Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including katG mutations in isoniazid resistance, rpoB mutations in rifampin resistance, pncA mutations in pyrazinamide resistance, and gyrA mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, Mycobacterium tuberculosis may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of Mycobacterium tuberculosis is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.
Humans ; Pyrazinamide/therapeutic use* ; Isoniazid/therapeutic use* ; Antitubercular Agents/therapeutic use* ; Tuberculosis, Multidrug-Resistant/microbiology* ; Mycobacterium tuberculosis/genetics* ; Tuberculosis/drug therapy* ; Rifampin/therapeutic use* ; Mutation ; Drug Resistance, Multiple, Bacterial/genetics*

pyrazinamide were prescribed orally. Group 2 consisted of 31 patients treated with the first-line anti-TB drugs orally. The concentrations of H and E in blood serum were detected using a chromatographic method.RESULTS: A significant improvement in the clinical symptoms and X-ray signs in patients treated intravenously with H and E was observed and compared to group 2. The sputum Mycobacterium tuberculosis positivity was observed during the second month of the treatment in 25.0% of patients from group 1 and 76.1% of the patients from the control group (p=0.003). In addition, nine patients (39.1%) died up to 6 months when H and E were prescribed intravenously compared with 22 (70.9%) in group 2 (p=0.023).CONCLUSION: In TB/TM with HIV, the intravenous H and E treatment was more effective than oral H and E treatment at 2 months of intensive treatment in sputum conversion as well as in clinical improvement, accompanied by significantly higher mean serum concentrations. In addition, the mortality rate was lower in intravenous H and E treatment compared to oral treatment.]]>
Coinfection ; Ethambutol ; HIV Infections ; HIV ; Humans ; Isoniazid ; Meningoencephalitis ; Methods ; Mortality ; Mycobacterium tuberculosis ; Pyrazinamide ; Rifampin ; Serum ; Sputum ; Tuberculosis ; Tuberculosis, Meningeal ; Tuberculosis, Pulmonary

PURPOSE: Although there have been reported cases of drug reactions with eosinophilia and systemic symptoms (DRESS) syndrome caused by antituberculosis drugs, there has been no research to examine its prevalence. This study assessed the prevalence and clinical characteristics of DRESS syndrome caused by antituberculosis drugs. METHODS: The electronic medical records of a cohort consisting of adult patients diagnosed with tuberculosis between July 2006 and June 2010 were reviewed and retrospectively inspected. We searched the surveillance system for adverse drug reactions and the electronic medical records to identify patients who reported severe cutaneous adverse reactions to antituberculosis drugs. These patients were then re-assessed using a European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) scoring system. Clinical characteristics, including the symptoms and latency of DRESS syndrome, the therapeutic dosage and period of steroids, and the final duration of tuberculosis therapy, were examined. RESULTS: Of the 1,253 adult patients with tuberculosis receiving antituberculosis drugs, 15 were identified as potential cases of DRESS syndrome (prevalence of 1.2%). Ethambutol was the most frequently used drug (53.5%), followed by rifampicin (26.7%), pyrazinamide (20.0%), streptomycin (13.3%), and isoniazid (6.7%). The median latency after day 1 of antituberculosis medication was 42 days. The median daily dose of steroids, expressed in prednisone-equivalent units, was 33-mg/day, and the median dosing period was 14 days. The duration of tuberculosis treatment was 76 days longer than the standard treatment period of 180 days. There was a significant difference in the peak eosinophil counts of DRESS syndrome patients according to RegiSCAR scores. Moreover, there was a significant quantitative correlation between the RegiSCAR score and peak eosinophil count. A negative correlation was also found between the RegiSCAR score and latency. CONCLUSIONS: This study confirmed the prevalence of DRESS syndrome in a cohort of adult patients with tuberculosis.
Adult ; Cohort Studies* ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Electronic Health Records ; Eosinophilia* ; Eosinophils ; Ethambutol ; Humans ; Isoniazid ; Prevalence* ; Pyrazinamide ; Retrospective Studies* ; Rifampin ; Steroids ; Streptomycin ; Tuberculosis

