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2.
BMC Infect Dis ; 21(1): 573, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34126952

RESUMO

BACKGROUND: The recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate. CASE PRESENTATION: A 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation. CONCLUSIONS: This is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted.


Assuntos
Aspergillus fumigatus/genética , Azóis/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Proteínas Fúngicas/genética , Aspergilose Pulmonar/microbiologia , Adulto , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/isolamento & purificação , Aspergillus fumigatus/patogenicidade , Azóis/uso terapêutico , Doença Crônica , Humanos , Masculino , Testes de Sensibilidade Microbiana , Mutação , Fenótipo , Aspergilose Pulmonar/tratamento farmacológico , Virulência/genética , Voriconazol/uso terapêutico
3.
Clin Case Rep ; 9(2): 707-710, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33598229

RESUMO

The treatment duration for candidemia with septic pulmonary embolism should be determined based on the clearance of fungus from the bloodstream and improvement of symptoms. The remaining lung nodules may not necessarily indicate persistent infection.

4.
J Infect Chemother ; 27(3): 537-539, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33309631

RESUMO

OBJECTIVE: To evaluate the annual variation in the frequency of patient-acquired azole-resistant Aspergillus fumigatus (ARAf), and correlate it to the amount of oral triazole prescribed, in Nagasaki, Japan. METHODS: A. fumigatus isolates from respiratory specimens collected in the Nagasaki University Hospital (NUH) between 1996 and 2017 were included in the study. The amount of oral triazole prescribed in NUH since 2001 was obtained from the medical ordering system. Mutations in cyp51A, hmg1, and erg6 genes of ARAf were also analysed. RESULTS: From a total of 240 ARAf strains, 12 (5%), 6 (2.5%), 15 (6.25%), and 3 (1.25%) strains were resistant to itraconazole (ITC), voriconazole (VRC), to either ITC or VRC, and both triazoles, respectively. The amount of prescribed VRC increased annually, and was three times as large as that of ITC in 2017. All eleven patients harbouring ITC-resistant strains had a history of prior ITC treatment, while only one of six patients harbouring VRC-resistant strains had a history of prior VRC treatment. cyp51A mutations were recorded in 10 strains; however, tandem repeat mutations of the promoter region of cyp51A were not observed. Several azole-resistant strains had non-cyp51A mutations. CONCLUSIONS: The frequency of patient-acquired ARAf is not increasing in Nagasaki, Japan. Furthermore, the prevalence of VRC-induced ARAf was rare despite the remarkable increase in the amount of prescribed VRC. Mutations in genes other than cyp51A should also be considered when ARAf strains are obtained from patients treated with azole antifungals.


Assuntos
Aspergillus fumigatus , Triazóis , Antifúngicos/farmacologia , Aspergillus fumigatus/genética , Azóis/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Humanos , Japão/epidemiologia , Testes de Sensibilidade Microbiana , Centros de Atenção Terciária , Triazóis/farmacologia
5.
Sci Rep ; 10(1): 17745, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082485

RESUMO

Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of ß-1,3-D-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Caspofungina/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular , Humanos , Testes de Sensibilidade Microbiana , Preparações Farmacêuticas
6.
Respir Investig ; 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32631765

RESUMO

BACKGROUND: Before advance care planning, it is essential to understand the differences in preferences for medical care of terminal-phase pneumonia in elderly patients among the patients, their families, and their doctors. This study aimed to clarify these differences and investigate the actual care provided to elderly patients with pneumonia in nursing hospitals. METHODS: Multicenter questionnaire surveys of 179 patients admitted to nursing homes and long-term care beds in hospitals of three healthcare corporations, their families, and their physicians were conducted between January and August 2018. The questionnaires mainly assessed preferences for life-prolonging medical care procedures, including antibiotic treatments, in terminal-phase pneumonia. A follow-up survey regarding the prognosis and the actual care provided by the physicians was conducted 1 year after the first survey. RESULTS: Only 16.2% of the patients had sufficient prior discussions with their families about their care. More families preferred cardiac massage, intubation, and tracheostomy, while fewer families preferred peripheral intravenous fluids or antibiotics than physicians. A total of 30 patients' families (16.7%) answered to withhold antibiotic treatment, while all physicians supported antibiotic administration. The only significant factor related to withholding antibiotics was high age (P = 0.0057). The follow-up survey administered to the doctors revealed that 49 patients (35.7%) had died within one year. Of the 137 patients, 54 patients (39.4%) had developed pneumonia during this observation period and all were treated with antibiotics. CONCLUSIONS: This study revealed large discrepancies between patients/families and physicians regarding preferences for care. Medical staff should make efforts to fill the gap by ensuring advance care planning.

