RESUMO
BACKGROUND: The incidence of fungal urinary tract infections (UTIs) has dramatically increased in the past decades, with Candida arising as the predominant etiological agent. Managing these infections poses a serious challenge to clinicians, especially with the emergence of fluconazole-resistant (FLC-R) Candida species. In this study, we aimed to determine the mechanisms of fluconazole resistance in urinary Candida spp. isolated from hospitalized patients in Alexandria, Egypt, assess the correlation between fluconazole resistance and virulence, and explore potential treatment options for UTIs caused by FLC-R Candida strains. RESULTS: Fluconazole susceptibility testing of 34 urinary Candida isolates indicated that 76.5% were FLC-R, with a higher prevalence of resistance recorded in non-albicans Candida spp. (88.9%) than in Candida albicans (62.5%). The calculated Spearman's correlation coefficients implied significant positive correlations between fluconazole minimum inhibitory concentrations and both biofilm formation and phospholipase production. Real-time PCR results revealed that most FLC-R isolates (60%) significantly overexpressed at least one efflux pump gene, while 42.3% significantly upregulated the ERG11 gene. The most prevalent mutation detected upon ERG11 sequencing was G464S, which is conclusively linked to fluconazole resistance. The five repurposed agents: amikacin, colistin, dexamethasone, ketorolac, and sulfamethoxazole demonstrated variable fluconazole-sensitizing activities in vitro, with amikacin, dexamethasone, and colistin being the most effective. However, the fluconazole/colistin combination produced a notable reduction (49.1%) in bladder bioburden, a 50% decrease in the inflammatory response, and tripled the median survival span relative to the untreated murine models. CONCLUSIONS: The fluconazole/colistin combination offers a promising treatment option for UTIs caused by FLC-R Candida, providing an alternative to the high-cost, tedious process of novel antifungal drug discovery in the battle against antifungal resistance.
Assuntos
Antifúngicos , Biofilmes , Candida , Candidíase , Reposicionamento de Medicamentos , Farmacorresistência Fúngica , Fluconazol , Testes de Sensibilidade Microbiana , Infecções Urinárias , Fluconazol/farmacologia , Egito , Humanos , Farmacorresistência Fúngica/genética , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candida/genética , Candida/isolamento & purificação , Candida/classificação , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Candidíase/urina , Infecções Urinárias/microbiologia , Infecções Urinárias/tratamento farmacológico , Animais , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Camundongos , Virulência/genética , Virulência/efeitos dos fármacos , Feminino , Masculino , Fosfolipases/genética , Fosfolipases/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMO
During opportunistic pathogenic episodes, Candida albicans employs classical strategies such as the yeast-to-hyphae transition and immunogenic masking. In this issue of Cell Host & Microbe, Luo et al. unveil that the effector protein Cmi1 can be translocated into host cells and targets TBK1, thereby negatively regulating the host's antifungal immune responses.
Assuntos
Candida albicans , Candidíase , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Candida albicans/imunologia , Humanos , Interações Hospedeiro-Patógeno/imunologia , Candidíase/imunologia , Candidíase/microbiologia , Proteínas Fúngicas/imunologia , Proteínas Fúngicas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Hifas/imunologiaRESUMO
Candida auris is a pathogenic yeast frequently exhibiting multidrug resistance and thus warrants special attention. The prompt detection and proper identification of this organism are needed to prevent its spread in healthcare facilities. The authors of this paper had previously developed LAMPAuris, a loop-mediated isothermal amplification assay, for the specific detection of C. auris. LAMPAuris is evaluated in this report for its ability to identify C. auris from five clades and to detect it from clinical specimens. A total of 103 skin swab samples were tested in comparison with a culture-based method and C. auris-specific SYBR green qPCR. The results show that the LAMPAuris assay had specificities ranging from 97 to 100% and sensitivities ranging from 66 to 86%. The lower sensitivity could be attributed to DNA degradation caused by the prolonged storage of the samples. In conclusion, LAMPAuris proved to be a rapid and reliable method for identifying C. auris and for detecting it in clinical specimens. Fresh specimens should ensure better yield and higher sensitivities.
