• Tuberculosis and Respiratory Diseases
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• v.82 no.2
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• pp.143-150
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• 2019

Background: The purpose of this study was to analyze the relationship between the gene mutation patterns by the GenoType MTBDRplus (MTBDRplus) assay and the phenotypic drug susceptibility test (pDST) results of isoniazid (INH) and prothionamide (Pto). Methods: A total of 206 patients whose MTBDRplus assay results revealed katG or inhA mutations were enrolled in the study. The pDST results were compared to mutation patterns on the MTBDRplus assay. Results: The katG and inhA mutations were identified in 68.0% and 35.0% of patients, respectively. Among the 134 isolated katG mutations, three (2.2%), 127 (94.8%) and 11 (8.2%) were phenotypically resistant to low-level INH, high-level INH, and Pto, respectively. Among the 66 isolated inhA mutations, 34 (51.5%), 18 (27.3%) and 21 (31.8%) were phenotypically resistant to low-level INH, high-level INH, and Pto, respectively. Of the 34 phenotypic Pto resistant isolates, 21 (61.8%), 11 (32.4%), and two (5.9%) had inhA, katG, and both gene mutations. Conclusion: It is noted that Pto may still be selected as one of the appropriate multidrug-resistant tuberculosis regimen, although inhA mutation is detected by the MTBDRplus assay until pDST confirms a Pto resistance. The reporting of detailed mutation patterns of the MTBDRplus assay may be important for clinical practice, rather than simply presenting resistance or susceptibility test results.

• Journal of Chest Surgery
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• v.43 no.6
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• pp.716-720
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• 2010

Background: Cervical tuberculous lymphadenitis is the most common form of peripheral tuberculous lymphadenitis. The American Thoracic Society recommends 6 months of isoniazid, ritampin, ethambutol and pyrazinamide for treatment of peripheral tuberculous lymphadenifls, but even with this recommended treatment, frequent relapse occurs in actual clinical situations. Material and Method: The medical records of 38 patients diagnosed and treated for cervical tuberculous lymphadenitis between February 1997 and February 2007 were retrospectively reviewed. Result: The study included 14 males (36.8%) and 24 females (63.2%), with a mean age of $36.9{\pm}16.3$ years. The most frequent symptom was palpable neck mass in 24 patients (63.2%); 10 patients (26.3%) complained of fever or chills. Only nine patients (23.7%) had radiologic abnormalities. All patients received anti-tuberculous medications for at least 7 months, with isoniazid, rifampin, ethambutol and pyrazinamide for the first 2 months, and then isoniazid, rifampin and ethambutol given for more than 5 months. Relapse occurred in 7 patients (21.2%). Conclusion: Since many patients with cervical tuberculous lymphadenitis have no symptoms and show no radiologic abnormalities, diagnosis and treatment tend to be delayed. Considering the high relapse rate, the anti-tuberculous medication period should be longer than 6 months and this is recommended by the American Thoracic Society.

• Tuberculosis and Respiratory Diseases
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• v.55 no.1
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• pp.41-58
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• 2003

Background : The resurgence of tuberculosis and the widespread emergence of multidrug-resistant M. tuberculosis have emphasized the importance of rapid and accurate diagnostic procedures. Recently, the oligonucleotide chip has proven to be a useful tool in the rapid diagnosis of infectious diseases. The purpose of this study was to rapidly and accurately detect specific mutations in the rpoB, katG and rpsL genes associated with rifampin, isoniazid and streptomycin resistance in M. tuberculosis, respectively, using a single oligonucleotide chip. Method : For detection of drug-resistance, 7 wild-type and 13 mutant-type probes for rifampin, 2 wild-type and 3 mutant-type probes for isoniazid, and 2 wild-type and 2 mutant-type probes for streptomycin were designed and spotted onto glass slides. Fifty-five cultured samples of M. tuberculosis were amplified by PCR, and then underwent hybridization and scanning. Direct sequencing was done to verify the results from the oligonucleotide chip and to analyze the types of mutations. Result : Thirty-five cases out of 40 rifampin-resistant strains(~88%) had mutations in the rpoB gene. One case had a new mutation(D516F, GAC R TTC) and another known mutation together. Twenty cases out of 42 isoniazid-resistant strains(~50%) had mutations in the katG gene, while 7 cases out of 9 streptomycin-resistant strains(~78%) had mutations in the rpsL gene. From these results, the oligonucleotide chip was confirmed to be able to detect the most frequent mutations from the genes associated with rifampin, isoniazid and streptomycin resistance. The results proved that the drug-resistance detection probes were specific. When the results from the oligonucleotide chip and DNA sequencing were compared, the types of mutations were exactly matched. Conclusion : The diagnostic oligonucleotide chip with mutation specific probes for drug resistance is a very reliable and useful tool for the rapid and accurate diagnosis of drug resistance against rifampin, isoniazid and streptomycin in M. tuberculosis infections.

