(Vol.73, No.7 July 1998) <1>Kekkaku Vol.73, No.7:459-470,1998 CHEMOTHERAPY FOR TUBERCULOSIS ; YESTERDAY, TODAY, AND TOMORROW (BASIC AND CLlNICAL STUDIES) Teruo AOYAGI* The discovery of streptomycin in 1944 had given rise to great flowering of chemother- apy for tuberculosis,. The times which triple treatment of SM ¥ PAS ¥ INH after the temporal time of SM ¥ PAS had been standard regimens on initial treatment had continued for more than twenty years. The shortening of duration for chermotherapy had become possible by the introduction of RFP, and the duration had reduced to one fourth compared with that of the regimens till then by the addition of PZA for two months at the beginning of treat- ment on the initial treatment cases. In this paper, historical aspects of early and present-day chemotherapy of tuberculosis and the reports of main studies have been summarized, and pharmacokinetics of INH, action of antituberculous drugs in short-course chemotherapy, MDR-TB and biological response modifiers for treatment of tuberculosis, etc. has been reviewed. It is urgently awaited that more new drugs without cross resistance to previous drugs will be developed for the more shortening of the duration and the improvement of the treatment for MDR-TB. Key words : Controlled clinical trial, Pharmacokinetics of INH, Short-course chemotherapy, MDR-TB (multi drug resistant tuberculosis), Biological response modifier *From the National Higashi Saitama Hospital, 4147,Kurohama, Hasuda-shi, Saitama 349-0101 Japan. <2>Kekkaku Vol.73, No.7 :471-476, 1998 ATTRIBUTABLE FACTORS TO THE EMERGENCE OF MULTIDRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS BASED ON THE OBSERVATION OF CONSECUTIVE DRUG RESISTANCE TEST RESULTS Tadahiko FUJlNO*, Naoki HASEGAWA, Reiko SATOU, Hirokazu KOMATSU, Kanemitsu KAWADA Thirty six cases with multidrug-resistant tuberculosis were retrospectively studied to define the causes attributable to the emergence of multidrug-resistant M. tuberculosis. All these tuberculosis cases were microbiologically confirmed and resistant to at least isoniazid and rifampicin. Data analysis using matched-pair sampling methods (1:3) demonstrated that the fol- lowings are the significant risk factors for the emergence of multidrug-resistant tubercu- losis ; incompliance to treatment (Odds ratio 21.0 : 95%Cl 4.10-107.63), alcohol abuse (Odds ratio 15.0 : 95%Cl 2.34-96.1) and the history of previous treatment (Odds ratio 5.0 : 95%Cl 2.04-12.21), while diabetes mellitus is not statistically significant. The incompliance to treatment which is primarily thought to be patient's responsibility results in non-optimal administration of antituberculous agents, Ieading to the multidrug -resistant tuberculosis. Other factors that may have contributed to the emergence of re- sistance included the unnecessary change of regimen before completion of chemotherapy. This is patient-unrelated situation where responsibility lies in the medical side. A clinical case presented here is an example. In this case RFP was replaced with ethambutol 3-months after the initiation of regimen including SM, INH and RFP because of abnormal elevation of GOT and GPT without any supporting evidence that RFP was causative. The readministration of RFP after 1-year cessation did not induce liver dys- function, while the drug resistance was observed not only to RFP but also to INH. This case suggests unnecessary interruption of RFP could lead to the emergence of resistance to INH as well as RFP. One known mechanism of drug resistance is random mutation and the selection by drugs administered during the course of chemotherapy. The cases with advanced cavitary lesions would have a higher probability of the occurrence of mutation. The more the number of mutant bacilli, the higher the probability of emergence of multidrug resistance. Those cases in which longer period of time is needed for the negative conver- sion of M. tuberculosis should be treated with potent chemotherapy regimens under the intensive supervision. Since both INH and RFP are the most potent among currently available antituberculous agents. It is crucial to preserve the potency of these essential agents before novel anti- tuberculous are developed. key words : Multidrug-resistant tuberculosis, Pulmonary tuberculosis, Incompliance, INH ¥ RFP *From the Division of Internal Medicine, National Sanatorium Minami-Yokohama Hospital, 2-6-1, Serigaya, Kohnan-ku, Yokohama 233-0006 Japan. (Received 4 Nov. 1997/ Accepted 24 Feb.1998) <3>Kekkaku Vol.73, No.7 :477-483, 1998 TIME TREND IN INCIDENCE AND MORTALITY OF TUBERCULOSIS AND CHARACTERISTICS OF NOTIFIED TUBERCULOSIS PATIENTS IN URBAN AREA OF MONGOLIA Makoto TOYOTA* Recent Mongolian political, social and economic changes have had a great impact on its health care system and tuberculosis control program. The objective of this study is to assess time trend in incidence and mortality of tuberculosis and characteristics of noti- fied tuberculosis cases in Mongolia. 