(Vol.74. No.1 January 1999) <1> Kekkaku Vol.74, No.1: 1-4, 1999 TUBERCULOUS SEQUELAE IN JAPAN Masashi MORI* Tuberculosis had been the leading cause of death in Japan until 1950, and in these days there were about 3 million patients with active tuberculosis every year. From about 1950 to 1960 surgery was the treatment of choice if there were cavities and the lesions were regional. The number of patients who had thoracoplasties and/or pulmonary resections at national sanatoriums during the period of 1954 to 1961 was about 200,000. Since national sanatoriums had about 25% of the total beds for tuberculosis in Japan at that time, the total number of surgically treated patients would be around four times this number, that is 0.8 to 1.0 million. Many of those who survived suffered later from complications, which included chronic respiratory failures, chronic hepatitis (hepatitis C), liber cirrhosis and/or hepatic cell carcinomas. There are at least 50,000 patients who are under home oxygen therapy (HOT) in Japan, of whom about 30% are those with pulmonary tuberculosis sequelae (TBS). The survival rate after the start of HOT in these patients was found better in those who had surgical treatments than in those who had medical treatments only. Since hypercapnea was more common in the former, better survival rates in the hypercapnic than in the normocapnic patients with TBS as a whole could be due to the fact that more of the surgically treated patients were included in the hypercapnic group. For this reason, it is premature to con- clude that hypercapnea is an independent favorable prognostic factor in TBS patients with chronic respiratory failure. Because more than one-forth of thoracoplasties and/or pulmonary resections were done in national sanatoriums, it is the responsibility of those who are now working in national hospitals to treat and support these patients with TBS who developed complications such as respiratory failures, chronic hepatitis, liver cirrhosis, and/or hepatic cell carcinomas. Key words : Tuberculosis sequelae (TBS), Home oxygen therapy (HOT), Chronic respiratory failure, Viral hepatitis, Hepatic cell carcinoma *From the National Tokyo Hospital, 3-1-1 Takeoka, Kiyose-shi, Tokyo 204-8585 Japan. (Received 6 Oct. 1998) <2> Kekkaku Vol.74, No.1: 5-18, 1999 INVESTIGATION OF PULMONARY HEMODYNAMICS AND CHEST X-RAY FINDINGS IN PATIENTS WITH PULMONARY TUBERCULOSIS SEQUELAE AND OBSTRUCTIVE VENTILATORY IMPAIRMENT Jun-ichi YASUDA*, Osamu OKADA, Takayuki KURIYAMA, Keiichi NAGAO, Fumio YAMAGISHI, Ikko HASHIZUME, and Akira SUZUKI We investigated pulmonary hemodynamics and chest X-ray findings to explore signifi- cance of obstructive ventilatory impairment in patients with pulmonary tuberculosis sequelae. One hundred and two patients underwent examinations of blood gases, spirometry, and right cardiac catheterization. The patients were divided into two groups, according to forced expiratory volume in one second as the percentage of forced vital capacity (FVC), which was expressed as FEV1%. Group A(n=38) had FEV1% of 55% or lower and Group B(n=64), FEV1% above 55%. First, the values of blood gases and hemodynamics were compared between the two groups, regarding the percent predicted value of FVC as a covariate. Secondly, between 26 of Group A and 42 of Group B, the change of pulmonary arteriolar resistance (PAR) before and after 100% oxygen breathing for 10 minutes was compared. These comparisons were made by exploratory data analysis. Lastly, we described every case with five items of chest X-ray findings and the extent of each finding we had defined. The items were emphysematous change;fibrosis, bronchiectasis and/or cavity;pulmonary resection and/or atelectasis;pleural thickening; and thoracoplasty. We explored X-ray findings influenced on airway obstruction by ridit (abbreviation for "relative to an identified distribution") analysis, taking smoking status into consideration. The results were as follows. (1)The patients of Group A tended to show severer hypoxemia and tissue