7.
Sci Rep ; 10(1): 9789, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555245

RESUMO

Elm1 is a serine/threonine kinase involved in multiple cellular functions, including cytokinesis, morphogenesis, and drug resistance in Saccharomyces cerevisiae; however, its roles in pathogenic fungi have not been reported. In this study, we created ELM1-deletion, ELM1-reconstituted, ELM1-overexpression, and ELM1-kinase-dead strains in the clinically important fungal pathogen Candida glabrata and investigated the roles of Elm1 in cell morphology, stress response, and virulence. The elm1Δ strain showed elongated morphology and a thicker cell wall, with analyses of cell-wall components revealing that this strain exhibited significantly increased chitin content relative to that in the wild-type and ELM1-overexpression strains. Although the elm1Δ strain exhibited slower growth than the other two strains, as well as increased sensitivity to high temperature and cell-wall-damaging agents, it showed increased virulence in a Galleria mellonella-infection model. Moreover, loss of Elm1 resulted in increased adhesion to agar plates and epithelial cells, which represent important virulence factors in C. glabrata. Furthermore, RNA sequencing revealed that expression levels of 30 adhesion-like genes were elevated in the elm1Δ strain. Importantly, all these functions were mediated by the kinase activity of Elm1. To our knowledge, this is the first report describing the functional characterization of Elm1 in pathogenic fungi.


Assuntos
Candida glabrata/enzimologia , Proteínas Fúngicas/fisiologia , Proteínas Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Animais , Antifúngicos/farmacologia , Candida glabrata/efeitos dos fármacos , Candida glabrata/patogenicidade , Candida glabrata/ultraestrutura , Candidíase/microbiologia , Adesão Celular , Linhagem Celular , Proliferação de Células , Parede Celular/genética , Parede Celular/fisiologia , Proteínas Fúngicas/genética , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Camundongos , Testes de Sensibilidade Microbiana , Mutagênese , Fenótipo , Proteínas Quinases/genética , RNA-Seq , Proteínas de Saccharomyces cerevisiae/genética , Estresse Fisiológico , Virulência
8.
BMC Infect Dis ; 20(1): 281, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295538

RESUMO

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that commonly has a lethal course caused by the tick-borne Huaiyangshan banyang virus [former SFTS virus (SFTSV)]. The viral load in various body fluids in SFTS patients and the best infection control measure for SFTS patients have not been fully established. CASE PRESENTATION: A 79-year-old man was bitten by a tick while working in the bamboo grove in Nagasaki Prefecture in the southwest part of Japan. Due to the occurrence of impaired consciousness, he was referred to Nagasaki University Hospital for treatment. The serum sample tested positive for SFTSV-RNA in the genome amplification assay, and he was diagnosed with SFTS. Furthermore, SFTSV-RNA was detected from the tick that had bitten the patient. He was treated with multimodal therapy, including platelet transfusion, antimicrobials, antifungals, steroids, and continuous hemodiafiltration. His respiration was assisted with mechanical ventilation. On day 5, taking the day on which he was hospitalized as day 0, serum SFTSV-RNA levels reached a peak and then decreased. However, the cerebrospinal fluid collected on day 13 was positive for SFTSV-RNA. In addition, although serum SFTSV-RNA levels decreased below the detectable level on day 16, he was diagnosed with pneumonia with computed tomography. SFTSV-RNA was detected in the bronchoalveolar lavage fluid on day 21. By day 31, he recovered consciousness completely. The pneumonia improved by day 51, but SFTSV-RNA in the sputum remained positive for approximately 4 months after disease onset. Strict countermeasures against droplet/contact infection were continuously conducted. CONCLUSIONS: Even when SFTSV genome levels become undetectable in the serum of SFTS patients in the convalescent phase, the virus genome remains in body fluids and tissues. It may be possible that body fluids such as respiratory excretions become a source of infection to others; thus, careful infection control management is needed.


