When CNS aspergillosis occurs, it can be combined with other systemic antifungal drugs and intrathecal injection of amphotericin B.


Assuntos
Aspergilose , Aspergilose Pulmonar Invasiva , Criança , Feminino , Humanos , Anfotericina B/uso terapêutico , Voriconazol/uso terapêutico , Aspergilose/diagnóstico , Antifúngicos , Aspergilose Pulmonar Invasiva/complicações , Sistema Nervoso Central
10.
J Investig Med High Impact Case Rep ; 12: 23247096241233042, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38375745

RESUMO

Blastomyces dermatitidis is a dimorphic fungus that can range from mild to severe disease presentation, including the acute respiratory distress syndrome (ARDS) based on the individual's immunity. Acute respiratory distress syndrome is an uncommon presentation having an incidence of about 10% to 15% but has a high mortality exceeding 90%. This is a case of a 50-year-old female with past medical history of asthma and type 2 diabetes mellitus who presented to the pulmonology clinic with worsening dyspnea for the last 2 months. She also had a lesion in the left lower back, which was draining purulent fluid. Chest radiographs showed bilateral infiltrates and was started empirically on vancomycin and piperacillin-tazobactam. Bronchoalveolar lavage was done and the cultures grew B dermatitidis. The patient was moved to a higher level of care and given amphotericin B. Unfortunately, the patient experienced septic shock, which later deteriorated into cardiac arrest, ultimately leading to their passing. The importance of early diagnosis of blastomycosis and timely treatment has been emphasized in this case report.


Assuntos
Blastomicose , Diabetes Mellitus Tipo 2 , Síndrome do Desconforto Respiratório , Feminino , Humanos , Pessoa de Meia-Idade , Blastomicose/complicações , Blastomicose/diagnóstico , Blastomicose/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Anfotericina B/uso terapêutico , Blastomyces , Síndrome do Desconforto Respiratório/etiologia
11.
Bioorg Med Chem ; 100: 117610, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38306882

RESUMO

Clinically available antifungal drugs have therapeutic limitations due to toxicity, narrow spectrum of activity, and intrinsic or acquired drug resistance. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. In this context, we have successfully identified several highly promising lead compounds, i.e., aromatic N'-(salicylidene)carbohydrazides, exhibiting excellent antifungal activities against Cryptococcus neoformans, Candida albicans, Aspergillus fumigatus and several other fungi both in vitro and in vivo. Building upon these highly promising results, 71 novel N'-(salicylidene)heteroarenecarbohydrazides 5 were designed, synthesized and their antifungal activities examined against fungi. Based on the SAR study, four highly promising lead compounds, i.e., 5.6a, 5.6b, 5.7b and 5.13a were identified, which exhibited excellent potency against C. neoformans, C. albicans and A. fumigatus, and displayed impressive time-kill profiles against C. neoformans with exceptionally high selectivity indices (SI ≥ 500). These four lead compounds also showed synergy with clinical antifungal drugs, fluconazole, caspofungin (CS) and amphotericin B against C. neoformans. For the SAR study, we also employed quantitative structure-activity relationship (QSAR) analysis by taking advantage of the accumulated data on a large number of aromatic and heteroaromatic N'-(salicylidene)carbohydrazides, which successfully led to rational design and selection of promising compounds for chemical synthesis and biological evaluation.


Assuntos
Antifúngicos , Cryptococcus neoformans , Hidrazinas , Anfotericina B , Antifúngicos/química , Candida albicans , Fluconazol , Testes de Sensibilidade Microbiana , Hidrazinas/química , Hidrazinas/farmacologia
12.
Appl Microbiol Biotechnol ; 108(1): 215, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363367

