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.
Biological Assay ; Disease Susceptibility ; Genotype ; Humans ; Isoniazid ; Mycobacterium ; Mycobacterium tuberculosis ; Prothionamide ; Research Design ; Tuberculosis, Multidrug-Resistant

PURPOSE: To assess the usefulness of flexible bronchoscopy in patients with suspected pulmonary tuberculosis (PTB) who have difficulty in sputum expectoration. METHODS: The subjects of this study were patients who were suspected of PTB and visited the Division of Pediatric Pulmonology at a tertiary hospital from April 2006 to March 2016. PTB suspects were determined by clinical symptoms, radiologic findings, and immunologic studies. We aimed to examine the value and safety of bronchoscopy in diagnosis and differential diagnosis of PTB in PTB-suspected patients. The diagnostic criteria for PTB were defined when Mycobacterium tuberculosis was cultured in the sputum specimen or in the bronchial washing fluid. RESULTS: A total of 19 PTB suspects were included. One patient was diagnosed with PTB by using the sputum study. However, the remaining 18 patients could not expectorate sputum or showed no evidence of Mycobacterium tuberculosis infection from the sputum study. Of the 18 patients, 15 underwent bronchoscopy. After bronchoscopy, 6 patients were diagnosed with PTB and 9 patients were diagnosed with Mycoplasma, viral, or fungal pneumonia, and tumors. For antituberculous drug resistance, there were 1 case of isoniazid (INH) resistance and 1 case of concurrent resistance to INH and prothionamide. There was no multidrug-resistant tuberculosis. None of the patients had significant complications due to bronchoscopy. CONCLUSION: Flexible bronchoscopy appears to be a definitive and safe procedure for the differential diagnosis of patients suspecting PTB in children who have difficulty expectorating sputum.
Bronchoscopy* ; Child* ; Diagnosis ; Diagnosis, Differential ; Diagnostic Imaging ; Drug Resistance ; Humans ; Isoniazid ; Mycobacterium tuberculosis ; Mycoplasma ; Pneumonia ; Prothionamide ; Pulmonary Medicine ; Sputum* ; Tertiary Care Centers ; Tuberculosis, Multidrug-Resistant ; Tuberculosis, Pulmonary*

We report a case of a 23-year-old female immigrant from China who was diagnosed with multidrug-resistant tuberculosis affecting her lung and brain, resistant to the standard first-line therapeutics and streptomycin. She was treated with prothionamide, moxifloxacin, cycloserine, and kanamycin. However, her headache and brain lesion worsened. After the brain biopsy, the patient was confirmed with intracranial tuberculoma. Linezolid was added to intensify the treatment regimen, and steroid was added for the possibility of paradoxical response. Kanamycin was discontinued 6 months after initiation of the treatment; she was treated for 18 months with susceptible drugs and completely recovered. To our knowledge, this case is the first multidrug-resistant tuberculosis that disseminated to the brain in Korea.
Biopsy ; Brain* ; China ; Cycloserine ; Emigrants and Immigrants ; Female ; Headache ; Humans ; Kanamycin ; Korea ; Linezolid ; Lung ; Mycobacterium tuberculosis ; Prothionamide ; Streptomycin ; Tuberculoma, Intracranial ; Tuberculosis, Central Nervous System ; Tuberculosis, Multidrug-Resistant* ; Tuberculosis, Pulmonary ; Young Adult

