ethionamide and Tuberculosis--Multidrug-Resistant

The World Health Organization (WHO) End TB Strategy stresses universal access to drug susceptibility testing (DST). DST determines whether Mycobacterium tuberculosis bacteria are susceptible or resistant to drugs. Xpert MTB/XDR is a rapid nucleic acid amplification test for detection of tuberculosis and drug resistance in one test suitable for use in peripheral and intermediate level laboratories. In specimens where tuberculosis is detected by Xpert MTB/XDR, Xpert MTB/XDR can also detect resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin.. To assess the diagnostic accuracy of Xpert MTB/XDR for pulmonary tuberculosis in people with presumptive pulmonary tuberculosis (having signs and symptoms suggestive of tuberculosis, including cough, fever, weight loss, night sweats). To assess the diagnostic accuracy of Xpert MTB/XDR for resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin in people with tuberculosis detected by Xpert MTB/XDR, irrespective of rifampicin resistance (whether or not rifampicin resistance status was known) and with known rifampicin resistance.. We searched multiple databases to 23 September 2021. We limited searches to 2015 onwards as Xpert MTB/XDR was launched in 2020.. Diagnostic accuracy studies using sputum in adults with presumptive or confirmed pulmonary tuberculosis. Reference standards were culture (pulmonary tuberculosis detection); phenotypic DST (pDST), genotypic DST (gDST),composite (pDST and gDST) (drug resistance detection).. Two review authors independently reviewed reports for eligibility and extracted data using a standardized form. For multicentre studies, we anticipated variability in the type and frequency of mutations associated with resistance to a given drug at the different centres and considered each centre as an independent study cohort for quality assessment and analysis. We assessed methodological quality with QUADAS-2, judging risk of bias separately for each target condition and reference standard. For pulmonary tuberculosis detection, owing to heterogeneity in participant characteristics and observed specificity estimates, we reported a range of sensitivity and specificity estimates and did not perform a meta-analysis. For drug resistance detection, we performed meta-analyses by reference standard using bivariate random-effects models. Using GRADE, we assessed certainty of evidence of Xpert MTB/XDR accuracy for detection of resistance to isoniazid and fluoroquinolones in people irrespective of rifampicin resistance and to ethionamide and amikacin in people with known rifampicin resistance, reflecting real-world situations. We used pDST, except for ethionamide resistance where we considered gDST a better reference standard.. We included two multicentre studies from high multidrug-resistant/rifampicin-resistant tuberculosis burden countries, reporting on six independent study cohorts, involving 1228 participants for pulmonary tuberculosis detection and 1141 participants for drug resistance detection. The proportion of participants with rifampicin resistance in the two studies was 47.9% and 80.9%. For tuberculosis detection, we judged high risk of bias for patient selection owing to selective recruitment. For ethionamide resistance detection, we judged high risk of bias for the reference standard, both pDST and gDST, though we considered gDST a better reference standard. Pulmonary tuberculosis detection - Xpert MTB/XDR sensitivity range, 98.3% (96.1 to 99.5) to 98.9% (96.2 to 99.9) and specificity range, 22.5% (14.3 to 32.6) to 100.0% (86.3 to 100.0); median prevalence of pulmonary tuberculosis 91.3%, (interquartile range, 89.3% to 91.8%), (2 studies; 1 study reported on 2 cohorts, 1228 participants; very low-certainty evidence, sensitivity and specificity). Drug resistance detection People irrespective of rifampicin resistance - Isoniazid resistance: Xpert MTB/XDR summary sensitivity and specificity (95% confidence interval (CI)) were 94.2% (87.5 to 97.4) and 98.5% (92.6 to 99.7) against pDST, (6 cohorts, 1083 participants, moderate-certainty evidence, sensitivity and specificity). - Fluoroquinolone resistance: Xpert MTB/XDR summary sensitivity and specificity were 93.2% (88.1 to 96.2) and 98.0% (90.8 to 99.6) against pDST, (6 cohorts, 1021 participants; high-certainty evidence, sensitivity; moderate-certainty evidence, specificity). People with known rifampicin resistance - Ethionamide resistance: Xpert MTB/XDR summary sensitivity and specificity were 98.0% (74.2 to 99.9) and 99.7% (83.5 to 100.0) against gDST, (4 cohorts, 434 participants; very low-certainty evidence, sensitivity and specificity). - Amikacin resistance: Xpert MTB/XDR summary sensitivity and specificity were 86.1% (75.0 to 92.7) and 98.9% (93.0 to 99.8) against pDST, (4 cohorts, 490 participants; low-certainty evidence, sensitivity; high-certainty evidence, specificity). Of 1000 people with pulmonary tuberculosis, detected as tuberculosis by Xpert MTB/XDR: - where 50 have isoniazid resistance, 61 would have an Xpert MTB/XDR result indicating isoniazid resistance: of these, 14/61 (23%) would not have isoniazid resistance (FP); 939 (of 1000 people) would have a result indicating the absence of isoniazid resista. Review findings suggest that, in people determined by Xpert MTB/XDR to be tuberculosis-positive, Xpert MTB/XDR provides accurate results for detection of isoniazid and fluoroquinolone resistance and can assist with selection of an optimised treatment regimen. Given that Xpert MTB/XDR targets a limited number of resistance variants in specific genes, the test may perform differently in different settings. Findings in this review should be interpreted with caution. Sensitivity for detection of ethionamide resistance was based only on Xpert MTB/XDR detection of mutations in the inhA promoter region, a known limitation. High risk of bias limits our confidence in Xpert MTB/XDR accuracy for pulmonary tuberculosis. Xpert MTB/XDR's impact will depend on its ability to detect tuberculosis (required for DST), prevalence of resistance to a given drug, health care infrastructure, and access to other tests.

Topics: Adult; Amikacin; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Ethionamide; Fluoroquinolones; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Lymph Node; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Multidrug-resistant tuberculosis (MDR TB) has become a major global health concern and is also an issue in children. Children with MDR TB need longer duration of treatment with multiple drugs. The MDR TB treatment regimen usually comprises of a fluoroquinolone, an aminoglycoside, ethionamide, cycloserine, pyrazinamide and ethambutol. In the absence of pediatric friendly tablets/formulations, in most cases the adult tablets are either crushed or broken. This is likely to lead to inaccurate dosing. Very limited information is available on the pharmacokinetics of second-line anti-TB drugs in children with MDR TB, except for few studies from South Africa and one from India. Drugs such as linezolid, clofazimine are also being considered for the treatment of MDR TB in children. However, their pharmacokinetics is not known in the pediatric population. It is important to generate pharmacokinetic studies of drugs used to treat MDR TB in children in different settings, which would provide useful information on the adequacy of drug doses.

Topics: Aminoglycosides; Aminosalicylic Acid; Antitubercular Agents; Child; Cycloserine; Ethionamide; Fluoroquinolones; Humans; Tuberculosis, Multidrug-Resistant

Hypothyroidism is one of the adverse drug reactions that associated with Multidrug Resistant Tuberculosis (MDR-TB) medications. Extremely variable magnitude of hypothyroidism in MDR-TB patients has been reported from different parts of the world. However, there is no evidence that tried to estimate the pooled prevalence of hypothyroidism to confirm the rareness of hypothyroidism in MDR-TB patients on treatment. Therefore, we did a systematic review and meta-analysis to estimate the prevalence of hypothyroidism in MDR-TB patients on treatment, and to summarize the demographic and clinical characteristics of the patients.. We conducted a systematic review and meta-analysis on studies reported around the world on the prevalence of hypothyroidism in MDR-TB patients on treatment. We searched electronic databases: PubMed/Medline, EMBASE, CINAHL, Science Direct, Academic Search Complete and Google scholar for English language articles without limiting publication year. We also reviewed the bibliographies of relevant studies and conducted an electronic search for relevant conference abstracts. Eligible studies were cross-sectional and cohort studies that included at least five participants. We used a random-effects model to estimate the pooled prevalence of hypothyroidism. The registration number of this review study protocol is CRD42018109237.. We included 30 studies and pooled data on a total of 6,241 MDR-TB patients. The crude prevalence of hypothyroidism was extremely heterogeneous. The pooled prevalence of hypothyroidism in MDR-TB patients on treatment was 17.0% (95% CI: 13.0-20.0). Ethionamide and para-aminosalicylic acid (PAS) were the most frequently reported drugs that associated with the occurrence of hypothyroidism.. This review revealed that hypothyroidism is not a rare adverse drug reaction in MDR-TB patients on treatment. Ethionamide and PAS were the most frequently reported drugs that associated with the occurrence of hypothyroidism. Screening of hypothyroidism in MDR-TB patients on treatment is important while targeting patients on Ethionamide and PAS based treatment regimen.

Topics: Aminosalicylic Acid; Antitubercular Agents; Cross-Sectional Studies; Drug-Related Side Effects and Adverse Reactions; Ethionamide; Humans; Hypothyroidism; Risk Factors; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Ethionamide; Humans; Prothionamide; Tuberculosis, Multidrug-Resistant

Childhood multidrug-resistant (MDR) tuberculosis is an emerging disease with increasing numbers being recognized. This review presents recent developments in childhood MDR tuberculosis.. New molecular-based diagnostic tests, although not optimal, have reduced the difficulty in confirming the diagnosis of MDR tuberculosis in children. However, the importance of making a diagnosis of probable MDR tuberculosis has been reaffirmed by contact tracing studies showing 80-90% of child contacts of MDR tuberculosis cases who develop disease have MDR tuberculosis themselves. Prevention of MDR tuberculosis in child contacts with appropriate preventive treatment regimens is supported by new observational data and deserves further study. When diagnosed and treated appropriately, outcomes for MDR tuberculosis and even extensively drug-resistant tuberculosis in children are good, despite limited pharmacokinetic data on second-line drugs. Novel anti-tuberculosis drugs and regimens are becoming available and should be studied in children for dose-finding and safety. Recording and reporting of MDR tuberculosis in children are frequently poor, leading to inaccurate estimates of disease burden and suboptimal resource planning.. Rapid diagnosis and appropriate treatment results in good outcomes in the majority of children with MDR tuberculosis. Additional research on optimal diagnosis, prevention and treatment of MDR tuberculosis in children remains a high priority.