Assuntos
Candida auris , Candidíase , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico , Sensibilidade e Especificidade , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Candidíase/diagnóstico , Candidíase/microbiologia , Candida auris/genética , Candida auris/isolamento & purificação , Pele/microbiologia , Fatores de Tempo , Candida/isolamento & purificação , Candida/genética , Candida/classificaçãoRESUMO
Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting ß-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like Candida glabrata, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (FKS1 and FKS2 in C. glabrata) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of C. glabrata colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this C. glabrata population during treatment and the emergence of both drug target (FKS2) and non-drug target mutations, the latter predominantly in the FEN1 gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The fen1 mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of YPC1 gene hypersensitized the wild type strain to caspofungin and was epistatic to fen1Δ. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in fen1Δ cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different fen1 mutations in clinical C. glabrata isolates, which phenocopied the fen1Δ mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with C. glabrata.
Assuntos
Antifúngicos , Candida glabrata , Candidíase , Caspofungina , Farmacorresistência Fúngica , Mutação , Esfingolipídeos , Candida glabrata/genética , Candida glabrata/efeitos dos fármacos , Candida glabrata/metabolismo , Caspofungina/farmacologia , Camundongos , Antifúngicos/farmacologia , Animais , Esfingolipídeos/biossíntese , Esfingolipídeos/metabolismo , Farmacorresistência Fúngica/genética , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Glucosiltransferases/genética , Glucosiltransferases/metabolismo , Testes de Sensibilidade Microbiana , Equinocandinas/farmacologia , HumanosRESUMO
Candida albicans invasive candidiasis is considered a global health problem. In such cases, biofilm formation on implanted devices represents a therapeutic challenge and the presence of metabolically inactive persistent cells (PCs) in these communities increases their tolerance to fungicidal drugs. This study investigated the influence of amoxicillin, AMX; cefepime, CEF; gentamicin, GEN; amikacin, AMK; vancomycin, VAN; and ciprofloxacin, CIP; on the production of PCs in biofilms of C. albicans bloodstream isolates. 48 h-mature biofilms (n = 6) grown in RPMI-1640 supplemented with antibiotics were treated with 100 µg ml-1 amphotericin B and then evaluated for PCs. Biofilms grown in the presence of antibiotics produced more PCs, up to 10×, when exposed to AMX and CIP; 5 × to CEF; and 6 × to GEN and VAN. The results indicate that antibiotics can modulate PC production in C. albicans biofilms. This scenario may have clinical repercussions in immunocompromised patients under broad-spectrum antibiotic therapy.
Biofilms are microbial communities tolerant to antifungals. Our research showed that antibiotics stimulate the formation of persistent cells within Candida albicans biofilms. These are dormant, metabolically silent cells that resist to therapy and can be related to metastatic and recalcitrant infections.
Assuntos
Antibacterianos , Biofilmes , Candida albicans , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/fisiologia , Antibacterianos/farmacologia , Humanos , Antifúngicos/farmacologia , Testes de Sensibilidade Microbiana , Ciprofloxacina/farmacologia , Gentamicinas/farmacologia , Amoxicilina/farmacologia , Vancomicina/farmacologia , Amicacina/farmacologia , Cefepima/farmacologia , Anfotericina B/farmacologia , Cefalosporinas/farmacologia , Candidíase/microbiologia , Candidíase/tratamento farmacológicoRESUMO
Healthcare-associated infections (HAIs) caused by multidrug-resistant organisms (MDROs) represent a global threat to human health and well-being. Because transmission of MDROs to patients often occurs via transiently contaminated hands of healthcare personnel (HCP), hand hygiene is considered the most important measure for preventing HAIs. Environmental surfaces contaminated with MDROs from colonized or infected patients represent an important source of HCP hand contamination and contribute to transmission of pathogens. Accordingly, facilities are encouraged to adopt and implement recommendations included in the World Health Organization hand hygiene guidelines and those from the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America/Association for Professionals in Infection Control and Epidemiology. Alcohol-based hand rubs are efficacious against MDROs with the exception of Clostridiodes difficile, for which soap and water handwashing is indicated. Monitoring hand hygiene adherence and providing HCP with feedback are of paramount importance. Environmental hygiene measures to curtail MDROs include disinfecting high-touch surfaces in rooms of patients with C. difficile infection daily with a sporicidal agent such as sodium hypochlorite. Some experts recommend also using a sporicidal agent in rooms of patients colonized with C. difficile, and for patients with multidrug-resistant Gram-negative bacteria. Sodium hypochlorite, hydrogen peroxide, or peracetic acid solutions are often used for daily and/or terminal disinfection of rooms housing patients with Candida auris or other MDROs. Products containing only a quaternary ammonium agent are not as effective as other agents against C. auris. Portable medical equipment should be cleaned and disinfected between use on different patients. Detergents are not recommended for cleaning high-touch surfaces in MDRO patient rooms, unless their use is followed by using a disinfectant. Facilities should consider using a disinfectant instead of detergents for terminal cleaning of floors in MDRO patient rooms. Education and training of environmental services employees is essential in assuring effective disinfection practices. Monitoring disinfection practices and providing personnel with performance feedback using fluorescent markers, adenosine triphosphate assays, or less commonly cultures of surfaces, can help reduce MDRO transmission. No-touch disinfection methods such as electrostatic spraying, hydrogen peroxide vapor, or ultraviolet light devices should be considered for terminal disinfection of MDRO patient rooms. Bundles with additional measures are usually necessary to reduce MDRO transmission.