hypoxia than the patients of Group B. (2)The patients of Group A tended to show worse values of pulmonary hemodynamics than the patients of Group B. Under an even level of the arterial oxygen tension that was 60 Torr or lower, pulmonary artery mean pressure was higher in Group A than in Group B. (3)PAR after oxygen breathing was less likely to decrease in Group A than in Group B. (4)As any mean ridit was standardized and adjusted to 0.5 in Group B, every mean ridit of "emphysematous change" in Group A was the largest-0.63 in non-smokers, 0.74 in ex-smokers and 0.70 in current smokers. Therefore, "emphysematous change" was more influenced on airway obstruction than any other finding because of the largest mean ridit. We conclude as follows. Pulmonary hypertension is more serious in patients suffering from severe airway obstruction with pulmonary tuberculosis sequelae, and it may be attributable to reduction in capacity of anatomical pulmonary vascular bed rather than hypoxic pulmonary vaso- constriction. Pathological changes such as "emphysematous change" on the radiograph might be con- sidered as an important cause of obstructibve ventilatory impairment. Key words : Pulmonary tuberculosis sequelae, Obstructive ventilatory impairment, Pulmonary hypertension, Hypoxic pulmonary vasoconstriction, Chest X-ray findings *From the Department of Chest Medicine, Institute of Pulmonary Cancer Research, School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 Japan. (Received 4 Jun.1998/Accepted 17 Aug.1998) <3> Kekkaku Vol.74, No.1: 19-25, 1999 EVALUATION OF MYCOBACTERIUM KANSASII ISOLATES FROM A CLINICAL LABORATORY IN A CITY HOSPITAL Setsuko TAZAWA, Kenji MARUMO, and Yoshiko NAKAMURA Fifteen isolates of Mycobacterium kansasii in Showa Universty Fujigaoka Hospital be- tween 1982 and 1995 were investigated. Comparing by gender, 13 were isolated from male patients and only two were isolated from female patients. The average of cases was 48 years old and 14 out of 15 cases (93%) were isolated from respiratory tract specimens. The rate of the smear and culture-positives was 64%, which was significantly higher than that (26%) of M. avium complex (p<0.01 by X(2) test). All 4 isolates were suscep- tible to rifampicin (10 g/ml) by drug susceptiblility testing using Ogawa egg medium, and only 1 was resistant to ethambutol (2.5 g/ml). Seven out of 10 patients whose medical record was available were diagnosed as pulmonary infection with M. kansasii. Two out of 4 patients with primary infection type had underlying diseases such as diabe- tes mellitus and leukemia, while the remaining two patients did not have any underlying disease. Two out of 3 patients with secondary infection type had a medical history of tu- berculosis and the remaining 1 patient had infected pulmonary cyst. Such as Pseudomonas aeruginosa, Enterobacter aerogenes and Flavobacterium spp., and Branhamella ca- tarrhalis, associated with M. kansasii, bacteria more than 10(7) cfu/ml were isolated from the sputa of 3 patients with leukemia, infected pulmonary cyst and post-tuberculosis, re- spectively. M.kansasii, Stenotrophomonas maltophilia (10(7) cfu/ml) and Candida albicans were detected from the sputum of 1 patient with nephrosis, for which steroid (predonin) and antibiotics (piperacillin and latamoxef) were administrated, however, this patient was not diagnosed as a case of M.kansasii infection. These findings suggest the fact that M.kansasii inhabits among compromised hosts of a city hospital. Key words:Mycobacterium kansasii, Underlying diseases, Compromised host, Respiratory tract infection *From the Division of Central Clinical Laboratory in Showa Universtiy Fujugaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama-shi, Kanagawa-ken 227 Japan. (Received 7 May 1998/Accepted 1 Sep. 1998) <4> Kekkaku Vol.74, No.1: 27-32, 1999 TUBERCULOUS MENINGITIS DEVELOPED DURING TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Kenji TSUSHIMA*, Keishi KUBO A 51-year-old woman was admitted to our hospital complaining of fever and general