• Tuberculosis and Respiratory Diseases
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• v.43 no.1
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• pp.8-13
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• 1996

Background: The 463 codon mutation of katG gene has been reported as an useful marker for the detection of isoniazid(INH) resistant strains of M. tuberculosis. This study aimed to elucidate relationship between 463 mutation in katG gene and INH resistance in M. tuberculosis. Method: DNA was extracted from 28 INH susceptible strains(MIC$\geq\;0.2{\mu}g/ml$ on the L$\ddot{o}$wenstein Jensen media) and used for amplification of 189bp fragment containing 463 codon by PCR. Amplified fragments were digested by restriction enzyme Msp I, analyzed by single strand conformation polymorphism(SSCP) in the MDE gel and sequenced to prove mutation. Result: Only 7(25%) out of 28 were digestible by restriction enzyme Msp I. The SSCP pattern of 21 strains were distinctly different from that of M. tuberculosis H37Rv. Msp I undigestible PCR fragment was substituted at 463 codon from Arg(CGG) to Leu(CTG). Conclusion: This finding clearly indicate no relationship between 463 codon mutation of the katG gene and INH resistance.

• Applied Microscopy
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• v.8 no.1
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• pp.1-8
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• 1978

The aim of this research was to discover the action mechanism of various antituberculosis agents (isoniazid, paraaminosalicylic acid and streptomycin) which act on Mycobacteria tuberculosis hominis $H_{37}R_v$ and also to study the relationship of ultrastructural changes and the growth pattern in Mycobacterium tuberculosis hominis. The ultrastructural change was observed with an electron microscope while the growth pattern was studied through in vitro culture. The results are summarized as follows: 1. The ultrastructural changes found in the group treated only with isoniazid were the loss of nuclear materials and the appearence of electron dense granules. 2. In the group treated with paraaminosalicylic acid, thickening of nuclear filaments and meso some arrangement disorders were observed. 3. In the group treated with streptomycin, the ribosome particles appeared indistinct and the cytoplasm was denaturalized. 4. In the group cross treated with all three agents, all the ultrastructural changes mentioned above could be observed in the cell just as they appeared in the single treated groups. 5. In all of the single and in the crossly treated group, there were no significant changes note in the cell wall or cytoplasmic membranes of any of the cells observed. 6. In the cultural data in vitro, through the crossly treated group and single treated group. growth was observed in 3-5 weeks of culture.

• Journal of Pharmaceutical Investigation
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• v.8 no.2
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• pp.26-34
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• 1978

Isoniazid(INH)는 체내(體內)에서 신속(迅速)히 흡수(吸收)되어 일부(一部)는 치료효과(治療?果)가 있는 유리(遊離) INH로 변(變)하고 일부(一部)는 치료효과(治療?果)가 없는 acetylisoniazid, isonicotinic acid, isonicotinuric acid등(等)으로 대사(代謝)되어 불활성화(不活性化)된다. 가토(家兎)의 뇨(尿) 및 혈장중(血?中)에서 총(總) INH에 대(對)한 유리(遊離) INH의 비(比)를 정색적(呈色的)으로 정량(定量) 산출(算出)함으로써 INH의 불활성화(不活性化)에 미치는 Ethambutol(EMB)의 영향(影響)을 실험(實驗)하였다. 가토(家兎)에 INH를 경구투여(經口投與)한 결과(結果) 그 대사(代謝)에 의(依)한 불활성화비(不活性化比)는 같은 가토(家兎)에서는 비교적(比較的) 일정(一定)하고 개체간(個體間)의 차이(差異)는 현저하였다. INH에 EMB를 배합투여(配合投與)하거나 분자화합물(分子化合物)을 투여(投與)했을 경우 EMB에 의(依)해 INH의 대사(代謝)가 억제(抑制)되어 INH 단독투여시(單獨投與時)보다 유리(遊離) INH가 뇨(尿) 및 혈장중(血漿中)에서 증가(增加)하였다. EMB에 의(依)한 유리(遊離) INH의 상승(上昇)은 INH단독투여(單獨投與)보다 평균(平均) 1.5배(倍)이며 EMB분자화합물(分子化合物)이 EMB배합물(配合物)보다 혈장중(血?中)에서 1.3배(倍) 높게 나타났다.

• Tuberculosis and Respiratory Diseases
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• v.76 no.6
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• pp.261-268
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• 2014

Patients with immune-mediated inflammatory diseases (IMIDs) are increasingly being treated with anti-tumor necrosis factor (TNF) agents and are at increased risk of developing tuberculosis (TB). Therefore, diagnosis and treatment of latent TB infection (LTBI) is recommended in these patients due to the initiation of anti-TNF therapy. Traditionally, LTBI has been diagnosed on the basis of clinical factors and a tuberculin skin test. Recently, interferon-gamma releasing assays (IGRAs) that can detect TB infection have become available. Considering the high-risk of developing TB in patients on anti-TNF therapy, the use of both a tuberculin skin test and an IGRA should be considered to detect and treat LTBI in patients with IMIDs. The traditional LTBI treatment regimen consisted of isoniazid monotherapy for 9 months. However, shorter regimens such as 4 months of rifampicin or 3 months of isoniazid/rifampicin are increasingly being used to improve treatment completion rates. In this review, the screening methods for diagnosing latent and active TB before anti-TNF therapy in patients with IMIDs will be briefly described, as well as the current LTBI treatment regimens, the recommendations for managing TB that develops during anti-TNF therapy, the necessity of regular monitoring to detect new TB infection, and the re-initiation of anti-TNF therapy in patients who develop TB.

