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1.
BMC Neurol ; 22(1): 247, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794548

RESUMO

BACKGROUND: Cryptococcal meningoencephalitis (CM) is a severe infection of central nervous system with high mortality and morbidity. Infection-related inflammatory syndrome is a rare complication of CM. Herein, we report a case of CM complicated by infection-related inflammatory syndrome. CASE PRESENTATION: A 42-year-old man with chronic hepatitis B presented with a 3-day history of aphasia and left hemiparesis at an outside medical facility. The brain magnetic resonance imaging (MRI) showed symmetric and confluent hyperintense signal abnormalities mainly located in the basal ganglia, internal capsule, external capsule, periventricular, corona radiata, frontal and temporal lobes. Cerebrospinal fluid (CSF) examinations revealed elevated leukocyte and protein. India ink staining was positive for Cryptococcus. CSF culture and metagenomic next-generation sequencing (mNGS) confirmed Cryptococcus neoformans. Initial response was observed with intravenous fluconazole (400 mg per day). However, 11 days later, he developed impaired consciousness and incontinence of urine and feces. A repeat brain MRI showed the lesions were progressive and enlarged. The patient was referred to our department at this point of time. Repeat CSF analysis (India ink staining, culture and mNGS) re-confirmed Cryptococcus. However, clinical worsening after initial improvement, laboratory examinations and brain MRI findings suggested a diagnosis of infection-related inflammatory syndrome. Therefore, a combination of corticosteroids and antifungal therapy was initiated. At follow-up, a complete neurological recovery without any relapse was documented. The repeat brain MRI showed complete resolution of the previous lesions. CONCLUSIONS: This case demonstrated that cryptococcal inflammatory syndromes must be suspected in cases of CM if an otherwise unexplained clinical deterioration is observed after initial recovery. The same can happen even before the primary infection is controlled. Thus, timely identification and prompt treatment is vital to reduce the mortality and disability of CM. The administration of corticosteroids in combination with antifungal therapy is an effective strategy in such cases. Clinical course and treatment process of the patient. Hemiparalysis and aphasia improved after the initiation of antifungal treatment. However, the patient developed impaired consciousness companied by deterioration of brain MRI findings. He was treated with adjunctive glucocorticoid taper therapy consisting of dexamethasone (20 mg/day, intravenously) for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response, along with amphotericin B (0.6 mg/kg/day, intravenously), voriconazole (400 mg/day in 2 divided doses, intravenously), and 5-flucytosine (100 mg/kg/day in 4 divided doses, orally). Two weeks later, his symptoms improved significantly. After discharge, he began oral voriconazole for consolidation and maintenance therapy for 8 weeks and 9 months respectively. He recovered without any neurological sequelae at 6-month follow-up. Note: MRI = magnetic resonance imaging.


Assuntos
Criptococose , Cryptococcus neoformans , Meningite Criptocócica , Meningoencefalite , Adulto , Antifúngicos/uso terapêutico , Criptococose/complicações , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Humanos , Masculino , Meningite Criptocócica/complicações , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/tratamento farmacológico , Meningoencefalite/complicações , Síndrome , Voriconazol
2.
Biol Pharm Bull ; 45(8): 1084-1090, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35908890

RESUMO

The pharmacokinetics of voriconazole shows large intra-individual and inter-individual variability and is affected by various factors. Recently, inflammation has been focused as a significant factor affecting the variability. This study aimed to compare the influence of C-reactive protein (CRP) and other clinical laboratory parameters on intra-individual variability in trough voriconazole concentration and examine the impact of inflammation in patients with hematological malignancies. We conducted a retrospective, single-center, observational cohort study. Forty-two patients with hematological malignancy who received oral voriconazole for prophylaxis against deep mycosis and underwent multiple measurements of trough plasma voriconazole concentration were recruited. Quantitative changes in pharmacological and clinical laboratory parameters (Δ) were calculated as the difference between the current and preceding measurements. Voriconazole concentration/maintenance dose per weight (C/D) was found to correlate positively with CRP level (n = 202, rs = 0.314, p < 0.001). Furthermore, ΔC/D correlated positively with ΔCRP level (n = 160, rs = 0.442, p < 0.001), and ΔCRP showed the highest correlation coefficient among the laboratory parameters. Univariate and multivariate analyses identified ΔCRP (p < 0.001) and Δgamma-glutamyl transpeptidase (γGTP) (p = 0.019) as independent factors associated with ΔC/D. Partial R2 were 0.315 for ΔCRP and 0.024 for ΔγGTP, suggesting markedly greater contribution of ΔCRP to ΔC/D. In conclusion, since clinical laboratory parameters other than CRP had little influence on trough plasma voriconazole concentration, therapeutic drug monitoring and dose adjustment considering fluctuation in CRP level would be important for proper use of voriconazole in patients with hematological malignancies.