Assuntos
Líquidos Corporais/virologia , Encefalopatias/virologia , Infecções por Bunyaviridae/epidemiologia , Hemorragia Gastrointestinal/virologia , Phlebovirus/genética , Pneumonia/virologia , RNA Viral/sangue , Idoso , Animais , Encefalopatias/tratamento farmacológico , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Bunyaviridae/tratamento farmacológico , Infecções por Bunyaviridae/virologia , Terapia Combinada , Hemorragia Gastrointestinal/tratamento farmacológico , Hospitais Universitários , Humanos , Japão/epidemiologia , Masculino , Técnicas de Amplificação de Ácido Nucleico , Phlebovirus/isolamento & purificação , Pneumonia/tratamento farmacológico , Escarro/virologia , Carrapatos/virologia , Resultado do Tratamento , Carga Viral
9.
Sci Rep ; 10(1): 3814, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123235

RESUMO

Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.


Assuntos
Candida/patogenicidade , Candidíase/microbiologia , Animais , Candidíase/patologia , Modelos Animais de Doenças , Intestinos/microbiologia , Camundongos , Virulência
10.
Respir Investig ; 58(3): 212-215, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32171700

RESUMO

Endobronchial volatile sulfur compounds in patients with lung abscess or lung cancer were measured using the Oral Chroma™ gas chromatograph. High levels of hydrogen sulfide and methyl mercaptan were observed in some patients with lung abscess but not in patients with lung cancer. Measuring endobronchial volatile sulfur compounds could be useful for the rapid diagnosis of lung abscess caused by obligate anaerobes.


Assuntos
Bactérias Anaeróbias , Infecções Bacterianas/diagnóstico por imagem , Infecções Bacterianas/microbiologia , Brônquios/metabolismo , Cromatografia Gasosa/métodos , Abscesso Pulmonar/diagnóstico , Abscesso Pulmonar/microbiologia , Compostos de Enxofre/análise , Biomarcadores/análise , Humanos , Sulfeto de Hidrogênio/análise , Projetos Piloto , Volatilização
11.
Med Mycol ; 58(7): 965-972, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31943043

RESUMO

There is an urgent need for development of better diagnostic strategies to improve outcomes in patients with invasive pulmonary aspergillosis (IPA). We hypothesized that lung perfusion single-photon emission computed tomography (SPECT) may be more sensitive and specific than computed tomography (CT) of the chest for detection of IPA because it is an angioinvasive pulmonary infection with characteristics that are different from those of bacterial pneumonia. We used SPECT with injection of technetium-99m-labeled macroaggregated albumin ([99mTc]MAA) to measure pulmonary perfusion in noninfected mice, mice with IPA, and mice with bacterial pneumonia. Histopathologic analysis was performed to evaluate the correlation between the perfusion defect and mould invasion. We also attempted to quantitatively evaluate the SPECT images to identify differences in decreased perfusion levels in affected areas in the mouse lung. Histopathologic analysis in the IPA mouse model showed a clear match between areas with a perfusion defect and the presence of mold, indicating that the location of the perfusion defect on a SPECT image reflects angioinvasion of the mould in the lungs. Some of these perfusion defects could be seen before appearance of the infiltrate of CT images. Quantitative analysis confirmed that perfusion in the affected areas was significantly decreased in the IPA model but not in the bacterial pneumonia model (P < .0001). This imaging method may be preferable to the alternative methods presently used to identify the presence of mold in a patient's lungs.


Assuntos
Aspergillus fumigatus/isolamento & purificação , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/veterinária , Doenças dos Roedores/diagnóstico , Agregado de Albumina Marcado com Tecnécio Tc 99m , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios X/métodos , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos ICR
12.
Clin Infect Dis ; 70(5): 835-842, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30959519

RESUMO

BACKGROUND: There are limited data for direct comparisons of the efficacy of oral itraconazole (ITCZ) and oral voriconazole (VRCZ) therapy in the treatment of chronic pulmonary aspergillosis (CPA). METHODS: We conducted a retrospective, follow-up, observational study of CPA patients enrolled in 2 previous multicenter trials. RESULTS: Of the 273 CPA patients, 59 and 101 patients started maintenance therapy with oral ITCZ and oral VRCZ, respectively, just after the end of acute intravenous therapy in each trial. At the end of the observation period in this follow-up study (median observation period, 731 days), the percentage of patients who showed improvement was lower in the ITCZ group than in the VRCZ group (18.2% vs 40.0%). However, after including stable patients, the percentages were 50.9% and 52.6%, respectively, in the ITCZ and VRCZ groups, which were not significantly different (P = .652). Multivariable Cox regression analysis showed no significant influence of the choice of initial maintenance treatment (ITCZ or VRCZ) on overall mortality as well as CPA-associated mortality. Multivariable logistic regression showed that oral ITCZ selection for initial maintenance therapy was an independent risk factor for hospital readmission and switching to other antifungal agents (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.5 and OR, 5.7; 95% CI, 2.0-15.7, respectively). CONCLUSIONS: Oral VRCZ for initial maintenance therapy showed better effectiveness than oral ITCZ for clinical improvement in CPA patients. There was no difference in crude mortality between initial maintenance therapy with VRCZ and ITCZ, especially in elderly CPA patients. CLINICAL TRIALS REGISTRATION: UMIN000007055.


