prothionamide and Tuberculosis

Ethionamide (ETH) and prothionamide (PTH), both thioamides, have proven efficacy in clinical studies and form important components for multidrug-resistant tuberculosis treatment regimens and for treatment of tuberculous meningitis in adults and children. ETH and PTH are pro-drugs that, following enzymatic activation by mycobacterial EthA inhibit InhA, a target shared with isoniazid (INH), and subsequently inhibit mycolic acid synthesis of Mycobacterium tuberculosis. Co-resistance to INH and ETH is conferred by mutations in the mycobacterial inhA promoter region; mutations in the ethA gene often underlie ETH and PTH monoresistance. An oral daily dose of ETH or PTH of 15-20 mg/kg with a maximum daily dose of 1000 mg is recommended in children to achieve adult-equivalent serum concentrations shown to be efficacious in adults, although information on optimal pharmacodynamic targets is still lacking. Gastrointestinal disturbances, and hypothyroidism during long-term therapy, are frequent adverse effects observed in adults and children, but are rarely life-threatening and seldom necessitate cessation of ETH therapy. More thorough investigation of the therapeutic effects and toxicity of ETH and PTH is needed in childhood TB while child-friendly formulations are needed to appropriately dose children.

Topics: Adolescent; Age Factors; Animals; Antitubercular Agents; Child; Child, Preschool; Drug Compounding; Drug Dosage Calculations; Drug Resistance, Bacterial; Ethionamide; Humans; Infant; Mycobacterium tuberculosis; Prothionamide; Treatment Outcome; Tuberculosis; Young Adult

Topics: Animals; Antitubercular Agents; Humans; Prothionamide; Treatment Outcome; Tuberculosis

Topics: Antitubercular Agents; Contraindications; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Prothionamide; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

Topics: Antitubercular Agents; Clofazimine; Drug Therapy, Combination; Humans; Isoniazid; Prothionamide; Pyrazinamide; Treatment Outcome; Tuberculosis

Topics: Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Prothionamide; Streptomycin; Tuberculosis

Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is a major cause of death amongst tuberculosis patients. Nanomedicine avoids some limitations of conventional drug treatment and increases therapeutic efficacy against bacterial infections. However, the effect of anti-TB drug nanoparticle (NP) compounds in anti-TB regimens against MDR-TB remains unclear.. The objective of this article is to prepare levofloxacin, linezolid, ethambutol, prothionamide, and pyrazinamide encapsulated NPs and to evaluate their therapeutic efficacy against MDR-TB in macrophages.. Drug-loaded PLGA NPs were prepared by the multiple emulsion method. The colocalization, intracellular release, and anti-TB activity of these NPs were investigated on cultured macrophages. The immune phenotype of the macrophages, including their mitochondrial membrane potential, reactive oxygen species (ROS), and nitric oxide (NO) production, was evaluated following treatment with NPs or free drug compounds.. All drug-loaded PLGA NPs were spherical in shape, 150 to 210 nm in size, and showed 14.22% to 43.51% encapsulation efficiencies and long-duration release. Drug-loaded PLGA NPs were mainly distributed in the cytoplasm of macrophages, showed high cellular compatibility, and maintained their concentration for at least 13 days. Compared with the free drug compounds, the number of colonies after exposure to PLGA NP compounds was significantly less. The enhanced antibacterial activity of the NP compounds may be due to the enhanced levels of ROS and NO and the increased early apoptosis stress within M. tuberculosis-infected macrophages additionally.. The application of PLGA NP compounds not only enhances drug efficacy but also induces innate bactericidal events in macrophages, confirming this as a promising approach for MDR-TB therapy.

Topics: Anti-Bacterial Agents; Antitubercular Agents; Ethambutol; Humans; Levofloxacin; Linezolid; Mycobacterium tuberculosis; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Prothionamide; Pyrazinamide; Reactive Oxygen Species; Tuberculosis; Tuberculosis, Multidrug-Resistant

Rifampin (RIF) has been widely used for the treatment of bacterial infections, including tuberculosis (TB). Treatment of drug-resistant TB is a global problem because of reduced drug efficacy. The present study determined the effect of RIF on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages and analyzed the intracellular concentration of the anti-TB drug prothionamide in the presence of RIF. RIF treatment significantly induced MDR1 protein and mRNA levels in phorbol 12-myristate 13-acetate-stimulated THP1 macrophages (p < 0.001 and 0.01, respectively). The pregnane X receptor inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (p < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular concentration of rhodamine-123 and prothionamide (p < 0.01 and 0.05, respectively). By contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular concentration of rhodamine-123 and prothionamide (p < 0.001 and 0.05, respectively). The present results suggest that the usage of RIF together with P-gp-substrate drugs to treat TB may lead to deteriorated treatment efficacy because of the lower intracellular drug concentration. Further studies would be necessary to know the influence of RIF-induced P-gp induction on the treatment outcome of patients with TB.