Topics: Antitubercular Agents; Child; Child, Preschool; Directly Observed Therapy; Drug Administration Schedule; Ethionamide; Fluoroquinolones; Humans; Infant; Moxifloxacin; Nitroimidazoles; Practice Guidelines as Topic; Prevalence; Pyrazinamide; Risk Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Ethionamide (ETH) is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant Mycobacterium. Although ETH is a structural analogue of isoniazid (INH), both are pro-drugs that need to be activated by mycobacterial enzymes to exert their antimicrobial activity. ETH mechanism of action is thought to be identical to INH although the pathway of activation is distinct from that of INH. ETH is activated by an EthA enzyme, leading to the formation of an Soxide metabolite that has considerably better activity than the parent drug. This review comprehensively examines the aspects related with the metabolism of ETH since its discovery up to today.

Topics: Antitubercular Agents; Ethionamide; Global Health; Humans; Mycobacterium tuberculosis; Prodrugs; Tuberculosis, Multidrug-Resistant

Antifolates inhibit de novo folate biosynthesis, whereas ethionamide targets the mycolate synthetic pathway in Mycobacterium tuberculosis. These antibiotics are effective against M. tuberculosis but their use has been hampered by concerns over toxicity and low therapeutic indexes. With the increasing spread of drug-resistant forms, interest in using old drugs for tuberculosis treatment has been renewed. Specific inhibitors targeting resistance mechanisms could sensitize M. tuberculosis to these available, clinically approved drugs. This review discusses recently developed strategies to boost the antituberculous activity of ethionamide and antifolates. These approaches might help broaden the currently limited chemotherapeutic options of not only drug-resistant but also drug-susceptible tuberculosis, which still remains one of the most common infectious diseases in the developing world.

Topics: Drug Design; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Ethionamide; Folic Acid Antagonists; Humans; Mycobacterium tuberculosis; Sulfonamides; Tuberculosis, Multidrug-Resistant

Drug-resistant tuberculosis has become a global problem and a major public health concern. While mechanisms of resistance are fairly well characterized for most agents, particularly the first line agents, our knowledge of drug resistance is by no means exhaustive, and strains continue to emerge that carry novel resistance-related mutations. The purpose of this review is to summarize our current understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis, highlighting emerging areas of research. The development of rapid detection methods has been a major breakthrough in the fight against drug-resistant tuberculosis. Rapid detection methods are available for both rifampin- and isoniazid-resistant tuberculosis, but have yet to be developed for other first line agents. Rapid detection methods will become increasingly important as multi-drug resistant strains of M. tuberculosis become more prevalent, even for detecting tuberculosis that is resistant to second line agents.

Topics: Aminoglycosides; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethionamide; Genes, Bacterial; Isoniazid; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant

Knowledge of the molecular genetic basis of resistance to antituberculous agents has advanced rapidly since we reviewed this topic 3 years ago. Virtually all isolates resistant to rifampin and related rifamycins have a mutation that alters the sequence of a 27-amino-acid region of the beta subunit of ribonucleic acid (RNA) polymerase. Resistance to isoniazid (INH) is more complex. Many resistant organisms have mutations in the katG gene encoding catalase-peroxidase that result in altered enzyme structure. These structural changes apparently result in decreased conversion of INH to a biologically active form. Some INH-resistant organisms also have mutations in the inhA locus or a recently characterized gene (kasA) encoding a beta-ketoacyl-acyl carrier protein synthase. Streptomycin resistance is due mainly to mutations in the 16S rRNA gene or the rpsL gene encoding ribosomal protein S12. Resistance to pyrazinamide in the great majority of organisms is caused by mutations in the gene (pncA) encoding pyrazinamidase that result in diminished enzyme activity. Ethambutol resistance in approximately 60% of organisms is due to amino acid replacements at position 306 of an arabinosyltransferase encoded by the embB gene. Amino acid changes in the A subunit of deoxyribonucleic acid gyrase cause fluoroquinolone resistance in most organisms. Kanamycin resistance is due to nucleotide substitutions in the rrs gene encoding 16S rRNA. Multidrug resistant strains arise by sequential accumulation of resistance mutations for individual drugs. Limited evidence exists indicating that some drug resistant strains with mutations that severely alter catalase-peroxidase activity are less virulent in animal models. A diverse array of strategies is available to assist in rapid detection of drug resistance-associated gene mutations. Although remarkable advances have been made, much remains to be learned about the molecular genetic basis of drug resistance in Mycobacterium tuberculosis. It is reasonable to believe that development of new therapeutics based on knowledge obtained from the study of the molecular mechanisms of resistance will occur.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Cycloserine; Drug Resistance, Multiple; Ethambutol; Ethionamide; Fluoroquinolones; Genes, Bacterial; Isoniazid; Mutation; Mycobacterium tuberculosis; Polymorphism, Genetic; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant; Virulence

Programmatic management of MDR-TB using a standardized treatment regimen (STR) is being implemented under the Revised National Tuberculosis Control Programme (RNTCP) in India. This study was undertaken to analyse the outcomes of MDR-TB patients treated at the Tuberculosis Research Centre, Chennai, with the RNTCP recommended 24 months STR, under programmatic conditions.. Patients failed to the category II re-treatment regimen and confirmed to have MDR-TB, were treated with the RNTCP's STR in a prospective field trial on a predominantly ambulatory basis. Thirty eight patients were enrolled to the trial from June 2006 to September 2007.. Time to culture conversion was two months or less for 82 per cent of patients. Culture conversion rates at 3 and 6 months were 84 and 87 per cent respectively. At the end of treatment, 25 (66%) were cured, 5 defaulted, 3 died and 5 failed. At 24 months, 30 (79%) patients, including 5 defaulters, remained culture negative for more than 18 months. Twenty two (58%) patients reported adverse drug reactions (ADRs) which required dose reduction or termination of the offending drug. No patient had XDR-TB initially, but 2 failure cases emerged as XDR-TB during treatment.. Outcomes of this small group of MDR-TB patients treated with the RNTCP's STR is encouraging in this setting. Close attention needs to be paid to ensure adherence, and to the timely recognition and treatment of ADRs.

Topics: Adult; Antibiotics, Antitubercular; Communicable Disease Control; Cycloserine; Directly Observed Therapy; Drug-Related Side Effects and Adverse Reactions; Ethambutol; Ethionamide; Female; Humans; India; Kanamycin; Male; Middle Aged; Ofloxacin; Prospective Studies; Pyrazinamide; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Department of tuberculosis and chest diseases of a tertiary referral tuberculosis institute in New Delhi, India.. To study the efficacy and safety of sparfloxacin, in combination with kanamycin (for the initial 3-4 months) and ethionamide, in multidrug-resistant (MDR) pulmonary tuberculosis patients.. Prospective, uncontrolled study of nine patients with pulmonary tuberculosis who had received adequate anti-tuberculosis treatment with first-line drugs, including supervised category II treatment regimen as per World Health Organization guidelines for 5 months, and were still sputum smear acid-fast bacilli positive. It was planned to give them kanamycin (initial 3-4 months), ethionamide and sparfloxacin for 2 years.. All nine patients achieved sputum conversion within 6 months. Seven patients converted within 3.5 months, two of these within 1 month. All patients reported improvement in clinical symptoms, and chest X-ray improved in seven patients. Four patients developed mild to moderate phototoxicity. Eight patients have completed treatment for an average of 19 months (range 15-24 months), and are still under follow-up. One patient defaulted after 7 months of treatment.. In MDR-TB patients, sparfloxacin, along with other anti-tuberculosis drugs, appears to be effective and safe. Mild to moderate phototoxicity is common. However, the long-term results, including relapses, are still awaited.

Topics: Adult; Anti-Infective Agents; Antitubercular Agents; Culture Media; Dermatitis, Phototoxic; Drug Therapy, Combination; Ethionamide; Fluoroquinolones; Humans; Kanamycin; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates.. We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model.. Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations.. We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

Topics: Adult; Amikacin; Aminosalicylic Acid; Antitubercular Agents; Ethionamide; Female; HIV Infections; Hospitals; Humans; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Retrospective Studies; South Africa; Tuberculosis, Multidrug-Resistant

The detection of pre-extensively (pre-XDR) and extensively drug-resistant tuberculosis (XDR-TB) is challenging. Drug-susceptibility tests for some anti-TB drugs, especially ethambutol (ETH) and ethionamide (ETO), are problematic due to overlapping thresholds to differentiate between susceptible and resistant phenotypes. We aimed to identify possible metabolomic markers to detect Mycobacterium tuberculosis (Mtb) strains causing pre-XDR and XDR-TB. The metabolic patterns of ETH- and ETO-resistant Mtb isolates were also investigated. Metabolomics of 150 Mtb isolates (54 pre-XDR, 63 XDR-TB and 33 pan-susceptible; pan-S) were investigated. Metabolomics of ETH and ETO phenotypically resistant subgroups were analyzed using UHPLC-ESI-QTOF-MS/MS. Orthogonal partial least-squares discriminant analysis revealed distinct separation in all pairwise comparisons among groups. Two metabolites (meso-hydroxyheme and itaconic anhydride) were able to differentiate the pre-XDR and XDR-TB groups from the pan-S group with 100% sensitivity and 100% specificity. In comparisons of the ETH and ETO phenotypically resistant subsets, sets of increased (ETH = 15, ETO = 7) and decreased (ETH = 1, ETO = 6) metabolites specific for the resistance phenotype of each drug were found. We demonstrated the potential for metabolomics of Mtb to differentiate among types of DR-TB as well as between isolates that were phenotypically resistant to ETO and ETH. Thus, metabolomics might be further applied for DR-TB diagnosis and patient management.

Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Extensively Drug-Resistant Tuberculosis; Humans; Metabolome; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tandem Mass Spectrometry; Tuberculosis, Multidrug-Resistant

Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in many high tuberculosis (TB) burden countries. Phenotypic drug susceptibility testing (DST) take several weeks or months to result, but line probe assays and Xpert/Rif Ultra assay detect a limited number of resistance conferring gene mutations. Whole genome sequencing (WGS) is an advanced molecular testing method which theoretically can predict the resistance of M. tuberculosis (Mtb) isolates to all anti-TB agents through a single analysis.. Here, we aimed to identify the level of concordance between the phenotypic and WGS-based genotypic drug susceptibility (DS) patterns of MDR-TB isolates. Overall, data for 12 anti-TB medications were analyzed.. In total, 63 MDR-TB Mtb isolates were included in the analysis, representing 27.4% of the total number of MDR-TB cases in Latvia in 2012-2014. Among them, five different sublineages were detected, and 2.2.1 (Beijing group) and 4.3.3 (Latin American-Mediterranean group) were the most abundant. There were 100% agreement between phenotypic and genotypic DS pattern for isoniazid, rifampicin, and linezolid. High concordance rate (> 90%) between phenotypic and genotypic DST results was detected for ofloxacin (93.7%), pyrazinamide (93.7%) and streptomycin (95.4%). Phenotypic and genotypic DS patterns were poorly correlated for ethionamide (agreement 56.4%), ethambutol (85.7%), amikacin (82.5%), capreomycin (81.0%), kanamycin (85.4%), and moxifloxacin (77.8%). For capreomycin, resistance conferring mutations were not identified in several phenotypically resistant isolates, and, in contrary, for ethionamide, ethambutol, amikacin, kanamycin, and moxifloxacin the resistance-related mutations were identified in several phenotypically sensitive isolates.. WGS is a valuable tool for rapid genotypic DST for all anti-TB agents. For isoniazid and rifampicin phenotypic DST potentially can be replaced by genotypic DST based on 100% agreement between the tests. However, discrepant results for other anti-TB agents limit their prescription based solely on WGS data. For clinical decision, at the current level of knowledge, there is a need for combination of genotypic DST with modern, validated phenotypic DST methodologies for those medications which did not showed 100% agreement between the methods.

Topics: Amikacin; Antitubercular Agents; Capreomycin; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Latvia; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

The WHO End TB Strategy requires drug susceptibility testing and treatment of all people with tuberculosis, but second-line diagnostic testing with line-probe assays needs to be done in experienced laboratories with advanced infrastructure. Fewer than half of people with drug-resistant tuberculosis receive appropriate treatment. We assessed the diagnostic accuracy of the rapid Xpert MTB/XDR automated molecular assay (Cepheid, Sunnyvale, CA, USA) to overcome these limitations.. We did a prospective study involving individuals presenting with pulmonary tuberculosis symptoms and at least one risk factor for drug resistance in four sites in India (New Delhi and Mumbai), Moldova, and South Africa between July 31, 2019, and March 21, 2020. The Xpert MTB/XDR assay was used as a reflex test to detect resistance to isoniazid, fluoroquinolones, ethionamide, amikacin, kanamycin, and capreomycin in adults with positive results for Mycobacterium tuberculosis complex on Xpert MTB/RIF or Ultra (Cepheid). Diagnostic performance was assessed against a composite reference standard of phenotypic drug-susceptibility testing and whole-genome sequencing. This study is registered with ClinicalTrials.gov, number NCT03728725.. Of 710 participants, 611 (86%) had results from both Xpert MTB/XDR and the reference standard for any drug and were included in analysis. Sensitivity for Xpert MTB/XDR detection of resistance was 94% (460 of 488, 95% CI 92-96) for isoniazid, 94% (222 of 235, 90-96%) for fluoroquinolones, 54% (178 of 328, 50-61) for ethionamide, 73% (60 of 82, 62-81) for amikacin, 86% (181 of 210, 81-91) for kanamycin, and 61% (53 of 87, 49-70) for capreomycin. Specificity was 98-100% for all drugs. Performance was equivalent to that of line-probe assays. The non-determinate rate of Xpert MTB/XDR (ie, invalid M tuberculosis complex detection) was 2·96%.. The Xpert MTB/XDR assay showed high diagnostic accuracy and met WHO's minimum target product profile criteria for a next-generation drug susceptibility test. The assay has the potential to diagnose drug-resistant tuberculosis rapidly and accurately and enable optimum treatment.. German Federal Ministry of Education and Research through KfW, Dutch Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and Trade.

Topics: Adult; Amikacin; Australia; Capreomycin; Cross-Sectional Studies; Drug Resistance, Bacterial; Ethionamide; Fluoroquinolones; Humans; Isoniazid; Kanamycin; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

Our objective was to evaluate the performance of whole-genome sequencing (WGS) from early positive liquid cultures for predicting Mycobacterium tuberculosis complex (MTBC) drug resistance. Clinical isolates were obtained from tuberculosis patients at Shanghai Pulmonary Hospital (SPH). Antimicrobial susceptibility testing (AST) was performed, and WGS from early Bactec mycobacterial growth indicator tube (MGIT) 960-positive liquid cultures was performed to predict the drug resistance using the TB-Profiler informatics platform. A total of 182 clinical isolates were enrolled in this study. Using phenotypic AST as the gold standard, the overall sensitivity and specificity for WGS were, respectively, 97.1% (89.8 to 99.6%) and 90.4% (83.4 to 95.1%) for rifampin, 91.0% (82.4 to 96.3%) and 95.2% (89.1 to 98.4%) for isoniazid, 100.0% (89.4 to 100.0%) and 87.3% (80.8 to 92.1%) for ethambutol, 96.6% (88.3 to 99.6%) and 61.8% (52.6 to 70.4%) for streptomycin, 86.8% (71.9 to 95.6%) and 95.8% (91.2 to 98.5%) for moxifloxacin, 86.5% (71.2 to 91.5%) and 95.2% (90.3 to 98.0%) for ofloxacin, 100.0% (54.1 to 100.0%) and 67.6% (60.2 to 74.5%) for amikacin, 100.0% (63.1 to 100.0%) and 67.2% (59.7 to 74.2%) for kanamycin, 62.5% (24.5 to 91.5%) and 88.5% (82.8 to 92.8%) for ethionamide, 33.3% (4.3 to 77.7%) and 98.3% (95.1 to 99.7%) for para-aminosalicylic acid, and 0.0% (0.0 to 12.3%) and 100.0% (97.6 to 100.0%) for cycloserine. The concordances of WGS-based AST and phenotypic AST were as follows: rifampin (92.9%), isoniazid (93.4%), ethambutol (89.6%), streptomycin (73.1%), moxifloxacin (94.0%), ofloxacin (93.4%), amikacin (68.7%), kanamycin (68.7%), ethionamide (87.4%), para-aminosalicylic acid (96.2%) and cycloserine (84.6%). We conclude that WGS could be a promising approach to predict MTBC resistance from early positive liquid cultures.

Topics: Amikacin; Aminosalicylic Acid; Antitubercular Agents; China; Cycloserine; Drug Resistance; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant

The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described.. To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen.. We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid.. A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransferase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC.. Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses >10 mg/kg. The safety implications of these phenomena remain unclear.

Topics: Antitubercular Agents; Arylamine N-Acetyltransferase; Ethionamide; Humans; Isoniazid; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis (TB) is a communicable, preventable and curable disease caused by the bacterium Mycobacterium tuberculosis (MTB). Peru is amongst the 30 countries with the highest burden of multidrug-resistant tuberculosis (MDR-TB) worldwide. In the fight against drug-resistant tuberculosis, the UKMYC6 microdilution plate was developed and validated by the CRyPTIC project. The objective of the study was to evaluate the use of the broth microdilution (BMD) plate methodology for susceptibility testing of drug-resistant MTB strains in Peru.. MTB strains isolated between 2015 and 2018 in Peru were used. 496 nationally-representative strains determined as drug-resistant by the routine 7H10 Agar Proportion Method (APM) were included in the present study. The Minimum Inhibitory Concentration (MIC) of 13 antituberculosis drugs were determined for each strain using the UKMYC6 microdilution plates. Diagnostic agreement between APM and BMD plate methodology was determined for rifampicin, isoniazid, ethambutol, ethionamide, kanamycin and levofloxacin. Phenotypes were set using binary (or ternary) classification based on Epidemiological cut-off values (ECOFF/ECV) proposed by the CRyPTIC project. Whole Genome Sequencing (WGS) was performed on strains with discrepant results between both methods.. MIC distributions were determined for 13 first- and second-line anti-TB drugs, including new (bedaquiline, delamanid) and repurposed (clofazimine, linezolid) agents. MIC results were available for 80% (397/496) of the strains at 14 days and the remainder at 21 days. The comparative analysis determined a good agreement (0.64 ≤ k ≤ 0.79) for the drugs rifampicin, ethambutol, ethionamide and kanamycin, and the best agreement (k > 0.8) for isoniazid and levofloxacin. Overall, 12% of MIC values were above the UKMYC6 plate dilution ranges, most notably for the drugs rifampicin and rifabutin. No strain presented MICs higher than the ECOFF/ECV values for the new or repurposed drugs. Discrepant analysis using genotypic susceptibility testing by WGS supported half of the results obtained by APM (52%, 93/179) and half of those obtained by BMD plate methodology (48%, 86/179).. The BMD methodology using the UKMYC6 plate allows the complete susceptibility characterization, through the determination of MICs, of drug-resistant MTB strains in Peru. This methodology shows good diagnostic performances for rifampicin, isoniazid, ethambutol, ethionamide, kanamycin and levofloxacin. It also allows for the characterization of MICs for other drugs used in previous years against tuberculosis, as well as for new and repurposed drugs recently introduced worldwide.

