(Vol.76 No.12 December 2001) <1> Kekkaku Vol.76,No.12:717-721, 2001 CLINICAL ANALYSIS OF MULTIDRUG-RESISTANT TUBERCULOSIS *Takenori YAGI, Fumio YAMAGISHI, Yuka SASAKI, Tomoko HAMAOKA, Fuminobu KURODA, and Hiromi HIGURASHI *Division of Thoracic Disease, National Chiba-Higashi Hospital Forty-three patients with multidrug-resistant tuberculosis at National Chiba-Higashi Hospital were studied retrospectively. TB cases excreting tubercle bacilli which are resistant to both 0.1 ƒÊg/ml of isoniazid and 50 ƒÊg/ml of rifampicin were defined as multidrug-resistant cases. From 1993 to 1997, we experienced 1627 patients with pulmo- nary tuberculosis, and among them 43 patients (23-79 years old, 35 males and 8 females) were proved to be multidrug-resistant. Six cases were initially treated cases and other 37 cases had been treated previously. On admission, 40 out of 43 cases (93.0%) were smear positive by sputum examination of mycobacteria and 38 out of 43 cases (88.4%) had cavitary lesions on chest X-ray. Six patients were complicated with diabetes mellitus, two with cancer, one with alcohol dependence, one with chronic hepatitis, and others did not have prominent complications. Three operated patients were cured, the fact shows that the surgical treatment is still a useful measure for cases with the indication. Sixteen patients were cured, eight were still under treatment, and thirteen were died of tubercu- losis. One of reasons of poor prognosis of multidrug-resistant tuberculosis is that multidrug-resistant tubercle bacilli are usually resistant to other drugs, too. In case of multidrug-resistant tuberculosis, patients were obliged to be treated in a hospital long- term to prevent the spread of tubercle bacilli. Therefore, it is very important to find out new tuberculosis cases as an early as possible, treat them with proper regimen and prevent dropout by directly observed therapy, thus preventing the emergence of multidrug- resistant tuberculosis. Development of new antituberculous agents is strongly expected. Key words:Pulmonary tuberculosis, Drug resistance, Multidrug-resistant tuberculosis, Incompliance *673, Nitona-cho, Chuo-ku, Chiba-shi, Chiba 260-8712 Japan. (Received 20 Jun. 2001/Accepted 29 Aug. 2001) <2> Kekkaku Vol.76,No.12:723-728, 2001 TREATMENT OUTCOMES OF MULTIDRUG-RESISTANT TUBERCULOSIS -Comparison between Success and Failure Cases- *Eriko SHIGETOH, Isao MURAKAMI, Yasuyuki YOKOSAKI, and Noriaki KURIMOTO *Department of Respiratory Diseases, National Hiroshima Hospital The thirty-two times of treatment in 27 patients with multidrug-resistant tuberculosis (MDR-TB) were analyzed retrospectively. In twenty-eight times of treatments cases had previous histories of antituberculosis chemotherapy. Drug sensitivity tests were performed by Microtiter method for isoniazid (INH), rifampicin (RFP), ethambutol, streptomycin, kanamycin, enviomycin, ethionamide, para-aminosalicylic acid and cycloserine. A drug is defined as 'Active drug' when the drug was proved to be sensitive by the drug sensitivity tests or never used in the past or used for not more than 2 months in case of pyrazinamide (PZA) and less than one month for fluoroquinolones. Outcomes of treat- ments were grouped as follows; A:bacteriologically negative for more than 24 months, B:bacteriologically negative for more than 6 months but less than 24 months, C: bacteriologically relapsed after negative conversion, D:continuously bacilli positive for M. tuberculosis. Mean age of patients in each group were;61.0 yrs for group A (n=10), 61.0 yrs for group B (n=7), 52.5 yrs for group C (n=4), 57.9 yrs for group D (n=11). All patients had cavitary disease and positive sputum smears for acid-fast bacilli. Mean numbers of 'active drugs' used per treatment in each group, were 3.6, 3.3, 2.5 and 1.8 respectively, while the mean number of resistant drug including INH and RFP were 2.8, 3.3, 2.5 and 3.7. The number of drugs, which was unable to use due to toxicity, were 0.20, 0.14, 0.50, and 0.73 per treatment respectively. All of 9 patients treated with four 'active drugs' were in group A or B and succeeded to achieve negative conversion. The duration of chemotherapy in group A was 13 to 44 months. Treatment