Assuntos
Antifúngicos , Neoplasias Hematológicas , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Proteína C-Reativa/análise , Monitoramento de Medicamentos , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Inflamação/patologia , Estudos Retrospectivos , Voriconazol/farmacocinética , Voriconazol/uso terapêutico
3.
BMC Pediatr ; 22(1): 427, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35854289

RESUMO

BACKGROUND: Pediatric gastrointestinal basidiobolomycosis is an unusual fungal infection caused by Basidiobolus ranarum, an environmental saprophyte found worldwide. Typically, basidiobolomycosis presents as a subcutaneous infection or soft tissue tumor-like lesion, and rarely involves the gastrointestinal tract. Gastrointestinal basidiobolomycosis is most common in young infants. It has no definitive clinical presentation, and almost all cases are misdiagnosed during the initial presentation. CASE PRESENTATION: We report the case of a 4-year-old Saudi boy who presented to the emergency department with abdominal pain, nausea, vomiting, and weight loss. Ultrasonography revealed a target sign. Based on the ultrasonography findings, surgery was performed, which revealed the presence of intussusception. Eventually, the patient was diagnosed with intussusception secondary to intra-abdominal basidiobolomycosis based on the histological findings. The patient was readmitted and intravenous voriconazole therapy was initiated. One week after the second admission, the patient developed abdominal pain, nausea, vomiting, inability to hold down food, and constipation. Computed tomography of the abdomen was suggestive of small bowel obstruction, which was managed conservatively. The patient responded well and was subsequently discharged with a prescription of oral voriconazole. CONCLUSIONS: This case reveals that gastrointestinal basidiobolomycosis can cause intussusception. This report will inform clinicians of the importance of considering gastrointestinal basidiobolomycosis in the differential diagnosis of chronic abdominal pain in children, even in the absence of fever or a clinically obvious abdominal mass, especially in countries such as Saudi Arabia, where cases have been reported.


Assuntos
Intussuscepção , Dor Abdominal , Antifúngicos/uso terapêutico , Criança , Pré-Escolar , Humanos , Intussuscepção/diagnóstico por imagem , Intussuscepção/etiologia , Masculino , Náusea/tratamento farmacológico , Vômito , Voriconazol/uso terapêutico , Zigomicose
4.
BMC Neurol ; 22(1): 274, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35869441

RESUMO

BACKGROUND: Our previous study explored Amphotericin B (AMB) plus 5-flucytosine (5-FC) combined with fluconazole (FLU) therapy in the induction period, which seemed to be better than the previous AMB + 5-FC antifungal therapy in non-HIV and non-transplant-associated CM. However, based on our clinical finding, the outcomes of some CM patients who received AMB plus 5-FC combined with FLU antifungal therapy were still poor. Therefore, we need to explore new antifungal methods in non-HIV and non-transplant-associated CM during the induction period. METHODS: Clinical data from 148 patients admitted to the Third Affiliated Hospital of Sun Yat Sen University from January 2011 to December 2020 were collected. These patients were stratified based on antifungal treatment methods in the induction period (group I with AMB + 5-FC + VOR, group II with AMB + 5-FC + FLU, group III with AMB + 5-FC). RESULTS: The first hospitalization time of Group I (median: 25 days, IQR: 20-34.5) was significantly shorter than that of Group II (median: 43 days, IQR: 29-62) (p < 0.001) and Group III (median: 50.5 days, IQR: 43-77.5) (p < 0.001). After 2 weeks of follow-up, Group I (26/49) had more patients reaching CSF clearance (p = 0.004) than Group II (18/71) and Group III (7/28). In multivariable analysis, Group II (OR: 3.35, 95%CI 1.43-7.82, p = 0.005) and Group III (OR: 3.8, 95%CI 1.23-11.81, p = 0.021) were associated with higher risk about CSF clearance failure at 2 weeks follow-up than Group I. After 10 weeks of follow-up, the incidence of hypokalemia in Group I was significantly lower than that in Group II (p = 0.003) and Group III (p = 0.004), and the incidence of gastrointestinal discomfort in Group I was significantly lower than that in Group II (p = 0.004). CONCLUSION: AMB plus 5-FC combined with VOR may rapidly improve clinical manifestation, decrease CSF OP and clear the cryptococci in CSF during the early phase, substantially shorten the hospitalization time, and reduce the incidences of hypokalemia and gastrointestinal discomfort.