Topics: Antitubercular Agents; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Levofloxacin; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Peru; Rifampin; Tuberculosis, Lymph Node; Tuberculosis, Multidrug-Resistant

Despite reinvigorated efforts in Tuberculosis (TB) drug discovery over the past 20 years, relatively few new drugs and candidates have emerged with clear utility against drug resistant TB. Over the same period, significant technological advances and learnings around target value have taken place. This has offered opportunities to re-assess the potential for optimization of previously discovered chemical matter against

Topics: Antitubercular Agents; beta-Lactams; Ethionamide; Humans; Spectinomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant

In Pakistan, the treatment of multidrug-resistant tuberculosis (MDR-TB) with a shorter treatment regimen (STR), that is, 4-6 months of amikacin, moxifloxacin (Mfx), ethionamide, clofazimine (Cfz), pyrazinamide (Z), ethambutol (E), and high-dose isoniazid, followed by 5 months of Mfx, Cfz, Z, and E, was initiated in 2018. However, there is a lack of information about its effectiveness in Pakistani healthcare settings. Therefore, this retrospective record review of MDR-TB patients treated with STR at eight treatment sites in Pakistan aimed to fill this gap. Data were analyzed using SPSS 23. Multivariate binary logistic regression (MVBLR) analysis was conducted to find factors associated with death and treatment failure, and lost to follow-up (LTFU). A P-value < 0.05 was considered statistically significant. Of 912 MDR-TB patients enrolled at the study sites, only 313 (34.3%) eligible patients were treated with STR and included in the current study. Of them, a total of 250 (79.9%) were cured, 12 (3.8%) completed treated, 31 (9.9%) died, 16 (5.1%) were LTFU, and four (1.3%) were declared as treatment failures. The overall treatment success rate was 83.7%. In MVBLR analysis, patients' age of 41-60 (odds ratio [OR] = 4.9, P-value = 0.020) and > 60 years (OR = 3.6, P-value = 0.035), being underweight (OR = 2.7, P-value = 0.042), and previous TB treatment (OR = 0.4, P-value = 0.042) had statistically significant association with death and treatment failure, whereas patients' age of > 60 years (OR = 5.4, P-value = 0.040) and previous TB treatment (OR = 0.2, P-value = 0.008) had statistically significant association with LTFU. The treatment success rate of STR was encouraging. However, to further improve the treatment outcomes, special attention should be paid to the patients with identified risk factors.

Topics: Adult; Amikacin; Antitubercular Agents; Clofazimine; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Female; Humans; Isoniazid; Lost to Follow-Up; Male; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Pakistan; Pyrazinamide; Retrospective Studies; Survival Analysis; Treatment Failure; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Ethionamide; Gynecomastia; Humans; Male; Middle Aged; Tuberculosis, Multidrug-Resistant

Topics: Anti-Bacterial Agents; Antitubercular Agents; Bangladesh; Ethionamide; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Tuberculosis, Multidrug-Resistant

Ethionamide is part of a group of drugs used in the treatment of drug resistant TB. With the advent of increasing drug resistance in pulmonary TB cases, use of Ethionamide, a second line anti tubercular drug is increasing. Vision changes are rare with ethionamide. Cyanopsia i.e., bluish tinted vision of surroundings with ethionamide is not known in literature. Here, we report a case of DRTB patient who developed cyanopsia soon after introducing ethionamide. Although reversible, ethionamide may sometimes need withdrawal because of significant distress caused to patient.

Topics: Aminosalicylic Acid; Antitubercular Agents; Color Vision Defects; Cycloserine; Ethionamide; Female; Humans; Kanamycin; Linezolid; Moxifloxacin; Tuberculosis, Multidrug-Resistant; Young Adult

Aminoglycosides are known to cause electrolyte disturbances. Approximately 8-26% of patients who receive an aminoglycoside for several days develop mild renal impairment that is almost always reversible (Brunton et al., 2013). A 46 year old male with multi-drug-resistant pulmonary tuberculosis with resistance to kanamycin is being presented, who was on injectable Capreomycin, Levofloxacin, Ethionamide, Cycloserine, pyrazinamide, linezolid and clofazamine for a period of four months. He presented to us with generalised weakness and pain in the lower limb muscles. Investigation revealed hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalceuria and hypocalcemia. This features mimic Gitelman's syndrome which is an autosomal recessive disorder affecting kidneys causing electrolyte disturbances. The drug was immediately withdrawn and electrolyte correction was given and the condition reversed gradually.

Topics: Alkalosis; Antitubercular Agents; Capreomycin; Clofazimine; Cycloserine; Deprescriptions; Ethionamide; Gitelman Syndrome; Humans; Hypocalcemia; Hypokalemia; Levofloxacin; Linezolid; Male; Middle Aged; Pyrazinamide; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Water-Electrolyte Imbalance

Drug resistance (DR) remains a major challenge for tuberculosis (TB) control. Whole-genome sequencing (WGS) provides the highest genetic resolution for genotypic drug-susceptibility tests (DST). We compared DST profiles of 60 Mycobacterium tuberculosis isolates which were drug resistant according to agar proportion tests (one poly DR-TB, 34 multidrug-resistant TB and 25 extensively drug-resistant TB). We additionally performed minimum inhibitory concentration (MIC) tests using Sensititre MYCOTBI plates (MYCOTB) and a WGS-based DST. Agreement between WGS-based DST and MYCOTB was high for all drugs except ethambutol (65%) and ethionamide (62%). Isolates harboring the -15 c/t inhA promoter mutation had a significantly lower MIC for isoniazid than did isolates with the katG Ser315Thr mutation (p < 0.001). Similar patterns were seen for ethambutol (embB Gly406Asp vs. embB Met306Ile), streptomycin (gid Gly73Ala vs. rpsL Lys43Arg), moxifloxacin (gyrA Ala90Val vs. gyrA Asp94Gly) and rifabutin (rpoB Asp435Phe/Tyr/Val vs. rpoB Ser450Leu). For genotypic heteroresistance, isolates with lower proportion of mapped read tended to has lower MIC of anti-TB drugs than those with higher proportion. These results emphasize the high applicability of WGS for determination of DR-TB and the association of particular mutations with MIC levels.

Topics: Adult; Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Ethionamide; Extensively Drug-Resistant Tuberculosis; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

Treatment of multi-drug resistant (MDR) tuberculosis (TB) includes aminoglycosides and ethionamide. A 16-year-old girl presented with sudden onset of paralysis, dyselectrolytemia mimicking Gitelman syndrome, and ethionamide-induced hypothyroidism. Monitoring electrolytes during MDR-TB treatment is recommended to prevent life-threatening complications.

Topics: Adolescent; Aminoglycosides; Antitubercular Agents; Diagnosis, Differential; Ethionamide; Female; Gitelman Syndrome; Humans; Kidney Tubules, Distal; Mycobacterium tuberculosis; Paralysis; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Water-Electrolyte Imbalance

Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant (MDR) tuberculosis, but the efficacy and safety of this strategy is unknown.. In this retrospective cohort study adults receiving bedaquiline substitution for MDR tuberculosis therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic tuberculosis register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow-up, or failure to achieve sustained culture conversion at 12 months of treatment.. Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were infected with human immunodeficiency virus. Unfavorable outcomes occurred in 35 of 146 (23.9%) patients in the bedaquiline group versus 51 of 141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval, .46 -.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient; 0.8%) than in controls (12 patients; 10.3%; P = .001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio for every 30-day delay, 1.5; 95% confidence interval, 1.1-1.9). Mortality rates were similar at 12 months (11 deaths in each group; P = .97).. Substituting bedaquiline for SLIs in MDR tuberculosis treatment resulted in improved outcomes at 12 months compared with patients who continued taking SLIs, supporting the use of bedaquiline for MDR tuberculosis treatment in programmatic settings.

Topics: Adult; Antitubercular Agents; Coinfection; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Female; HIV; HIV Infections; Humans; Isoniazid; Isoxazoles; Levofloxacin; Male; Mycobacterium tuberculosis; Oxazolidinones; Pyrazinamide; Retrospective Studies; South Africa; Survival Analysis; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Multidrug-resistant tuberculosis (MDR-TB) outcomes are poor partly because of the long treatment duration; the World Health Organization conditionally recommends a shorter course regimen to potentially improve treatment outcomes. Here, we describe the drug susceptibility patterns of a cohort of MDR-TB patients in Haiti and determine the number of likely effective drugs if they were treated with the recommended shorter course regimen. We retrospectively examined drug susceptibility patterns of adults initiating MDR-TB treatment between 2008 and 2015 at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections in Port-au-Prince, Haiti. First- and second-line drug susceptibility testing (DST) was analyzed and used to determine the number of presumed effective drugs. Of the 239 patients analyzed, 226 (95%), 183 (77%), 135 (57%), and 38 (16%) isolates were resistant to high-dose isoniazid, ethambutol, pyrazinamide, and ethionamide, respectively. Eight patients (3%) had resistance to either a fluoroquinolone or a second-line injectable and none had extensively resistant TB. Of the 239 patients, 132 (55%) would have fewer than five likely effective drugs in the intensive phase of the recommended shorter course regimen and 121 (51%) would have two or fewer likely effective drugs in the continuation phase. Because of the high rates of resistance to first-line TB medications, about 50% of MDR-TB patients would be left with only two effective drugs in the continuation phase of the recommended shorter course regimen, raising concerns about the effectiveness of this regimen in Haiti and the importance of using DST to guide treatment.

