Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.
Antitubercular Agents/blood/*therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Chromatography, High Pressure Liquid ; Drug Monitoring ; Humans ; Nutritional Status ; Pharmacogenetics ; Tandem Mass Spectrometry ; Tuberculosis/*drug therapy

As dried blood spots (DBSs) have various advantages over conventional venous blood sampling, some assays for detection of one or two anti-tuberculosis (TB) drugs in DBSs have been developed. However, there are no assays currently available for the simultaneous measurement of three or more anti-TB drugs in DBSs. In this study, we developed and evaluated a multiplex method for detecting nine anti-TB drugs including streptomycin, kanamycin, clarithromycin, cycloserine, moxifloxacin, levofloxacin, para-aminosalicylic acid, prothionamide, and linezolid in DBSs by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Seventy-nine patient samples of DBS were analyzed on the UPLC-MS/MS system. All drug concentrations were determined within 4 min, and assay performance was evaluated. All drugs were clearly separated without ion suppression. Within-run and between-run precisions were 1.7-13.0% and 5.7-17.0%, respectively, at concentrations representing low and high levels for the nine drugs. Lower limits of detection and quantification were 0.06-0.6 and 0.5-5.0 µg/mL, respectively. Linearity was acceptable at five level concentrations for each drug. Correlations between drug concentrations in plasma and DBSs by using Passing-Bablock regression and Pearson's rho (ρ, 0.798-0.989) were acceptable. In conclusion, we developed a multiplex assay to measure nine second-line anti-TB drugs in DBSs successfully. This assay provided convenient and rapid drug quantification and could have applications in drug monitoring during treatment.
Antitubercular Agents/*blood ; Chromatography, High Pressure Liquid ; *Dried Blood Spot Testing ; Humans ; Limit of Detection ; Reproducibility of Results ; *Tandem Mass Spectrometry

BACKGROUND/AIMS: We investigated the time of onset of antituberculous drug-induced hepatotoxicity (ADIH) and related characteristics. METHODS: Adult patients (n = 1,031) treated with first-line antituberculous drugs between February 2009 and January 2013 were enrolled. RESULTS: Of the 1,031 patients, 108 patients (10.5%) developed ADIH a mean of 39.6 +/- 43.7 days after treatment initiation. Twenty-eight patients (25.9%) developed ADIH within 7 days, 73 (67.6%) within 30 days, and the rest after 30 days. The < or = 30-day group was characterized by higher peak alanine aminotransferase (ALT) level and a high proportion of patients with maintenance of first-line antituberculous drugs compared to the > 30-day group. In subgroup analysis, the < or = 7-day group was characterized by higher baseline aspartate aminotransferase and ALT, high proportion of patients with maintenance of first-line antituberculous drugs, and high proportion of patients with extrapulmonary tuberculosis compared to patients with ADIH that developed beyond 7 days. In multivariate analysis, serum ALT > 40 IU/L (odds ratio [OR], 2.995; 95% confidence interval [CI], 1.580 to 5.680; p = 0.001) and presence of anti-hepatitis C virus (OR, 4.204; 95% CI, 1.822 to 9.700, p = 0.001) were independent risk factors for development of ADIH. CONCLUSIONS: Approximately 70% of the cases of ADIH occurred in the first month of antituberculous treatment, and were associated with continuation of the first-line drug regimen.
Adult ; Aged ; Alanine Transaminase/blood ; Antitubercular Agents/*adverse effects ; Aspartate Aminotransferases/blood ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/blood/*diagnosis/etiology ; Chi-Square Distribution ; Clinical Enzyme Tests ; Coinfection ; Drug Monitoring/*methods ; Drug Therapy, Combination ; Early Diagnosis ; Female ; Hepatitis/complications/diagnosis ; Humans ; *Liver Function Tests ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Predictive Value of Tests ; Retrospective Studies ; Risk Factors ; Time Factors