Topics: Antitubercular Agents; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Drug Antagonism; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Intracellular Fluid; Macrophages; Prothionamide; Rifampin; Tuberculosis; Up-Regulation

Rifampin (RIF) mono-resistant tuberculosis (RMR-TB) is a rare disease. Current guidelines recommend that RMR-TB be treated as multidrug-resistant TB (MDR-TB) but the evidence is scarce.. We conducted a retrospective cohort study on pulmonary TB patients to investigate the characteristics and outcomes of RMR-TB. The characteristics of RMR-TB were compared with those with adverse events to rifampin (RAE-TB).. Forty-four RMR-TB and 29 RAE-TB patients were enrolled. RMR-TB patients showed more alcohol use, prior history of TB, and radiologically severe disease, while RAE-TB patients were older and had more comorbidities and combined extrapulmonary TB. A fluoroquinolone (FQ) was the drug most commonly added (70.5%, RMR-TB; 82.8%, RAE-TB). Median treatment duration was 453 days in RMR-TB and 371 days in RAE-TB (p = 0.001) and treatment success rates were 87.2% (34/39) and 80.0% (20/25), respectively (p = 0.586). Subanalysis of the RMR-TB group by treatment regimen (standard regimen [n = 11], standard regimen + FQ [n = 12], MDR-TB regimen [n = 21]) revealed a higher rate of radiologically severe disease in the MDR-TB subgroup, with similar treatment success rates for the subgroups (85.7% [6/7]), 91.7% [11/12], and 85.0% [17/20], respectively) despite different durations of treatment (345, 405, and 528 days, respectively). Two recurrences (33.3% [2/6]) developed only in standard regimen subgroup, suggesting that standard regimen is not enough to treat RMR-TB patients.. The treatment outcome of RMR-TB with 1

Topics: Adult; Age Distribution; Aged; Alcohol Drinking; Aminosalicylic Acid; Antitubercular Agents; Cohort Studies; Comorbidity; Cycloserine; Ethambutol; Female; Fluoroquinolones; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Prothionamide; Pyrazinamide; Republic of Korea; Retrospective Studies; Rifampin; Severity of Illness Index; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Anti-tuberculosis drugs can produce levels of hepatotoxicity ranging from mild elevation of aminotransferase to severe acute hepatitis. A few cases of drug-induced autoimmune hepatitis or the drug reaction with eosinophilia and systemic symptom (DRESS) syndrome by anti-tuberculosis medications have been reported. However, concomitant occurrence of these two disorders has not been reported. Here, we present a case of severe acute hepatitis with DRESS syndrome and autoimmune hepatitis resulting from primary standard anti-tuberculosis drugs. Both conditions were successfully treated with a systemic steroid regimen.

Topics: Alanine Transaminase; Antitubercular Agents; Cycloserine; Drug Hypersensitivity Syndrome; Drug Therapy, Combination; Eosinophilia; Ethambutol; Female; Hepatitis, Autoimmune; Humans; Isoniazid; Levofloxacin; Liver; Prothionamide; Severity of Illness Index; Tuberculosis; Young Adult