fatigue. Physical examination revealed butterfly-like erythema in face, facial edema and diffuse purpura all over her body. Laboratory data showed renal dysfunction, nephrotic syndrome and active phase of SLE. She was administered first methylprednisolone (1g/ day/3days by intravenous drip) then prednisolone (60mg/day/month, orally) and had im- mune adsorption therapy for eight times. However, 14 days after the last session of im- mune adsorption, she developed fever of 39 and mild headache, and then 3 days later, she gradually became unconscious. Brain CT showed hydrocephalus. We diagnosed her as having tuberculous meningitis based on the detection of acid-fast bacillus in cerebrospinal fluid, and began treatment with antituberculous agents. We suspected that tuberculus meningitis had caused hydrocephalus. We tried percutaneous drainage of the left ventricle for hydrocephalus. Brain MRI showed a tuberculoma depicted as a mass of low intensity in the right cerebellum on the T1-weighted image, and of high intensity on the T2- weighted image, and the meninx in the basal cistern was enhanced. After treatment with antituberculous agents, we performed serial brain MRI and examined cerebrospinal adeno- sine deaminase activity (ADA). Despite treatment with antituberculous agents, new intracerebral tuberculomas had developed in some areas, whereas they had disappeared in other areas. After treatment for 4 months, the level of cerebrospinal ADA became nor- mal, and the patient recovered consciousness despite the presence of multiple tuberculomas. Both the cell conts and the level of ADA in cerebrospinal fluid are the good indicators of the activity of tuberculous meningitis and reflected its clinical course. Furthermore, the level of ADA in cerebrospinal fluid changed with brain MRI image. Serial brain MRI and examination of ADA in cerebrospinal fluid were useful to know the activity of tuberculous meningitis and to evaluate the response to treatment. Key words:Tuberculous meninigitis, Intra- cranial tuberculoumas, Adenosine deaminase activity, Brain MRI *From the Department of Internal Medicine, Nagano Red Cross Hospital, 1512-1 Oaza-Wakasato, Nagano 380-8582 Japan (Received 13 May 1998/Accepted 26 Aug. 1998) <5> Kekkaku Vol.74, No.1: 33-41, 1999 The 73rd Annual Meeting President Lecture DRUG-INDUCED PNEUMONITIS Ariyoshi KONDO* Drug can cause various types of lung damages, with drug-induced pneumonitis (includ- ing acute interstitial pneumonia, usual interstitial pneumonia, desquamative interstitial penumonia, nonspecific interstitial pneumonia, bronchiolitis obliterans with organizing pneumonia, eosinophilic pneumonia and hypersensitivity pneumonitis) being the most im- portant among them. The incidence and the causative agents of drug induced pneumonitis have varied over time. Before 1980, anticancer agents and gold salts were the main drugs, and the number of causative drugs (61) and case reports was small. Recently, pneumonitis has increasingly been caused by Chinese herbal medicines, antibiotics, chemo- therapy agents, anti-inflammatory drugs, analgesics, cytokines, and gold salts, and the number of case reports and drugs involved (177) has increased. Drug-induced pneumonitis has characteristics that depend on the causative agent. Re- view of our patients and reports in Japan revealed the following. Pneumonitis caused by anti-inflammatory drugs, analgesics, and antibiotics generally develops at 1-2 weeks after starting administration, and bronchoalveolar lavage and histologic examination of lung biopsies reveals the features of eosinophilic pneumonia. Such pneumonitis is associ- ated with a high frequency of a positive drug lymphocyte stimulation test (DLST), and has a good outcome. Conversely, with pneumonitis caused by anticancer and immunosu- ppressive agents, the onset is often delayed and the disease has features of diffuse inter- stitial pneumonia and pulmonary fibrosis. The frequency of a positive DLST is low. and the outcome is generally poor. Pneumonitis induced by Chinese