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Lange C.,Research Center Borstel | Mori T.,Research Institute of Tuberculosis
Respirology | Year: 2010

Tuberculosis ranges among the leading causes of morbidity and mortality worldwide. A diagnostic approach to a patient with possible tuberculosis includes a detailed medical history and clinical examination as well as radiological, microbiological, immunological, molecular-biological and histological investigations, where available. Recently, important advances have been achieved in these fields that have led to substantial improvements in the accuracy and the timing of the diagnosis of tuberculosis. Novel methods allow for a better identification of latently infected individuals who are at risk of developing active tuberculosis, they also offer the possibility for a rapid diagnosis of active tuberculosis in patients with negative sputum smears for acid-fast bacilli and enable prompt identification of drug-resistant strains of Mycobacterium tuberculosis directly from respiratory specimen with a high accuracy. In addition, promising methods that will further optimize the diagnosis of tuberculosis are under development. In the future, therapeutic interventions based on the results of novel diagnostic procedures can be made earlier leading to improvements in patient care. © 2009 Asian Pacific Society of Respirology.


Chiang C.-Y.,International Union Against Tuberculosis and Lung Disease | Van Weezenbeek C.,World Health Organization | Mori T.,Research Institute of Tuberculosis | Enarson D.A.,International Union Against Tuberculosis and Lung Disease
Respirology | Year: 2013

Diagnosis and treatment of tuberculosis (TB) will likely navigate a historical turning point in the 2010s with a new management paradigm emerging. However, global control of TB remains a formidable challenge for the decades to come. The estimated case detection rate of TB globally was 66%, and there were 310 000 estimated multidrug-resistant TB (MDR-TB) cases among the 6.2 million TB patients notified in 2011. Although new tools are being introduced for the diagnosis of MDR-TB, there are operational and cost issues related to their use that require urgent attention, so that the poor and vulnerable can benefit. World Health Organization (WHO) estimated that globally, 3.7% of new cases and 20% of previously treated cases have MDR-TB. However, the scale-up of programmatic management of drug-resistant TB is slow, with only 60 000 MDR-TB cases notified to WHO in 2011. The overall proportion of treatment success of MDR-TB notified globally in 2009 was 48%, far below the global target of 75% success rate. Although new tools and drugs have the potential to significantly improve both case detection and treatment outcome, adequate health systems and human resources are needed for rapid uptake and proper implementation to have the impact required to eliminate TB. Hence, the global TB community should broaden its scope, seek intersectoral collaboration and advocate for cost reduction of new tools, while ensuring that the basics of TB control are implemented to reduce the TB burden through the current 'prevention through case management' paradigm. © 2013 Asian Pacific Society of Respirology.


Disratthakit A.,Research Institute of Tuberculosis | Doi N.,Research Institute of Tuberculosis
Antimicrobial Agents and Chemotherapy | Year: 2010

The in vitro activities of DC-159a against seven species of Mycobacterium were compared with moxifloxacin, gatifloxacin, levofloxacin, and rifampin. DC-159a was the most active compound against quinolone-resistant multidrug-resistant M. tuberculosis (MIC90, 0.5 μg/ml) as well as drug-susceptible isolates (MIC90, 0.06 μg/ml). The anti-tubercle bacilli activity of DC-159a was 4- to 32-fold more potent than those of currently available quinolones. DC-159a also demonstrated the highest activities against clinically important nontuberculous mycobacteria. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Sekiguchi J.-I.,Research Institute of Tuberculosis | Disratthakit A.,Research Institute of Tuberculosis | Maeda S.,Research Institute of Tuberculosis | Doi N.,Research Institute of Tuberculosis
Antimicrobial Agents and Chemotherapy | Year: 2011

A G88C mutation in GyrA is one of the key alterations by which Mycobacterium tuberculosis mutants acquire DC-159a resistance in vitro. A novel double mutation in GyrA, G88C D94H, conferred high DC-159a resistance. Different mutation patterns in GyrA were demonstrated for DC-159a-resistant mutants and quinolone-resistant multidrug-resistant (QR-MDR) M. tuberculosis isolates, with a mutation either at position 90 or 94 and double mutations at 90 and 91 or at 90 and 94. DC-159a might be promising for QR M. tuberculosis treatment. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Kato S.,Research Institute of Tuberculosis
Kekkaku : [Tuberculosis] | Year: 2012