had failed in 4 out of 11 patients treated with 3 'active drugs' and 11 out of 12 patients treated with less than 2 'active drugs'. Fluoroquinolones (ofloxacin, levofloxacin or sparfloxacin) were used in 7 out of 10 patients in group A and in 6 out of 9 patients treated with four-drug regimens while they were used only in 3 out of 11 patients in group D. Regimens with at least 4 sensitive drugs are mandatory for the successful treatment of MDR-TB and fluoroquinolones are needed in the majority of cases to ensure the four-drug regimen, because of frequent drug resistance or toxicity to other antituberculosis drugs. Key words:Multidrug-resistant tuberculosis, Outcome of treatment, Guidelines for treatment, Fluoroquinolones, Drug sensitivitiy test *513, Jike, Saijo-cho, Higashihiroshima-shi, Hiroshima 739-0041 Japan. (Received 13 Jul. 2001/Accepted 7 Sep. 2001) <3> Kekkaku Vol.76,No.12:729-739, 2001 COMPARISON OF THE NEWLY DEVELOPED MYCOACID SYSTEM WITH MYCOBACTERIA GROWTH INDICATOR TUBE (MGIT) AND NEWLY DEVELOPED 2% OGAWA MEDIUM(S) FOR RECOVERY OF MYCOBACTERIA IN CLINICAL SPECIMENS 1*Hiromi ANO, 1Hiroko YOSHIDA, 1Chieko ISHIDA, 1Nobuko TANIGAWA, 1Masanori KIKUI, 2Tetsuya TAKASHIMA, and 3Izuo TSUYUGUCHI 1*Department of Clinical Pathology, 2First Department of Medicine, Osaka Prefectural Habikino Hospital, 3President of Osaka Prefectural Habikino Hospital The detection rate of mycobacteria from patients' specimens and the time required to get positive culture were compared among newly developed MYCOACID SYSTEM, MGIT, Ogawa K medium and 2% Ogawa medium (S). A total of 249 sputum samples taken from patients were used as the study subjects and 124 kinds of mycobacteria were isolated. For 135 cases clinically diagnosed as pulmonary tuberculosis, the detection rate was 44.4% for MYCOACID, 47.4% for MGIT and 38.5% for Ogawa K medium, showing that there are no significant differences in the detection rate between MYCOACID and MGIT, and MYCOACID and Ogawa K medium but the differences was significant be- tween MGIT and Ogawa K medium (p=0.02). The mean days needed for detection of My- cobacterium tuberculosis complex was 12.3 days for MYCOACID, 13.4 days for MIGT, and 26.8 days for Ogawa K medium, indicating significant differences in the time to get positive culture between Ogawa K medium and either of both liquid media (p<0.001). Furthermore, 2% Ogawa medium (S) was used only for the detection of mycobacteria among previously untreated tuberculosis and there were no significant differences in the detection rate between 2% Ogawa medium (S) and either of both liquid media. The time to get positive culture for 2% Ogawa medium(S) was 18.2 days, which was longer than that for either of liquid media, MYCOACID and MIGT, but it was significantly shorter (7.9 days) than that for Ogawa K medium (p=0.003). These results demonstrate that the liquid culture systems both MYCOACID and MGIT were very useful for the detection of mycobacteria compared with Ogawa K medium. Key words:Rapid detection of mycobacteria, MYCOACID, MGIT, 2% Ogawa medium (S), Ogawa K medium *3-7-1, Habikino, Habikino-shi, Osaka 583-8588 Japan. (Received 13 Jun. 2001/Accepted 10 Sep. 2001) <4> Kekkaku Vol.76,No.12:741-747, 2001 The 76th Annual Meeting President Lecture A PUTATIVE IMMUNOTHERAPY WITH BIOLOGICAL RESPONSE MODIFIERS (BRM) AGAINST INTRACTABLE PULMONARY TUBERCULOSIS *Atsushi SAITO *First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus The problem of tuberculosis is emerging again with increase in the population of aged people and immunocompromised patients in Japan. It has been well documented that cell- mediated immunity play a central role in host resistance to infection with Mycobacterium tuberculosis. Many recent studies have provided evidences suggesting that the Th1-Th2 cytokine balance may determine the outcome of some diseases:predominant production of Th1 cytokines may prevent the occurrence of infectious diseases caused by intracellularly growing pathogens and Th2 cytokines may be involved in the exacerbation of allergic diseases. On the other hand, IL-12 plays an essential role in the differentiation of Th1 cells from native T cells, and IL-18 potentiates this