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1.
Cancer Sci ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794206

RESUMO

ATL (adult T-cell leukemia/lymphoma) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by the HTLV-1 (human T-cell leukemia virus type 1) infection and there is an urgent need for more effective therapeutic options. The molecular chaperone HSP90 (heat shock protein 90) plays a crucial role in NF-κB (nuclear factor κB)-mediated anti-apoptosis in ATL cells, and HSP90 inhibitors are new candidate therapeutics for ATL. Accordingly, we investigated the anti-ATL effects of a novel oral HSP90 inhibitor TAS-116 (pimitespib) and the mechanisms involved in ex vivo and in vivo preclinical models. TAS-116 achieved IC50 (half maximal inhibitory concentration) values of < 0.5 µM in ten ATL-related cell lines and < 1 µM in primary peripheral blood cells of nine ATL patients; no toxicity was observed toward CD4+ lymphocytes from healthy donors, indicating the safety of this agent. Orally administered TAS-116 also exhibited significant inhibitory effects against tumor cell growth in ATL cell-xenografted mice. Furthermore, gene expression profiling of TAS-116-treated Tax-positive or -negative cell lines and primary ATL cells using DNA microarray and multiple pathway analysis revealed the significant downregulation of the NF-κB pathway in Tax-positive cells and the cell-cycle arrest in Tax-negative cells and primary ATL cells. TAS-116 suppressed the activator protein-1 and tumor necrosis factor pathways in all examined cells. These findings strongly demonstrate the efficacy of TAS-116, regardless of the stage of ATL progression, and its potential application as a novel clinical anti-ATL therapeutic agent.

2.
Int J Antimicrob Agents ; : 106480, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34801675

RESUMO

BACKGROUND: The plasmid-mediated bacterial colistin-resistant gene, mcr, is of global concern in clinical health care. However, there are few reports of surveillance for mcr in Japan. This study aimed to study the prevalence of colistin resistance by identifying nine mcr genes in ESBL-producing Enterobacteriaceae and CRE isolates in Japan. METHODS: We collected 273 ESBL and CRE clinical isolates from the patients in five tertiary hospitals between August 2016 to March 2017. MIC of colistin was measured using the microdilution method. PCR was performed to detect mcr-1 to mcr-9 genes in all strains. Additionally, if we identified a mcr-gene that had not been reported from patients in Japan, we performed a WGS analysis. RESULTS: The rate of colistin resistance was 7.7% in all strains. The rate of colistin resistance in the CRE strains was higher than that in the ESBL-producing strains (20.4% versus 1.1%). The mcr-5 and mcr-9 gene were detected in one ESBL-producing E. coli strain (1/273, 0.37%) and three CRE strains (3/273, 1.1%), respectively. Since the ESBL-producing E. coli strain was the first clinical strain with mcr-5 in Japan, whole-genome sequencing analysis was performed for the strain. The sequence type of the mcr-5 positive strain was ST1642 and it carried two distinct plasmids, ESBL gene-carrying pN-ES-6-1, and mcr-5.1-carrying pN-ES-6-2. CONCLUSIONS: We showed that the frequency of colistin resistance and mcr-positive strains is not high in Japan. Since the MIC for colistin was low in the mcr-5.1 and mcr-9 gene-positive strain, continuous monitoring of mcr genes is necessary.