Assuntos
Clostridioides difficile , Infecção Hospitalar , Higiene das Mãos , Staphylococcus aureus Resistente à Meticilina , Humanos , Clostridioides difficile/efeitos dos fármacos , Infecção Hospitalar/prevenção & controle , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Candida/efeitos dos fármacos , Desinfecção das Mãos/métodos , Controle de Infecções/métodos , Farmacorresistência Bacteriana Múltipla , Candidíase/prevenção & controle , Candidíase/microbiologia , Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/transmissão , Infecções por Clostridium/microbiologia , Infecções por Clostridium/epidemiologia , Desinfetantes/farmacologia , Mãos/microbiologia , Pessoal de SaúdeRESUMO
Candida albicans Is a leading cause of nosocomial bloodstream infections, particularly in immunocompromised patients. Current therapeutic strategies are insufficient, highlighting the need for effective vaccines. This study aimed to evaluate the efficacy of a dual-antigen fusion protein vaccine (AH) targeting the Als3 and Hyr1 proteins of C. albicans, using AlPO4 as an adjuvant. The AH vaccine was constructed by fusing Als317-432 and Hyr125-350 proteins, and its immunogenicity was tested in BALB/c mice and New Zealand white rabbits. Mice received three intramuscular doses of the vaccine combined with AlPO4, followed by a lethal challenge with C. albicans SC5314. Survival rates, antibody responses, cytokine production, fungal burdens, and organ pathology were assessed. The vaccine's efficacy was also validated using rabbit serum. Mice vaccinated with the AH-AlPO4 combination exhibited significantly higher antibody titers, particularly IgG and its subclasses, compared to controls (p < .001). The survival rate of vaccinated mice was 80% post-infection, significantly higher than the control group (p < .01). Vaccinated mice showed reduced fungal loads in the blood, kidneys, spleen, and liver (p < .05). Increased levels of interferon gamma and interleukin (IL)-17A were observed, indicating robust T helper (Th) 1 and Th17 cell responses. Vaccination mitigated organ damage, with kidney and liver pathology scores significantly lower than those of unvaccinated mice (p < .05). Rabbit serum with polyclonal antibodies demonstrated effective antifungal activity, confirming vaccine efficacy across species. The AH-AlPO4 vaccine effectively induced strong immune responses, reduced fungal burden, and protected against organ pathology in C. albicans infections. These findings support further development of dual-antigen vaccine strategies.
Candida, a fungus, is a major cause of bloodstream infections, especially in critical care settings. This study focused on developing a vaccine to protect against Candida infection. The vaccine targeted two key proteins, Als3p and Hyr1p, found on the surface of Candida, using a combination of these proteins. To create the vaccine, we used Als3p and Hyr1p to form a fusion protein called AH, and tested the vaccine on mice, administering it with different adjuvants (substances that enhance the immune response). The results showed that the AH vaccine, particularly when combined with the adjuvant AlPO4, induced a strong immune response in mice. This response included the production of specific antibodies and immune cells that are crucial for defending against Candida infections. Furthermore, mice receiving the AH-AlPO4 vaccine showed significantly better survival rates and lower levels of fungal infection compared to the control group or another experimental group. The vaccine also protected vital organs, such as the kidneys and liver, from Candida-induced damage. Additionally, we used rabbit serum to validate the efficacy of the vaccine, providing cross-species confirmation of its effectiveness. The study demonstrated the potential of the AH vaccine in eliciting robust immune responses and reducing the severity of Candida albicans infections. In summary, this research introduces a promising AH vaccine, which shows effectiveness in protecting against Candida infections. The study's innovative approach and positive results contribute to the ongoing efforts to develop vaccines against fungal infections, addressing a critical healthcare challenge. Further research is needed to explore the vaccine's long-term effectiveness and safety for potential use in clinical settings.