herbal medicines, gold salts, and antituberculosis agents has intermediate features between the above two types :i.e., it develops after 2-3 months or six months (gold salts), and resembles either eosinophilic pneumonia, BOOP or interstitial pneumonia. For in vitro identification of causative drugs, the DLST and the leukocyte migration inhibition test (LMIT) are generally used. The latter test is superior in sensitivity, sug- gesting that the mechanism of this test ivolves cytokines such as IL-1, IL-1, Il-2, TNF-, and Il-8. Key words:Drug-induced pneumonitis, Drug lymphocyte stimulation test(DLST), Leukocyte migration inhibition test (LMIT), Bronchoalveolar lavage (BAL) *From the Department of Respiratory Medicine, Na- tional Sanatorium Nishi-Niigata-Chuo-Byoin, 1-14-1 Masago, Niigata-shi, Niigata 950-2085 Japan. (Received 24 Nov. 1998) <5> Kekkaku Vol.74, No.1: 43-46, 1999 The 73rd Annual Meeting Symposium K. PROSPECTS FOR DECELOPMENT OF NEW ANTIMICROBIALS FOR CLINICAL CONTROL OF TUBERCULOSIS Chairpersons:Fumiyuki KUZE*, Haruaki TOMIOKA** Symposium Topics and Presenters: 1. View of development of fluoroquinolones:Kenji NAMBA(Daiichi Pharmaceutical Co.) 2. Current status and perspectives on the development of rifamycin derivative antibi- otics:Takayoshi HIDAKA(Kaneka Corporation) 3. In vitro antimicrobial activities of quinolones, rifamycins and macrolides against Mycobacterium tuberculosis and M.avium complex:Attempt ot establish new assay methods which accurately reflect therapeutic effects of test agents in vivo: Katsumasa SATO and Haruaki TOMIOKA(Shimane Medical University) 4. Clinical evaluation of new quinolones as antituberculosis drugs:Shin KAWAHARA, Atsuhiko TADA, and Hitoshi NAGARE(National Minami-Okayama Hospital) 5. The need for new antituberculosis agents in Japan:Katsuhiro SUZUKI, Eisaku TANAKA, and Ryoichi AMITANI(Kyoto University Hosptal) The resurgence of tuberculosis (TB) in industrialized countries and the worldwide in- crease in the prevalence of atypical mycobacterial infections in immunicompromised hosts have promoted the quest for new antimycobacterial drugs. The appearance of multidrug-resistant (MDR) strains of M. tuberculosis, which exhibit in vitro resistance to at least two major antituberculous drugs (usually INH and RFP) and cause intracta- ble TB, has greatly contributed to the increased incidence of TB. For instance, well-docu- mented outbreaks or mini-epidemics of MDR-TB in the U.S. have indicated extremely rapid progression of the desease with high mortality, particulary in HIV-infected pa- tients. At present, the most effective therapy for TB is the use of the most active antituberculous drugs, such as INH, RFP, PZA, EB, and SM, in combination, and a cure rate approaching nearly 100% can be achieved for drug-sensitive TB, using multi-drug regimens such as INH + RFP + SM (or EB) and INH + RFP + PZA + SM (or EB). How- ever, because of the recent emergence of MDR-TB, some of which are significantly resis- tant to all known antimycobacterial drugs, the development of new potent antituberculous drugs without cross-resistance with kown antimycobacterial agents is urgently desired. The principal classed of new antituberculous drugs that have been dis- cussed in this symposium include the fluoroquinolones and rifamycin derivatives. First, fluoroquinolones including OFLX, CPFX, and levofloxacin (LVFX) may be promising agents for the treatment of TB, particularly MDR-TB. The incidence of mycobacterial resistance to fluoroquinolones is relatively low at present, and there are no reports of cross-resistance or antagonism with other classes of antimycobacterial drugs. Fluoroquinolones can be administered orally with good absorption and favorable pharmacokinetics such as extremely efficient penetration into tissues and host macro- pahges. Moreover, the incidence and severity of adverse effects are generally low for the fluoroquinolones. Thus, fluoroquinolones may be used for long-term therapy of tuberculo- sis patients, especially those with HIV infection, in