3.
Microorganisms ; 9(10)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34683416

RESUMO

Acute bacterial conjunctival infections are common, and this study identified the conjunctival bacterial community in infectious conjunctivitis cases seen at the outpatient clinic of Khanh Hoa General Hospital in Nha Trang, Vietnam from October 2016 through December 2017. Conjunctival swabs were collected and tested using conventional culture, PCR, and 16S ribosomal RNA sequencing. The study included 47 randomly selected patients. More than 98% of all DNA reads represented five bacterial phyla. Three of these phyla constituted 92% of all sequences (Firmicutes (35%), Actinobacteria (31%), and Proteobacteria (26%)). At the genus level, there were 12 common genera that constituted about 61% of all sequence reads. Seven of those genera were common (Streptococcus (10%), Cutibacterium (10%), Staphylococcus (7%), Nocardioides (7%), Corynebacterium 1 (5%), Anoxybacillus (5%), and Acinetobacter (5%)), which encompassed 49% of all reads. As for diversity analysis, there was no difference on PERMANOVA analysis (unweighted UniFrac) for sex (p = 0.087), chemosis (p = 0.064), and unclassified eyedrops (p = 0.431). There was a significant difference in cases with bilateral conjunctivitis (p = 0.017) and for using antibiotics (p = 0.020). Of the predominant phyla, Firmicutes had the highest abundance in bacterial conjunctivitis in this study. Pseudomonas as a resident commensal microbiota may have an important role in the prevention of infection.

4.
Microbiol Spectr ; 9(2): e0031821, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34468195

RESUMO

Streptococcus pneumoniae, the most common cause of community-acquired pneumonia, causes severe invasive infections, including meningitis and bacteremia. The widespread use of macrolides has been reported to increase the prevalence of macrolide-resistant S. pneumoniae (MRSP), thereby leading to treatment failure in patients with pneumococcal pneumonia. However, previous studies have demonstrated that several macrolides and lincosamides have beneficial effects on MRSP infection since they inhibit the production and release of pneumolysin, a pneumococcal pore-forming toxin released during autolysis. In this regard, we previously demonstrated that the mechanisms underlying the inhibition of pneumolysin release by erythromycin involved both the transcriptional downregulation of the gene encoding pneumolysin and the impairment of autolysis in MRSP. Here, using a cell supernatant of the culture, we have shown that clarithromycin inhibits pneumolysin release in MRSP. However, contrary to previous observations in erythromycin-treated MRSP, clarithromycin upregulated the transcription of the pneumococcal autolysis-related lytA gene and enhanced autolysis, leading to the leakage of pneumococcal DNA. On the other hand, compared to erythromycin, clarithromycin significantly downregulated the gene encoding pneumolysin. In a mouse model of MRSP pneumonia, the administration of both clarithromycin and erythromycin significantly decreased the pneumolysin protein level in bronchoalveolar lavage fluid and improved lung injury and arterial oxygen saturation without affecting bacterial load. Collectively, these in vitro and in vivo data reinforce the benefits of macrolides on the clinical outcomes of patients with pneumococcal pneumonia. IMPORTANCE Pneumolysin is a potent intracellular toxin possessing multiple functions that augment pneumococcal virulence. For over 10 years, sub-MICs of macrolides, including clarithromycin, have been recognized to decrease pneumolysin production and release from pneumococcal cells. However, this study indicates that macrolides significantly slowed pneumococcal growth, which may be related to decreased pneumolysin release recorded by previous studies. In this study, we demonstrated that clarithromycin decreases pneumolysin production through downregulation of ply gene transcription, regardless of its inhibitory activity against bacterial growth. Additionally, administration of clarithromycin resulted in the amelioration of lung injury in a mouse model of pneumonia induced by macrolide-resistant pneumococci. Therefore, therapeutic targeting of pneumolysin offers a good strategy to treat pneumococcal pneumonia.