Assuntos
Adjuvantes Imunológicos , Anticorpos Antifúngicos , Antígenos de Fungos , Candida albicans , Candidíase , Vacinas Fúngicas , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão , Animais , Vacinas Fúngicas/imunologia , Vacinas Fúngicas/administração & dosagem , Candida albicans/imunologia , Candidíase/prevenção & controle , Candidíase/imunologia , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Coelhos , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/genética , Camundongos , Feminino , Antígenos de Fungos/imunologia , Antígenos de Fungos/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Proteínas Fúngicas/imunologia , Proteínas Fúngicas/administração & dosagem , Citocinas , Vacinação/métodos , Imunoglobulina G/sangue , Modelos Animais de Doenças , Interleucina-17/imunologia , Interferon gama/imunologia , Eficácia de Vacinas , Análise de Sobrevida , Compostos de AlúmenRESUMO
Systemic infection with Candida albicans poses a significant risk for people with weakened immune systems and carries a mortality rate of up to 60%. However, current therapeutic options have several limitations, including increasing drug tolerance, notable off-target effects, and severe adverse reactions. Over the past four decades, the progress in developing drugs to treat Candida albicans infections has been sluggish. This comprehensive review addresses the limitations of existing drugs and summarizes the efforts made toward redesigning and innovating existing or novel drugs through nanotechnology. The discussion explores the potential applications of nanomedicine in Candida albicans infections from four perspectives: nano-preparations for anti-biofilm therapy, innovative formulations of "old drugs" targeting the cell membrane and cell wall, reverse drug resistance therapy targeting subcellular organelles, and virulence deprivation therapy leveraging the unique polymorphism of Candida albicans. These therapeutic approaches are promising to address the above challenges and enhance the efficiency of drug development for Candida albicans infections. By harnessing nano-preparation technology to transform existing and preclinical drugs, novel therapeutic targets will be uncovered, providing effective solutions and broader horizons to improve patient survival rates.
Assuntos
Antifúngicos , Candida albicans , Candidíase , Nanotecnologia , Humanos , Candida albicans/efeitos dos fármacos , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Nanotecnologia/métodos , Animais , Farmacorresistência Fúngica/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Nanomedicina/métodos , Nanopartículas/química , Nanopartículas/uso terapêutico , Sistemas de Liberação de Medicamentos/métodosRESUMO
Candida albicans, a part of normal flora, is an opportunistic fungal pathogen and causes severe health issues in immunocompromised patients. Its pathogenicity is intricately linked to the transcriptional regulation of its metabolic pathways. Paf1 complex (Paf1C) is a crucial transcriptional regulator that is highly conserved in eukaryotes. The objective of this study was to explore the role of Paf1C in the metabolic pathways and how it influences the pathogenicity of C. albicans. Paf1C knockout mutant strains of C. albicans (ctr9Δ/Δ, leo1Δ/Δ, and cdc73Δ/Δ) were generated using the CRISPR-Cas9 system. To investigate the effect of Paf1C on pathogenicity, macrophage interaction assays and mouse survival tests were conducted. The growth patterns of the Paf1C knockout mutants were analyzed through spotting assays and growth curve measurements. Transcriptome analysis was conducted under yeast conditions (30°C without serum) and hyphal conditions (37°C with 10% FBS), to further elucidate the role of Paf1C in the pathogenicity of C. albicans. CTR9 deletion resulted in the attenuation of C. albicans virulence, in macrophage and mouse models. Furthermore, we confirmed that the reduced virulence of the ctr9Δ/Δ mutant can be attributed to a decrease in C. albicans cell abundance. Moreover, transcriptome analysis revealed that metabolic processes required for cell proliferation are impaired in ctr9Δ/Δ mutant. Notably, CTR9 deletion led to the downregulation of methionine biosynthetic genes and the cAMP-PKA signaling pathway-related hypha essential genes, which are pivotal for virulence. Our results suggest that Ctr9-regulated methionine metabolism is a crucial factor for determining C. albicans pathogenicity.
