November-December

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結核第 91 巻第 11_12号 2016年11_12月 684

Abstract In recent years, administration of biologics for immunologic infl ammatory diseases, particularly rheumatoid arthritis, has increased obviously. These substances have dramatic effects, but complications of various infections such as tuberculosis are increasing. Biologics is an antonym for synthetic products (compounds), which are the most common type of pharmaceuticals, made by bioengineering materials derived from living organisms including humans. As concerns preparations which inhibit TNF-αα that constitutes the basis of human immunity to tuberculosis, there was a fear that there might be an increase in tuberculosis in Japan, where many people have a history of tuberculosis infection due to past epidemics. However, it was confi rmed in post-marketing all-case surveillance in Japan that tuberculosis can be prevented by screening for latent tuberculosis infection (LTBI) in the target patient population, and administering an anti-tubercu-losis drug to patients with the fi nding of infection before administering a TNF-αα inhibitor. The effi cacy of prophylaxis is not 100％, however, so there were some patients who not only had complications of tuberculosis, but in whom symp-toms rapidly exacerbated and resulted in death. Since there is a high possibility that death was due to an immune

reconstitu-tion inﬂ ammatory syndrome, it is necessary to consider re-administering biologics, or administer them continuously without interruption. As concerns non-tuberculous mycobac-teriosis (NTM) which is rapidly increasing in Japan, on the other hand, its clinical manifestation is non-uniform and lacks effective therapeutic drugs, so administration of biologics had been considered to be contraindicated, but from a close analysis of clinical cases, there is a growing recognition that biologics can be administered under certain conditions. Key words : Biologics, TNF-αα, Acid-fast bacilli, Tubercu-losis, Non-tuberculous mycobacteriosis

Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku Univer-sity

Correspondence to: Akira Watanabe, Research Division for Development of Anti-Infective Agents, Institute of Develop-ment, Aging and Cancer, Tohoku University, 4_1, Seiryocho, Aoba-ku, Sendai-shi, Miyagi 980_8575 Japan.

(E-mail: akira.watanabe.b3@tohoku.ac.jp) −−−−−−−−Review Article−−−−−−−−

MYCOBACTERIOSIS ASSOCIATED WITH ADMINISTRATION OF BIOLOGICS

Akira WATANABE Dis. 2013 ; 72 : 37 42.

26） Winthrop KL, Chang E, Yamashita S, et al.: Nontuberculous mycobacteria infections and anti-tumor necrosis factor-αα therapy. Emerg Infect Dis. 2009 ; 15 : 1556 1561.

27） Mori S, Tokuda H, Sakai F, et al.: Radiological features and therapeutic responses of pulmonary nontuberculous myco-bacterial disease in rheumatoid arthritis patients receiving biological agents: a retrospective multicenter study in Japan. Mod Rheumatol. 2012 ; 22 : 727 737.

28） Mori S, Sugimoto M: Is continuation of anti-tumor necrosis factor-αα therapy a safe option for patients who have devel-oped pulmonary mycobacterial infection?: Case presentation

and literature review. Clin Rheumatology. 2012 ; 31 : 203 210. 29）日本リウマチ学会調査研究委員会生物学的製剤使用ガイドライン策定小委員会：関節リウマチ（RA）に対するTNF阻害薬使用ガイドライン（2015年 3 月12日改訂第 7 版）. http://www.ryumachi-jp.com/info/guideline_tnf. pdf 30）徳田均：各論 2, 抗酸菌感染症, b.非結核性抗酸菌症. 生物学的製剤と呼吸器疾患・診療の手引き」, 日本呼吸器学会生物学的製剤と呼吸器疾患・診療の手引き作成委員会編集, 克誠堂, 東京, 2014, 59 70.

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NTM Pulmonary Disease / S. Kitada 689

of Mycobacterium avium-complex pulmonary disease using an enzyme immunoassay kit. Am J Respir Crit Care Med. 2008 ; 177 : 793 797.

15） Shibata Y, Horita N, Yamamoto M, et al.: Diagnostic test accuracy of anti-glycopeptidolipid-core IgA antibodies for Mycobacterium avium complex pulmonary disease: system-atic review and meta-analysis. Scientiﬁ c reports. 2016 ; 6 : 29325.