5.
BMJ Open ; 11(9): e053325, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548368

RESUMO

INTRODUCTION: The COVID-19 pandemic has emerged worldwide. Although several medications have been approved for treating moderate-to-severe COVID-19, very few treatment strategy has been established for patients with mild COVID-19 who do not require oxygen administration. Clarithromycin is a macrolide antimicrobial agent that has been widely used for bacterial respiratory infectious diseases. Clarithromycin also acts an immunomodulating drug and suppresses cytokine storms in viral respiratory diseases, including influenza. In this study, we aim to evaluate the efficacy of clarithromycin in patients with mild COVID-19. METHODS AND ANALYSIS: This is an exploratory, multicentre, open-label, randomised controlled trial. This study was initiated in May 2021 and will end in July 2022. Patients with mild COVID-19 pneumonia who do not require oxygen administration will be enrolled and randomly assigned in a 1:1:1 ratio to group A (administration of clarithromycin 800 mg/day), group B (administration of clarithromycin 400 mg/day) or group C (standard treatment without clarithromycin). The planned number of enrolled patients is 60 (20 patients × three groups). The primary endpoint is the number of days required to improve the clinical symptoms as measured by the severity score. Secondary endpoints include days for recovery of the body temperature, proportion of patients with oxygen administration, inflammatory cytokines, viral load, serum immunoglobulins, peripheral blood lymphocytes, blood biomarkers and pneumonia infiltrations. ETHICS AND DISSEMINATION: The study protocol was approved by the Clinical Research Review Board of Nagasaki University in accordance with the Clinical Trials Act in Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported as journal publications. TRIAL REGISTRATION NUMBER: jRCTs071210011.


Assuntos
COVID-19 , Claritromicina , Humanos , Estudos Multicêntricos como Assunto , Oxigênio , Pandemias , Porfirinas , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
6.
PLoS One ; 16(9): e0257452, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34582459

RESUMO

OBJECTIVES: A few studies on antibody testing have focused on asymptomatic or mild coronavirus disease 2019 (COVID-19) patients with low initial anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody responses. Anti-SARS-CoV-2 antibody-testing performance was evaluated using blood samples from asymptomatic or mild COVID-19 patients. METHODS: Blood samples were collected from 143 COVID-19 patients during an outbreak on a cruise ship 3 weeks after diagnosis. Simultaneously, a follow-up SARS-CoV-2 genetic test was performed. Samples stored before the COVID-19 pandemic were also used to evaluate the lateral flow immunochromatographic assay (LFA) and electrochemiluminescence immunoassay (ECLIA). Titers of anti-SARS-CoV-2 IgM and IgG antibodies against the nucleocapsid and spike proteins were measured using the enzyme-linked immunosorbent assay to confirm which antibodies were influenced on LFA- and ECLIA- false-negative result in crew-member samples. RESULTS: Sensitivity, specificity, positive-predictive, and negative-predictive values of LFA-detected IgM antibodies were 0.231, 1.000, 1.000, and 0.613, respectively; those of LFA-detected IgG antibodies were 0.483, 0.989, 0.972, and 0.601, respectively; and those of ECLIA-detected total antibodies were 0.783, 1.000, 1.000, and 0.848, respectively. All antibody titers measured using ELISA were significantly lower in blood samples with negative results than in those with positive results in both LFA and ECLIA. In the patients with negative results from the follow-up genetic testing, IgM-, IgG-, and total-antibody positivity rates were 22.9%, 47.6%, and 72.4%, respectively. CONCLUSIONS: These findings suggest that anti-SARS-CoV-2 antibody testing has lower performance in asymptomatic or mild COVID-19 patients than required in the guidelines.


Assuntos
Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , COVID-19/imunologia , Adulto , Anticorpos Antivirais/imunologia , Infecções Assintomáticas/epidemiologia , Teste Sorológico para COVID-19/tendências , Teste para COVID-19/métodos , Surtos de Doenças/prevenção & controle , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Imunoensaio/métodos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/imunologia , Sensibilidade e Especificidade , Navios
7.
Anaerobe ; 72: 102448, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34537378