combination with other antimycobacterial drugs. Drs. Namba, Sato, Kawahara, and Suzuki have reviewed the in vitro and in vivo activities of new fluoroquinolones against M. tuberculousis and other mycobacterial pathogens, especially in terms of structure-activity relationship, structure -adverse effect relationship, in vitro antimicrobial activities against M. tuberculosis and M. avium complex (MAC) residing in professional and non-professional phagocytes, MICs for cinical isolates of M. tuberculosis, and clinical outcome of TB therapy using fluoroquinolones. Second, rifamycins are among the most important anti-mycobacterial agents, RFP and rifabutin (RBT) are included in drug regimens for the treatment of TB and other mycobacterial infections in AIDS patients. RBT is about 4 to 6 times more active than RFP against M. tuberculosis by MIC determination, although there is partial cross-resis- tance between RBT and RFP. Moreover, RBT possesses favorable pharmacokinetic fea- tures such as a long half-life and good tissue penetration. Rifapentine (RPT) is also much more active than RFP in vitro, and has pharmacokinetic properties better than those of RFP, such as long half-life. This drug is in phase II trials as a new component of multi-drug regimens for the treatment of TB. A new benzoxazinorifamycin, KRM- 1648, is about 100 times more active than RFP against M.tubercxulosis and exhibits markedly potentiated therapeutic efficacies against M. tuberculosis and MAC infections induced in mice. This drug is in the preclinical or early phase II stages of development. Drs. Hidaka, Sato, and Suzuki have reviewed the status of these new rifamycins, espe- cially KRM-1648, in terms of in vitro and in vivo antimycobacterial activities, adverse interactions with other drugs in relation to activities in inducing hepatic metabolism, in vitro antimicrobial activities against mycobacterial organisms residing in professional and non-professional phagocytes, and their clinical usefulness in treatment of TB pa- tients. This symposium has thoroughly reviewed the status of development of new antituberculous drugs. There are a number of difficulties in performing drug-design in de- velopment of new drug formulations with increased potential for antimycobacterial ef- fects, excellent phamacokinetics, and tolerability. Also, for the fluoroquinolones and rifamycins, further efforts are required to improve their properties as antimycobacterial drugs for clinical use. Moreover, it should be emphasized that the most urgent goal for chemotherapy of TB, especially that associated with HIV infection, is to develop ex- tremely active, low-cost agents which can be used not only in industrialized countries but also in developing countries, since the incidence of HIV infection-associated intractable TB is now rapidly increasing in the latter countries. Key words:Multidrug-resistant tuberculosis, Antituberculous drug, Fluoroquinolone, Rifamycin *From Kyoto University, Sakyo-ku, Kyoto 606-8397 Japan. **From Shimane Medical University, Izumo Shimane 693-8501 Japan. (Received 5 Oct. 1998) <6> Kekkaku Vol.74, No.1: 47-52, 1999 The 73rd Annual Meeting Symposium II. PROSPECTS FOR DEVELOPMENT OF NEW ANTIMICROBIALS FOR CLINICAL CONTROL OF TUBERCULOSIS 1. VIEW OF DEVELPOMENT OF FLUOROQUINOLONES Kenji NAMBA* The global resurgence of tuberculosis and the emergence of multidrug-resistant tubercu- losis have emphasized an urgent need for new, effective antimycobacterial drugs. A new antimycobacterial drugs should have a different mechanism of action to the standard drugs and should not show cross-resistance with them. Favorable pharmacokinetic prop- erties, low incidence of side effects and low cost are the characteristics that would make antimycobacterial drugs suitable for extenisive use. The fluoroquinolones would appear to fullfill most of the criteria for an ideal class of antimycobacterial drugs. The fluoro- quinolones have been proposed for the treatment of Mycobacterium tuberculosis (M.tu- berculosis) infections, with