Assuntos
Hipopotassemia , Meningite Criptocócica , Anfotericina B/efeitos adversos , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Quimioterapia Combinada , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Humanos , Hipopotassemia/induzido quimicamente , Hipopotassemia/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Voriconazol
5.
Front Cell Infect Microbiol ; 12: 936814, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865820

RESUMO

Multiple cellular activities, including protein and lipid synthesis, ribosome biogenesis, and metabolic processes, are regulated by the target of rapamycin (TOR) pathway. Recent research suggests that the TOR might play an important role in various physiological functions of pathogenic fungi, such as nutrient sensing, stress response, and cell cycle progression. Given their robust immunosuppressant and antitumor activities, TOR inhibitors are widely used in clinical settings. In the present study, a microdilution checkerboard-based approach was employed to assess the interactions between the oral mammalian target of rapamycin (mTOR) inhibitor everolimus (EVL) and antifungal agents in the treatment of Aspergillus species derived from 35 clinical isolates in vitro. The results revealed that EVL exhibited promising inhibitory synergy with itraconazole (ITC), posaconazole (POS), and amphotericin B (AMB) for 85.7%, 74.2%, and 71.4%, respectively. In contrast, EVL exhibited minimal synergistic inhibitory activity (14.3%) when applied in combination with voriconazole (VRC). Antagonistic interactions were not observed. In vivo experiments conducted in Galleria mellonella revealed that EVL in combination with antifungal agents improved the larva survival rates in the ITC, VRC, POS, and AMB groups by 18.3%, 13.3%, 26.7%, and 13.3%, respectively. These data suggest that the combination treatment with antifungal agents and antifungal agents holds promise as a means of alleviating clinical aspergillosis.


Assuntos
Antifúngicos , Everolimo , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergillus , Everolimo/farmacologia , Testes de Sensibilidade Microbiana , Voriconazol/farmacologia
6.
Rev Chilena Infectol ; 39(2): 203-207, 2022 04.
Artigo em Espanhol | MEDLINE | ID: mdl-35856994

RESUMO

We present a 10-year-old male patient with a diagnosis of relapsed acute myeloid leukemia (AML), presenting with high-risk febrile neutropenia (HRFN), after a cycle of intensive chemotherapy, evolving with an invasive fungal infection demonstrated by histopathology. Treatment with intravenous voriconazole was started, with erratic plasmatic levels, which require successive dose adjustments which also occurred with oral administration. Finally, he had a favorable response to treatment, despite of the dosing difficulties to reach therapeutic levels. Active search as well as preemptive antifungal therapy, together with plasmatic level monitorization of voriconazole allowed a prompt recovery and improved the patient prognosis.


Assuntos
Infecções Fúngicas Invasivas , Leucemia Mieloide Aguda , Antifúngicos/uso terapêutico , Criança , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/microbiologia , Masculino , Estudos Retrospectivos , Voriconazol/uso terapêutico
8.
Rev Iberoam Micol ; 39(2): 50-53, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35701335

RESUMO

BACKGROUND: The rise in antifungal resistance and drug class limitations are causing higher morbidity and mortality rates all over the world. This issue highlights the urgent need for new and improved antifungal drugs with a novel target. AIMS: In order to evaluate whether juglone can be served as an alternative antifungal to cure drug-resistant Candida infections, we studied the in vitro susceptibility of juglone against fluconazole-susceptible and -resistance Candida isolates, alone and in combination. METHODS: Antifungal susceptibility testing was performed according to the CLSI (Clinical and Laboratory Standards Institute) guidelines. RESULTS: Juglone exhibited the highest minimal inhibitory concentration (MIC) values, followed by fluconazole and nystatin. Voriconazole showed significantly better antifungal activity than juglone, fluconazole, and nystatin, with MIC50 and MIC90 of 0.031 and 0.5µg/mL. There were significant differences in MICs of fluconazole (p<0.001) and juglone (p<0.0003) between Candidaalbicans and the rest of the species. Combination of juglone with fluconazole revealed insignificant effects against fluconazole-susceptible and -resistant Candida isolates. Juglone increased the antifungal activity of fluconazole; however, no synergism effects were observed for any combination, and only an insignificant effect was found against all tested Candida species. CONCLUSIONS: Although obtaining new antifungal drugs is a critical point, a completely novel approach should be implemented.