Currently, Japan has a near low incidence of tuberculosis (TB); the incidence is below 20/100,000. Considering this incidence, the medical service provision system needs to be restructured and related policies need to be revised. The Revised National Guidelines for TB Control, issued in May 2011 by the Ministry of Health, Labour, and Welfare, provided the policy towards achieving a low incidence of TB. This study aims to provide suggestions for restructuring the medical service system in Japan by analyzing the systems in selected countries with low incidence. Between 2004 and 2010, we conducted tours to study TB control and medical services in the UK, the USA, Germany, The Netherlands, and Norway. In these tours, we visited the medical facilities, agencies implementing preventive activities, health departments of central and local governments, reference laboratories, technical agencies, non-governmental organizations, and other organizations involved in TB control in these countries. In addition, we collected information from published papers and related documents through the internet. This paper reports the policies and strategies adopted in these low-incidence countries, especially pertaining to medical service systems, directly observed treatment, short-course (DOTS) services, hospital beds and facilities, objectives and duration of hospitalization, and mechanisms for maintaining quality medical services. In all the visited countries, except Germany, TB patients were diagnosed and treated, as well as provided support such as DOTS, by a single organization or agency. In the US and Norway, DOTs was provided to all TB patients at chest centers and/or health centers. On the other hand, in the UK, guidelines from the National Institute for Health and Clinical Excellence (NICE) stated that DOT is not necessary for managing most active TB cases. In these countries there were 3 modes of treating infectious patients: home isolation, hospitalization for the first 2 weeks after initiating treatment, and hospitalization until smear examination results are negative. None of the countries had official standards for hospitalization. Measures to maintain service quality were integrating service providers, strengthening technical support, training and/or educating experts, and networking of personnel in charge. The study tours were conducted over 6 years, but no follow-up surveys were conducted. In each visit, we visited only a limited number of medical facilities, which may not be representative of that country. Obviously, this report does not aim to be a comparative study but to provide useful information for discussing the future direction of the medical service system in Japan. In Japan, TB is diagnosed and treated in hospitals and clinics, but contact surveys and other preventive activities are conducted in health centers. In this regard, Japan seems to be unique in that the ways to achieve collaboration among hospitals, health centers, and related organizations are emphasized in the revised National Guidelines for TB Control. Regardless of the DOT target group of a patient, healthcare providers in Japan are expected to ensure patient's adherence through patient-centered support in order to achieve successful treatment. In Japan, the central Government is expected to take responsibility to prevent infection. We suggest that the standards for lengths of hospital stay of TB patients should be revised such that the lengths are based on each patient's bacteriological condition and social setting. The revised National Guidelines for TB Control provide frameworks for ensuring the quality of medical services, but further discussions are warranted in order to plan and implement an effective strategy.


Mitarai S.,Research Institute of Tuberculosis
International Journal of Tuberculosis and Lung Disease | Year: 2015

OBJECTIVE: To determine the prevalence of anti-tuberculosis drug resistance in Japan. DESIGN: A nationwide drug resistance survey was conducted by convenience sampling based on a voluntary hospital consortium. Mycobacterium tuberculosis isolates (n = 2292) were collected from August 2007 to July 2008. Drug susceptibilities were analysed according to the patients' treatment history, age, sex, comorbidities and residential area. We determined susceptibility to the following drugs: isoniazid (INH), rifampicin (RMP), streptomycin (SM), ethambutol (EMB) and levofloxacin (LVX). RESULTS: The frequencies of drug-resistant isolates from new cases were as follows: INH, 3.1%; RMP, 0.7%; SM, 5.6%; EMB, 1.3%; and 8.5% to any drug. The frequencies of drug-resistant isolates from previously treated patients were as follows: INH, 12.3%; RMP, 6.7%; SM, 12.3%; and EMB, 2.6%. The frequencies of LVX-resistant isolates from new and previously treated patients were respectively 3.2% and 6.1% (n = 852). The frequencies of multidrug-resistant isolates from new and previously treated patients were respectively 0.4% and 4.1%, with only one extensively drug-resistant case. CONCLUSION: In general, the prevalence of drugresistant TB in Japan during this period was low. However, LVX resistance among new patients was relatively high. Japan should establish a nationwide surveillance system. © 2015 The Union.