the results of in vitro, animal model and clinical studies sug- gesting that ofloxacin, ciprofloxacin, sparfloxacin and levofloxacin are the most promis- ing of these drugs. However, these fluoroquinolones should not be used as first-line drugs, but rather, they should be reserved for treatment of tuberculosis that is resistant to rifampicin and isoniazid. Recently, a new investigational fluoroquinolone derivative, AM- 1155, DU-6859a and CS-940, have excellent in vitro activity against M.tuberculosis, fur- ther studies are required to assess its clinical activity. We discussed the future of view of development of fluoroquinolones for mycoabcterial deseases on the basis of structure-activity and structure-side-effect relationship studies. The comparative analysis enabled us to elucidate the structural requirements for the anti- mycobacteriual activity and side-effects of fluoroquinolones. In addition, we summarized the newer methods for high-throughput screening of compounds against M.tubercuosis and discussed the problem of develpoment of fluoroquinolones for mycobacterial diseases. Key words:New drugs, Fluoroquinolones, Structure-activity relationship *From the New Product Research Laboratories 1, Daiichi Pharmaceutical Co., Ltd., 16-13, Kitakasai 1- chome Edogawa-ku, Tokyo 134-8630 Japan. (Received 10 Oct. 1998) <7> Kekkaku Vol.74, No.1: 53-61, 1999 The 73rd Annual Meeting Symposium II. PROSPECTS FOR DEVELOPMENT OF NEW ANTIMICROBIALS FOR CLINICAL CONTROL OF TUBERCULOSIS 2. CURRENT STATUS AND PERSPECTIVES ON THE DEVELOPMENT OF RIFAMYCIN DERIVATIVE ANTIBIOTICS Takayoshi HIDAKA* Rifampicin (RFP) was develpoed as one of the anti-tuberculosis drugs in 1996 and has been used for almost 30 years. Establishment of combination therapy using RFP has been contributing to the treatment/eradication of tuberculosis. A number of rifamycin deriva- tives, as post RFPs, have been synthesized/developed over the years. Chemical modifica- tion of rifamycins has largely been concentrated on the moiety of naphthalene ring because modification of the ansa chain moiety reduces the activity. In 1992, rifabutin was approved as a preventive durg for MAC infection in AIDS patients in the United States and in European coutries. It is noteworthy that rifapentine (RPT) was approved as an anti-tuberculosis drug in 1998 by FDA in the United States. A newly synthesized rifamycin derivative (KRM-1648, rifalazil) possesses a potent ac- tivity against both M. Tuberculosis and MAC, and it is now under clinical trial for the treatment of Tuberculosis in the United States. KRM-1648 is metabolized to 30-hydroxy KRM and 25-deacetyl KRM in the body, and its 30-hydroxylation is caused by liver cytochrome P450 3A. It is well known that RFP, RFB and RPT induce liver cytochrome P450 in animals and human, and these accelerate the metabolism of concomitant drugs such as HIV protease inhibitors resulting in lowering their blood levels. While KRM-1648 did not induce liver P450 in animals, but it is not examined yet in human. Clinical study of DOT with intermittent therapy of RPT in combination with INH re- sulted in the preferable therapeutic effect comparable to the RFP therapy. Since KRM- 1648 has a potent activity, a high tissue distribution and a long half-life, it may be also suitable for intermittent therapy. For the future novel anti-tuberculosis durgs and therapy for tuberculosis, it is prerequisite to develop new drugs with a preferable antimicrobial activity, to shorten fur- ther the treatment period, and to be effective against multi-drug resistant bacilli. It is expected that more effective novel rifamycin derivatives can be developed with the above view points. Key words:Rifamycin derivatives, KRM-1648, Rifampicin, Rifabutin, Rifapentine, Tuberculosis *From the Takasago Research Laboratories, Kaneka Corporation, Miyamae-machi, Takasago-cho, Takasago-shi, Hyogo 676-8688 Japan. (Received 5 Oct. 1998) <8> Kekkaku Vol.74, No.1: 63-70, 1999 The 73rd Annual Meeting Symposium II. PROSPECTS FOR DEVELOPMENT OF NEW ANTIMICROBIALS