Assuntos
Candida , Fluconazol , Antifúngicos/farmacologia , Farmacorresistência Fúngica , Fluconazol/farmacologia , Testes de Sensibilidade Microbiana , Naftoquinonas , Nistatina/farmacologia , Voriconazol/farmacologia
9.
Antimicrob Agents Chemother ; 66(7): e0215621, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35766509

RESUMO

Invasive aspergillosis (IA) is associated with significant morbidity and mortality. Voriconazole remains the drug of choice for the treatment of IA in children; however, the complex kinetics of voriconazole in children make dosing challenging and therapeutic drug monitoring (TDM) essential for treatment success. The overarching goal of this review is to discuss the role of voriconazole, posaconazole, isavuconazole, liposomal amphotericin B, echinocandins, and combination antifungal therapy for the treatment of IA in children. We also provide a detailed discussion of antifungal TDM in children.


Assuntos
Aspergilose , Infecções Fúngicas Invasivas , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Criança , Equinocandinas/uso terapêutico , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/uso terapêutico
10.
Pharm Res ; 39(8): 1921-1933, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35725843

RESUMO

PURPOSE: Venetoclax (VEN), an anti-tumor drug that is a substrate of cytochrome P450 3A enzyme (CYP3A4), is used to treat leukemia. Voriconazole (VCZ) is an antifungal medication that inhibits CYP3A4. The goal of this study is to predict the effect of VCZ on VEN exposure. METHOD: Two physiological based pharmacokinetics (PBPK) models were developed for VCZ and VEN using the bottom-up and top-down method. VCZ model was also developed to describe the effect of CYP2C19 polymorphism on its pharmacokinetics (PK). The reversible inhibition constant (Ki) of VCZ for CYP3A4 was calibrated using drug-drug interaction (DDI) data of midazolam and VCZ. The clinical verified VCZ and VEN model were used to predict the DDI of VCZ and VEN at clinical dosing scenario. RESULT: VCZ model predicted VCZ exposure in the subjects of different CYP2C19 genotype and DDI related fold changes of sensitive CYP3A substrate with acceptable prediction error. VEN model can capture PK of VEN with acceptable prediction error. The DDI PBPK model predicted that VCZ increased the exposure of VEN by 4.5-9.6 fold. The increase in VEN exposure by VCZ was influenced by subject's CYP2C19 genotype. According to the therapeutic window, VEN dose should be reduced to 100 mg when co-administered with VCZ. CONCLUSION: The PBPK model developed here could support individual dose adjustment of VEN and DDI risk assessment. Predictions using the robust PBPK model confirmed that the 100 mg dose adjustment is still applicable in the presence of VCZ with high inter-individual viability.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Citocromo P-450 CYP3A , Modelos Biológicos , Sulfonamidas , Voriconazol , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Humanos , Sulfonamidas/farmacocinética , Voriconazol/farmacocinética
11.
Zhonghua Yan Ke Za Zhi ; 58(6): 433-440, 2022 Jun 11.
Artigo em Chinês | MEDLINE | ID: mdl-35692025

RESUMO

Objective: To analyze the etiological changes of children with infectious keratitis. Methods: Retrospective study. Data of patients diagnosed as bacterial, fungal, and amoebic keratitis from 2007 to 2016, aged no more than 14 years old, were collected in the Department of Ophthalmology, Beijing Tongren Hospital. A total of 649 samples were obtained for routine laboratory culture identification and drug sensitivity tests. There were 361 males and 278 females, aged (5.6±4.4) years. The data were analyzed according to age ≤3 years, 4 to 7 years and>7 years. The qualitative data were analyzed by the Chi-square test. Results: Among 649 samples, 140 were culture positive, and the positive rate was 21.6%. Bacteria were the main pathogens, accounting for 81.4%. The positive rate was 31.0% among bacterial samples (114/368), and the bacterial flora was mainly Gram-positive cocci, followed by Gram-negative bacilli. Streptococcus (34.2%) ranked first, followed by Staphylococcus (27.2%) and Pseudomonas (7.9%). For children no more than 7 years old, Streptococcus pneumoniae was the most common bacterial species, while Staphylococcus epidermidis was most common in those aged 8-14 years. Gram-positive cocci were sensitive to vancomycin. Most bacteria were more sensitive to fluoroquinolones and less sensitive to cephalosporins and aminoguanidine. The detection rate of methicillin-resistant Staphylococcus was 68% (17/25). Gatifloxacin had the highest sensitivity, while the difference between gatifloxacin and moxifloxacin, levofloxacin, ofloxacin were not statistically significant (χ²=0.836,0.358, 1.490; P=0.361,0.550,0.222). A total of 254 specimens were cultured for fungi, of which 22 were positive, and the positive rate was 8.7%. The isolated fungi included Fusarium (34.8%, 8/22), Aspergillus (26.1%, 6/22) and Candida (13.0%, 3/22). The positive rate of fungal culture was 9.2% (11/119) from 2007 to 2011, and 8.1% (11/135) from 2012 to 2016, no significant difference was found between two period (χ²=0.096, P=0.757). Fusarium showed a relatively high sensitivity to terbinafine, but it was not sensitive to fluconazole and itraconazole. The sensitivities of Aspergillus to terbinafine and voriconazole were high, followed by amphotericin. Candida had high sensitivities to amphotericin, fluconazole, itraconazole and voriconazole. In 27 specimens for Acanthamoeba culture, 4 specimens were positive, and the positive rate was 14.8%. Risk factors of Acanthamoeba infection included wearing orthokeratology lenses and trauma. Conclusions: Bacteria are the main pathogenic agent of infectious keratitis in children. Streptococcus pneumoniae is the most common in children aged 7 and below, and Staphylococcus epidermidis is the most common in children aged 8-14. Fungal infection was significantly lower than that of bacteria, mainly Fusarium, Aspergillus and Candida.