Anagen effluvium is an abrupt loss of hair in its growing phase due to an event that impairs the mitotic or metabolic activity of the hair follicle. Anagen effluvium is commonly associated with the administration of chemotherapy, radiation, and drugs as well as exposure to toxic chemicals. However, alopecia due to the administration of anti-tuberculosis drugs has rarely been reported in the literature. A 50-year-old female was diagnosed with intestinal tuberculosis and was started on anti-tuberculosis therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide. After starting the treatment, erythematous to brown patches appeared all over her body, which was followed by diffuse hair loss on the scalp and body. Hair examination showed intact inner and outer root sheaths with fully pigmented hair bulbs, and histopathological examination of a scalp biopsy showed vacuolar degeneration in the interfollicular epidermis and perifollicular infiltration of mononuclear cells and eosinophils. The condition was diagnosed as anagen effluvium with drug eruption, and a potent corticosteroid lotion was prescribed for scalp application twice a day. After complete hair loss, the anti-tuberculosis medications were withdrawn, and hair regrowth started 4 months later. Here, we report a rare case of anagen effluvium with generalized drug eruption due to anti-tuberculosis medication.
Alopecia ; Biopsy ; Drug Eruptions* ; Drug Therapy ; Eosinophils ; Epidermis ; Ethambutol ; Female ; Hair ; Hair Follicle ; Humans ; Isoniazid ; Middle Aged ; Pyrazinamide ; Rifampin ; Scalp ; Tuberculosis

Tuberculosis (TB) remains the world's leading cause of death from a single infectious disease. In addition, the incidence of TB is high in South Korea. Effective TB control requires early diagnosis and initiation of appropriate treatment. Therefore, it is very important for clinicians to understand evidence-based practical recommendations and to be familiar with up-to-date treatment regimens. In this review, we first describe anti-TB drugs, including new drugs. Secondly, we discuss the treatment of drug-susceptible TB. Finally, we present treatment strategies for drug-resistant TB, which is divided into isoniazid-resistant TB, rifampin-resistant TB, and multi-drug resistant TB. For the treatment of drug-susceptible TB, we recommend 2 months of 4 drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) followed by 4 months of 2 drugs (isoniazid and rifampin). For the treatment of isoniazid-resistant TB, we recommend 6 to 9 months of 4 drugs (rifampin, ethambutol, pyrazinamide, and levofloxacin or moxifloxacin). For the treatment of multi-drug resistant TB (MDR-TB), we recommend a minimum of 5 secondary drugs, including an injectable agent and quinolone. Although the World Health Organization recommended a shorter MDR-TB regimen in 2016, the Korean guidelines for tuberculosis have not yet accepted the shorter regimen. The treatment regimen of TB differs depending on the drug resistance pattern. Therefore, it is important to treat TB properly after confirming the drug resistance pattern. In addition, as new drugs are developed, new treatment guidelines for MDR-TB should be developed that are appropriate for circumstances in Korea.
Cause of Death ; Communicable Diseases ; Drug Resistance ; Early Diagnosis ; Ethambutol ; Incidence ; Korea ; Levofloxacin ; Pyrazinamide ; Rifampin ; Tuberculosis ; Tuberculosis, Multidrug-Resistant ; Tuberculosis, Pulmonary ; World Health Organization