Assuntos
Candida albicans , Candidíase , Proteínas Fúngicas , Regulação Fúngica da Expressão Gênica , Macrófagos , Metionina , Candida albicans/patogenicidade , Candida albicans/genética , Candida albicans/metabolismo , Animais , Camundongos , Virulência , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Metionina/metabolismo , Candidíase/microbiologia , Macrófagos/microbiologia , Camundongos Endogâmicos BALB C , Feminino , Células RAW 264.7 , Hifas/crescimento & desenvolvimento , Hifas/genética , Hifas/metabolismo , Perfilação da Expressão GênicaRESUMO
OBJECTIVES: The Fluconazole pharmacokinetic-pharmacodynamic relationship was investigated in a few clinical settings and only limited studies regarding burned patients are available. Thus, the authors aimed to investigate fluconazole pharmacokinetics changes and its impact on antifungal therapy coverage against dose-dependent Candida spp. applying the PK/PD approach in critically ill severely burned patients. METHODS: Fluconazole was administered as a one-hour intravenous infusion of 200 mg q12h. Doses were increased according to the coverage based on the PK/PD approach. Blood samples were collected at the end of the infusion (1st hour), two hours after (3rd hour), and before the next dose (12th or 24th hour). Serum concentrations were obtained by HPLC-UV. Pharmacokinetic parameters were estimated by noncompartmental analysis and compared with data described in healthy subjects. The effectiveness predictive index was based on the AUCss0-24h/MIC ratio, with a target above 25. RESULTS: Every pharmacokinetic parameter was reduced throughout all three sets of the study. Compared to healthy subjects, the volume of distribution was decreased about 3â7 times, biological half-life was 2â3 times shorter and total body clearance was slightly altered but statistically significant. Both half-life and total body clearance were correlated to the volume of distribution. Consequently, an increase in fluconazole daily dose was necessary to improve empiric coverage. CONCLUSIONS: Fluconazole pharmacokinetics is altered in critically ill severely burned patients, mainly related to the volume of distribution. Doses higher than usual may be necessary to reach the PK/PD target and guarantee antifungal coverage against dose-dependent Candida spp. up to MIC 32 mg/L.
Assuntos
Antifúngicos , Queimaduras , Estado Terminal , Fluconazol , Humanos , Fluconazol/farmacocinética , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Fluconazol/administração & dosagem , Queimaduras/tratamento farmacológico , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagem , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Testes de Sensibilidade Microbiana , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Infusões Intravenosas , Área Sob a Curva , Fatores de Tempo , Idoso , Adulto Jovem , Resultado do Tratamento , Relação Dose-Resposta a Droga , Valores de ReferênciaRESUMO
Fungal pathogens within the urine, specifically Candida species, are a common finding amongst hospitalized patients. Risk factors for the development of candiduria involve patients with indwelling urinary drainage devices, surgical patients, patients undergoing urologic instrumentation, and diabetic patients. Candiduria often presents with an asymptomatic course but can also be a severe life-threatening process. This article will review the epidemiology and risk factors associated with fungal urinary tract infections, and the diagnosis and categorization of these infections along with a review of current medical and surgical treatments for this condition.
Assuntos
Antifúngicos , Infecções Urinárias , Humanos , Infecções Urinárias/terapia , Infecções Urinárias/diagnóstico , Infecções Urinárias/microbiologia , Infecções Urinárias/epidemiologia , Antifúngicos/uso terapêutico , Candidíase/epidemiologia , Candidíase/diagnóstico , Candidíase/terapia , Fatores de RiscoRESUMO
Candida sp. infections are a threat to global health, with high morbidity and mortality rates due to drug resistance, especially in immunocompromised people. For this reason, the search for new alternatives is urgent, and in recent years, a combined therapy with natural compounds has been proposed. Considering the biological potential of isoespintanol (ISO) and continuing its study, the objective of this research was to assess the effect of ISO in combination with the antifungals fluconazole (FLZ), amphotericin B (AFB) and caspofungin (CASP) against clinical isolates of C. tropicalis and to evaluate the cytotoxic effect of this compound in the acute phase (days 0 and 14) and chronic phase (days 0, 14, 28, 42, 56, 70 and 84) in female mice (Mus musculus) of the Balb/c lineage. The results show that ISO can potentiate the effect of FLZ, AFB and CASP, showing synergism with these antifungals. An evaluation of the mice via direct observation showed no behavioral changes or variations in weight during treatment; furthermore, an analysis of the cytokines IFN-γ and TNF in plasma, peritoneal cavity lavage (PCL) and bronchoalveolar lavage (BAL) indicated that there was no inflammation process. In addition, histopathological studies of the lungs, liver and kidneys showed no signs of toxicity caused by ISO. This was consistent with an analysis of oxaloacetic transaminases (GOT) and pyruvic transaminases (GPT), which remained in the standard range. These findings indicate that ISO does not have a cytotoxic effect at the doses evaluated, placing it as a monoterpene of interest in the search for compounds with pharmacological potential.