Assuntos
Ceratite , Staphylococcus aureus Resistente à Meticilina , Adolescente , Anfotericina B , Antibacterianos/uso terapêutico , Bactérias , Criança , Feminino , Fluconazol , Gatifloxacina , Humanos , Itraconazol , Ceratite/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Terbinafina , Voriconazol
12.
Eye Contact Lens ; 48(6): 272-275, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35703836

RESUMO

PURPOSE: To report the clinical profile and treatment outcomes of patients with culture-positive Acremonium keratitis. METHODS: This is a retrospective observational study. Medical records of all patients treated in a tertiary eye hospital for culture positive infective keratitis from March 2016 to February 2021 were screened, of which those positive for Acremonium species on fungal culture were reviewed. Demographic details, clinical presentation, clinical course, treatment given, total follow-up duration, time taken for ulcer to heal, scar size, and final visual acuity in the last follow-up were recorded. RESULTS: Fifty three cases of fungal keratitis caused by Acremonium species were identified, 22 females and 31 males, with average age of 46.39±18.64 years. The mean duration of symptoms being 54.47±50 days. Only five patients had a history of trauma with vegetative matter. Clinical presentation of patients showed a large number of variations, with 2 patients presenting as peripheral ulcerative keratitis and 1 with epithelial plaque. The mean visual acuity of patients at presentation was 2.43±0.46 logMAR units. Thirty-three of 53 patients presented with perforated corneal ulcer and underwent penetrating keratoplasty; 20 patients were medically managed on topical voriconazole 1%, natamycin 5%, and oral voriconazole. The mean duration of healing of epithelial defect was 95±60.62 days (range 60-165 days). CONCLUSION: Acremonium keratitis has a long and indolent course. A prolonged combination therapy of natamycin and voriconazole seems to be effective in the management. A delay in the diagnosis of Acremonium keratitis often leads to clinical worsening requiring keratoplasty.


Assuntos
Acremonium , Úlcera da Córnea , Infecções Oculares Fúngicas , Ceratite , Adulto , Idoso , Antifúngicos/uso terapêutico , Úlcera da Córnea/diagnóstico , Úlcera da Córnea/tratamento farmacológico , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Ceratite/diagnóstico , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Masculino , Pessoa de Meia-Idade , Natamicina/uso terapêutico , Resultado do Tratamento , Voriconazol/uso terapêutico
13.
Microbiol Spectr ; 10(3): e0111222, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35652640

RESUMO

Aspergillus fumigatus is the primary mold pathogen in humans. It can cause a wide range of diseases in humans, with high mortality rates in immunocompromised patients. The first-line treatments for invasive A. fumigatus infections are the triazole antifungals that inhibit Cyp51 lanosterol demethylase activity, blocking ergosterol biosynthesis. However, triazole-resistant strains of A. fumigatus are increasingly encountered, leading to increased mortality. The most common triazole resistance mechanisms in A. fumigatus are alterations in the cyp51A gene or promoter. We tested the hypothesis that A. fumigatus can acquire triazole resistance by horizontal gene transfer (HGT) of resistance-conferring gene cyp51A. HGT has not been experimentally analyzed in filamentous fungi. Therefore, we developed an HGT assay containing donor A. fumigatus strains carrying resistance-conferring mutated cyp51A, either in its chromosomal locus or in a self-replicating plasmid, and recipient strains that were hygromycin resistant and triazole sensitive. Donor and recipient A. fumigatus strains were cocultured and transferred to selective conditions, and the recipient strain tested for transferred triazole resistance. We found that chromosomal transfer of triazole resistance required selection under both voriconazole and hygromycin, resulting in diploid formation. Notably, plasmid-mediated transfer was also activated by voriconazole or hypoxic stress alone, suggesting a possible route to HGT of antifungal resistance in A. fumigatus, both in the environment and during host infection. This study provides, for the first time, preliminary experimental evidence for HGT mediating antifungal resistance in a pathogenic fungus. IMPORTANCE It is well known that bacteria can transfer antibiotic resistance from one strain to another by horizontal gene transfer (HGT), leading to the current worldwide crisis of rapidly emerging antibiotic-resistant bacteria. However, in fungi, HGT events have only been indirectly documented by whole-genome sequencing. This study directly examined fungal HGT of antibiotic resistance in a laboratory setting. We show that HGT of antifungal triazole resistance occurs in the important human fungal pathogen Aspergillus fumigatus. Importantly, we show a plasmid-mediated transfer of triazole resistance occurs under conditions likely to prevail in the environment and in infected patients. This study provides an experimental foundation for future work identifying the drivers and mechanistic underpinnings of HGT in fungi.