Topics: Adult; Antitubercular Agents; Coinfection; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Female; Fluoroquinolones; Haiti; HIV; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Bedaquiline (BDQ) was approved for treatment of drug resistant TB (DR-TB) under Conditional Access Programme (CAP) of Revised National Tuberculosis Control Programme (RNTCP) and was also implemented in the National Institute of TB and Respiratory Diseases (NITRD). We present early efficacy and safety of BDQ containing regimens for DR-TB.. To ascertain the early efficacy and safety of Bedaquline containing regimens in treatment of DR-TB.. BDQ containing regimens along with other drugs were designed as per WHO recommendations for DR-TB patients. They were followed up for sputum smear and culture conversion, adverse events during the treatment.. A cohort of 290 DR-TB patients (Median age-29.77) were initiated on BDQ containing regimens. Of the available Sputum results, smear conversion was seen in 51% and 91% patients at the end of 1st week and 3rd month respectively. Similarly, 93% and 98% patients had culture conversion at the end of 3rd and 6th month respectively. 201 adverse events (AE) including 47 deaths were reported among 109 patients. QTc prolongation was seen in 29% patients but only 4 required discontinuation of BDQ. Lost to follow up of treatment was about 6%.. Bedaquiline along with an optimized background regimen has shown early sputum conversion in larger number of difficult to treat patients having additional resistance of second line drugs along with INH and Rifampicin. The regimen is feasible in programmatic conditions and is relatively safe.

Topics: Adult; Antitubercular Agents; Cardiotoxicity; Clofazimine; Cycloserine; Diarylquinolines; Drug Therapy, Combination; Electrocardiography; Ethionamide; Female; Humans; India; Linezolid; Male; Moxifloxacin; National Health Programs; Sputum; Time Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Ethionamide is used to treat multidrug-resistant tuberculosis (MDR-TB). The antimicrobial pharmacokinetics/pharmacodynamics, the contribution of ethionamide to the multidrug regimen, and events that lead to acquired drug resistance (ADR) are unclear.. We performed a multidose hollow fiber system model of tuberculosis (HFS-TB) study to identify the 0-24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios that achieved maximal kill and ADR suppression, defined as target exposures. Ethionamide-resistant isolates underwent whole-genome and targeted Sanger sequencing. We utilized Monte Carlo experiments (MCEs) to identify ethionamide doses that would achieve the target exposures in 10000 patients with pulmonary tuberculosis. We also identified predictors of time-to-sputum conversion in Tanzanian patients on ethionamide- and levofloxacin-based regimens using multivariate adaptive regression splines (MARS).. An AUC0-24/MIC >56.2 was identified as the target exposure in the HFS-TB. Early efflux pump induction to ethionamide monotherapy led to simultaneous ethambutol and isoniazid ADR, which abrogated microbial kill of an isoniazid-ethambutol-ethionamide regimen. Genome sequencing of isolates that arose during ethionamide monotherapy revealed mutations in both ethA and embA. In MCEs, 20 mg/kg/day achieved the AUC0-24/MIC >56.2 in >95% of patients, provided the Sensititre assay MIC was <2.5 mg/L. In the clinic, MARS revealed that ethionamide Sensititre MIC had linear negative relationships with time-to-sputum conversion until an MIC of 2.5 mg/L, above which patients with MDR-TB failed combination therapy.. Ethionamide is an important contributor to MDR-TB treatment regimens, at Sensititre MIC <2.5 mg/L. Suboptimal ethionamide exposures led to efflux pump-mediated ADR.

Topics: Antitubercular Agents; Ethionamide; Humans; Isoniazid; Levofloxacin; Monte Carlo Method; Mutation; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, "green" β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.

Topics: Administration, Inhalation; Animals; Antitubercular Agents; beta-Cyclodextrins; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Synergism; Drug Therapy, Combination; Ethionamide; Female; Humans; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nanoparticles; Oxadiazoles; Piperidines; Polylactic Acid-Polyglycolic Acid Copolymer; RAW 264.7 Cells; Solubility; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Genetics-based drug susceptibility testing has improved the diagnosis of drug-resistant tuberculosis but is limited by our lack of knowledge of all resistance mechanisms. Next-generation sequencing has assisted in identifying the principal genetic mechanisms of resistance for many drugs, but a significant proportion of phenotypic drug resistance is unexplained genetically. Few studies have formally compared the transcriptomes of susceptible and resistant

Topics: Antitubercular Agents; Bacterial Proteins; Base Sequence; Drug Resistance, Multiple, Bacterial; Endoribonucleases; Ethionamide; Gene Expression Regulation, Bacterial; Genome, Bacterial; High-Throughput Nucleotide Sequencing; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Promoter Regions, Genetic; Repressor Proteins; RNA, Bacterial; Transcriptome; Tuberculosis, Multidrug-Resistant

Ethionamide (ETH) is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant Mycobacterium tuberculosis. Recently, we reported that the loading of ETH into thermally carbonized-porous silicon (TCPSi) nanoparticles enhanced the solubility and permeability of ETH at different pH-values and also increased its metabolization process. Based on these results, we synthesized carboxylic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) conjugated with ETH and its antimicrobial effect was evaluated against Mycobacterium tuberculosis strain H37Rv. The activity of the conjugate was increased when compared to free-ETH, which suggests that the nature of the synergy between the NPs and ETH is likely due to the weakening of the bacterial cell wall that improves conjugate-penetration. These ETH-conjugated NPs have great potential in reducing dosing frequency of ETH in the treatment of multidrug-resistant tuberculosis (MDR-TB).

Topics: Antitubercular Agents; Ethionamide; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nanoparticles; Particle Size; Porosity; Silicon; Solubility; Tuberculosis, Multidrug-Resistant

Xpert MTB/RIF (Xpert) detects rifampicin-resistant tuberculosis (RR-tuberculosis), enabling physicians to rapidly initiate a World Health Organization-recommended 5-drug regimen while awaiting second-line drug-susceptibility test (DST) results. We quantified the second-line DST results time and proportion of patients potentially placed on suboptimal therapy.. We included RR-tuberculosis patients detected using Xpert at the South African National Health Laboratory Services (NHLS) of the Western Cape between November 2011 and June 2013 and at Eastern Cape, Free State, and Gauteng NHLS between November 2012 and December 2013. We calculated time from specimen collection to phenotypic second-line DST results. We identified isoniazid and ethionamide resistance mutations on line probe assay and performed pyrazinamide sequencing.. Among 1332 RR-tuberculosis patients, only 44.7% (596) had second-line DST for both fluoroquinolones and second-line injectable: 55.8% (466 of 835) in the Western Cape and 26.2% (130 of 497) in the other provinces. Patients with smear negative disease and age ≤10 years were less likely to have a result (risk ratio [RR] = 0.72; 95% CI, 0.64-0.81 and RR = 0.49; 95% CI, 0.26-0.79). Median time to second-line DST was 53 days (range, 8-259). Of the 252 patients with complete second-line DST, 101 (40.1%) potentially initiated a suboptimal regimen: 46.8% in the Western Cape and 25.3% in the other provinces.. Many South Africans diagnosed with RR-tuberculosis by Xpert initiate a suboptimal regimen, with information to adjust therapy available in half of all patients after a median 7 weeks. Algorithm completion and time delays remain challenging.

Topics: Adult; Drug Resistance, Bacterial; Ethionamide; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Rifampin; South Africa; Sputum; Tuberculosis, Multidrug-Resistant; Young Adult

Mutations in several genetic loci have been implicated in the development of resistance to second-line anti-tuberculosis (TB) drugs (SLDs). The purpose of this study was to investigate the prevalence of resistance to SLDs and its association with specific mutations in multidrug-resistant (MDR) Mycobacterium tuberculosis clinical isolates.. The study included 46 MDR-TB isolates. Mutation profiling was performed by amplifying and sequencing the following six genes: gyrA/gyrB, rrs, tlyA, and ethA/ethR, in which mutations are implicated in resistance of tubercle bacilli to ofloxacin (OFX), amikacin (AMK), capreomycin, and ethionamide (ETH), respectively.. Of the strains analyzed, 14 (30.4%) showed resistance to at least one of the four SLDs tested. Mutations in the gyrA gene occurred in 34 (73.9%) strains, with the most common amino acid change being Ser95Thr. The Asp94Asn and Ala90Val substitutions in the gyrA were present exclusively in OFX-resistant strains, yet represented only 40% of all OFX-resistant strains. The only mutation in the gyrB gene was substitution Ser447Phe, detected in one OFX-resistant isolate. None of the AMK-resistant strains carried a mutation in the rrs gene. Mutations in the ethA/ethR loci were found in one ETH-resistant and 11 ETH-susceptible strains.. The results of this study challenge the usefulness of sequence analyses of tested genes (except gyrA) for the prediction of SLD resistance patterns and highlight the need for searching other genetic loci for detection of mutations conferring resistance to SLDs in M. tuberculosis.