Assuntos
Antifúngicos , Aspergilose Pulmonar , Idoso , Antifúngicos/uso terapêutico , Seguimentos , Humanos , Itraconazol/uso terapêutico , Manutenção , Aspergilose Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Voriconazol/uso terapêutico
13.
Emerg Infect Dis ; 25(11): 2127-2128, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31625854

RESUMO

Severe fever with thrombocytopenia syndrome virus (SFTSV) can be transmitted between humans. We describe a case of severe fever with thrombocytopenia syndrome in which SFTSV RNA was detected in semen after its disappearance from serum. Our findings indicate possible sexual transmission of this emerging virus.


Assuntos
Infecções por Bunyaviridae/epidemiologia , Infecções por Bunyaviridae/virologia , Phlebovirus/genética , RNA Viral , Sêmen/virologia , Infecções por Bunyaviridae/transmissão , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública
14.
J Med Case Rep ; 13(1): 287, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31511062

RESUMO

BACKGROUND: Rapid diagnosis and appropriate treatment of Munchausen syndrome is important not only for the patient but also for health care workers because a delay in diagnosis can worsen patients' clinical outcomes, and result in a substantial medical cost. CASE PRESENTATION: A young and previously healthy 24-year-old Japanese woman, a nurse, presented with complaints of refractory abscess on her left upper limb for 3 months. A physical examination on admission revealed low-grade fever and a subcutaneous abscess in her left forearm. Laboratory data suggested mild systemic inflammation and liver dysfunction, but no abnormalities of the immune system, including changes in the number of lymphocytes and neutrophils, neutrophil phagocytic capacity, and natural killer (NK) cell activity, were observed. A human immunodeficiency virus test was also negative. Multiple modalities, including positron emission tomography-computed tomography, failed to detect any cause and focus of infection except her left upper limb. Streptococcus mitis and Prevotella buccae were detected from the wound, but no microorganisms were detected in a blood culture. The cellulitis promptly resolved; however, exacerbation of the subcutaneous abscess with polymicrobial bacteremia repeatedly occurred unexpectedly. Because of this puzzling clinical course, the possibility of self-injury was finally suspected. Three syringes with needles, with a turbid liquid, were found in our patient's bag. Enterobacter cloacae and Enterococcus faecalis were detected in the liquid, and an analysis via repetitive element sequence-based polymerase chain reaction determined that Enterococcus faecalis in the wound and syringe contents were genetically identical. She was diagnosed as having Munchausen syndrome and treated with the collaboration of a psychiatrist. She finally confessed that she had injected her own saliva and toilet water into the drip line and wound. CONCLUSIONS: This case report is valuable in that it is the first case in which this syndrome was diagnosed by a genetic method. Munchausen syndrome should not be neglected as a possible cause of refractory and recurrent infection.


Assuntos
Abscesso/microbiologia , Bacteriemia/microbiologia , Enterococcus faecalis/genética , Síndrome de Munchausen/diagnóstico , Tela Subcutânea/microbiologia , Celulite (Flegmão)/microbiologia , Enterococcus faecalis/isolamento & purificação , Feminino , Antebraço/microbiologia , Infecções por Bactérias Gram-Positivas/diagnóstico , Humanos , Injeções Subcutâneas , Recursos Humanos de Enfermagem no Hospital/psicologia , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-31182539

RESUMO

The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.


Assuntos
Amidinas/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Saccharomyces cerevisiae/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Candida albicans/metabolismo , Bovinos , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Testes de Sensibilidade Microbiana , Mitocôndrias/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , NADH Desidrogenase/metabolismo , Ratos , Saccharomyces cerevisiae/metabolismo
16.
Sci Rep ; 9(1): 9331, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249356