Assuntos
Antifúngicos , Sinergismo Farmacológico , Camundongos Endogâmicos BALB C , Animais , Antifúngicos/farmacologia , Camundongos , Feminino , Monoterpenos/farmacologia , Testes de Sensibilidade Microbiana , Anfotericina B/farmacologia , Anfotericina B/toxicidade , Candidíase/tratamento farmacológico , Candida tropicalis/efeitos dos fármacos , Fluconazol/farmacologia , Citocinas/metabolismo , Citocinas/sangue , Caspofungina/farmacologiaAssuntos
Balanite (Inflamação) , Candida albicans , Foliculite , Humanos , Balanite (Inflamação)/microbiologia , Balanite (Inflamação)/diagnóstico , Balanite (Inflamação)/patologia , Foliculite/microbiologia , Foliculite/patologia , Foliculite/diagnóstico , Candida albicans/isolamento & purificação , Masculino , Candidíase/microbiologia , Candidíase/diagnóstico , Antifúngicos/uso terapêutico , AdultoRESUMO
This case report discusses a rare instance of polymicrobial pericarditis in a man in his early 60s with a history of substance abuse. The patient presented with chest pain and shortness of breath, later diagnosed as pericarditis caused by Streptococcus anginosus, S. intermedius and Candida glabrata, likely originating from a large adjacent oesophageal ulcer. The condition led to critical illness, requiring pericardiocentesis, antibiotic and antifungal therapy. Despite initial improvement, the patient experienced recurrence and ultimately underwent pericardectomy. The article emphasises the rarity and severity of polymicrobial pericarditis, often associated with high mortality. It underscores the importance of prompt recognition, broad-spectrum antibiotics and source control, particularly when the gastrointestinal tract is implicated. The case highlights the challenges in managing such cases and the potential need for surgical intervention for optimal outcomes.
Assuntos
Candida glabrata , Candidíase , Doenças do Esôfago , Pericardite , Úlcera , Humanos , Masculino , Pericardite/microbiologia , Pericardite/diagnóstico , Candidíase/complicações , Candidíase/diagnóstico , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Úlcera/microbiologia , Candida glabrata/isolamento & purificação , Doenças do Esôfago/microbiologia , Streptococcus anginosus/isolamento & purificação , Antibacterianos/uso terapêutico , Pessoa de Meia-Idade , Streptococcus intermedius/isolamento & purificação , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/tratamento farmacológico , Antifúngicos/uso terapêutico , Translocação Bacteriana , Coinfecção , Pericardiocentese , PericardiectomiaRESUMO
The global rate of Amphotericin B (AmB) resistance in Candida auris has surpassed 12%. However, there is limited data on available clinical treatments and microevolutionary analyses concerning reduced AmB sensitivity. In this study, we collected 18 C. auris isolates from five patients between 2019 and 2022. We employed clinical data mining, genomic, and transcriptomic analyses to identify genetic evolutionary features linked to reduced AmB sensitivity in these isolates during clinical treatment. We identified six isolates with a minimum inhibitory concentration (MIC) of AmB below 0.5â µg/mL (AmB0.5) and 12 isolates with an AmB-MIC of 1â µg/mL (AmB1) or ≥ 2â µg/mL (AmB2). All five patients received 24-hour AmB (5â mg/L) bladder irrigation treatment. Evolutionary analyses revealed an ERG3 (c923t) mutation in AmB1 C. auris. Additionally, AmB2 C. auris was found to contain a t2831c mutation in the RAD2 gene. In the AmB1 group, membrane lipid-related gene expression (ERG1, ERG2, ERG13, and ERG24) was upregulated, while in the AmB2 group, expression of DNA-related genes (e.g. DNA2 and PRI1) was up-regulated. In a series of C.auris strains with reduced susceptibility to AmB, five key genes were identified: two upregulated (IFF9 and PGA6) and three downregulated (HGT7, HGT13,and PRI32). In this study, we demonstrate the microevolution of reduced AmB sensitivity in vivo and further elucidate the relationship between reduced AmB sensitivity and low-concentration AmB bladder irrigation. These findings offer new insights into potential antifungal drug targets and clinical markers for the "super fungus", C. auris.