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase/blood ; Antitubercular Agents/adverse effects/*blood/therapeutic use ; Aspartate Aminotransferases/blood ; Drug-Induced Liver Injury/*blood ; Ethambutol/adverse effects/blood/therapeutic use ; Female ; Humans ; Isoniazid/adverse effects/blood/therapeutic use ; Liver/*pathology ; Liver Function Tests ; Male ; Middle Aged ; Pyrazinamide/adverse effects/blood/therapeutic use ; Retrospective Studies ; Rifampin/adverse effects/blood/therapeutic use ; Tuberculosis, Pulmonary/drug therapy ; Young Adult

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase/blood ; Antitubercular Agents/adverse effects/*blood/therapeutic use ; Aspartate Aminotransferases/blood ; Drug-Induced Liver Injury/*blood ; Ethambutol/adverse effects/blood/therapeutic use ; Female ; Humans ; Isoniazid/adverse effects/blood/therapeutic use ; Liver/*pathology ; Liver Function Tests ; Male ; Middle Aged ; Pyrazinamide/adverse effects/blood/therapeutic use ; Retrospective Studies ; Rifampin/adverse effects/blood/therapeutic use ; Tuberculosis, Pulmonary/drug therapy ; 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

BACKGROUND/AIMS: The goal of this study was to monitor tuberculosis (TB)-specific T-cell responses in cerebrospinal fluid-mononuclear cells (CSF-MCs) and peripheral blood mononuclear cells (PBMCs) in patients with tuberculous meningitis (TBM) over the course of anti-TB therapy. METHODS: Adult patients (> or = 16 years) with TBM admitted to Asan Medical Center, Seoul, South Korea, were prospectively enrolled between April 2008 and April 2011. Serial blood or CSF samples were collected over the course of the anti-TB therapy, and analyzed using an enzyme-linked immunosorbent spot (ELISPOT) assay. RESULTS: Serial ELISPOT assays were performed on PBMCs from 17 patients (seven definite, four probable, and six possible TBM) and CSF-MC from nine patients (all definite TBM). The median number of interferon-gamma (IFN-gamma)-producing T-cells steadily increased during the first 6 months after commencement of anti-TB therapy in PBMCs. Serial CSF-MC ELISPOT assays revealed significant variability in immune responses during the first 6 weeks of anti-TB therapy, though early increases in CSF-MC ELISPOT results were associated with treatment failure or paradoxical response. CONCLUSIONS: Serial analysis of PBMCs by ELISPOT during the course of treatment was ineffective for predicting clinical response. However, increases in TB-specific IFN-gamma-producing T-cells in CSF-MC during the early phase of anti-TB therapy may be predictive of clinical failure.
Adult ; Antitubercular Agents/therapeutic use ; Biological Markers/blood/cerebrospinal fluid ; *Enzyme-Linked Immunospot Assay ; Female ; Humans ; Interferon-gamma/blood/cerebrospinal fluid ; *Interferon-gamma Release Tests ; Kinetics ; Male ; Middle Aged ; Predictive Value of Tests ; Prospective Studies ; Republic of Korea ; T-Lymphocytes/drug effects/*immunology/metabolism/microbiology ; Treatment Outcome ; Tuberculosis, Meningeal/blood/cerebrospinal fluid/*diagnosis/drug therapy/immunology/microbiology

OBJECTIVETo evaluate the effect of different immune status on the incidence of hepatic lesions in patients with hepatitis B virus (HBV) infection undergoing anti-tuberculosis therapy.

METHODSThe PubMed (1966-2013), Embase (1966-2013), Wanfang (1998-2013), Chinese National Knowledge Infrastructure (CNKI; 1997-2013), and Chinese Biomedical (CBMdisc; 1860-2013) literature databases were searched for case-control studies of hepatic lesions in patients undergoing anti-tuberculosis therapy with or without concomitant HBV infection. The HBV patients were divided into subgroups according to hepatitis B e antigen (HBeAg) positivity or negativity, all members of the control group were HBsAg⁻. The data from all 7 studies included in the meta-analysis were extracted and analysed using RevMan5.2 soft-ware.