PURPOSE: Low serum concentrations of drugs used to treat multi-drug resistant tuberculosis (MDR-TB) have occasionally been associated with treatment failure. We determined the frequencies of low serum concentrations of anti-MDR-TB drugs, and assessed the effects of these concentrations on 2-month sputum conversion. MATERIALS AND METHODS: The serum levels of moxifloxacin (MF), prothionamide (PTH), and cycloserine (CS) were determined for 89 serum samples by high-pressure liquid chromatography-tandem mass spectrometry. RESULTS: Low serum concentrations of MF, PTH, and CS below the minimal levels of the normal ranges were 83.3% (20/24), 59.2% (29/49), and 71.2% (47/66), respectively. There were no significant differences between the 2-month sputum conversion group (n=25) and the 2-month sputum non-conversion group (n=4) in median drug concentrations (microg/mL) of MF (1.46 vs. 1.60), PTH (0.91 vs. 0.70), and CS (14.90 vs. 14.90). However, a poor compliance rate was significantly greater in the 2-month sputum non-conversion group (75.0%, 3/4) than in the 2-month sputum conversion group (0%, 0/25) (p=0.001). CONCLUSION: The frequency of low serum concentrations of anti-MDR-TB drugs was substantial and might not affect the 2-month sputum conversion rate. Larger prospective studies with timely sampling are needed to investigate the role of therapeutic drug monitoring in MDR-TB.
Adult ; Aged ; Antitubercular Agents/blood/*pharmacokinetics/therapeutic use ; Chromatography, High Pressure Liquid ; Cycloserine/blood/*pharmacokinetics/therapeutic use ; Fluoroquinolones/blood/*pharmacokinetics/therapeutic use ; Humans ; Medication Adherence ; Middle Aged ; Prothionamide/blood/*pharmacokinetics/therapeutic use ; Retrospective Studies ; Sputum/*microbiology ; Tandem Mass Spectrometry ; Tuberculosis, Multidrug-Resistant/blood/*drug therapy ; Young Adult

Despite global efforts to control tuberculosis (TB), multidrug-resistant TB (MDR-TB) is still a serious problem worldwide. The diagnosis of MDR-TB is based on mycobacterial culture followed by drug susceptibility testing, with results available in weeks to months. This requirement calls for rapid direct tests, especially genotypic tests, in which specimens are amplified directly for the detection of MDR-TB. The treatment of MDR-TB is challenging because of the high toxicity of second-line drugs and the longer treatment duration required compared to drug-susceptible TB. The selection of drugs in MDR-TB is based on the treatment history, drug susceptibility results, and TB drug resistance patterns in each region. Recent World Health Organization guidelines recommend the use of at least four second-line drugs (i.e., a newer fluoroquinolone, an injectable agent, prothionamide, and cycloserine or para-aminosalicylic acid) in addition to pyrazinamide. Kanamycin is the initial choice of an injectable drug, and newer fluoroquinolones include levofloxacin and moxifloxacin. For extensively drug-resistant TB, group 5 drugs such as linezolid and clofazimine need to be included. New drugs such as delamanid and bedaquiline have recently been approved for treating MDR-TB and other agents with novel mechanisms of action that can be given for shorter durations (6-12 months) for MDR-TB are under investigation.
Clofazimine ; Cycloserine ; Diagnosis* ; Drug Resistance ; Fluoroquinolones ; Kanamycin ; Levofloxacin ; Prothionamide ; Pyrazinamide ; Tuberculosis ; Tuberculosis, Multidrug-Resistant* ; World Health Organization

Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration required compared with drug-susceptible TB. The efficacy of treatment for MDR-TB is poorer than that for drug-susceptible TB. The selection of drugs in MDR-TB is based on previous treatment history, drug susceptibility results, and TB drug resistance patterns in the each region. Recent World Health Organization guidelines recommend the use of least 4 second-line drugs (a newer fluoroquinolone, an injectable agent, prothionamide, and cycloserine or para-aminosalicylic acid) in addition to pyrazinamide. The kanamycin is the initial choice of injectable durgs, and newer fluoroquinolones include levofloxacin and moxifloxacin. For MDR-TB, especially cases that are extensively drug-resistant, group 5 drugs such as linezolid, clofazimine, and amoxicillin/clavulanate need to be included. New agents with novel mechanisms of action that can be given for shorter durations (9-12 months) for MDR-TB are under investigation.
Clofazimine ; Cycloserine ; Drug Resistance ; Extensively Drug-Resistant Tuberculosis ; Fluoroquinolones ; Kanamycin ; Levofloxacin ; Linezolid ; Prothionamide ; Pyrazinamide ; Tuberculosis ; Tuberculosis, Multidrug-Resistant* ; World Health Organization