Assuntos
Anfotericina B , Antifúngicos , Candida auris , Candidíase , Farmacorresistência Fúngica , Testes de Sensibilidade Microbiana , Humanos , Anfotericina B/farmacologia , Antifúngicos/farmacologia , China/epidemiologia , Farmacorresistência Fúngica/genética , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Candida auris/genética , Candida auris/efeitos dos fármacos , Evolução Molecular , Masculino , Mutação , Feminino , Pessoa de Meia-Idade , Proteínas Fúngicas/genéticaRESUMO
Hepatosplenic candidiasis (HSC) is a rare type of candidiasis that can occur in patients with hematologic malignancies, hematopoietic stem cell transplantation. At present, there is still a lack of studies on HSC in patients with hematologic disorders. Based on The Chinese Guidelines for the Diagnosis and Treatment of Invasive Fungal Disease in Patients with Hematological Disorders and Cancers (the 6th revision), We retrospectively analyzed the clinical characteristics and prognosis of patients with HSC treated in Peking University Institute of Hematology from 2008 to 2022. Finally, eighteen patients were included, with 1 (5.6%) proven, 2 (11.1%) probable, and 15 (83.3%) possible HSC. Among them, 3 (16.7%) patients occurred after haploid hematopoietic stem cell transplantation and 15 (83.3%) patients occurred after chemotherapy. 6 (33.3%) patients had positive blood cultures, including 4 cases of Candida tropicalis and 2 cases of Candida albicans. At 4 weeks of antifungal therapy, 10 (58.8%) patients achieved partial response (PR), At 8 weeks, 1 (6.3%) patients achieved complete response and 10 (62.5%) patients achieved PR. At 6 months after diagnosis, 3 (16.7%) patients died of hematopoietic recurrence, and none of them died of HSC. As a rare fungal infection disease, HSC has a low positive rate of microbiological and histological examinations, a persistent treat cycle, and has difficulty in remission, reminding us of the need for vigilance in patients with hematopoietic disorders and persistent fever.
Assuntos
Candidíase , Esplenopatias , Humanos , Estudos Retrospectivos , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , Candidíase/diagnóstico , Adulto , Adulto Jovem , Esplenopatias/diagnóstico , Esplenopatias/microbiologia , Esplenopatias/etiologia , Adolescente , Idoso , Transplante de Células-Tronco Hematopoéticas , Doenças Hematológicas/complicações , Hepatopatias/microbiologia , Hepatopatias/diagnósticoRESUMO
Candida auris has emerged as a significant healthcare-associated pathogen due to its multidrug-resistant nature. Ongoing constraints in the discovery and provision of new antifungals create an urgent imperative to design effective remedies to this pressing global blight. Herein, we screened a chemical library and identified aryl-carbohydrazide analogs with potent activity against both C. auris and the most prevalent human fungal pathogen, C. albicans. SPB00525 [N'-(2,6-dichlorophenyl)-5-nitro-furan-2-carbohydrazide] exhibited potent activity against different strains that were resistant to standard antifungals. Using drug-induced haploinsufficient profiling, transcriptomics and metabolomic analysis, we uncovered that Ole1, a Δ(9) fatty acid desaturase, is the likely target of SPB00525. An analog of the latter, HTS06170 [N'-(2,6-dichlorophenyl)-4-methyl-1,2,3-thiadiazole-5-carbohydrazide], had a superior antifungal activity against both C. auris and C. albicans. Both SPB00525 and HTS06170 act as antivirulence agents and inhibited the invasive hyphal growth and biofilm formation of C. albicans. SPB00525 and HTS06170 attenuated fungal damage to human enterocytes and ameliorate the survival of Galleria mellonella larvae used as systemic candidiasis model. These data suggest that inhibiting fungal Δ(9) fatty acid desaturase activity represents a potential therapeutic approach for treating fungal infection caused by the superbug C. auris and the most prevalent human fungal pathogen, C. albicans.
Assuntos
Antifúngicos , Candida auris , Candidíase , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Animais , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Candida auris/efeitos dos fármacos , Candida auris/genética , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/antagonistas & inibidores , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Humanos , Inibidores Enzimáticos/farmacologia , Mariposas/microbiologia , Mariposas/efeitos dos fármacos , Metabolômica , Larva/microbiologia , Larva/efeitos dos fármacos , Modelos Animais de Doenças , Hidrazinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Perfilação da Expressão GênicaRESUMO
Candida albicans is an opportunistic fungal pathogen that can cause systemic infections in immunocompromised individuals. Morphological transition and biofilm formation are major virulence factors of C. albicans. Moreover, biofilm enhances resistance to antifungal agents. Therefore, it is urgent to identify new and effective compounds to target the biofilm of C. albicans. In the present study, the antifungal activities of equol against C. albicans were investigated. In vitro, the microdilution analysis and spot assay result showed that equol exhibited potent inhibitory activities against C. albicans. Further investigations confirmed that the antifungal effects of equol involved interference with the transition from yeast to hypha and biofilm formation of C. albicans. In addition, transcriptome sequencing and reverse transcription-quantitative PCR (qRT-PCR) analysis showed that equol significantly downregulated the expression of several genes in the Ras1-cAMP-PKA pathway related to hyphae and biofilm formation and significantly upregulated the expression of the negative transcriptional repressors RFG1 and TUP1. Moreover, equol effectively reduced the production of cAMP, a key messenger in the Ras1-cAMP-PKA pathway, while supplementation with cAMP partly rescued the equol-induced defects in hyphal development. Furthermore, in a mouse model of systemic candidiasis (SC), equol treatment significantly decreased the fungal burden (liver, kidneys, and lung) in mice and local tissue damage, while enhancing the production of interleukin-10 (IL-10). Together, these findings confirm that equol is a potentially effective agent for treatment of SC.