• Clinical and Experimental Pediatrics
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• v.52 no.5
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• pp.529-537
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• 2009

Drug-resistant tuberculosis in children has important implications for both the patients and tuberculosis control programs. In Korea, among all new patients, the isoniazid resistance rate was 9.9% and multidrug-resistant tuberculosis rate was 2.7% in 2004 (in patients aged 10-19 yr, the multidrug-resistant tuberculosis rate reached 2.1%). Tuberculosis in pediatric patients is difficult to diagnose because many children have nonspecific clinical signs and the detection rates of acid-fast bacilli smears and cultures are low. Therefore, every effort should be made to identify adult sources and obtain information on drug susceptibility because symptomatic adult patients have a higher chance of culture positivity and drug-susceptibility patterns are the same in most adult-child pair patients. Korean children are at significant risk of drug-resistant tuberculosis. As the isoniazid resistance rate is greater than 4% among the new cases in Korea, a four-drug regimen should be considered for initial treatment of children with active tuberculosis, unless drug-susceptibility test results are available. Treatment of drug-resistant tuberculosis in children is challenging and there are only few available data. Tuberculosis control programs should be continuous with specific focus on pediatric populations because they can serve as reservoirs for future active cases. Further studies are needed regarding treatment of drug-resistant tuberculosis in children.

• Tuberculosis and Respiratory Diseases
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• v.60 no.1
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• pp.44-48
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• 2006

Background : Isoniazid (INH) is one of the most effective anti-tuberculosis (TB) drugs. In Korea, the dose of INH normally used in patients over 50 kg is 400 mg/day, which differs from the dose recommended by other countries. Indeed, the metabolism of INH shows ethnic variations, and Koreans are predominantly rapid acetylators. However, two reports suggested 300 mg of INH might be sufficient to reach an ideal peak level in Korean patients over 50 kg. Therefore, the aim of this study was to compare the effectiveness and adverse reactions between INH 300 mg and 400 mg in Korean TB patients. Method : Patients who were culture-positive, susceptible to all 1st-line drugs, initially on HREZ, and weighed over 50 kg were selected from patients with pulmonary TB between April 2003 and March 2005. The treatment results and adverse reactions in the INH 300 mg and 400 mg group were compared. Since April 2004, most TB patients at Asan Medical Center were administered INH 300 mg irrespective of the body weight. Results : The study included 123 patients in the 300 mg INH group and 128 in the 400 mg INH group. There were no significant differences between the groups in terms of age, gender, weight, history of TB treatment, initial smear strength, and frequency of cavitary lesions. There was no difference in the treatment duration between the groups. One hundred eleven (90%) patients in the INH 300 mg group and 102 (80%) in the INH 400 mg group completed treatment (p>0.05). There were no differences in the frequency of modification of the initial regimen between groups due to any adverse reactions (300 mg : 9.0%, 400 mg : 13.7%) and hepatotoxicity (300 mg : 2.7% ; 400 mg : 7.8%). Conclusion : Considering treatment results and adverse reactions of two groups, 300mg of INH may be sufficient for treating Korean TB patients. Further studies comparing the frequency of relapse will be needed.

• Tuberculosis and Respiratory Diseases
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• v.59 no.2
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• pp.179-185
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• 2005

Background : To evaluate the clinical efficacy of pulmonary resection combined with first-line antituberculous drug therapy in patients with well-localized, cavities-containing pulmonary multidrug-resistant tuberculosis (MDR-TB). Method : From February 1998, seventeen patients with well-localized, cavities-containing pulmonary MDR-TB were enrolled and followed prospectively up to December 2004. After radical pulmonary resection, the patients were treated with antituberculous drugs comprising of isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S) (3HERZS/3HERS/6HER). Results : All recovered isolates of M. tuberculosis were resistant to both isoniazid and rifampin, and to a mean of 4.8 antituberculous drugs (range, 2 to 7 drugs). Surgical procedures included lobectomy (13 patients), lobectomy plus segmentectomy (3 patients), and pneumonectomy (1 patient). The median time for postoperative sputum smear and culture conversion was 2 days (range, 1 to 23 days). Fifteen (94%) patients had durable cures (mean follow-up period, 39.0 months). One patient failed to convert her sputum and was successfully switched to second-line therapy; one patient developed active disease again almost 7 years later, likely due to re-infection with a new M. tuberculosis strain. Conclusion : Radical resection combined with administration of first-line antituberculous agents was effective in patients with well-localized, cavities-containing pulmonary MDR-TB.