RESUMO

The metabolite urolithin A, a metabolite of the dietary polyphenol ellagic acid (EA), has significant health benefits for humans. However, studies on the gut microbiota involved in ellagic acid metabolism are limited. In this study, we conducted in vitro fermentation of EA using human intestinal microbiome combined with antibiotics (vancomycin, polymyxin B sulfate, and amphotericin B). Liquid chromatography-mass spectrometry (LC-MS/MS) analysis demonstrated that the production capacity of urolithin A by gut microbiota co-treated with polymyxin B sulfate and amphotericin B (22.39 µM) was similar to that of untreated gut microbiota (24.26 µM). Macrogenomics (high-throughput sequencing) was used to analyze the composition and structure of the gut microbiota. The results showed that the abundance of Bifidobacterium longum, Bifidobacterium adolescentis, and Bifidobacterium bifidum in the gut microbiota without antibiotic treatment or co-treated with polymyxin B sulfate and amphotericin B during EA fermentation was higher than that in other antibiotic treatment gut microbiota. Therefore, B. longum, B. adolescentis, and B. bifidum may be new genera involved in the conversion of EA to urolithin A. In conclusion, the study revealed unique interactions between polyphenols and gut microbiota, deepening our understanding of the relationship between phenolic compounds like EA and the gut microbiota. These findings may contribute to the development of gut bacteria as potential probiotics for further development. KEY POINTS: • Intestinal microbiome involved in ellagic acid metabolism. • Gram-positive bacteria in the intestinal microbiome are crucial for ellagic acid metabolism. • Bifidobacterium longum, Bifidobacterium adolescentis, and Bifidobacterium bifidum participate in ellagic acid metabolism.


Assuntos
Bifidobacterium longum , Cumarínicos , Microbioma Gastrointestinal , Humanos , Ácido Elágico/metabolismo , Cromatografia Líquida , Polimixina B , Anfotericina B , Espectrometria de Massas em Tandem , Bifidobacterium longum/metabolismo , Antibacterianos
13.
Med Mycol ; 62(2)2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38308518

RESUMO

Candida glabrata is the most common non-albicans Candida species that causes vulvovaginal candidiasis (VVC). Given the intrinsically low susceptibility of C. glabrata to azole drugs, investigations into C. glabrata prevalence, fungal susceptibility profile, and molecular epidemiology are necessary to optimise the treatment of VVC. This molecular epidemiological study was conducted to determine antifungal drug profile, single nucleotide polymorphisms (SNPs) associated with phenotypic antifungal resistance and epidemic diversity of C. glabrata isolates from women with VVC in Namibia. Candida glabrata isolates were identified using phenotypic and molecular methods. Antifungal susceptibility of strains was determined for fluconazole, itraconazole, amphotericin B, and anidulafungin. Whole genome sequencing was used to determine SNPs in antifungal resistance genes and sequence type (ST) allocation. Among C. glabrata isolates, all (20/20; 100%) exhibited phenotypic resistance to the azole class antifungal drug, (fluconazole), and phenotypic susceptibility to the polyene class (amphotericin B), and the echinocandins (anidulafungin). Non-synonymous SNPs were identified in antifungal resistance genes of all fluconazole-resistant C. glabrata isolates including ERG6 (15%), ERG7 (15%), CgCDR1 (25%), CgPDR1 (60%), SNQ2 (10%), FKS1 (5.0%), FKS2 (5.0%), CgFPS1 (5.0%), and MSH2 (15%). ST15 (n = 8/20, 40%) was predominant. This study provides important insight into phenotypic and genotypic antifungal resistance across C. glabrata isolates from women with VVC in Namibia. In this study, azole resistance is determined by an extensive range of SNPs, while the observed polyene and echinocandin resistance-associated SNPs despite phenotypic susceptibility require further investigation.


Candida glabrata is inherently resistant to azole drugs. In this study, we identified a clone that was predominant in women with vulvovaginal candidiasis in Namibia, and that harboured various mutations in resistance-associated genes. This study provides important insight into antifungal resistance across C. glabrata isolates in a sub-Sahara African setting.