Assuntos
Aspergillus fumigatus , Triazóis , Antifúngicos/farmacologia , Aspergillus fumigatus/genética , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Fungos , Transferência Genética Horizontal , Humanos , Testes de Sensibilidade Microbiana , Triazóis/farmacologia , Voriconazol
14.
Clin Lab ; 68(6)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35704741

RESUMO

BACKGROUND: The aim of the study was to investigate the Candida species distribution and their antifungal sensitivities, clinical characteristics, and risk factors of the critically ill patients with invasive Candida infections in a tertiary hospital. METHODS: Candida strains from critically ill patients were isolated in a tertiary hospital of Anhui Province from June 2019 to June 2020 through fungal cultures and identified with MALDI-TOF MS system. The antifungal susceptibility was measured by ATB Fungus-3 method. Demographic information and laboratory data were retrieved from the computerized hospital data system. RESULTS: Candida albicans (C. albicans, 41.49%) was the predominant species in sterile body sites of critically ill patients developing invasive candidiasis, followed by C. glabrata (24.47%) and C. tropicalis (20.21%). The specimen sources were mainly urine (47.87%), then bronchoalveolar lavage fluid (18.09%) and blood (14.89%). In vitro, common Candida species were observed to be highly sensitive to amphotericin B and 5-fluorocytosine. All C. albicans exhibited susceptibility to both fluconazole and voriconazole, as did C. glabrata and C. parapsilosis. However, some C. tropicalis identified were frequently resistant to fluconazole, itraconazole, and voriconazole. The rate of Candida infection was positively correlated with certain risk factors including invasive interventions, age, length of stay in hospital, etc. Conclusions: C. albicans was the main species of invasive Candida infections in critically ill patients, followed by C. glabrata and C. tropicalis. Candida spp. showed the highest rate (10.60%) of resistance to fluconazole, followed by itraconazole (5.30%), voriconazole (5.30%), and 5-fluorocytosine (1.10%). All invasive Candida isolates were sensitive to amphotericin B. In addition, several C. tropicalis were tested and exhibited a high-level resistance to azoles. Notably, a variety of specific risk factors for candidiasis were identified in critically ill patients which need to be taken into consideration.


Assuntos
Antifúngicos , Candidíase Invasiva , Anfotericina B , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Candidíase , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/epidemiologia , Candidíase Invasiva/microbiologia , Estado Terminal , Farmacorresistência Fúngica , Fluconazol , Flucitosina , Humanos , Itraconazol , Testes de Sensibilidade Microbiana , Fatores de Risco , Voriconazol
15.
Rev Chilena Infectol ; 39(1): 14-19, 2022 02.
Artigo em Espanhol | MEDLINE | ID: mdl-35735275

RESUMO

BACKGROUND: Voriconazole is the antifungal of choice for the treatment of invasive aspergillosis (IA). Plasma concentrations (PCs) > 1 µg / mL llave been associated with better therapeutic results which have not always been achieved during treatment in immunocompromised children. In the necessity to initiate early and effective therapy for the infection, it is relevant to establish the voriconazole administration regimen that is associated with optimal PCs in this population. AIM: To compare the PC and safety of intravenous (IV) voriconazole, dosed BID and TID in immunocompromised children with indication of antifungal treatment. METHOD: Retrospective observational study since January 2015 until July 2018 in a highly complex pediatric hospital in Santiago of Chile, in patients aged 0 to 17 years who received treatment with IV voriconazole. Those with renal replacement therapy, liver failure and / or renal failure were excluded. Trough PCs were compared between a group with BID dosing regimen versus another group with TID administration. Adverse reactions were evaluated in both groups. RESULTS: 137 trough PCs were obtained in 76 children, with a median age of 9 years (0-17 years) in the BID group and 9 years (0-16) in the TID group with a median weight of 27 kg (6-83 kg) and 28 kg (9.3-60 kg), respectively. Patients < 12 years old exposed to TID dosages are 4.65 times (OR: 4.65, 95% CI 1.93-11.2) more likely to have PC > 1 gg/mL compared to BID administration (p = 0.001). Eight adverse reactions were reported, mainly photophobia, with no significant difference found between the BID and TID groups. CONCLUSION: TID dosages are associated with a greater probability of obtaining adequate exposure to voriconazole in patients < 12 years old compared to BID dosages, with a low frequency of adverse reactions.