effect although it does not show such effect by itself. In previous investigations using gene-disrupted mice, the essential roles for IFN-ƒÁ, IL-12 and IL-18 have been demonstrated. There are several host factors which determines the outcome of mycobacterial infection. Among them, steroid treatment and AIDS are important factors. In this lecture, I addressed the effect of these pathological conditions on Th1-Th2 cytokine balance and outcome of mycobacterial infection using murine models. In both conditions, the exacer- bated infection was well correlated with the reduced production of IFN-ƒÁ. Furthermore, I also talked about the relationship between other host factors and balance in the production of Th1 and Th2 cytokines. Using a murine model of fatal infection with M.tuberculosis, we demonstrated the therapeutic effect of Th1-type cytokines against this infection and suggested that immunotherapy with these cytokines may be clinically effective in the intractable infection. We tried a combined therapy with anti-tuberculous agents and IFN-ƒÁ in intractable pulmonary tuberculosis caused by multidrug-resistant pathogen in a patient with insulin- dependent diabetes mellitus. Although no report showing the clinical use of IL-12 in infectious diseases has been seen, clinical trials already commenced for the therapy of malignant neoplastic diseases. It may not be in for future that this cytokine is clinically used for the treatment of infectious diseases. IL-18 has not yet been under the clinical trials. Key words:Anti-tuberculous immunity, Th1 cytokines, Intractable tuberculosis, BRM therapy *207, Uehara, Nishihara-cho, Nakagami-gun, Okinawa 903-0215 Japan. (Received 3 Oct. 2001) <5> Kekkaku Vol.76,No.12:749-753, 2001 The 76th Annual Meeting Educational Lecture DOTS IN JAPAN-TOKYO AREA *Emiko TOYOTA *Department of Respiratory Disease, International Medical Center of Japan The resurgence of tuberculosis has required a successful strategy to control TB in Japan. The World Health Organization has recommended the so-called DOTS (Directly Observed Therapy, Short-Course) strategy since 1995 and DOTS has been used with great success in not only in many developing countries, but also in many developed countries. In Tokyo, especially in urban areas with a high prevalence of TB, DOT has been started. Using DOT, Sanya in Taito-ku (ward) and Arakawa-ku (ward), have shown high treat- ment completion-more than 90% since 1997. In 2000, other health care offices in Shinjuku-ku (ward), Yokohama city, Kawasaki city and Nagoya city started DOT for groups of homeless with TB. Presently, DOT is applied only to homeless people. However, the number of people who need DOT is much higher, due to poor adherence. It is also important to reconsider cost-efficiency for TB control in Japan. Key words:Tuberculosis, DOTS, DOT, Treat-ment completion, TB control *1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655 Japan. (Received 16 Jul. 2001) <6> Kekkaku Vol.76,No.12:755-757, 2001 The 76th Annual Meeting Educational Lecture DOTS IN OSAKA CITY *Yohichi TATSUMI *Infectious Diseases Prevention Division, Osaka City Public Health and Welfare Bureau The tuberculosis (TB) incidence rate and the smear positive TB incident rate in Osaka City were 107.7 and 34.7 per 100,000 respectively in 1999, which were approximately 3 times higher than the national average. The TB mortality rate in Osaka City was 6.9 per 100,000 in 1999, which was highest in Japan. The TB incidence in the "AIRIN" area, where about 20% TB patients are homeless, shows highest rate of above 1,000/100,000. The treatment defaulter rate in Osaka City is about 10% against the average rate of 4 % in Japan. A new strategic plan to intensify TB control is now being prepared by Osaka City government. A goal has been set up to make the TB incidence half in ten years. The plans consists of 4 points of "DOTS", "early detection of patient", "education and campaign", and "cohort analysis of treatment outcome". "DOTS" is being expanded in Osaka City. DOT is applied not only for the special group of homeless patients but also to the patients in the hospitals and in the community. Further systematic development of "DOTS" is necessary