FOR CLINICAL CONTROL OF TUBERCULOSIS 3. IN VITRO ANTIMICROBIAL ACTIVITIES OF QUINOLONES, RIFAMYCINS AND MACROLIDES AGAINST MYCOBACTERIUM TUBERCULOSIS AND M.AVIUM COMPLEX:ATTEMPT TO ESTABLISH NEW ASSAY METHODS WHICH ACCURATERY REFLECT THERAPEUTIC EFFECTS OF TEST AGENTS IN VIVO Katsumasa SATO* and Haruaki TOMIOKA Profiles of expression of the antimicrobial activities of LVFX, KRM-1648 (KRM), and CAM against M.tuberculosis (MTB) and M.avium complex (MAC) residing in MONO- MAC-6 human macrophage like cells (MM6-Ms) and A-549 human type II alveolar pneumocyte cells (A-549 cells) were determined. First, the antimicrobial activities of LVFX, KRM, and CAM against intracellular organisms of MTB Kurono and MAC N-444 strains were examined under conditions in which infected MM6-Ms and A-549 cells were cultured for up to 7 days or longer in medium containing the antimicrobials at their Cmaxs in the blood, achievable after oral administration of clinical dosages of these drugs. The antimicrobial effects of LVFX and KRM against respectively MTB and MAC within A-549 cells were significantly less than the activities they displayed against the same organisms residing in MM6-Ms. Notably, it was also found that KRM had a markedly larger MIC (0.25g/ml) for MAC N-444 within A-549 cells than its MIC (0.008g/ml) for the same strain residing in MM6-Ms. Thus, the profiles of LVFX- and KRM-mediated killing or inhibition of intracellular MTB or MAC organisms in A -549 cells were markedly different from those observed for the organisms residing in MM6-Ms. Second, invasive and multiplicative phenotypes of MTB and MAC organisms, which had been adapted to either an extracellular or intracellular environment (designated as E- and I-type organisms, respectively), were studied. In the case of MTB, I-type organisms (retrieved from infected MM6-Ms after bacterial growth within the Ms during 5-day cultivation) were less efficient than E-type organisms (prepared by cultivationg the organisms in 7H9 medium)in entering MM6-Ms, whereas I-type organ- isms were more efficient than E-type organisms in invading A-549 cells. On the other hand, in the case of MAC, infectivity of I-type organisms not only in MM6-Ms but also in A-549 cells was larger than that of E-type organisms. Next, while I-type organ- isms of MTB and MAC displayed more vigorous replication within MM6-Ms than E -type organisms, the growth rate of E-type organisms within A-549 cells was more rapid than that of I-type organisms residing in A-549 cells. These findings indicate that there are significant differences between E- and I-type organisms of MTB or MAC in ability to invade and multiply within Ms (professional phagocytes) and alveolar epithe- lial cells (nonprofessional phagocytic cells). Key words:Levofloxacin, KRM-1648, Clarithromycin, Type II alveolar pneumocytes, A-549 cell, MONO-MAC-6 cell, In vitro antimicrobial activity, Invivo antimicrobial activity *From the Department of Microbiology and Immunology, Shimane Medical University, Izumo, Shimane 693-8501 Japan. (Received 5 Oct. 1198) <9> Kekkaku Vol.74, No.1: 71-75, 1999 The 73rd Annual Meeting Symposium II. PROSPECTS FOR DEVELOPMENT OF NEW ANITIMICROBIALS FOR CLINICAL CONTROL OF TUBERCULOSIS 4. CLINICAL EVALUATION OF NEW QUINOLONES AS ANTITUBERCULOSIS DRUGS Shin KAWAHARA*, Atsuhiko TADA and Hitoshi NAGARE Compared with the recent rapid advances in the diagnosis of tuberculosis, advances in the treatment of tuberculosis have been quite slow. For example, as long as six months are required for initial treatment, even with addition of pyrazinamide in the first two months to isoniazid, rifampicin, and streptomycin or ethambutol. Moreover, it is not al- ways easy to treat patients who cannot receive standard agents including isoniazid and rifampicin due to adverse effects of these drugs or drug resistance. For these reasons, the development of new agents with potent antituberculous activities and fewer adverse ef- fects is urgently desired. However, at present, few new antituberculosis agents are