RESUMO

OBJECTIVES: To perform surveillance of cfiA-positive Bacteroides fragilis using new subtyping software module, MALDI Biotyper Subtyping Module (MBT Subtyping Module), on MALDI-TOF MS system, and to evaluate the detection ability of the module. METHODS: cfiA-positive strains were presumed using the module against B. fragilis isolated between 2006 and 2019. The cfiA gene was confirmed using PCR. In cfiA-positive B. fragilis, the insertion sequence (IS) elements were examined and the MBT STAR-BL assay was performed to examine meropenem hydrolysis activity. RESULTS: Of the 396 B. fragilis strains included, the MBT Subtyping Module detected 33 presumptive cfiA-positive strains (8.3%), of which 32 harbored the cfiA gene. The sensitivity and specificity of the MBT Subtyping Module for detecting cfiA-positive B. fragilis were 100.0% and 99.7%, respectively. Of the 32 strains harboring the cfiA gene, seven strains possessed IS elements, which were thought to induce high cfiA expression. Meropenem hydrolysis was detected in all seven strains that were positive for both cfiA and IS elements, and they exhibited resistance to meropenem and imipenem. The overall non-susceptibility rates to meropenem and imipenem were 84.8% and 36.4%, respectively, in the 33 presumptive cfiA-positive strains. CONCLUSION: The MBT Subtyping Module can detect cfiA-positive B. fragilis rapidly and accurately, supporting its use for surveillance of cfiA-positive B. fragilis in clinical settings.

9.
Respir Investig ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34531175

RESUMO

BACKGROUND: This study aimed to clarify the involvement of anaerobes in aspiration pneumonia by measuring volatile sulfur compounds (VSCs), which are metabolites of anaerobic bacteria in the mouth. METHODS: This study included 84 older adult patients (mean age, 82.5 ± 7.34 years) who had dementia and were hospitalized for more than 6 months. We measured the VSCs in the patient's mouth with Oral Chroma and obtained the data of pneumonia development in the past 6 months. We also evaluated the association or correlation of VSCs and some factors which might be the risk factors of aspiration pneumonia. RESULTS: The development of pneumonia had no significant association with the VSCs in the patient's mouth. CONCLUSION: The present pilot study suggests that anaerobes might not be the main causative pathogens of aspiration pneumonia in older adult patients.

10.
Front Immunol ; 12: 652677, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349754

RESUMO

The contributions of the complement system have been elucidated in the process of solid organ transplantation, including kidney transplantation. However, the role of complement in liver transplantation is unknown. We sought to elucidate the time-dependent changes of peritransplantational serum complement levels and the relationships with posttransplant outcomes and other immunological biomarkers. We enrolled 82 patients who underwent living-related donor liver transplantation (LDLT). Nine patients (11%) died within 90 days after LDLT (non-survivors). The following immunomarkers were collected preoperatively and at 1, 2, and 4 week(s) after LDLT: serum C3, C4, immunoglobulin G (IgG), and peripheral blood leukocyte populations characterized by CD3, CD4, CD8, CD16, CD19, CD20, CD22, and CD56. Consequently, C3 and C4 increased time-dependently after LDLT. Preoperatively, C3 was negatively correlated with the MELD score, Child-Pugh score, CD16-positive leukocyte percentage, and the CD56-positive leukocyte percentage. Non-survivors had lower levels of C3 at 2 weeks in comparison to survivors (median [interquartile range]: 56 [49-70] mg/dL vs. 88 [71-116] md/dL, p=0.0059). When the cutoff value of C3 at 2 weeks to distinguish non-survivors was set to 71 mg/dL, the sensitivity, specificity, and area under the ROC curve were 87.5%, 75.0%, and 0.80, respectively. A principal component analysis showed an inverse relationship between the C3 and C4 levels and the percentage of CD8-, CD16-, and CD56-positive leukocytes at 1 and 2 week(s). All non-survivors were included in the cluster that showed higher percentages of CD8-, CD16-, and CD56-positive leukocytes at 2 weeks. In conclusion, we demonstrated the relationship between complement, outcomes, and other immunomarkers in LDLT and suggested the usefulness of C3 at 2 weeks after LDLT in distinguishing the mortality.