RESUMO

Candida peritonitis is a crucial disease, however the optimal antifungal therapy regimen has not been clearly defined. Peritoneal fibrosis (PF) can be caused by abdominal surgery, intra-abdominal infection, and malignant diseases, and is also widely recognized as a crucial complication of long-term peritoneal dialysis. However, the influence of PF on Candida peritonitis prognosis remains unknown. Here, we evaluated the severity of Candida peritonitis within the context of PF and the efficacy of micafungin using mice. A PF mouse model was generated by intraperitoneally administering chlorhexidine gluconate. Candida peritonitis, induced by intraperitoneal inoculation of Candida albicans, was treated with a 7-day consecutive subcutaneous administration of micafungin. Candida infection caused a higher mortality rate in the PF mice compared with the control mice on day 7. Proliferative Candida invasion into the peritoneum and intra-abdominal organs was confirmed pathologically only in the PF mice. However, all mice in both groups treated with micafungin survived until day 20. Micafungin treatment tends to suppress inflammatory cytokines in the plasma 12 h after infection in both groups. Our results suggest that PF enhances early mortality in Candida peritonitis. Prompt initiation and sufficient doses of micafungin had good efficacy for Candida peritonitis, irrespective of the underlying PF.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Micafungina/farmacologia , Fibrose Peritoneal/complicações , Peritonite/complicações , Peritonite/microbiologia , Animais , Biomarcadores , Citocinas , Modelos Animais de Doenças , Histocitoquímica , Humanos , Camundongos , Fibrose Peritoneal/patologia , Peritonite/tratamento farmacológico , Peritonite/patologia , Prognóstico , Resultado do Tratamento
17.
J Infect Chemother ; 25(11): 886-893, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31113725

RESUMO

Oral treatment for elderly outpatients with pneumonia is becoming increasingly important in this super-aged society from the perspective of cost-effectiveness and limited hospital capacities. We evaluated the efficacy and safety of two oral respiratory quinolones, sitafloxacin and garenoxacin, in elderly patients with pneumonia. This randomized, multicenter, open-label trial was conducted among patients aged ≥65 years with clinically and radiographically confirmed pneumonia in Japan. Patients were randomly assigned (1:1) to receive either sitafloxacin (100 mg/day) or garenoxacin (400 mg/day) for 3-10 days. The primary efficacy endpoint was the clinical cure rate at 5-10 days after the end of treatment. From December 2013 to November 2017, we enrolled 120 patients at 11 hospitals and randomly assigned 59 patients to the sitafloxacin group (1 patient withdrew) and 61 patients to the garenoxacin group. These included 30 patients with nursing and healthcare-associated pneumonia (NHCAP) (18 receiving sitafloxacin, 12 receiving garenoxacin) and 37 patients with aspiration pneumonia (16 receiving sitafloxacin, 21 receiving garenoxacin). The clinical cure rates in the sitafloxacin and garenoxacin groups were 88.5% (95% confidence interval: 76.6-95.6) and 88.9% (95% confidence interval: 77.4-95.8), respectively. No significant differences were observed in the incidence rates of drug-related adverse events between the sitafloxacin (20.7%; 12/58 patients) and garenoxacin (27.9%; 17/61 patients) groups. The most common adverse event was hepatic dysfunction, which occurred in seven patients in each group. We conclude that sitafloxacin and garenoxacin are comparably effective and safe for the treatment of pneumonia, including NHCAP and aspiration pneumonia, in elderly patients.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/uso terapêutico , Pneumonia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Infecções Comunitárias Adquiridas/tratamento farmacológico , Feminino , Humanos , Japão , Masculino , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico
18.
J Infect Chemother ; 25(9): 702-707, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30982729

RESUMO

Oral antibiotic therapy for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) usually involves an aminopenicillin with clavulanic acid, a macrolide, or a quinolone. To date, however, the clinical efficacy and safety of the oral cephalosporin cefditoren pivoxil has not been evaluated in Japanese patients with acute exacerbations of COPD. We conducted a prospective, multicenter, single arm, interventional study from January 2013 to March 2017 to determine the efficacy and safety of oral administration of 200 mg cefditoren pivoxil three times daily for 7 days in a cohort of 29 eligible patients from 15 hospitals. The mean age (SD) of participants was 73.1 (8.1) years and 28 had a smoking history (the mean [SD] of smoking index, 1426.7 [931.7]). The primary efficacy endpoint was clinical response (cure rate) at test of cure, which was set at 5-10 days after treatment ceased. Of the 23 patients finally analyzed, cure was achieved in 15 (65.2%), while 8 (34.8%) remained uncured. Previous experience of acute exacerbations significantly affected the cure rate: none of the three patients who had at least two prior exacerbations were cured, while 15 of the 20 patients with one or fewer prior exacerbations were cured (p = 0.032). The microbiological eradication rate was 88.9% at test of cure. During treatment, mild pneumonia was reported as an adverse event in one patient (3.4%) but resolved within 10 days of onset. We conclude that cefditoren pivoxil represents a viable alternative for antibiotic therapy in patients with few prior exacerbations.