Assuntos
Antifúngicos , Candidíase Vulvovaginal , Feminino , Humanos , Antifúngicos/farmacologia , Candida glabrata , Candidíase Vulvovaginal/microbiologia , Candidíase Vulvovaginal/veterinária , Fluconazol , Anfotericina B , Antibacterianos , Anidulafungina , Epidemiologia Molecular , Namíbia/epidemiologia , Testes de Sensibilidade Microbiana/veterinária , Farmacorresistência Bacteriana , Equinocandinas , Azóis , Polienos , Farmacorresistência Fúngica/genética
15.
Int J Antimicrob Agents ; 63(3): 107090, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38242250

RESUMO

This study examined the geographic distribution of minimum inhibitory concentrations (MICs) of antifungals against Cryptococcus isolates. Data were collected on the MICs of specific antifungals (amphotericin B, 5-flucytosine, fluconazole, voriconazole, posaconazole, and isavuconazole) against various Cryptococcus species for the period 2010 to 2020 from the Antimicrobial Testing Leadership and Surveillance database. Cryptococcus isolates were collected from samples of blood and cerebrospinal fluid (CSF) from patients hospitalized in different regions worldwide. We applied the epidemiological cutoff values (ECVs) of antifungals against various Cryptococcus species to distinguish wild-type (WT) from non-WT Cryptococcus isolates. A total of 395 isolates of Cryptococcus species cultured from blood (n = 201) or CSF (n = 194) were analyzed. C. grubii (n = 270), C. neoformans (n = 111), and C. gattii (n = 11) were the three predominant species causing bloodstream infections (BSI) or meningitis/meningoencephalitis (MME). The proportion of MICs above the ECV (1 mg/L) for amphotericin B among C. neoformans isolates was significantly lower than that among C. gattii isolates (MICs >0.5 mg/L; P < 0.001), as evaluated using the chi-square test. For most isolates of the three predominant Cryptococcus species, the MICs of new triazoles were ≤0.25 mg/L. The MICs of fluconazole and amphotericin B in the BSI/MME-causing Cryptococcus isolates collected from patients hospitalized in the Asia-Western Pacific region and Europe were significantly lower (i.e., the distributions were more leftward) than those in North America and Latin America. Ongoing monitoring of MIC data for important antifungals against cryptococcosis is crucial.


Assuntos
Anti-Infecciosos , Cryptococcus gattii , Cryptococcus neoformans , Endrin/análogos & derivados , Humanos , Antifúngicos/farmacologia , Anfotericina B , Fluconazol/farmacologia , Liderança
16.
Nanomedicine (Lond) ; 19(5): 383-396, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38293893

RESUMO

Aim: To develop nanoemulsions (NEs) loading amphotericin B (AmB) and to evaluate the influence of different excipients on the stability and the supramolecular organization, retention and toxicity of AmB. Materials & methods: The NEs were developed from different oils, surfactants, external media and anionic lipids (disteaoryl phosphatidylglycerol [DSPG] and dioleoyl phosphatidylglycerol [DOPG]). Their impact on the size, pH, zeta potential, AmB encapsulation efficiency, AmB retention and hemolytic potential of the NEs was evaluated. Results & conclusion: The use of soybean oil (lipid matrix), Span 80 (surfactant), phosphate buffer (external phase) and DSPG or DOPG (hydrophobic ion pair) provided better NE stability, higher AmB retention within the NEs and a safer formulation profile in hemolysis tests.


Assuntos
Anfotericina B , Fosfatidilgliceróis , Anfotericina B/toxicidade , Tensoativos , Antifúngicos/química
17.
Pathog Dis ; 822024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38204138

RESUMO

Infections caused by Cryptococcus gattii mainly affect immunocompetent individuals and the treatment presents important limitations. This study aimed to validate the efficacy of selective serotonin reuptake inhibitors (SSRI), fluoxetine hydrochloride (FLH), and paroxetine hydrochloride (PAH) in vitro against C. gattii. The antifungal activity of SSRI using the microdilution method revealed a minimal inhibitory concentration (MIC) of 31.25 µg/ml. The combination of FLH or PAH with amphotericin B (AmB) was analyzed using the checkerboard assay and the synergistic effect of SSRI in combination with AmB was able to reduce the SSRI or AmB MIC values 4-8-fold. When examining the effect of SSRI on the induced capsules, we observed that FLH and PAH significantly decreased the size of C. gattii capsules. In addition, the effects of FLH and PAH were evaluated in biofilm biomass and viability. The SSRI were able to reduce biofilm biomass and biofilm viability. In conclusion, our results indicate the use of FLH and PAH exhibited in vitro anticryptococcal activity, representing a possible future alternative for the cryptococcosis treatment.