being developed, and new quinolones are considered the most promising new antituberculosis agents due to their lack of cross-resistance to previously existing antituberculosis agents, their excellent in vitro and in vivo antituberculous activities, and good pharmacokinetics. We therefore reviewed experimental studies and clinical reports useful for evaluation of potential clinical use of new quinolones as antituberculosis drugs. Our conclusions are summarized below: 1) Of nine new quinolones on the market, ofloxacin, ciprofloxacin, aparfloxacin and levofloxacin have excellent in vitro and in vivo antituberculous activities without cross- resistance to previously existing antituberculosis agents. 2) Ofloxacin appears to be useful clinically for intractable multidrug-resistant tubercu- losis. The incidence and severity of adverse effects of ofloxacin were very low on long- term administration. 3) Ofloxacin resistance emerged from two to four months after initiation of admini- stration of ofloxacin, and ofloxacin exhibited cross-resistance to other new quinolones. 4) The usefulness of new quinolones for initial treatment of tuberculosis is unclear. 5) New quinolones should be used to treat patients with drug-resistant tuberculosis and those patients for whom adverse effects have limited the use of standard agents. How- ever, monotherapy with new quinolones is not recommended, due to the significant risk of emergence of quinolone resistance. 6) Not only ofloxacin, ciprofloxacin, sparfloxacin and levofloxacin, which are on the market, but also gatifloxacin, CS-940, Du-6859a and other newly developed new quinolones are candidates for new antituberculosis agents. However, careful studey not only of antituberculous activities and pharmacokinetic but also drug interactions and chronic cumulative toxicities due to long-term administration are needed prior to clinical application ot these drugs. Key words:New quinolones, Antituberculousis drugs, Clinical evaluation *From the Department of Internal Medicine, National Minami-Okayama Hospital, 4066 Hayashima, Okayama 701-0304 Japan. (Received 5 Oct. 1998) <10> Kekkaku Vol.74, No.1: 77-82, 1999 The 73rd Annual Meeting Symposium II. PROSPECTS FOR DEVELOPMENT OF NEW ANITIMICROBIALS FOR CLINICAL CONTROL OF TUBERCULOSIS 5. THE NEED FOR NEW ANTITUBERCULOSIS AGENTS IN JAPAN Katsuhiro SUZUKI*, Eisaku TANAKA, and Ryoici AMITANI We duscussed the need of new antituberculosis agents in Japan concerning drug adverse reactions in particular as well as drug interactions and drug resistance. We reviewed medical charts of hospitalized patients receiving standard antituberculosis chemotherapy (INH+RFP+EB/SM}PZA), and analyzed all symptoms, signs and abnormal labora- tory data presumably caused by the chemotherapy. About 48% of 228 cases analyzed had at least 1 episode of adverse reactions:77 episodes of hepatotoxicity, 15 episodes of ototoxicity, 14 episodes of eruption, 14 episodes of ocular toxicity and so on. About 23% cases treated with RFP, 20% cases with SM, 12% cases with INH and 7.7% cases with EB had at least 1 episode of adverse reactions due to the corresponding agent. In 59 cases, at least one agent was stopped to administer because of adverse reactions. Finally, standard chemotherapy could not be completed in 23% of all cases, and in stead, the other agents, mainly new quinolones, were administered. RFP induces cytochrome P450 3A in the liver to decrease the activities of many drugs, such as cyclosporin A, tacrolimus, protease inhibitor, itraconazole, and clarithromycin. In some clinical settings, RFP cannot be administered in combination with such drugs. In conclusions, new antituberculosis agents that have strong activities with less adverse reactions and drug interactions are needed in Japan, even without considering drug resistance. Key words:Antituberculosis drug, Adverse reaction, Drug interaction, New quinolone *From the Department of Infectious Disease, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8397 Japan (Received 5 Oct. 1998)