Assuntos
Aspergilose , Infecções Fúngicas Invasivas , Antifúngicos , Aspergilose/tratamento farmacológico , Criança , Humanos , Preparações Farmacêuticas , Voriconazol
16.
Molecules ; 27(12)2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35745009

RESUMO

The Scedosporium genus is an emerging pathogen with worldwide prevalence and high mortality rates that gives multidrug resistance to antifungals; therefore, pharmacological alternatives must be sought for the treatment of diseases caused by this fungus. In the present project, six new α-aminophosphates were synthesized by the Kabachnik-Fields multicomponent reaction by vortex agitation, and six new monohydrolyzed α-aminophosphonic acids were synthesized by an alkaline hydrolysis reaction. Antifungal activity was evaluated using the agar diffusion method as an initial screening to determine the most active compound compared to voriconazole; then it was evaluated against 23 strains of the genus Scedosporium following the M38-A2 protocol from CLSI (activity range: 648.76-700 µg/mL). Results showed that compound 5f exhibited the highest antifungal activity according to the agar diffusion method (≤1 mg/mL). Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay and it was shown that compound 5f exhibits a lower toxicity in comparison to voriconazole at the same concentration (1000 µM). A docking study was conducted afterwards, showing that the possible mechanism of action of the compound is through the inhibition of allosteric 14-α-demethylase. Taking these results as a basis, 5f is presented as a compound with attractive properties for further studies.


Assuntos
Scedosporium , Ágar , Antifúngicos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Triazóis/farmacologia , Voriconazol/farmacologia
17.
Front Cell Infect Microbiol ; 12: 895329, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35770068

RESUMO

Background: Due to more attentions paid to melanized fungi over the past few decades and under the background of the global coronavirus disease 2019 pandemic (COVID-19) the fact that the virus itself and the immunosuppressive agents such as glucocorticoids can further increase the risk of infections of deep mycoses, the number of patients with phaeohyphomycosis (PHM) has a substantial increase. Their spectrum is broad and the early diagnosis and treatments are extremely sticky. This study aims to more comprehensively understand the clinical features of phaeohyphomycosis in China over 35 years and to establish a more applicable systematical classification and severity grades of lesions to guide treatments and prognosis. Methods: We reviewed 174 cases of proven phaeohyphomycosis reported in Chinese and English language literature from 1987 to 2021 and we also made the accurate classification definitions and detailed information about the epidemiology, species of clinical dematiaceous fungi, minimum inhibitory concentration values, clinical features, treatments, and prognosis. Results: The mortality of cerebral, disseminated and pulmonary phaeohyphomycosis are 55%, 36%, and 25%. Nearly 19% of patients had poor quality of life caused by the complications such as disability, disfigurements, and blindness. The overall misdiagnosis rate of phaeohyphomycosis was 74%. Moderate to severe rashes are accounting for 82% of subcutaneous phaeohyphomycosis. The areas of the head and face are mostly affected accounting for 16% of severe rashes. Nearly 30% of invasive infections of phaeohyphomycosis are triggered by recurrent lesions. Voriconazole, itraconazole, amphotericin B deoxycholate (AmB-DOC), and terbinafine were most commonly used but diagnosis and treatments of phaeohyphomycosis remain challenging in reality. Conclusions: Our classifications are likely to be more practical and easier to popularize, and there are still also plenty of characteristics in these non-specific lesions. There're no significant variations in cure rates, or death rates between three grades of lesions. But patients with severe rashes have longer courses and lower effective rates.