Topics: Adult; Aged; Amikacin; Antitubercular Agents; Base Sequence; Capreomycin; DNA Gyrase; Drug Resistance, Multiple, Bacterial; Ethionamide; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Ofloxacin; Oxidoreductases; Rifampin; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant

Depending on the presence of mutations that determine isoniazid (INH) susceptibility (katG and inhA), Mycobacterium tuberculosis may be susceptible to high doses of INH or ethionamide (ETH).. To describe the INH resistance profile and association of katG mutation with previous INH treatment and level of drug resistance based on rapid molecular drug susceptibility testing (DST) in southern Brazil and central Mozambique.. Descriptive study of 311 isolates from Ribeirão Preto, São Paulo, Brazil (2011-2014) and 155 isolates from Beira, Mozambique (2014-2015). Drug resistance patterns and specific gene mutations were determined using GenoType(®) MTBDRplus.. katG gene mutations were detected in 12/22 (54.5%) Brazilian and 32/38 (84.2%) Mozambican isolates. inhA mutations were observed in 9/22 (40.9%) isolates in Brazil and in 4/38 (10.5%) in Mozambique. Both katG and inhA mutations were detected in respectively 1/22 (5%) and 2/38 (5.2%). The difference in the frequency of katG mutations in Brazil and Mozambique was statistically significant (P = 0.04). katG mutations were present in 68.8% (33/48) of patients previously treated with INH and 31.2% (15/48) of patients without previous INH. This difference was not statistically significant (P = 0.223).. INH mutations varied geographically; molecular DST can be used to guide and accelerate decision making in the use of ETH or high doses of INH.

Topics: Antitubercular Agents; Bacterial Proteins; Brazil; Catalase; Clinical Decision-Making; DNA Mutational Analysis; Drug Resistance, Multiple, Bacterial; Ethionamide; Humans; Isoniazid; Microbial Sensitivity Tests; Mozambique; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Patient Selection; Predictive Value of Tests; Tuberculosis, Multidrug-Resistant

Multidrug-resistant tuberculosis (MDR-TB) is considered to be a worldwide problem with notoriously difficult and challenging treatment. Adverse events associated with second-line drugs (SLDs) can have severe impact on efficient management.. To know the frequency of adverse events due to SLDs in patients of MDR-TB.. A prospective cohort analysis of 98 MDR-TB patients enrolled between June 2009 to February 2010 was conducted in Department of Pulmonary Medicine, King George Medical University, Lucknow, India. All the patients were provided standardized regimen. Adverse events associated with treatment were recognized primarily by clinical evidence and/or laboratory investigations that were advised at baseline and whenever clinically indicated during course of treatment. Adverse events were considered major if required permanent discontinuation or substitution of drugs.. 119 adverse events were reported in 46 (46.9%) patients. The grouped adverse events were most commonly gastrointestinal that was observed with a frequency of 48 (40.3%) followed by ototoxicity in 28 (23.6%), and neurological in 21 (17.6%). 17 (17.4%) patients had major adverse events requiring permanent discontinuation or substitution of drugs that included deafness and tinnitus in 5 (5.1%) followed by psychosis in 4 (4.1%). None of the patients stopped complete regimen due to adverse events. The treatment success rate was observed to be 71 (72.4%).. MDR-TB can be cured successfully with appropriate combination of drugs if adverse events associated with them can be managed aggressively and timely. Newer and less toxic drugs are urgently needed to treat MDR-TB patients.

Topics: Adult; Antitubercular Agents; Cohort Studies; Cycloserine; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; Humans; Kanamycin; Male; Ofloxacin; Pyrazinamide; Tuberculosis, Multidrug-Resistant; Young Adult

To determine the prevalence and resistance pattern of multidrug-resistant tuberculosis.. This cross-sectional study was carried out from January 2010 to June 2014 in nine tertiary care hospitals implementing programmatic management of drug-resistant tuberculosis in Punjab, and comprised retreatment tuberculosis cases. Data was collected from the Electronic Nominal Review System. SPSS 17 was used for data analysis.. Of the 1,250 cases, 861(69%) were of multidrug-resistant tuberculosis confirmed through drug sensitivity testing. The mean age was 32 (±13.5 SD) years. Besides, 664(53%) were males and 1,208(97%) resided in urban areas of Punjab. Multidrug-resistant tuberculosis was found to be more prevalent in the most productive age group, i.e. 15-45 years, with 709(57%) cases (p<0.05), in urban areas1, 208(97%) cases (p<0.05) and in the pulmonary site 852(68%) cases (p<0.05). Overall, 391(41%) cases showed resistance to all first-line anti-tuberculosis drugs while 239(28%) showed resistance to oral first-line drugs. Besides, 526(42%) cases showed resistance to fluoroquinolones and 650(52%) to second-line drugs. Of them, 420(81%), (p<0.05) patients showed highly significant resistance to fluoroquinolones and 26(5%) to ethionamide.. There is a need to fully implement national tuberculosis guidelines with a focus on expansion and effective implementation of directly observed therapy short course in order to prevent further emergence of drug resistance.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Ethionamide; Female; Fluoroquinolones; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pakistan; Prevalence; Retreatment; Tuberculosis, Multidrug-Resistant; Young Adult

Ethionamide (ETH), a second-line anti-tubercular drug that is regaining a lot of interest due to the increasing cases of drug-resistant tuberculosis, is a pro-drug that requires an enzymatic activation step to become active and to exert its therapeutic effect. The enzyme responsible for ETH bioactivation in Mycobacterium tuberculosis is a monooxygenase (EthA) that uses flavin adenine dinucleotide (FAD) as a cofactor and is NADPH- and O

Topics: Antitubercular Agents; Bacterial Proteins; Biomimetics; Ethionamide; Humans; Models, Molecular; Mycobacterium tuberculosis; Oxidants; Oxidoreductases; Prodrugs; Tuberculosis, Multidrug-Resistant

A 22 year-old lady with multi-drug-resistant pulmonary tuberculosis was on Kanamycin, Cycloserine, Ethionamide, Pyrazinamide and Moxifloxacin since more than two months. She presented with muscle cramps and carpopedal spasm. Investigation revealed hypokalemia and metabolic alkalosis. She also had hypomagnesemia, hypochloremia and hypocalciuria. Serum urea and creatinine levels were normal. Patient was treated with intravenous and oral potassium chloride. Kanamycin was stopped. Metabolic alkalosis and hypokalemia improved gradually over one month. Biochemical parameters were like Gitelman's syndrome but it reversed with stoppage of Kanamycin. Gitelman-like syndrome with Kanamycin toxicity has not been reported in literature previously.

Topics: Adult; Alkalosis; Anti-Bacterial Agents; Antitubercular Agents; Cycloserine; Ethionamide; Female; Fluoroquinolones; Humans; Hypokalemia; Kanamycin; Moxifloxacin; Muscle Cramp; Potassium; Pyrazinamide; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tyrosinase catalyzes two distinct sequential reactions in melanin biosynthesis: the hydroxylation of tyrosine to DOPA followed by the oxidation of DOPA to dopaquinone. The central roles of melanin in living species have motivated researchers to maintain constant efforts to discover new agents that modulate tyrosinase activity. In this study, we report on the inhibition of tyrosinase by ethionamide and its analogues. Ethionamide, 2-ethylpyridine-4-carbothioamide, is a second-line antituberculosis drug used for the treatment of multidrug-resistant tuberculosis. The chemical similarity of ethionamide to phenylthiourea, a well-known tyrosinase inhibitor, led us to investigate its inhibitory effects on mushroom tyrosinase and the IC50 was calculated as 4 μM. Five analogues of ethionamide, including another antituberculosis drug, prothionamide, were also inhibitory, with values for IC50 in the range of 3-43 μM. Fluorescence quenching experiments supported a mechanism of direct binding. In contrast, isoniazid, a structural analogue and first-line antituberculosis drug, was a poor inhibitor of tyrosinase. We also tested the effects of ethionamide and its analogues on melanin content in B16F10 cells. At a concentration of 50 μM, the molecules, pyridine-2-carbothioamide and thiobenzamide substantially decreased the melanin content by 44% and 37%, respectively. In addition to identifying other interactions, docking simulations showed that the carbothioamide groups of the molecules make essential contacts with the catalytic di-copper atoms. Our results suggest that carbothioamide can be a central moiety for the development of new and potent tyrosinase inhibitors.