Assuntos
Biomarcadores/sangue , Complemento C3/imunologia , Transplante de Fígado/mortalidade , Doadores Vivos , Idoso , Complemento C4/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunofenotipagem , Contagem de Leucócitos , Leucócitos/metabolismo , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Prognóstico , Fatores de Tempo
11.
Emerg Infect Dis ; 27(9): 2251-2260, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34423761

RESUMO

In April 2020, a coronavirus disease (COVID-19) outbreak occurred on the cruise ship Costa Atlantica in Nagasaki, Japan. Our outbreak investigation included 623 multinational crewmembers onboard on April 20. Median age was 31 years; 84% were men. Each crewmember was isolated or quarantined in a single room inside the ship, and monitoring of health status was supported by a remote health monitoring system. Crewmembers with more severe illness were hospitalized. The investigation found that the outbreak started in late March and peaked in late April, resulting in 149 laboratory-confirmed and 107 probable cases of infection with severe acute respiratory syndrome coronavirus 2. Six case-patients were hospitalized for COVID-19 pneumonia, including 1 in severe condition and 2 who required oxygen administration, but no deaths occurred. Although the virus can spread rapidly on a cruise ship, we describe how prompt isolation and quarantine combined with a sensitive syndromic surveillance system can control a COVID-19 outbreak.


Assuntos
COVID-19 , Navios , Adulto , Surtos de Doenças , Humanos , Japão/epidemiologia , Masculino , SARS-CoV-2
12.
J Clin Med ; 10(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34441847

RESUMO

The relationship between microorganisms present in the lower respiratory tract and the subsequent incidence of pneumonia in patients with rheumatoid arthritis is unclear. A retrospective cohort study was designed to include a total of 121 patients with rheumatoid arthritis who underwent bronchoscopy at three hospitals between January 2008 and December 2017. Data on patient characteristics, microorganisms detected by bronchoscopy, and subsequent incidences of pneumonia were obtained from electronic medical records. Patients were divided into groups based on the microorganisms isolated from the lower respiratory tract. The cumulative incidence of pneumonia was assessed using the Kaplan-Meier method, and decision tree analysis was performed to analyze the relation between the presence of microorganisms and the occurrence of pneumonia. The most frequently isolated microbes were Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae. Patients whose samples tested negative for bacteria or positive for normal oral flora were included in the control group. The rate of the subsequent incidence of pneumonia was higher in the P. aeruginosa group than in the control group (p = 0.026), and decision tree analysis suggested that P. aeruginosa and patient performance status were two important factors for predicting the incidence of pneumonia. In patients with rheumatoid arthritis, the presence of P. aeruginosa in the lower respiratory tract was associated with the subsequent incidence of pneumonia.

13.
J Infect Chemother ; 27(10): 1525-1528, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34294531

RESUMO

Polymerase chain reaction (PCR) testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is necessary for confirming a diagnosis of Coronavirus disease 2019 (COVID-19). Here we present a COVID-19 case of an elderly woman whose SARS-CoV-2 PCR tests showed false negative repeatedly by evaluating with different sampling sites and procedures. Nasopharyngeal swabs, suctioned sputum, and tongue swabs were collected for SARS-CoV-2-PCR. As for tongue swabs, we compared between two different sample conditions; one obtained with dry condition and the other obtained with moistened condition inside the oral cavity. SARS-CoV-2-PCR showed positive for an extended period with suctioned sputum samples compared with nasopharyngeal swabs and tongue swabs. No SARS-CoV-2 from a nasopharyngeal swab sample obtained on day 46 after symptoms onset was isolated despite high viral load (183740.5 copies/5µL). An adequate production of neutralizing antibody in a serum sample on day 46 was also confirmed. The number of RNA copies of the tongue swab samples was higher with moistened condition than with dry condition. The present case suggests that the difference of sampling site or sample condition can affect PCR results. High loads viral RNA detection does not always correlate with infectivity.