RESULTSPatients with HBV infection who were undergoing anti-tuberculosis therapy had a higher risk factor than the control patients (OR =5.81, 95% CI =[4.26, 7.39]). The HBV patients with HBeAg positivity who were undergoing anti-tuberculosis therapy had a high risk factor than the HBV patients with HBeAg negativity (OR =2.56, 95% CI=[1.90, 3.44]).

CONCLUSIONHBV infection is a risk factor for hepatic lesions when undergoing anti-tuberculosis therapy, and HBeAg-positive status may put a patient at higher risk.

Antitubercular Agents ; adverse effects ; therapeutic use ; Hepatitis B ; complications ; pathology ; Hepatitis B e Antigens ; blood ; Humans ; Liver ; drug effects ; pathology ; Tuberculosis ; complications ; drug therapy ; pathology

BACKGROUND: Chitotriosidase is an accepted marker of macrophage activation. In this study, we investigated serum chitotriosidase levels in pulmonary tuberculosis (PTB). METHODS: Forth-two patients with PTB and 30 healthy subjects were enrolled in the study. The radiological extent of PTB, radiological sequela after treatment, and the degree of smear positivity were assessed. Chitotriosidase levels were measured by a fluorometric method. RESULTS: The serum chitotriosidase levels of the PTB patients were significantly higher than those of the control subjects (39.73+/-24.97 vs. 9.63+/-4.55 nmol/mL/h, P<0.001). After completion of the standard 6-month antituberculous treatment, chitotriosidase levels in PTB patients significantly decreased (10.47+/-4.54 nmol/mL/h, P<0.001). Chitotriosidase levels correlated significantly with the radiological extent of PTB, degree of smear positivity, and post-treatment radiological sequela score (r=0.439, r=0.449, and r=0.337, respectively). CONCLUSIONS: This study demonstrated that serum chitotriosidase levels increase in PTB; therefore, chitotriosidase can be used as a marker of disease activity, severity, and response to treatment.
Adult ; Antitubercular Agents/therapeutic use ; Biological Markers/blood ; Fluorometry ; Hexosaminidases/*blood ; Humans ; Male ; ROC Curve ; Severity of Illness Index ; Tuberculosis, Pulmonary/drug therapy/*enzymology/radiography ; Young Adult

OBJECTIVETo study the distribution of isoniazid and its metabolite in spinal tuberculosis following chemotherapy.

METHODSTwenty-three patients with spinal tuberculosis received chemotherapy with 2SHRZ/16HRZ (for a total of 18 months). Four weeks after the chemotherapy, all the patients underwent surgery and specimens of the serum, ilium and vertebral tissue including the sclerotic wall, focus inside the sclerotic wall (if present) and destructed foci were obtained. CT was performed in all the cases to test the HU of the foci before operation, and the levels of isoniazid and its metabolite in the specimen were measured with high-performance liquid chromatography (HPLC).

RESULTSThe levels of isoniazid and its metabolite were the highest in the serum, followed by normal ilium and non-sclerotic bone, and were extremely low in the sclerotic wall and foci. Their levels in the non-sclerotic bone of the compromised vertebra and normal vertebra showed no significant difference (P>0.05), but in the sclerotic bone, their levels were significantly higher than in the normal vertebra (P<0.05). Isoniazid and its metabolite are hardly detectable in the sclerotic foci in the compromised vertebrae.

CONCLUSIONIsoniazid and its metabolite may reach therapeutic concentration in normal vertebra and nonsclerotic bones of the compromised vertebra, but not in the disease foci or the sclerotic bone of the compromised vertebrae.

Adult ; Aged ; Antitubercular Agents ; blood ; pharmacokinetics ; therapeutic use ; Chromatography, High Pressure Liquid ; Female ; Humans ; Isoniazid ; analogs & derivatives ; blood ; pharmacokinetics ; therapeutic use ; Lumbar Vertebrae ; metabolism ; Male ; Middle Aged ; Tuberculosis, Spinal ; drug therapy ; Young Adult