To investigate drug-induced liver injury (DILI) in tuberculosis (TB) patients treated with protionamide (Pto) and (or) para-aminosalicylic acid (PAS), and therefore to provide data for using second-line anti-tuberculosis drugs and risk prediction of liver damage.. A retrospective analysis was performed for TB patients treated with regimens containing Pto and (or) PAS in Beijing Chest Hospital during Jan. 2008 to Jan. 2013. Cases with DILI were identified, and associated factors including patients' age and gender, time of onset, severity, clinical manifestations and prognosis of DILI were analyzed. The 2 groups were compared with χ(2) test. P < 0.05 was considered to be significant.. A total of 1714 cases were admitted, among whom 226 experienced liver damage during treatment, of which 97 cases were excluded because of underlying alcoholic liver disease, viral hepatitis B and C. Finally, 129 cases were diagnosed as having DILI, resulting in an overall incidence of 7.5% (129/1714), being 9.2% (59/641) in females, and 6.5% (70/1073) in males (χ(2) = 4.143, P < 0.05). DILI in most patients occurred between 1 week to 2 months, with 30.2% (39/129) within 2-4 weeks. 47.3% (61/129) of the patients showed no obvious clinical symptoms of hepatotoxicity. Among different regimens, combination of Pto, PAS and PZA resulted in the highest rate of DILI (20.7%, 19/92), while the rate was 9.8% (8/82) for the combination of Pto and PZA, P < 0.05.. DILI caused by Pto and PAS should be taken into account, especially in female patients and for multi-drug combination therapy. Liver function should be monitored even in patients without related clinical manifestations for early identification and treatment, and therefore avoiding severe liver damage.

Topics: Adolescent; Adult; Aged; Aminosalicylic Acid; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Prothionamide; Retrospective Studies; Risk Factors; Tuberculosis; Young Adult

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

Topics: Antitubercular Agents; Bacterial Proteins; Crystallography, X-Ray; Drug Design; Drug Resistance, Multiple, Bacterial; Ethionamide; Humans; In Vitro Techniques; Leprostatic Agents; Leprosy; Models, Molecular; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium leprae; Mycobacterium tuberculosis; NAD; Oxidoreductases; Prothionamide; Tuberculosis; Tuberculosis, Multidrug-Resistant

This study documents the course of a tuberculosis epidemic in an immunologically naive group of South American Indians within fewer than 20 years after first sustained contact with outsiders. Groups of Northern Aché (ah-CHAY) of eastern Paraguay were contacted and settled on reservations between 1971-1979. Not surprisingly, the Aché are very susceptible to tuberculosis, and the epidemiological characteristics of the disease are quite different from those of populations that have had tuberculosis for centuries. Within 6 years of the first detected case of tuberculosis among the Aché, the prevalence rate of active tuberculosis cases reached 18.2%, and of infected cases among adults, 64.6%, some of the highest rates ever reported for any human group. Remarkably, males and females are equally likely to have been diagnosed with active tuberculosis, Aché children between birth and 5 years of age are least vulnerable to tuberculosis, high nutritional and socioeconomic status do not decrease the risk of disease or infection, and children immunized with BCG are less responsive to tuberculin challenge than are other children. Moreover, similar to the Yanomamö, but unlike populations of European or African descent, a high percentage of Aché with active disease test negative on tuberculin challenge tests (purified protein derivative; PPD). These differences may be due to a high prevalence of diminished cell-mediated immunity, and T-helper 2 dominance. We also hypothesize that these immunological characteristics, low genetic diversity, hostile intergroup interactions, and behavioral noncompliance to treatment protocols together contribute to the high rates of active disease observed. Existing tuberculosis control programs are poorly equipped to handle the impact of these causal complexities on the course of recent tuberculosis epidemics that have quickly spread throughout native communities of Latin America during the last decade.

Topics: Adolescent; Adult; Age Distribution; Asian People; BCG Vaccine; Child; Child, Preschool; Dapsone; Disease Outbreaks; Drug Combinations; Female; Humans; Indians, South American; Infant; Isoniazid; Longitudinal Studies; Male; Middle Aged; Paraguay; Prevalence; Prothionamide; Risk Factors; Sex Distribution; Tuberculosis

Topics: Dapsone; Drug Combinations; Drug Therapy, Combination; Humans; Isoniazid; Leprostatic Agents; Leprosy; Paraguay; Prothionamide; Rifampin; Tuberculosis

Topics: Adult; Aged; Airway Obstruction; Aspergillosis; Carrier State; Dapsone; Female; Germany, West; Humans; Infectious Mononucleosis; Isoniazid; Male; Middle Aged; Prothionamide; Spondylitis, Ankylosing; Tuberculosis

Topics: Aminosalicylic Acids; Capreomycin; Ethambutol; Ethionamide; Humans; Isoniazid; Prothionamide; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Prothionamide; Rifampin; Sulfones; Tuberculosis