Assuntos
COVID-19 , SARS-CoV-2 , Idoso , Feminino , Humanos , Nasofaringe , Reação em Cadeia da Polimerase , RNA Viral , Manejo de Espécimes
14.
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
15.
PLoS One ; 16(6): e0252964, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34111203

RESUMO

OBJECTIVES: The accurate detection of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is essential for the diagnosis of coronavirus disease 2019 (COVID-19). We compared the quantitative RT-PCR results between nasopharyngeal swabs and saliva specimens. METHODS: A COVID-19 outbreak occurred on a cruise ship at Nagasaki port, Japan. We obtained 123 nasopharyngeal swabs and saliva each from asymptomatic or mild patients in the late phase of infection. RESULTS: The intervals from the diagnosis to the sampling were 25.5 days for nasopharyngeal swabs and 28.9 days for saliva. The positive rate was 19.5% (24/123) for nasopharyngeal swabs and 38.2% (47/123) for saliva (P = 0.48). The quantified viral copies (mean ± SEM copies/5 µl) were 9.3±2.6 in nasopharyngeal swabs and 920±850 in saliva (P = 0.0006). CONCLUSIONS: The advantages of saliva specimens include positive rate improvement and accurate viral load detection. Saliva may be used as a reliable sample for SARS-CoV-2 detection.


Assuntos
Teste de Ácido Nucleico para COVID-19 , COVID-19/diagnóstico , Nasofaringe/virologia , SARS-CoV-2/isolamento & purificação , Saliva/virologia , Humanos , Manejo de Espécimes
16.
Trials ; 22(1): 309, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910617

RESUMO

OBJECTIVES: The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. TRIAL DESIGN: The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. PARTICIPANTS: Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: (1) Japanese male or female patients aged ≥ 20 years (2) SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent (3) Provide informed consent Exclusion criteria: (1) Symptoms developed ≥ 8 days prior to enrolment (2) SpO2 < 96 % (room air) (3) Any of the following screening criteria: a) ALT or AST ≥ 5 × upper limit of the reference range b) Child-Pugh class B or C c) Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min (4) Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) (5) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator (6) Hemophiliac or patients with a marked hemorrhagic tendency (7) Severe diarrhea (8) Hypersensitivity to the investigational drug (9) Breastfeeding or pregnancy (10) With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug (11) Receiving rifampicin within the previous 2 weeks (12) Participated in other clinical trials and received drugs within the previous 12 weeks (13) Undergoing treatment for HIV infection (14) History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 (15) Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator INTERVENTION AND COMPARATOR: Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). MAIN OUTCOMES: The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. RANDOMIZATION: Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). BLINDING (MASKING): Only the assessors of the primary outcome will be blinded (blinded outcome assessment). NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman's equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. TRIAL STATUS: Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jRCT) ( jRCT2071200023 ) on 21 July 21, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
COVID-19 , Infecções por HIV , COVID-19/tratamento farmacológico , Vacinas contra COVID-19 , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Nelfinavir/efeitos adversos , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
17.
J Infect Chemother ; 27(7): 931-939, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33795192

RESUMO

Inappropriate antimicrobial therapy for surgical site infections (SSIs) can lead to poor outcomes and an increased risk of antibiotic resistance. A nationwide survey was conducted in Japan from 2018 to 2019 to investigate the antimicrobial susceptibility of pathogens isolated from SSIs. The data were compared with those obtained in 2010 and 2014-2015 surveillance studies. Although the rate of detection of extended-spectrum ß-lactamase producing strains of Escherichia coli was increased from 9.5% in 2010 to 23% in 2014-2015, the incidence decreased to 8.7% in 2018-2019. Although high susceptibility rates were detected to piperacillin/tazobactam (TAZ), the geometric mean MICs were substantially higher than to meropenem (2.67 vs 0.08 µg/mL). By contrast, relatively low geometric mean MICs (0.397 µg/mL) were demonstrated for ceftolozane/TAZ. Although the MRSA incidence rate decreased from 72% in the first surveillance to 53% in the second, no further decrease was detected in 2018-2019. For the Bacteroides fragilis group species, low levels of susceptibility were observed for moxifloxacin (65.3%), cefoxitin (65.3%), and clindamycin (CLDM) (38.9%). In particular, low susceptibility against cefoxitin was demonstrated in non-fragilis Bacteroides, especially B. thetaiotaomicron. By contrast, low susceptibility rates against CLDM were demonstrated in both B. fragilis and non-fragilis Bacteroides species, and a steady decrease in susceptibility throughout was observed (59.3% in 2010, 46.9% in 2014-2015, and 38.9% in 2018-2019). In conclusion, Japanese surveillance data revealed no significant lowering of antibiotic susceptibility over the past decade in organisms commonly associated from SSIs, with the exception of the B. fragilis group.