Horita Y.,Research Institute of Tuberculosis | Maeda S.,Research Institute of Tuberculosis | Kazumi Y.,Research Institute of Tuberculosis | Doi N.,Research Institute of Tuberculosis
Antimicrobial Agents and Chemotherapy | Year: 2014

We evaluated the antituberculosis (anti-TB) activity of five β-lactams alone or in combination with β-lactamase inhibitors against 41 clinical isolates of Mycobacterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Of those, tebipenem, an oral carbapenem, showed the most potent anti-TB activity against clinical isolates, with a MIC range of 0.125 to 8 μg/ml, which is achievable in the human blood. More importantly, in the presence of clavulanate, MIC values of tebipenem declined to 2 μg/ml or less. © 2014, American Society for Microbiology. All Rights Reserved.


Horita Y.,Research Institute of Tuberculosis | Doi N.,Research Institute of Tuberculosis
Antimicrobial Agents and Chemotherapy | Year: 2014

Predicting drug-drug interactions (DDIs) related to cytochrome P450 (CYP), such as CYP3A4 and one of the major drug transporters, P-glycoprotein (P-gp), is crucial in the development of future chemotherapeutic regimens to treat tuberculosis (TB) and TB/AIDS coinfection cases. We evaluated the effects of 30 anti-TB drugs, novel candidates, macrolides, and representative antiretroviral drugs on human CYP3A4 activity using a commercially available screening kit for CYP3A4 inhibitors and a human hepatocyte, HepaRG. Moreover, in order to estimate the interactions of these drugs with human P-gp, screening for substrates was performed. For some substrates, P-gp inhibition tests were carried out using P-gp-expressing MDCK cells. As a result, almost all the compounds showed the expected effects on human CYP3A4 both in the in vitro screening and in HepaRG cells. Importantly, the unproven mechanisms of DDIs caused byWHOgroup 5 drugs, thioamides, and p-Aminosalicylic acid were elucidated. Intriguingly, clofazimine (CFZ) exhibited weak inductive effects on CYP3A4 at>0.25 μMin HepaRG cells, while an inhibitory effect was observed at 1.69 μM in the in vitro screening, suggesting that CFZ autoinduces CYP3A4 in the human liver. Our method, based on one of the pharmacokinetics parameters in humans, provides more practical information associated with not only DDIs but also with drug metabolism. © 2014, American Society for Microbiology.


Wada T.,Nagasaki University | Maeda S.,Research Institute of Tuberculosis
Electrophoresis | Year: 2013

As one genotyping method for Mycobacterium tuberculosis, variable number of tandem repeats (VNTR) is a promising tool to trace the undefined transmission of tuberculosis, but it often requires large equipment such as a genetic analyzer for DNA fragment analysis or CE system to conduct systematic analyses. For convenient genotyping at low cost in laboratories, we designed a multiplex PCR system that is applicable to agarose gel electrophoresis using fluorescent PCR primers. For tuberculosis genotyping by VNTR, the copy quantities of minisatellite DNA must be determined in more than 12 loci. The system can halve laborious electrophoresis processes by presenting an image of two VNTR amplicons on a single lane. No expensive equipment is necessary for this method. Therefore, it is useful even in developing countries. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kazumi Y.,Research Institute of Tuberculosis
Kansenshōgaku zasshi. The Journal of the Japanese Association for Infectious Diseases | Year: 2013

Mycobacteria consist of 2 large groups: one is the tuberculosis complex, and the other is nontuberculous mycobacterium (NTM). Most of the NTM are generally non-virulent bacteria, but some NTMs have pathogenicity to humans. There are many reports of nosocomial infection cases caused by common bacteria such as multidrug-resistant Pseudomonas aeruginosa. Also, some cases of in-hospital infection due to NTM were reported. Unlike common bacteria, detection of mycobacteria is affected by various factors, such as stainability, time for colony forming, temperature and nutrition Mycobacterium chelonae chemovar niacinogenes was isolated from 5 patients in 73 nosocomial infection cases (60 patients and 13 suspected cases) at a certain hospital during the period from March 2007 until January 2009. One of the reasons for the expansion of infection and difficulty in identification of the bacteria was the properties of this mycobacterium. This bacterium was very faintly stained with Gram-staining. Therefore, this mycobacterium could only be detected at a hospital when Ziehl-Neelsen stain and the cultivation at 28 degrees C for more than 5 days were performed. MICs for Cefmenoxime and Tosufloxacin of the isolates were more than 128 microg/mL. The isolates and type strasin of M. chelonae chemovar niacinogenes were also resistant to other drugs.

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