Assuntos
Antifúngicos , Biofilmes , Candida albicans , Candidíase , Equol , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Animais , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Camundongos , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Equol/farmacologia , Feminino , Modelos Animais de Doenças , Testes de Sensibilidade Microbiana , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMO
Candida species are common human pathogens that cause a wide range of diseases ranging from superficial to invasive candidiasis. However, basic studies focusing on the mechanisms underlying these diseases are limited. This article reviews our previous research on the mechanisms of superficial and invasive candidiasis, the virulence of Candida species, and Candida species fitness to hosts. Regarding invasive candidiasis, we focused on two types of infections: ocular candidiasis and endogenous candidiasis from the gastrointestinal tract. Using an established ocular candidiasis mouse model, along with retrospective epidemiological research, we found a strong association between Candida albicans and ocular candidiasis. Regarding endogenous candidiasis, research using Candida auris indicated that invasive strains had a higher capability for gastrointestinal tract colonization and showed greater dissemination compared with non-invasive strains. In terms of superficial candidiasis, we focused on the defense mechanism in vulvovaginal candidiasis. The results suggested that stimulated invariant natural killer T cells played a protective role against C. albicans vaginal infection and might be a therapeutic target for vulvovaginal candidiasis. Concerning Candida species fitness, we focused on environmental factors, particularly oxygen concentration, and evaluated biofilm formation under various oxygen concentrations, revealing that each Candida species favored different oxygen concentrations. In particular, Candida tropicalis showed greater biofilm formation under hypoxic conditions. Our research revealed several insights for understanding the exact mechanisms of candidiasis, which might lead to better control of Candida species infections and appropriate treatment.
Assuntos
Biofilmes , Candida , Candidíase , Modelos Animais de Doenças , Animais , Camundongos , Candida/patogenicidade , Candidíase/microbiologia , Humanos , Biofilmes/crescimento & desenvolvimento , Virulência , Feminino , Candidíase Vulvovaginal/microbiologia , Infecções Oculares Fúngicas/microbiologia , Candida albicans/patogenicidade , Candidíase Invasiva/microbiologiaRESUMO
INTRODUCTION: Candida auris is a globally disseminated invasive ascomycetous yeast, that imposes a substantial burden on healthcare systems. It has been documented to have spread to over 40 countries across six continents, necessitating in-depth comprehension through advanced techniques like Whole-Genome Sequencing. METHOD: This study entailed the isolation and Whole-Genome Sequencing of a fluconazole-resistant C. auris strain (CA01) obtained from a patient's blood in Beijing. Genome analysis was conducted to classify the strain, and molecular docking was performed to understand the impact of mutations on drug resistance. RESULTS: Genome analysis revealed that CA01 belongs to the South Asia Clade (I) and shares the closest genetic relationship with previously reported strains BJCA001 and BJCA002. Notably, unlike BJCA001, CA01 exhibits significant resistance to fluconazole primarily due to the A395T mutation in the ERG11 gene. Molecular docking studies demonstrated that this mutation leads to geometric changes in the active site where fluconazole binds, resulting in decreased binding affinity. Additionally, the present findings have identified several core virulence genes in C. auris, such as RBF1. DISCUSSION: The findings from this study expand the understanding of the genetic diversity and adaptive mechanisms of C. auris within the South Asia Clade (I). The observed fluconazole resistance driven by the ERG11 mutation A395T highlights the need for heightened awareness and adaptation in clinical treatment strategies in China. This study provides critical insights into drug resistance and virulence profiles at a genetic level, which could guide future therapeutic and management strategies for C. auris infections.