The prevalence of multi-drug resistant tuberculosis (MDR-TB), which is resistant to isoniazid and rifampin, has been increasing in Korea. And the side effects of 2nd line anti-tuberculosis medications, including drug-induced hepatitis, are well known. Although prothionamide (PTH) is one of the most useful anti-TB medications and although TB medication-induced acute hepatitis is a severe complication, there are only a few published case reports about prothionamide induced hepatitis. In this case report, a 22 year old male was diagnosed with pulmonary MDR-TB and was administered 2nd line anti-TB mediations, including PTH. Afterwards, he had a spiking fever and his liver enzymes were more than 5 times greater than the upper limit of the normal range. He was then diagnosed with drug-induced hepatitis by liver biopsy. His symptoms and liver enzyme elevation were improved after stopping PTH. Accordingly, we report this case of an association between PTH and acute hepatitis.
Biopsy ; Drug-Induced Liver Injury ; Fever ; Hepatitis ; Humans ; Isoniazid ; Korea ; Liver ; Male ; Prevalence ; Prothionamide ; Reference Values ; Rifampin ; Tuberculosis, Multidrug-Resistant ; Tuberculosis, Pulmonary

BACKGROUND: The purposes of the current study were to evaluate the concordant rates of anti-mycobacterial drug susceptibility test (DST) results in different solid media performed in different institutes, and to determine reliable susceptible testing methods. METHODS: One hundred and twenty two Mycobacterium tuberculosis strains were isolated from patients in A Hospital in 2005. DSTs were performed by the absolute concentration method using L?wenstein Jensen medium in both A Hospital (method A-1) and B Institute (method B-1) and by the proportion method using Middlebrook 7H10 agar in B Institute (method B-2). Nine drugs were used including isoniazid and rifampin. Sensitivity and specificity of each method were estimated by using the acceptable standard of 90% for isoniazid and rifampin and 80% for other drugs. The therapeutic outcomes of quinolone-administered patients were evaluated according to ofloxacin susceptibility results. RESULTS: Method B-1 showed sensitivity and specificity levels over the acceptable standard levels for all drugs. Method B-2 showed specificity lower than the acceptable levels for rifampin and cycloserine. Method A-1 showed specificity lower than the acceptable levels for isoniazid, streptomycin, p-aminosalicylic acid, and ofloxacin and sensitivity lower than the acceptable levels for prothionamide and cycloserine. The concordance rates of therapeutic outcomes with method B-1, method B-2, and method A-1 were 77%, 74%, and 65%, respectively. CONCLUSION: The drug susceptibility results for some drugs were discordant between the testing laboratories and media, requiring an urgent application of quality control programs to raise the reliability of anti-mycobacterial DST.
Academies and Institutes ; Agar ; Aminosalicylic Acid ; Culture Media ; Cycloserine ; Humans ; Isoniazid ; Mycobacterium tuberculosis ; Ofloxacin ; Prothionamide ; Quality Control ; Rifampin ; Sensitivity and Specificity ; Streptomycin

