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 μg/ml of isoniazid and 50 μg/ml of rifampicin were defined as multidrug-resistant cases. From 1993 to 1997, we experienced 1627 patients with pulmonary 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 37cases 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 tuberculosis. 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 longterm 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 multidrugresistant tuberculosis. Development of new antituberculous agents is strongly expected.

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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 treatments were grouped as follows; A: bacteriologically negative for more than 24 months, B: bacteriologically negative for more than 6 months but less than 24 mont hs, 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 1.8respectively, 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 4out 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 regime n, because of frequent drug resistance or toxicity to other antituberculosis drugs.

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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 between MGIT and Ogawa K medium (p=0.02). The mean days needed for detection of Mycobacterium tuberculosis complex was 12.3 days for MYCOACID, 13.4 days for MGIT, 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 MGIT, 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.

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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-Th2cytokine balance may determine the outcome of some diseases: predominant production of Th 1 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 Th 1cells from naive 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-γ, IL-12 and IL-18 have been demonstrated. There are several host factors which dete rmines 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 exacerbated infection was well correlated with the reduced production of IFN-γ 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-γin 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 far future that this cytokine is clinically used for the treatment of infectious diseases. IL-18 has not yet been under the clinical trials.

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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 th e 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 inv estigation, 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 transmission following only sporadic contact was documented. Among the strongly positive reactors to tuberculin skin test of third-grade students and school staffs, out of 105persons 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 I n ternal Medicine, Kurume University School of Medicine)
The outbreak of TB has increased in variou s workplaces. To clarify factors contributing to TB outbreaks in the office/workplace, Japanese articles published between January 1987 and November 2000 were reviewed.

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