Assuntos
COVID-19 , Feoifomicose , Antifúngicos/uso terapêutico , Fungos , Humanos , Feoifomicose/diagnóstico , Feoifomicose/tratamento farmacológico , Feoifomicose/epidemiologia , Qualidade de Vida , Voriconazol
18.
Front Cell Infect Microbiol ; 12: 817315, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493738

RESUMO

Persons with cystic fibrosis (CF) frequently suffer from Pseudomonas aeruginosa and Aspergillus fumigatus co-infections. There is evidence that co-infections with these interacting pathogens cause airway inflammation and aggravate deterioration of lung function. We recently showed that P. aeruginosa laboratory isolates synergistically interact with the anti-fungal azole voriconazole (VCZ), inhibiting biofilm metabolism of several A. fumigatus laboratory strains. Interaction was usually mediated via pyoverdine, but also via pyocyanin or pyochelin. Here we used planktonic filtrates of 7 mucoid and 9 non-mucoid P. aeruginosa isolates from CF patients, as well as 8 isolates without CF origin, and found that all of these isolates interacted with VCZ synergistically at their IC50 as well as higher dilutions. CF mucoid isolates showed the weakest interactive effects. Four non-mucoid P. aeruginosa CF isolates produced no or very low levels of pyoverdine and did not reach an IC50 against forming A. fumigatus biofilm; interaction with VCZ still was synergistic. A VCZ-resistant A. fumigatus strain showed the same level of susceptibility for P. aeruginosa anti-fungal activity as a VCZ-susceptible reference strain. Filtrates of most Pseudomonas isolates were able to increase anti-fungal activity of VCZ on a susceptible A. fumigatus strain. This was also possible for the VCZ-resistant strain. In summary these data show that clinical P. aeruginosa isolates, at varying degrees, synergistically interact with VCZ, and that pyoverdine is not the only molecule responsible. These data also strengthen the idea that during co-infections of A. fumigatus and P. aeruginosa lower concentrations of VCZ might be sufficient to control fungal growth.


Assuntos
Coinfecção , Fibrose Cística , Aspergillus fumigatus/metabolismo , Biofilmes , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Humanos , Pseudomonas aeruginosa/metabolismo , Voriconazol/farmacologia
19.
Rom J Ophthalmol ; 66(1): 69-74, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35531444

RESUMO

Objective: Treating fungal keratitis is always a challenge due to limited antifungal medication, their poor penetration, and often, the delay in diagnosis. The purpose of this study is to present new routes of medication delivery, such as intrastromal application for advanced cases not responding to topical therapy. Methods: A 60-year-old female presented with fungal keratitis, complaining of decreased vision, redness in her left eye followed by frequent pain, which got worse a few days prior. Visual acuity was limited to hand motion. Slit-lamp examination showed advanced conjunctival hyperemia, a very deep white feathery lesion in the central cornea, with satellite lesions on the periphery, and pseudohypopyon of 3 mm in the anterior chamber. She was started on oral fluconazole 100 mg b.i.d, followed by corneal debridement and topical hourly voriconazole eye drops and intrastromal voriconazole application as her local findings did not show any improvement. Results: After repeating the procedure three times, the inflammatory reaction was decreased, the central ulcer healed, satellite lesions disappeared and pseudohypopyon did not recur even after discontinuation of the topical therapy. Conclusion: Intrastromal voriconazole application showed its safety and efficacy in treating advanced fungal keratitis with deep intrastromal lesions. Abbreviations: NSAID = non-steroid anti-inflammatory drugs, BCVA = best corrected visual acuity, MIC = mean inhibitory concentration.


Assuntos
Úlcera da Córnea , Infecções Oculares Fúngicas , Ceratite , Antifúngicos/uso terapêutico , Úlcera da Córnea/diagnóstico , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/microbiologia , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Ceratite/diagnóstico , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Pessoa de Meia-Idade , Voriconazol/uso terapêutico
20.
Emerg Microbes Infect ; 11(1): 1435-1438, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35536092

RESUMO

Aspergillus luchuensis, an industrially important member of Aspergillus species belonging to section Nigri used in fermentation in East Asia, was isolated from an immunocompromised patient with probable invasive pulmonary aspergillosis who failed voriconazole therapy in China. This isolate showed non-wild-type susceptibility to itraconazole, voriconazole, isavuconazole, and posaconazole. A G1378A mutation in cyp51A, resulting in the G441S amino acid substitution, which is the homolog to G448S conferring triazole-resistance in A. fumigatus, was detected in the A. luchuensis isolate.


Assuntos
Aspergilose Pulmonar Invasiva , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergillus/genética , Aspergillus/metabolismo , Aspergillus fumigatus/genética , China , Farmacorresistência Fúngica/genética , Fermentação , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Testes de Sensibilidade Microbiana , Triazóis/farmacologia , Triazóis/uso terapêutico , Voriconazol/metabolismo , Voriconazol/farmacologia , Voriconazol/uso terapêutico
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