Assuntos
Cryptococcus gattii , Cryptococcus neoformans , Humanos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antifúngicos/farmacologia , Anfotericina B/farmacologia , Testes de Sensibilidade Microbiana , Fluoxetina/farmacologia , Paroxetina/farmacologia , Biofilmes
18.
Nat Microbiol ; 9(2): 346-358, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38225460

RESUMO

Antibiotic tolerance is the ability of a susceptible population to survive high doses of cidal drugs and has been shown to compromise therapeutic outcomes in bacterial infections. In comparison, whether fungicide tolerance can be induced by host-derived factors during fungal diseases remains largely unknown. Here, through a systematic evaluation of metabolite-drug-fungal interactions in the leading fungal meningitis pathogen, Cryptococcus neoformans, we found that brain glucose induces fungal tolerance to amphotericin B (AmB) in mouse brain tissue and patient cerebrospinal fluid via the fungal glucose repression activator Mig1. Mig1-mediated tolerance limits treatment efficacy for cryptococcal meningitis in mice via inhibiting the synthesis of ergosterol, the target of AmB, and promoting the production of inositolphosphorylceramide, which competes with AmB for ergosterol. Furthermore, AmB combined with an inhibitor of fungal-specific inositolphosphorylceramide synthase, aureobasidin A, shows better efficacy against cryptococcal meningitis in mice than do clinically recommended therapies.


Assuntos
Cryptococcus neoformans , Meningite Criptocócica , Humanos , Animais , Camundongos , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/microbiologia , Antifúngicos/farmacologia , Encéfalo , Ergosterol/uso terapêutico
19.
Int J Artif Organs ; 47(3): 223-226, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38281934

RESUMO

With rates of ECMO utilization on the rise, prevention of nosocomial infections is of paramount importance. Candida auris, an emerging highly pathogenic multidrug resistant fungus, is of particular concern as it is associated with persistent colonization of environmental surfaces, inability to be recognized by many diagnostic platforms, inconsistent laboratory susceptibility results, and high mortality rates. We describe a case of C. auris in a VV-ECMO patient successfully managed with a combination of anidulafungin, amphotericin B, and flucytosine.


Assuntos
Antifúngicos , Candida auris , Humanos , Antifúngicos/uso terapêutico , Candida , Anfotericina B , Testes de Sensibilidade Microbiana
20.
Arch Biochem Biophys ; 753: 109884, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38218361

RESUMO

The spread of fungi resistant to conventional drugs has become a threatening problem. In this context, antimicrobial peptides (AMPs) have been considered as one of the main alternatives for controlling fungal infections. Here, we report the antifungal and antibiofilm activity and some clues about peptide RQ18's mechanism of action against Candida and Cryptococcus. This peptide inhibited yeast growth from 2.5 µM and killed all Candida tropicalis cells within 2 h incubation. Moreover, it showed a synergistic effect with antifungal agent the amphotericin b. RQ18 reduced biofilm formation and promoted C. tropicalis mature biofilms eradication. RQ18's mechanism of action involves fungal cell membrane damage, which was confirmed by the results of RQ18 in the presence of free ergosterol in the medium and fluorescence microscopy by Sytox green. No toxic effects were observed in murine macrophage cell lines and Galleria mellonella larvae, suggesting fungal target selectivity. Therefore, peptide RQ18 represents a promising strategy as a dual antifungal and antibiofilm agent that contributes to infection control without damaging mammalian cells.


Assuntos
Anfotericina B , Antifúngicos , Animais , Camundongos , Antifúngicos/farmacologia , Anfotericina B/farmacologia , Peptídeos/farmacologia , Candida tropicalis , Biofilmes , Testes de Sensibilidade Microbiana , Mamíferos
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