BACKGROUND: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that can affect many organs of the body but usually affects the lungs. The prevalence of TB in Korea is considerably higher than that in other countries with similar economic levels, and is much higher in elderly people. Pharmacotherapy is important in the treatment of TB and requires relatively high compliance for a prolonged duration. METHODS: We analyzed sample data of elderly patients obtained from the Health Insurance Review and Assessment Service. We used logistic regression analysis and frequency analysis to identify factors that could affect prevalence of TB in elderly patients, compliance with prescribed medication regimes in these patients, and use of medical institutions. Korean Standard Classification of Diseases, version 7 (KCD-7) was used to diagnose pulmonary TB, and medications were analyzed using Korean standardized drug classification codes. RESULTS: 1,276,331 patients were analyzed in the sample of the elderly population, and 16,658 TB patients were included in the study. The mean age of the TB patients was 76.19 years (SD 6.899). A total of 699 patients were prescribed isoniazid, rifampicin, ethambutol, or pyrazinamide at least once. Of these, 352 (50.4%) were prescribed all four medications and 101 (14.4%) were prescribed only isoniazid, rifampicin, and ethambutol. The mean duration of prescription was 28.75 days (SD 36.13). CONCLUSION: In the elderly population, old age and poor socioeconomic conditions correlated with TB prevalence. Most patients did not meet the criteria for effective pharmacotherapy of TB.
Aged ; Classification ; Communicable Diseases ; Compliance ; Drug Therapy ; Ethambutol ; Humans ; Insurance, Health ; Isoniazid ; Korea ; Logistic Models ; Lung ; Mycobacterium tuberculosis ; Prescription Drugs* ; Prescriptions* ; Prevalence ; Pyrazinamide ; Rifampin ; Tuberculosis ; Tuberculosis, Pulmonary*

Pyrazinamide (PZA) is an anti-tuberculosis drug and an essential component of the standard four-drug regimen for tuberculosis. Here, we report a case of immediate angioedema secondary to PZA administration intended for pulmonary tuberculosis treatment. A previously healthy 48-year-old woman was diagnosed with pulmonary tuberculosis and tuberculous lymphadenitis. Thirty minutes after taking the first dose of isoniazid, rifampicin, pyrazinamide, and ethambutol, the patient developed facial edema, generalized rash, and dizziness. An oral provocation test was performed on the four drugs, and 1,000 mg pyrazinamide showed a positive result characterized by 50 minutes of urticaria, angioedema, and hypotension. As the prevalence of tuberculosis increases, prescriptions for anti-tuberculosis drugs may increase as well. Clinicians should be aware of the possibility of immediate hypersensitivity as well as delayed hypersensitivity to anti-tuberculosis drugs.
Angioedema* ; Dizziness ; Drug Hypersensitivity ; Edema ; Ethambutol ; Exanthema ; Female ; Humans ; Hypersensitivity, Delayed ; Hypersensitivity, Immediate ; Hypotension ; Isoniazid ; Middle Aged ; Prescriptions ; Prevalence ; Pyrazinamide ; Rifampin ; Tuberculosis ; Tuberculosis, Lymph Node ; Tuberculosis, Pulmonary ; Urticaria*

BACKGROUND: We examined the feasibility of a full-length gene analysis for the drug resistance-related genes inhA, katG, rpoB, pncA, rpsL, embB, eis, and gyrA using ion semiconductor next-generation sequencing (NGS) and compared the results with those obtained from conventional phenotypic drug susceptibility testing (DST) in multidrug-resistant Mycobacterium tuberculosis (MDR-TB) isolates. METHODS: We extracted genomic DNA from 30 pure MDR-TB isolates with antibiotic susceptibility profiles confirmed by phenotypic DST for isoniazid (INH), rifampin (RIF), ethambutol (EMB), pyrazinamide (PZA), amikacin (AMK), kanamycin (KM), streptomycin (SM), and fluoroquinolones (FQs) including ofloxacin, moxifloxacin, and levofloxacin. Enriched ion spheres were loaded onto Ion PI Chip v3, with 30 samples on a chip per sequencing run, and Ion Torrent sequencing was conducted using the Ion AmpliSeq TB panel (Life Technologies, USA). RESULTS: The genotypic DST results revealed good agreement with the phenotypic DST results for EMB (Kappa 0.8), PZA (0.734), SM (0.769), and FQ (0.783). Agreements for INH, RIF, and AMK+KM were not estimated because all isolates were phenotypically resistant to INH and RIF, and all isolates were phenotypically and genotypically susceptible to AMK+KM. Moreover, 17 novel variants were identified: six (p.Gly169Ser, p.Ala256Thr, p.Ser383Pro, p.Gln439Arg, p.Tyr597Cys, p.Thr625Ala) in katG, one (p.Tyr113Phe) in inhA, five (p.Val170Phe, p.Thr400Ala, p.Met434Val, p.Glu812Gly, p.Phe971Leu) in rpoB, two (p.Tyr319Asp and p.His1002Arg) in embB, and three (p.Cys14Gly, p.Asp63Ala, p.Gly162Ser) in pncA. CONCLUSIONS: Ion semiconductor NGS could detect reported and novel amino acid changes in full coding regions of eight drug resistance-related genes. However, genotypic DST should be complemented and validated by phenotypic DSTs.
Amikacin ; Clinical Coding ; Complement System Proteins ; DNA ; Drug Resistance* ; Ethambutol ; Fluoroquinolones ; Isoniazid ; Kanamycin ; Levofloxacin ; Mycobacterium tuberculosis* ; Mycobacterium* ; Ofloxacin ; Pyrazinamide ; Rifampin ; Semiconductors* ; Streptomycin