BACKGROUND: Although various standard anti-tuberculosis chemotherapy regimens were suggested by World Health Organization in pulmonary tuberculosis, as yet, treatment regimen has not been established in intractable pulmonary tuberculosis. Also those surveys for intractable pulmonary tuberculosis were few. Therefore, the purpose of this study is to investigate the clinical course of radiological finding and pulmonary function pattern in intractable pulmonary tuberculosis, to assess the factors that affect the fate and so to make some suggestions for the management of intractable pulmonary tuberculosis. METHODS: This study population was composed of 40 patients with culture-proven pulmonary tuberculosis hospitalized. Although all 40 patients were received regular standard anti-tuberculosis chemotherapy which was individualized on the basis of susceptibility results, all patients were chronic excretors of mycobacterium tuberculosis bacilli (chronics), whose sputum cultures tested positive at both 11 and 12 months after admission. RESULTS: The rate of male and female was about 6:1 and mean age was 47.8+/-14.6 years old. Resistance to most of anti-tuberculosis drugs was observed and especially high degree resistance of isoniazid (95%), rifampicin (92.5%), ethambutol (87.5%), prothionamide and ofloxacin was found. Irrespective of the type of anti-tuberculosis chemotherapy and use of sensitive drug, clinical course was not significantly changed. On the pulmonary function test, most represented restrictive (57.5%) or combined pattern (27.5%) and had no significant interval change. Also arterial blood gas analysis finding was not changed. On chest X-ray findings, 80% had cavitary lesions, 87.5% showed far advanced stage and most (85%) had no significant interval change. However, 15% has changed to aggravation state, which had high frequency in patient with more than 3 susceptible drugs and significant decrease of FEV1 and FEV1/FVC on pulmonary function test findings that did not affect the mortality. The mortality rate was 30%, the average interval from diagnosis to death was 30.6+/-20.3 months and the fate was not associated with radiological findings, arterial blood gas analysis findings and pulmonary function test findings but only body weight at diagnosis of intractable pulmonary tuberculosis. CONCLUSIONS: The clinical course of intractable pulmonary tuberculosis that had no specific treatment did not depend on radiological findings and pulmonary function test findings but nutrition state at diagnosis. Therefore, in addition to anti-tuberculosis treatment, intractable pulmonary tuberculosis patient is recommended to be received aggressive conservative treatment that focuses on nutrition balance. Also it is probably essential to prevent the spread of intractable pulmonary tuberculosis to healthy person.
Blood Gas Analysis ; Body Weight ; Diagnosis ; Drug Therapy ; Ethambutol ; Female ; Humans ; Isoniazid ; Male ; Mortality ; Mycobacterium tuberculosis ; Ofloxacin ; Prothionamide ; Respiratory Function Tests ; Rifampin ; Sputum ; Thorax ; Tuberculosis, Pulmonary* ; World Health Organization

BACKGROUND: Tuberculosis is still one of the most seriously threatening infections in Korea, because of multidrug resistant tuberculosis. Results of antituberculosis drug susceptibility test can provide clinicians very important informations for selection of proper regimens for treatment. METHODS: In this study the results of antituberculosis drug susceptibility test of 298 cases at Kyunghee Medical Center from 2000 to 2003 were retrospectively analysed to evaluate the trend of antituberculosis drug susceptibility. The procedure of drug susceptibility test was based on the absolute concentration method using Lowenstein-Jensen solid media. RESULTS: The resistance rate of Mycobacterium tuberculosis to one or more drugs was increased from 29.3% in 2000 to 48.2% in 2003, and the rates of multiple resistance to two or more drugs increased from 13.3% in 2000 to 20.5% in 2003. The increase in resistance rate to individual drug during study period were 20.0% to 24.1% in isoniazid, 9.3% to 19.3% in rifampicin, 5.3% to 15.7% in ethambutol, 4.0% to 10.8% in para-aminosalicylic acid, 2.7% to 6.0% in kanamycin, 1.3% to 7.2% in ethionamide, 1.3% to 6.0% in capreomycin, 1.3% to 7.2% in prothionamide, 0.0% to 12.1% in ofloxacin, 6.7%to 3.6% in streptomycin, 6.7% to 7.2% in cycloserine, 10.7% to 8.4% in pyrazinamide, respectively. CONCLUSIONS: The resistance rate of M. tuberculosis has been increased with years and multidrug resistant M. tuberculosis was commonly encountered in the specimens from the patients visited Kyunghee Medical center.
Aminosalicylic Acid ; Capreomycin ; Cycloserine ; Ethambutol ; Ethionamide ; Humans ; Isoniazid ; Kanamycin ; Korea ; Mycobacterium tuberculosis ; Ofloxacin ; Prothionamide ; Pyrazinamide ; Retrospective Studies ; Rifampin ; Streptomycin ; Tuberculosis