16） Benson CA, Williams PL, Currier JS, et al.: A prospective, randomized trial examining the efﬁ cacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immuno-deﬁ ciency syndrome. Clin Infect Dis. 2003 ; 37 : 1234 1243. 17） Chaisson RE, Keiser P, Pierce M, et al.: Clarithromycin and

ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex disease in patients with HIV infection. AIDS. 1997 ; 11 : 311 317. 18） Gordin FM, Sullam PM, Shafran SD, et al.: A randomized,

placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect

Dis. 1999 ; 28 : 1080 1085.

19） Parenti DM, Williams PL, Hafner R, et al.: A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals. AIDS Clinical Trials Group Protocol 135 Study Team. AIDS. 1998 ; 12 : 2439 2446. 20） Sullam PM, Gordin FM, Wynne BA.: Efﬁ cacy of rifabutin

in the treatment of disseminated infection due to Mycobac-terium avium complex. The Rifabutin Treatment Group. Clin Infect Dis. 1994 ; 19 : 84 86.

21） Lam PK, Grifﬁ th DE, Aksamit TR, et al.: Factors related to response to intermittent treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2006 ; 173 : 1283 1289.

22） Miwa S, Shirai M, Toyoshima M, et al.: Efﬁ cacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. A preliminary study. Annals of the American Thoracic Society. 2014 ; 11 : 23 29.

23） Komiya K, Kurashima A, Ihi T, et al.: Long-term, low-dose erythromycin monotherapy for Mycobacterium avium complex lung disease: a propensity score analysis. Int J Antimicrob Agents. 2014 ; 44 : 131 135.

Abstract The prevalence of nontuberculous mycobacterial (NTM) pulmonary disease is increasing in Japan and worldwide, and the importance of proper diagnosis and management of the disease has been recently recognized. Mycobacterium avium complex (MAC) is the most common and important causative agent of pulmonary disease among nontuberculous mycobacteria. I have described the latest epidemiology of NTM lung disease, clinical feature, disease type, disease progression, diagnosis including serodiagnosis, and treatment strategy of MAC lung disease in this report. There are a lot of unsolved problems in the ﬁ eld of NTM lung disease, therefore, further investigations are required.

Key words : Epidemiology, Mycobacterium avium complex pulmonary disease, Clinical feature, Diagnosis, Serodiagnosis, Treatment

Department of Respiratory Medicine, National Hospital Organization Toneyama National Hospital

Correspondence to: Seigo Kitada, Department of Respiratory Medicine, National Hospital Organization Toneyama National Hospital, 5_1_1, Toneyama, Toyonaka-shi, Osaka 560_8552 Japan. (E-mail: kitadase@toneyama.go.jp)

−−−−−−−−Review Article−−−−−−−−

NONTUBERCULOUS MYCOBACTERIAL PULMONARY DISEASE

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結核第 91 巻第 11_12号 2016年11_12月 702

5 ）森亨, 小川賢二, 重藤えり子, 他：多剤耐性結核治療のための新規結核薬の使用を巡って. 結核. 2014 ; 89 :

813 815.

Abstract [Objective] We experienced use of new anti-tuberculous drug, Delamanid in multi- and extensively drug resistant tuberculosis (M (X) DR-TB) in our hospital.

[Materials and Methods] Fifteen cases who were diagnosed M(X)DR-TB had been used Delamanid in our hospital from 2014 to 2015.

[Results] The gender distribution consisted of eleven males and four females in M(X)DR-TB. The mean age was 53.3 years old in male and 28.3 years old in female. Japanese were eight cases, and Chinese were fi ve cases, and other countries patients were two cases. Twelve cases were MDR-TB cases, and three cases were XDR-TB cases. Six cases of fi fteen cases were sputum culture positive before using Delamanid. Two cases (13.3％) had been appearanced QTc extension in EKG by using Delamanid. But these cases had not seen symptom. Other typical side effects had not seen. Six cases (40.0％) of fi fteen cases had done surgical resection. One case of fi fteen cases had been died with intractable pneumothorax, and one case had been discontinued for leukopenia. All cases containing two discontinued cases had obtained negative conversion of sputum culture.