to achieve the goal. Key words:DOTS, DOT, Osaka City, TB control measures *1-3-20, Nakanoshima, Kita-ku, Osaka-shi, Osaka 530-0005 Japan. (Received 9 Oct. 2001) <7> Kekkaku Vol.76,No.12:759-764, 2001 The 76th Annual Meeting Symposium ‡T. OUTBREAK OF TUBERCULOSIS:THE CURRENT SITUATIONS AND PERSPECTIVE IN JAPAN Chairpersons:1*Tadayuki AHIKO 2Makoto TOYOTA 1*Yamagata Prefectural Murayama Public Health Center, 2Kochi City Public Health Center The prevalence rate of tuberculosis (TB) infection has remarkably decreased not only in young people but also in middle-aged and elderly people in Japan. On the other hand, the outbreak of TB has been increasing and has become a serious social problem. Since 1997, more than 40 outbreaks have been reported annually. TB outbreaks have occurred among persons in schools, hospitals, nursing homes, prisons, amusement facilities, day laborers' accommodations with sauna, and various workplaces. To clarify current problems concerning the outbreak and to propose effective measures against TB outbreaks, we discussed about 1) preventable factors contributed to recent outbreaks, 2) urgent problems such as the outbreak of multidrug resistant tuberculosis (MDR-TB), 3) the collaboration of relevant organizations for outbreak investigation, and 4) the practical application of new technologies such as DNA fingerprinting methods (e.g., restriction fragment length polymorphism analysis). Intractable problems, by which many participants of this symposium were troubled, were as follows:1) the problem how to diagnose the latent TB infection by the tuberculin skin test on persons who have received BCG vaccine, and 2) the problem how to provide the preventive treatment for contacts of patients with MDR-TB. To solve these problems, the development of new methods to improve the diagnosis and the treatment is essential. In addition, new approaches combining methods from conventional epidemiology, molecular biology and computerized network analysis should be used in investigation and control of TB outbreaks. 1. Tuberculosis outbreak in a junior high school:Mie KUSUNOSE, Makoto TOYOTA (Kochi City Public Health Center) We experienced a large outbreak of TB in a junior high school. The index (source) patient with smear-positive pulmonary TB was a third-grade student of the school. Contact investigation was carried out in more than 700 persons. Tuberculin skin test revealed an excess of strongly positive reactors in the third-grade students. During 2 years after the detection of the source case, a total of 31 TB patients were newly diagnosed. Delayed diagnosis of the source case and poor ventilation of the classrooms were attributable to the outbreak. In addition the source patient seems to be highly infectious, because trans- mission following only sporadic contact was documented. Among the strongly positive reactors to tuberculin skin test of third-grade students and school staffs, out of 105 persons who received preventive therapy, 2 cases (1.9%) were newly diagnosed as TB, while out of 24 cases without preventive therapy, 6 cases (25%) developed clinical TB. A 15-year-old man, who was compliant with preventive therapy, was found to have pulmonary TB. Drug susceptibility tests revealed that the organism isolated from this patient was resistant to isoniazid, although the organism obtained from the source patient was sensitive to isoniazid. 2. Tuberculosis outbreak in the workplace:Yoshiko SUEYASU, Sachiko TANOUE, Hisashi WATANABE, Toru RIKIMARU and Kotaro OIZUMI(The 1st Department of Internal Medicine, Kurume University School of Medicine) The outbreak of TB has increased in various workplaces. To clarify factors contributing to TB outbreaks in the office/workplace, Japanese articles published between January 1987 and November 2000 were reviewed. The main causal factor of the outbreak was delayed diagnosis of the source patient. Other preventable factors contributing to the outbreak were as follows: 1) workplaces with inadequate health care system to employees; 2) working environment with enclosed spaces or with poor ventilation system; 3) inadequate contacts investigation; and 4) inadequate identification of contacts with latent TB infection and poor adherence to preventive therapy. To solve these problems, public health centers should ensure the effective implementation of TB prevention and control programs and should strengthen collaboration with occupational health partners, including local enterprises, industrial health promotion centers, occupational physicians, and medical institutions. 