1) Data on statistics of tuberculosis are obtained from reports of the National Tuber- culosis Center in Mongolia. The mortality of tuberculosis in Mongolia shows a downward trend during 1985 - 1995. The number of notified tuberculosis cases had gradually de- creased during 1985 - 1989. It suddenly dropped in 1990 and was the lowest in 1993. After that, about two fold increase in the notified cases was observed in recent three years from 1993 to 1995. Such a large fluctuation in the number of notified cases after 1990 is unlikely to be associated with the epidemiologic situation of tuberculosis, but rather due to a reporting bias. The shortage of drugs and economic hardship prevented patients from consulting medical facilities. The shortage of drugs also prevented doctors from no- tifying patients to the tuberculosis registry, because the notification did not lead to treating the disease. The improvement of health care system and the supply of essential drugs since 1994 seems to contribute to the increase in the number of notified cases. 2) The study subjects include 618 patients who were diagnosed as active tuberculosis at ten tuberculosis specialized facilities in Ulaanbaatar, Mongolia from May 1995 to March 1996. Patients were interviewed about their demographic factors and their medical records were reviewed. Fifty one percent of the cases were female. The mean age was 26.9 years old. Ninety percent of the cases underwent chest X-ray examination, while 72% of the cases underwent bacteriological examination and only 21% were confirmed bacterio- logically. It is necessary to improve the quality control of sputum smear examination and the validity of diagnosis of tuberculosis in Mongolia. As for treatment regimens, only 29% of the cases were being treated with at least four drugs (isoniazid, rifampicin, pyrazinamide, ethambutol and/or streptomycin). It is needed to provide directly observed treatment using the WHO recommended standard regimen to at least smear positive tu- berculosis cases. Key words : Mongolia, Tuberculosis, Notification, Detection rate, Quality control, Diagnosis, Tuberculosis control program *From the Department of Public Health, Kochi Medical School, Kohasu, Okoh-cho, Nankoku-shi, Kochi 783-8505 Japan. (Received 17 Dec. 1997/ Accepted 26 Feb.1998) <4>Kekkaku Vol.73, No.7: 485-490, 1998 ADVERSE REACTIONS OF ANTITUBERCULOUS AGENTS Yoshihiro KOBASHI, Yoshihito NIKI, Hiroshi KAWANE, Toshiharu MATSUSHIMA We experienced adverse reactions to antituberculous agents in 17 patients (53% ) out of 32 patients treated for tuberculosis and nontuberculous pulmonary mycobacteriosis. Side effects were seen in 15 pat,ients (47% ) , and abnormal laboratory findings were ob- served in 9 patients (28% ) . Most side effects mostly appeared within two weeks after the administration, and were of short duration. However, there were also side effects such as neurological symptoms, arthralgia, and general fatigue which appeared after one month and lasted for a long duration. These results suggest that careful observation for adverse reactions in antituberculous treatment is required. Finally, 11 patients with adverse reac- tions were successfully treated by changing antituberculous agents or readministration after temporary stop of the administration. Four patients improved even with continued use of agents causing side-effects. However, in the case of two patients who had to change antituberculous agents, adverse reactions to all antituberculous agents appeared and the treatment for tuberculosis and nontuberculous pulmonary mycobacteriosis had to be stopped. Key words : Adverse reactions, Antituberculous agents, Side effects, Abnormal labo- ratory findings *From the Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School Kawasaki Hospital, Nakasange 2-1-80, Okayama 700-8505 Japan. (Received 16 Jan. 1998/ Accepted 2 Mar. 1998) <5>Kekkaku Vol.73, No.7: 491-495, 1998 A CASE OF AIDS WITH PLEUROPULMONARY TUBERCULOSIS IN WHICH PCR WAS USEFUL IN MAKlNG DEFlNITIVE DIAGNOSIS Koji OHTOMO*, Isamu SUGAWARA and Atsuko MASUNAGA A case of 24-year-old male patient with AIDS complicated with pleuropulmonary tu- berculosis was presented. It was difficult initially to make a definite diagnosis of tuber- culosis by routine sputum culture and pleural biopsy. DNA diagnosis of tuberculosis using PCR is useful in some clinical cases. Key words : PCR, AIDS, M.tuberculosis, DNA diagnosis *From the Molecular Pathology Division, The Research Institute of Tuberculosis, Japan Anti-tuberculosis Association, 3-1-24 Matsuyama, Kiyose, Tokyo 204-0022 Japan. (Received 26 Dec. 1997/ Accepted 8 Apr. 1998)