[Conclusion] We experienced new anti-tuberculous drug, Delamanid. If we add Delamanid only for MDR-TB patients with only one or two sensitive anti-tuberculous drugs, it will be possible to make anew resistance. We used one more another new drug, for example Linezolid or high dose isoniazid or Meropenem and Ampicilin Clavulanate acid with Delamanid and sensitive anti-tuberculous drugs. We need to investigate risk and beneﬁ t when we use new anti-tuberculous drug. We need not to make more another MDR-TB cases.

Key words : Delamanid, MDR-TB, XDR-TB, Chemotherapy, Surgical resection

Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association (JATA)

Correspondence to: Masao Okumura, Department of Respi-ratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association (JATA), 3_1_24, Matsuyama, Kiyose-shi, Tokyo 204_8522 Japan. (E-mail: okumuram@fukujuji.org) −−−−−−−−Review Article−−−−−−−−

EXPERIENCE OF USE OF NEW ANTI-TUBERCULOUS DRUG,

DELAMANID IN MULTI- AND EXTENSIVELY DRUG RESISTANT

TUBERCULOSIS CASES IN OUR HOSPITAL

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結核第 91 巻第 11_12号 2016年11_12月 708

Abstract Controlling tuberculosis (TB) among foreign-born persons is an important issue in Japan. The number of foreign-born patients with TB has been slightly increasing yearly, whereas that of Japan-born patients with TB has been decreasing. Some foreign-born persons visited Japan with active TB due to the lack of useful medical checks performed before immigration. The percentage of those with TB among foreign-born persons is high (up to 43％) in the younger generation, especially those in their 20s. Currently, multidrug-resistant TB occurs at a low frequency in Japan; however, there is a danger of persons being easily immigrated into Japan from high-burden countries. Physicians need to be aware that TB is an imported infection. Additionally, a strategy for controlling TB in foreign-born persons (e.g., performing medical checkups before immigration, conducting target

medical checkups of high-risk people for TB, administering chemoprophylaxis to foreigners, reconsidering the public medical insurance system for TB treatment, and offering patient support) needs discussed.

Key words: Tuberculosis, Foreign-born persons, Japan Department of Respiratory Medicine, National Center of Global Health and Medicine, Shinjuku, Tokyo

Correspondence to: Eriko Morino, Department of Respiratory Medicine, National Center of Global Health and Medicine, 1_21_1, Toyama, Shinjuku-ku, Tokyo 162_8655 Japan. (E-mail: emorino@hosp.ncgm.go.jp)

−−−−−−−−Review Article−−−−−−−−

CONTROLLING TUBERCULOSIS IN FOREIGN-BORN PERSONS IN JAPAN

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Clinical Investigation of Tuberculous Spondylitis / T. Masuda et al. 715

Abstract [Objective] A delay in the diagnosis of tubercu-lous spondylitis can result in worsening of the condition. We investigated previously reported cases of tuberculous spondylitis, as well as cases experienced in our hospital, to identify factors that are useful in the diagnosis.

[Materials and Methods] We retrospectively evaluated six cases of tuberculous spondylitis diagnosed in our hospital between October 2007 and September 2012, and an additional 23 cases that had been reported in Japan between 1994 and 2014.

[Results] The median age of our six patients was 78.5 years and ﬁ ve were women. In all cases, the focal lesion was seen in 2_3 adjacent vertebrae; four patients had miliary tuberculosis and ﬁ ve had lower back pain. All patients received oral treatment for 10_12 months. Among the 23 patients previously reported, 57％ were women, and a focal lesion was found in 2_3 adjacent vertebrae in 86％. In addition, 57％ had miliary tuberculosis and 65％ had lower back pain. A personal and family history of tuberculosis was found in 20％ and 26％. [Discussion] Radiographic assessment and microbiological

testing of areas other than the chest and spine are useful in the diagnosis of tuberculous spondylitis. Furthermore, lower back pain, lower extremity symptoms, and personal and family history of tuberculosis are important factors.

[Conclusion] When tuberculous spondylitis is suspected, diagnosis may be possible by investigating focal lesions in areas other than the spine.