Assuntos
Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração Oral , Adulto , Idoso , Antibacterianos/administração & dosagem , Gestão de Antimicrobianos , Cefalosporinas/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
19.
J Clin Microbiol ; 57(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30842231

RESUMO

The Aspergillus-specific lateral-flow device (AspLFD) test is a newly developed point-of-care diagnostic method for invasive pulmonary aspergillosis. However, evidence of the diagnostic performance of the AspLFD for chronic pulmonary aspergillosis (CPA) is limited. Therefore, we conducted a retrospective study to investigate this in comparison with the galactomannan (GM) ß-d-glucan (BDG) test. Fifty patients with chronic pulmonary aspergillosis and 65 patients with respiratory disease, as a control, were enrolled in this study. The majority of the CPA disease entities were chronic pulmonary aspergillosis (64.0%, n = 32), followed by subacute invasive pulmonary aspergillosis (IPA) (20.0%, n = 10) and simple pulmonary aspergilloma (SPA) (16.0%, n = 8). The sensitivity and specificity of the AspLFD test in serum samples were 62.0% and 67.7%, respectively. The GM test (cutoff index, 1.54) showed a sensitivity of 22% and a specificity of 92.3%, while the sensitivity and specificity of the BDG test (cutoff, 19.3 pg/ml) were 48% and 90.8%, respectively. In bronchoalveolar lavage fluid samples, the AspLFD test showed a sensitivity of 66.7% and a specificity of 69.2%, while those of the GM test (cutoff index, 0.6) were 72.7% and 83.1%, respectively. The Aspergillus precipitating antibody test had 70% sensitivity. Unlike the Aspergillus precipitating antibody test, the AspLFD on serum samples showed similar sensitivity to non-fumigatus Aspergillus species. Patients with false-positive results for the AspLFD on serum samples were of a significantly higher age and had a higher prevalence of cavitary lesions in chest computed tomography than patients with negative results in the control group. Given the results in this study, the performance of the AspLFD using serum was acceptable as a point-of-care test for the diagnosis of CPA.


Assuntos
Líquido da Lavagem Broncoalveolar/microbiologia , Testes Imediatos , Aspergilose Pulmonar/diagnóstico , Soro/microbiologia , Idoso , Idoso de 80 Anos ou mais , Antígenos de Fungos/imunologia , Aspergillus/genética , Ação Capilar , Feminino , Humanos , Aspergilose Pulmonar Invasiva/diagnóstico , Masculino , Mananas/sangue , Mananas/imunologia , Pessoa de Meia-Idade , Aspergilose Pulmonar/sangue , Estudos Retrospectivos , Sensibilidade e Especificidade , Testes Sorológicos/instrumentação , Testes Sorológicos/métodos
20.
Front Microbiol ; 10: 27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30761093

RESUMO

Candida glabrata is one of the leading causes of candidiasis and serious invasive infections in hosts with weakened immune systems. C. glabrata is a haploid budding yeast that resides in healthy hosts. Little is known about the mechanisms of C. glabrata virulence. Autophagy is a 'self-eating' process developed in eukaryotes to recycle molecules for adaptation to various environments. Autophagy is speculated to play a role in pathogen virulence by supplying sources of essential proteins for survival in severe host environments. Here, we investigated the effects of defective autophagy on C. glabrata virulence. Autophagy was induced by nitrogen starvation and hydrogen peroxide (H2O2) in C. glabrata. A mutant strain lacking CgAtg1, an autophagy-inducing factor, was generated and confirmed to be deficient for autophagy. The Cgatg1Δ strain was sensitive to nitrogen starvation and H2O2, died rapidly in water without any nutrients, and showed high intracellular ROS levels compared with the wild-type strain and the CgATG1-reconstituted strain in vitro. Upon infecting mouse peritoneal macrophages, the Cgatg1Δ strain showed higher mortality from phagocytosis by macrophages. Finally, in vivo experiments were performed using two mouse models of disseminated candidiasis and intra-abdominal candidiasis. The Cgatg1Δ strain showed significantly decreased CFUs in the organs of the two mouse models. These results suggest that autophagy contributes to C. glabrata virulence by conferring resistance to unstable nutrient environments and immune defense of hosts, and that Atg1 is a novel fitness factor in Candida species.

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