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially fatal drug-induced systemic hypersensitivity response characterized by erythematous eruption, fever, leukocytosis with eosinophilia, and internal organ involvement. Antitubercular agents are potential causative agents for DRESS syndrome but difficult to verify as a culprit drug, since antitubercular agents are coadministered as a combination regimen. A 42-year-old female with endobronchial tuberculosis was diagnosed with DRESS syndrome after 4-week treatment of isoniazid, rifampicin, ethambutol, and pyrazinamide with prednisolone 50 mg. All the antitubercular agents were stopped and replaced with levofloxacin, cycloserine, p-aminosalicylic acid, and kanamycin. However, severe exacerbation of DRESS syndrome compelled the patient to discontinue the administration of the second-line antitubercular agents. Two months later, the patient underwent a patch test for all the antitubercular agents which had been used, and the results showed positivity to isoniazid and cycloserine. We report a rare case of DRESS syndrome that reacted to cycloserine as well as isoniazid. Development of coreactivity to other drugs should be differentiated with a flare-up reaction in the management of DRESS syndrome.
Adult ; Aminosalicylic Acid ; Antitubercular Agents ; Cycloserine ; Drug Hypersensitivity Syndrome ; Eosinophilia* ; Ethambutol ; Female ; Fever ; Humans ; Hypersensitivity ; Isoniazid ; Kanamycin ; Leukocytosis ; Levofloxacin ; Patch Tests ; Prednisolone ; Pyrazinamide ; Rifampin ; Tuberculosis

The incidence of drug-resistant tuberculosis (DR-TB) in pediatric populations is a critical indicator of national TB management and treatment strategies. Limited data exist regarding the rate of pediatric DR-TB. In this study, we aimed to analyze the status of DR-TB in Korean children from 2007 to 2013. We analyzed specimens submitted to the Korean Institute of Tuberculosis using Mycobacterium tuberculosis culture and drug susceptibility tests (DSTs) from January 2007 through December 2013. Specimens from patients ≤ 19 years of age were included. Among the 2,690 cases, 297 cases were excluded because of insufficient data, leaving 2,393 cases for the final analysis. In total, resistance to one or more TB drugs was 13.5%. The resistance rates of each of the drugs were as follows: isoniazid (INH) 10.2%, rifampin (RFP) 5.1%, ethambutol (EMB) 3.7%, and pyrazinamide (PZA) 3.1%. The resistance rate of multidrug-resistant TB (MDR-TB) was 4.2%, and that of extensively drug-resistant TB (XDR-TB) was 0.8%. The overall drug resistance rate demonstrated significant increase throughout the study period (P < 0.001) but showed no significant difference compared to previous study from 1999 to 2007. The drug resistance rate of PZA in ≤ 15 years of age group was significantly greater than that of > 15 years (P < 0.001). The drug resistance rate has increased throughout the study period.
Adolescent* ; Child* ; Drug Resistance ; Ethambutol ; Humans ; Incidence ; Isoniazid ; Mycobacterium tuberculosis ; Pyrazinamide ; Rifampin ; Tuberculosis ; Tuberculosis, Multidrug-Resistant*