3. A small outbreak of multidrug-resistant Mycobacterium tuberculosis infection:Yuka SASAKI(Division of Thoracic Disease, National Chiba-Higashi Hospital) A small outbreak of MDR-TB occurred among playmates at a mah-jongg parlor. The source patient (48-year-old-man) with smear-positive pulmonary TB acquired resistance to several drugs including isoniazid, refampicin, and streptomycin during a period of unsupervised therapy. Four persons, who were companions playing mah-jongg with the source patient, were newly diagnosed as MDR-TB. These five patients had identical Mycobacterium tuberculosis isolates on the RFLP analysis. Now in Japan, MDR-TB is not a serious problem and only three small outbreaks have been reported. But the prevalence of MDR-TB infection has increased actually. When the new MDR-TB patient is detected, the physician should connect to public health centers promptly. Public health centers should conduct appropriate identification and examination of contacts of MDR-TB patients. MDR-TB originally is the product of inadequate treatment. Adequate prescription of chemotherapy, proper case management, and correct process of drug delivery to the patients (e.g., Directly Observed Treatment) are the best measures against MDR-TB. 4. Future problems of tuberculosis outbreaks in terms of the molecular epidemiological analysis: Mitsuyoshi TAKAHASHI (The Research Institute of Tuberculosis, JATA) IS6110 based RFLP analysis has been widely used and has provided important insight into the pathogenesis and the epidemiology of TB. This technique is effective in detecting the source patient of outbreaks. This analysis enables us to notice an outbreak of TB at early stage. This is also useful to detect pseudo-outbreaks due to the cross-contamination of M.tuberculosis in clinical laboratories. The incidence of TB has decreased remarkably in Japan, and most of elderly patients with secondary or recurrent TB appear to be caused by endogenous reactivation of old infection. However, recent studies on TB outbreaks using the RFLP analysis suggest that exogenous reinfection is much more significant than previously believed. Reports on drug resistant TB cases among foreign-born persons have increased espe- cially in urban areas. Combining the RFLP analysis with the PCR-based typing method called "spoligotyping" will be useful to trace the roots of drug resistant strains. The computerized information management system, which must protect personal infor- mation appropriately, is essential for using these techniques effectively. 5. Collaboration in tuberculosis outbreaks:Masanobu FUJIOKA, Masahiro KATO(The Health and Public Welfare Department of Aichi Prefecture) Effective control of TB outbreaks requires the collaboration of many partners. Pro- gram evaluation of the examination of contacts (non-household) in settings at risk for the outbreak was conducted by review of TB management records in public health centers (PHCs) in Aichi prefecture from 1997 to 1999. The examination was carried out in 390 groups that belonged to various workplaces, schools, hospitals and so on. 105 (26.9%) out of 390 groups were investigated in collaboration with two or more PHCs. The necessity of collaboration with other prefectural PHCs had increased. Methods of the examination and collaboration patterns varied according the kind of facilities to which contacts belonged. Aichi prefecture published the manual for prevention and control of TB in health care facilities in 1998, since when the collaboration of hospitals and PHCs was promoted. PHCs will hold the key to successful collaboration in outbreak investigation of TB. Key words:Outbreak of tuberculosis, Collaboration, Public health center, RFLP analysis, Multi-drug resistant tuberculosis *1-6-6, Tokamachi, Yamagata-shi, Yamagata 990-0031 Japan. (Received 21 Sept. 2001)