Key words : Tuberculous spondylitis, Miliary tuberculosis, Extrapulmonary tuberculosis, Diagnosis, Clinical feature

1_{Division of Respiratory Medicine, Kasukabe Medical Center;} 2_{Division of Respiratory Medicine,} 3_{Division of Clinical}

Laboratory, National Hospital Organization Higashisaitama National Hospital

Correspondence to: Takashi Masuda, Division of Respiratory Medicine, Kasukabe Medical Center, 6_7_1, Chuo, Kasukabe-shi, Saitama 344_8588 Japan.

(E-mail: xhrkr710@ybb.ne.jp) −−−−−−−−Original Article−−−−−−−−

CLINICAL INVESTIGATION OF 6 CASES OF TUBERCULOUS SPONDYLITIS

1_{Takashi MASUDA,}2_{Masahide HORIBA,}2_{Tomoki HIROSE,}2_{Shigefumi NAKANO,} 2_{Ayako MOROI,}2_{Erina SEKI,}2_{Masashi GOTO,}3_{Takayuki HAGA,}

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EQA of DST / S. Mitarai et al. 725

Abstract [Objective] The infectious disease control law has been amended in May 2015, and the category deﬁ nition of Mycobacterium tuberculosis as infectious pathogen has been changed, following the deﬁ nition of extensively drug-resistant M. tuberculosis (XDR-TB) by World Health Organization. To assess the diagnostic capacity of XDR-TB, we conducted an external quality assessment (EQA) for the anti-tuberculosis drug susceptibility testing (DST).

[Method] A total of 10 M.tuberculosis strains with known drug susceptibility were sent to each participating laboratory. The drugs assessed were isoniazid (INH), rifampicin (RFP), streptomycin (SM), ethambutol (EB), levofl oxacin (LVFX), and kanamycin (KM). DST was performed using each routine method(s), and the results were compared with the judicial diagnoses. The sensitivity, specifi city, overall agreement (effi -ciency) and kappa coeffi cient were calculated for each drug tested. In addition, the diagnostic accuracy of multidrug-resis-tant M.tuberculosis (MDR-TB) and XDR-TB was assessed. [Results] A total of 88 institutes including 67 hospitals, 16 commercial laboratories, and 5 public health laboratories par-ticipated in the EQA. With 2 laboratories submitting 2 sets of results, a total of 90 independent data sets were analyzed. As for INH, RFP and LVFX, the effi ciency was over 95％, but we found two strains each for SM, EB and KM with the effi ciency less than 95％. Especially, strain 1 and strain 2 showed effi ciency of 72.2％ and 71.1％ to SM, respectively.

This error was mainly found in a certain test kit. If we consider the passing score as showing ≧ 95％ sensitivity and speciﬁ city both to INH and RFP, the diagnostic accuracy of MDR-TB was 92.2％ (83/90) in this study. With the same criteria to INH, RFP, LVFX and KM, that of XDR-TB was 79.7％ (63/79). [Discussion] The diagnostic capacity of XDR-TB was not sufﬁ cient in the current study. Good case management and pathogen control requires higher accuracy. The government may need to conduct a constant EQA and relevant remedial actions.

Key words: Mycobacterium tuberculosis, Drug susceptibility testing, External quality assessment, Extensively drug-resistant Mycobacterium tuberculosis

1_{Department of Mycobacterium Reference and Research,}

Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 2_{Department of Clinical Laboratory, Kyoto}

University Hospital

Correspondence to: Satoshi Mitarai, Department of Myco-bacterium Reference and Research, Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 3_1_24, Matsuyama, Kiyose-shi, Tokyo 204_8533 Japan.

(E-mail: mitarai@jata.or.jp) −−−−−−−−Original Article−−−−−−−−

EXTERNAL QUALITY ASSESSMENT OF ANTI-TUBERCULOSIS

DRUG SUSCEPTIBILITY TESTING FOR DIAGNOSING

EXTENSIVELY DRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS

1_{Satoshi MITARAI,}1_{Hiroyuki YAMADA,}1_{Akio AONO,}1_{Kinuyo CHIKAMATSU,} 2_{Takeshi HIGUCHI,}1_{Yuriko IGARASHI, and}1_{Akiko TAKAKI}