Assuntos
Bacteroides fragilis , Infecção da Ferida Cirúrgica , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Japão/epidemiologia , Testes de Sensibilidade Microbiana , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/epidemiologia
18.
Ann Palliat Med ; 10(5): 5098-5107, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33894712

RESUMO

BACKGROUND: The current use of prophylactic antibiotics for lung cancer surgery requires modification in aging individuals with impaired lung function. A sustained-release formulation of azithromycin (AZM-SR) could help resolve some of these challenges with its sustained antibacterial and anti-inflammatory effects. The aim of this study was to examine the safety and efficacy of AZM-SR in lung cancer surgery as well as its anti-inflammatory effect. METHODS: Fifty patients were included in the study, and AZM-SR was administered 1 day prior to the surgery. The clinical course, including postoperative complications, was monitored, and the concentration of AZM, bacterial culture, and inflammatory cytokine levels of resected lung specimens were evaluated. RESULTS: No side effects related to AZM-SR were observed. Five cases of postoperative pneumonia (10%) were observed; technical issues were involved in 3 cases. All patients recovered well. Four cases showed positive bacterial culture upon lung tissue examination; however, this was not significantly correlated with postoperative complications. A negative correlation was observed between AZM concentration in lung tissue and interleukin-6 (IL-6) expression. CONCLUSIONS: Prophylactic utilization of AZM-SR in lung cancer surgery seems feasible. The anti-inflammatory effect of AZM might contribute additional beneficial effects in the perioperative management of lung cancer surgery.


Assuntos
Azitromicina , Neoplasias Pulmonares , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Preparações de Ação Retardada , Humanos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia
19.
Genome Med ; 13(1): 52, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785076

RESUMO

BACKGROUND: The hospital-adapted A1 group of Enterococcus faecium remains an organism of significant concern in the context of drug-resistant hospital-associated infections. How this pathogen evolves and disseminates remains poorly understood. METHODS: A large, globally representative collection of short-read genomic data from the hospital-associated A1 group of Enterococcus faecium was assembled (n = 973). We analysed, using a novel analysis approach, global diversity in terms of both the dynamics of the accessory genome and homologous recombination among conserved genes. RESULTS: Two main modes of genomic evolution continue to shape E. faecium: the acquisition and loss of genes, including antimicrobial resistance genes, through mobile genetic elements including plasmids, and homologous recombination of the core genome. These events lead to new clones emerging at the local level, followed by the erosion of signals of clonality through recombination, and in some identifiable cases producing new clonal clusters. These patterns lead to new, emerging lineages which are able to spread globally over relatively short timeframes. CONCLUSIONS: The ability of A1 E. faecium to continually present new combinations of genes for potential selection suggests that controlling this pathogen will remain challenging but establishing a framework for understanding genomic evolution is likely to aid in tracking the threats posed by newly emerging lineages.

20.
Microbes Infect ; 23(4-5): 104812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33781868

RESUMO

This retrospective study evaluated stored nasopharyngeal swab samples from Japanese patients with influenza-like illness during the 2019/2020 season. We aimed to determine whether COVID-19 had spread in the community before the first confirmed case. The period of influenza season during 2019/2020 in Nagasaki was shorter than in previous influenza seasons. When the first COVID-19 case was reported in Nagasaki prefecture, the number of influenza cases were very low. No positive results for SARS-CoV-2 were detected in 182 samples that were obtained from adult outpatients. Our results revealed no large-scale spread of COVID-19 in the community before the first confirmed case.


Assuntos
COVID-19/diagnóstico , COVID-19/epidemiologia , Teste de Ácido Nucleico para COVID-19 , Humanos , Influenza Humana/epidemiologia , Japão/epidemiologia , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação
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