Topics: Animals; Antitubercular Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethionamide; Mice; Microbial Sensitivity Tests; Molecular Structure; Monophenol Monooxygenase; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant

While the high burden of multidrug-resistant tuberculosis (MDR-TB) itself is a matter of great concern, the emergence and rise of advanced forms of drug-resistance such as extensively drug-resistant TB (XDR-TB) and extremely drug-resistant TB (XXDR-TB) is more troubling. The aim of this study was to investigate the trends over time of patterns of drug resistance in a sample of MDR-TB patients in greater metropolitan Mumbai, India.. This was a retrospective, observational study of drug susceptibility testing (DST) results among MDR-TB patients from eight health care facilities in greater Mumbai between 2005 and 2013. We classified resistance patterns into four categories: MDR-TB, pre-XDR-TB, XDR-TB and XXDR-TB.. A total of 340 MDR-TB patients were included in the study. Pre-XDR-TB was the most common form of drug-resistant TB observed overall in this Mumbai population at 56.8% compared to 29.4% for MDR-TB. The proportion of patients with MDR-TB was 39.4% in the period 2005-2007 and 27.8% in 2011-2013, while the proportion of those with XDR-TB and XXDR-TB was changed from 6.1% and 0% respectively to 10.6% and 5.6% during the same time period. During the same periods, the proportions of patients with ofloxacin, moxifloxacin and ethionamide resistance significantly increased from 57.6% to 75.3%, from 60.0% to 69.5% and from 24.2% to 52.5% respectively (p<0.05).. The observed trends in TB drug-resistance patterns in Mumbai highlight the need for individualized drug regimens, designed on the basis of DST results involving first- and second-line anti-TB drugs and treatment history of the patient. A drug-resistant TB case-finding strategy based on molecular techniques that identify only rifampicin resistance will lead to initiation of suboptimal treatment regimens for a significant number of patients, which may in turn contribute to amplification of resistance and transmission of strains with increasingly advanced resistance within the community.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Ethionamide; Female; Fluoroquinolones; Humans; India; Infant; Male; Microbial Sensitivity Tests; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Precision Medicine; Retrospective Studies; Tuberculosis, Multidrug-Resistant; Young Adult

Multidrug-resistant (MDR) tuberculosis (TB) constitutes a restricting factor for the effective treatment of TB worldwide. Early diagnosis and appropriate treatment of patients are the most effective strategy in the control of MDR-TB. Therefore, knowledge of drug resistance patterns of the MDR-TB clinical isolates are necessary in planning of an appropriate treatment regimen for the patient. The aims of this study were to detect the susceptibilities of MDR-TB isolates to second-line anti-TB drugs by E-test method, and to compare their results with Löwenstein-Jensen (LJ) proportion method. A total of 122 MDR (resistant to isoniazid and rifampicin) Mycobacterium tuberculosis complex (MTC) strains isolated from samples of patients with pulmonary TB were included in the study. The isolates were identified by conventional methods and first-line anti-TB drug susceptibility testing was performed by the proportion method using LJ medium. The susceptibilities of the isolates to second-line anti-TB drugs [kanamycin (KN), ofloxacin (OFL), ethionamid (ETN), linezolid (LIN)] were tested by proportion method on LJ medium and E-test method on Middlebrook 7H11 medium. For this purpose, E-test strips (bioMerieux, Fransa) of KN (0.016-256 mg/ml), OFL (0.02-32 mg/ml), ETN (0.016-256 mg/ml), and LIN (0.016-256 mg/ml) were used. The susceptibility tests were evaluated in 5., 7., and 10. days after application of the E-test strips, and proportion method on LJ medium was evaluated 28 days later. Second line-anti-TB drug susceptibility results were obtained in 5 to 10 days by E-test. Of the MDR MTC strains 98% (119/122) were susceptible to KN, OFL and LIN, while 2% (3/122) of the strains were resistant to KN and ETN. The correlation between E-test and LJ proportion method was estimated as 96% for KN and ETN, 98% for OFL, and 100% for LIN. When compared with LJ proportion method, the specificity of E-test in the detection of susceptibility to KN, OFL, ETN and LIN were 60%, 38%, 60%, and 100%, respectively, while the sensitivity was 100% for all drugs. Our results indicated that E-test method exhibited high sensitivity and specificity (100%) for LIN, so it may be used alone in susceptibility testing for this drug, however since the specificity is low (38%) for OFL it should be used together with the proportion method. In conclusion, E-test method might contribute for initiation of an early and effective anti-TB drug treatment and control of infection by rapid diagnosis in MDR-TB ca

Topics: Acetamides; Antitubercular Agents; Culture Media; Drug Resistance, Multiple, Bacterial; Ethionamide; Humans; Kanamycin; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Oxazolidinones; Reagent Strips; Sensitivity and Specificity; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Drug-resistant tuberculosis (TB) remains extremely difficult to treat because there are often few remaining active medications and limited diagnostic options to detect resistance. Resistance to isoniazid is typically caused by mutations in either katG or the inhA promoter. inhA mutations confer low-level resistance to isoniazid and cross-resistance to ethionamide while katG mutations confer high-level isoniazid resistance and no cross-resistance. Line Probe Assays (LPAs) that detect mutations in katG and inhA are currently performed on all positive TB cultures in KwaZulu-Natal province, South Africa, but the frequency of inhA mutations in drug-resistant TB patients has not been examined.. We sought to determine the proportion of patients who could potentially benefit from high-dose isoniazid and who may be resistant to ethionamide. We reviewed 994 LPA (Hain MTBDRplus) results at the TB reference laboratory in KwaZulu-Natal to determine the frequency of mutations in either katG or the inhA promoter. We stratified these results by drug-resistance category (i.e., MDR-TB, pre-XDR-TB, and XDR-TB) as determined by phenotypic drug-susceptibility testing.. Among MDR- and XDR-TB isolates, the prevalence of inhA mutations without a concurrent katG mutation was 14.8% and 10.3% respectively. The prevalence of inhA mutations with OR without a katG mutation was 30.3% and 82.8%, respectively.. More than 10% of patients with MDR- and XDR-TB may benefit from high-dose isoniazid. Although ethionamide is empirically included in all MDR- and XDR-TB regimens, nearly a third of MDR-TB patients and a majority of XDR-TB patients likely have resistance to ethionamide. Laboratories performing line probe assays should report specific band patterns so that clinicians may adjust treatment regimens accordingly.

Topics: Antitubercular Agents; Bacterial Proteins; Catalase; Ethionamide; Extensively Drug-Resistant Tuberculosis; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Prevalence; Promoter Regions, Genetic; South Africa; Tuberculosis, Multidrug-Resistant

Ethionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in the Mycobacterium tuberculosis population. ETH resistance in M. tuberculosis is phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in the inhA promoter and in the following genes: katG, ethA, ethR, mshA, ndh, and inhA. We sequenced the above genes in 64 M. tuberculosis isolates (n = 57 ETH-resistant MDR-TB isolates; n = 3 ETH-susceptible MDR-TB isolates; and n = 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% in katG, 72% in ethA, 45.6% in mshA, 8.7% in ndh, and 33.3% in inhA or its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations in katG; one had a mutation in ethA, and another, in mshA and inhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations in mshA gene unrelated to the resistance. Mutations not previously reported were found in the ethA, mshA, katG, and ndh genes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in the M. tuberculosis isolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

Topics: Antitubercular Agents; Bacterial Proteins; Catalase; Drug Resistance, Multiple, Bacterial; Ethionamide; Fimbriae Proteins; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; NADH Dehydrogenase; Oxidoreductases; Promoter Regions, Genetic; Repressor Proteins; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Dreams; Ethionamide; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant

Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.

Topics: Adolescent; Adult; Amikacin; Antitubercular Agents; Cycloserine; Ethionamide; Female; Fluoroquinolones; Humans; Kanamycin; Levofloxacin; Male; Microbial Sensitivity Tests; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Pyrazinamide; Sputum; Tanzania; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Childhood tuberculosis (TB) is a marker of TB transmission within a community. We present the fourth consecutive survey of children with culture-confirmed TB at a hospital in Cape Town, South Africa, from 2009 to 2011. In comparison to the previous survey, the rate of multidrug-resistant TB (MDR-TB) has stabilised and the human immunodeficiency virus infection rate has declined. We also report on the first systematic surveillance of resistance to second-line drugs. Two concerns following from this are the high rate (22%) of ofloxacin resistance in MDR-TB isolates, and the discordance between isolates with an inhA promoter region mutation, usually implying ethionamide (ETH) resistance, and phenotypic ETH results in these isolates showing ETH susceptibility.

Topics: Age Factors; Antitubercular Agents; Bacterial Proteins; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Ethionamide; Female; HIV Infections; Humans; Infant; Male; Mycobacterium tuberculosis; Ofloxacin; Oxidoreductases; Promoter Regions, Genetic; South Africa; Tuberculosis, Multidrug-Resistant

St Peter's TB Specialized Hospital, Addis Ababa, Ethiopia.. To estimate the prevalence of mutations that cause resistance to isoniazid (INH) and rifampicin (RMP) and assess the effects of these mutations on second-line anti-tuberculosis treatment.. GenoType(®)MTBDRplus assay results and clinical data documented at St Peter's TB Specialized Hospital over 3 years were retrospectively collected and analysed.. The results indicated that 68.7% (n = 470) of RMP-resistant isolates had mutations at codon 531 (S531L) of the rpoB gene, while 93% (n = 481) of the INH-resistant isolates had mutations at codon 315 (S315T1) of the katG gene. The proportion of inhA mutations was 0.8% (n = 481). Treatment outcome was unfavourable in 23.7% (n = 76) of patients treated with second-line anti-tuberculosis drugs. Mutations in other codons of the rpoB gene (P > 0.05) and in the inhA promoter region (P > 0.05) were not associated with unfavourable treatment outcomes.. The predominant mutations in RMP and INH resistance were observed at codons 531 and 315 in the rpoB and katG genes, respectively. Mutations in the inhA region were rare, which shows its minimal contribution to the development of resistance to ethionamide. This also suggests that treating multidrug-resistant TB patients with high doses of INH may have little effect.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Codon; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Ethionamide; Ethiopia; Female; Humans; Isoniazid; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult

The aim of the study was to elucidate the profile of adverse drug reactions (ADRs) associated with second-line anti-tubercular treatment for drug-resistant tuberculosis.. ADR profile of diagnosed drug-resistant tuberculosis cases on supervised second-line anti-tubercular drug regimen under Programmatic Management of Drug-resistant Tuberculosis under Revised National Tuberculosis Control Programme, were studied over two years' period. Adverse reactions were categorised into mild, moderate and severe types with subsequent systematic data-analysis.. Out of total 207 patients in the study, 81.16% reported with adverse drug reactions. Out of total 195 adverse events, 63.58%, 18.46% and 17.94% were of mild, moderate and severe types respectively. Gastrointestinal events, hepatitis, hearing impairment, arthralgia, psychosis, hypothyroidism, visual disturbances, giddiness, peripheral neuropathy, skin reactions, swelling or pain at injection site, anorexia and sleep disturbances were important amongst these. High proportion of drug and/or alcohol abuse was an important observation. The offending drug(s) had to be terminated in 12.08% of the patients.. Early detection, management and pharmaco-vigilance reporting of ADRs remain key factors in the management of drug-resistant tuberculosis with remarkable relevance of the need for early diagnosis and treatment of 'drug-sensitive tuberculosis', to prevent emergence of drug-resistant tuberculosis.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Arthralgia; Ataxia; Chemical and Drug Induced Liver Injury; Child; Cycloserine; Drug Eruptions; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; Gastrointestinal Diseases; Hearing Loss; Humans; Hypothyroidism; India; Kanamycin; Levofloxacin; Male; Middle Aged; Peripheral Nervous System Diseases; Psychoses, Substance-Induced; Pyrazinamide; Severity of Illness Index; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Vision Disorders; Young Adult

In Japan, the incidence of severe pediatric tuberculosis (TB) has decreased dramatically in recent years. However, children in Japan can still have considerable opportunities to contract TB infection from adult TB patients living nearby, and infants infected with TB may develop severe disseminated disease. A 3-month-old girl was admitted to our hospital with dyspnea and poor feeding. After admission, miliary TB and multiple brain tuberculomas were diagnosed. Anti-tuberculous therapy was initiated with streptomycin (SM), isoniazid (INH), rifampicin and pyrazinamide. Symptoms persisted after starting the initial treatment and mycobacterial cultures of gastric fluid remained positive. Drug sensitivity testing revealed the TB strain isolated on admission as completely resistant to INH and SM. Treatments with INH and SM were therefore stopped, and treatment with ethambutol and ethionamide was started in addition to rifampicin and pyrazinamide. After this change to the treatment regimen, symptoms and laboratory data gradually improved. The patient was treated with these four drugs for 18 months, and then pyrazinamide was stopped. After another 2 months, ethambutol was stopped. Treatment of tuberculosis was completed in 24 months. No adverse effects of these anti-TB drugs were observed. The patient achieved a full recovery without any sequelae. On the other hand, the infectious source for this patient remained unidentified, despite the extensive contact investigations. The incidence of drug-resistant TB is increasing in many areas of the world. Continuous monitoring for pediatric patients with drug-resistant TB is therefore needed.

Topics: Antitubercular Agents; Drug Substitution; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; Humans; Infant; Isoniazid; Microbial Sensitivity Tests; Pyrazinamide; Radiography, Thoracic; Rifampin; Streptomycin; Treatment Outcome; Tuberculoma, Intracranial; Tuberculosis, Miliary; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The purpose of this study was to determine the levels of isoniazid and ethionamide resistance and to identify associated mutations in endemic multidrug-resistant (MDR) strains of Mycobacterium tuberculosis from the Lisbon metropolitan area, Portugal.. Seventeen clinical MDR tuberculosis (TB) strains were characterized by standard and semi-quantitative drug susceptibility testing to assess the level of isoniazid and ethionamide resistance. The genes katG, inhA, ethA and ndh were screened for mutations. All strains were genotyped by 24 loci mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) analysis.. All strains showed high-level resistance to both isoniazid (>1 mg/L) and ethionamide (>25 mg/L). MIRU-VNTR typing revealed the presence of two main clusters, Lisboa3 and Q1, in 16/17 strains, all of which showed the C-15T mutation in the promoter region of the inhA gene. The 16 strains belong to the Latino-American-Mediterranean (LAM) genotype and the other strain belongs to the Beijing genotype. Sequencing of the inhA open reading frame revealed that the 16 strains also had mutations in the structural region of the gene, leading to the S94A substitution in 9 strains and the I194T substitution in 7 strains.. The results reveal that the presence of a mutation in the inhA regulatory region together with a mutation in the inhA coding region can lead to the development of high-level isoniazid resistance and cross-resistance to ethionamide among the MDR-TB strains circulating in Lisbon. This mutational pattern also hints to a possible involvement of strain-specific factors that could be a feature of the Portuguese MDR-TB strains where the LAM family is the major circulating genotype.

Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Ethionamide; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Molecular Typing; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Portugal; Tuberculosis, Multidrug-Resistant

Kibong'oto National Tuberculosis Hospital (KNTH), Kilimanjaro, Tanzania.. Characterize the diagnostic process and interim treatment outcomes from patients treated for multidrug-resistant tuberculosis (MDR-TB) in Tanzania.. A retrospective cohort study was performed among all patients treated at KNTH for pulmonary MDR-TB between November 2009 and September 2011.. Sixty-one culture-positive MDR-TB patients initiated therapy, 60 (98%) with a prior history of TB treatment. Forty-one (67%) were male and 9 (14%) were HIV infected with a mean CD4 count of 424 (±106) cells/µl. The median time from specimen collection to MDR-TB diagnosis and from diagnosis to initiation of MDR-TB treatment was 138 days (IQR 101-159) and 131 days (IQR 32-233), respectively. Following treatment initiation four (7%) patients died (all HIV negative), 3 (5%) defaulted, and the remaining 54 (89%) completed the intensive phase. Most adverse drug reactions were mild to moderate and did not require discontinuation of treatment. Median time to culture conversion was 2 months (IQR 1-3) and did not vary by HIV status. In 28 isolates available for additional second-line drug susceptibility testing, fluoroquinolone, aminoglycoside and para-aminosalicylic acid resistance was rare yet ethionamide resistance was present in 9 (32%).. The majority of MDR-TB patients from this cohort had survived a prolonged referral process, had multiple episodes of prior TB treatment, but did not have advanced AIDS and converted to culture negative early while completing an intensive inpatient regimen without serious adverse event. Further study is required to determine the clinical impact of second-line drug susceptibility testing and the feasibility of alternatives to prolonged hospitalization.

Topics: Adult; Aminoglycosides; Aminosalicylic Acid; Antitubercular Agents; Comorbidity; Drug Resistance, Multiple, Bacterial; Ethionamide; Female; Fluoroquinolones; HIV; HIV Infections; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Tanzania; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Adverse events (AEs) among HIV-infected patients with multidrug-resistant tuberculosis (MDR-TB) receiving anti-TB and antiretroviral treatments (ART) are under-researched and underreported. Hypothyroidism is a common AE associated with ethionamide, p-aminosalicylic acid (PAS), and stavudine. The aim of this study was to determine the frequency of and risk factors associated with hypothyroidism in HIV/MDR-TB co-infected patients.. This was a prospective, observational cohort study, using routine laboratory data in a Médecins Sans Frontières (MSF) clinic in collaboration with Sewri TB Hospital, Mumbai, India. Hypothyroidism was defined as a thyroid stimulating hormone (TSH) result >10 mIU/L at least once during treatment. Patients having a baseline result and one additional result after 3 months were eligible for enrolment.. Between October 2006 and March 2013, 116 patients were enrolled, 69 of whom were included. The median (IQR) age was 38 years (34-43) and 61% were male. By March 2013, 37/69 (54%) had hypothyroidism after at least 90 days of treatment. Age, gender, CD4 counts and stavudine-based ART were not associated with the occurrence of hypothyroidism in multivariate models. The co-administration of PAS and ethionamide was found to double the risk of hypothyroidism (RR: 1.93, 95% CI: 1.06-3.54).. High rate of hypothyroidism was recorded in a Mumbai cohort of MDR-TB/HIV co-infected patients on treatment. This is a treatable and reversible AE, however, it may go undiagnosed in the absence of regular monitoring. Care providers should not wait for clinical symptoms, as this risks compromising treatment adherence. Simple, affordable and reliable point-of-care tools for measuring TSH are needed, especially in high MDR-TB burden countries. Our findings suggest the need for TSH screening at baseline, three months, six months, and every six months thereafter for HIV-infected patients on MDR-TB treatment regimens containing PAS and/or ethionamide, until newer, safer and more efficacious MDR-TB regimens become available.

Topics: Adult; Aminosalicylic Acid; Cohort Studies; Coinfection; Ethionamide; Female; HIV Infections; Humans; Hypothyroidism; Incidence; India; Male; Multivariate Analysis; Prospective Studies; Risk Factors; Stavudine; Thyrotropin; Tuberculosis, Multidrug-Resistant

Standardized methodology for drug susceptibility testing of second line drugs is vital for treatment of multi/extensively drug resistant tuberculosis. Discrepancy between laboratory methods and clinical interpretation is well established for bacteriostatic drugs such as ethionamide. Optimization of the standard proportion sensitivity testing (PST) method for ethionamide was under taken in 235 Mycobacterium tuberculosis isolates from new and previously treated pulmonary tuberculosis patients. An additional higher concentration of 57 μg/ml was evaluated against at the standard 40 μg/ml concentration in PST method. Performance parameters and agreement between the two drug concentrations was higher indicating the efficiency of PST method at its present format at 40 μg/ml and additional higher concentration of 57 μg/ml as an alternative when required.

Topics: Antitubercular Agents; Drug Resistance, Bacterial; Ethionamide; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant

Topics: Adolescent; Adult; Antitubercular Agents; Ethionamide; Female; Humans; Hypothyroidism; Male; Thyroid Function Tests; Tuberculosis, Multidrug-Resistant; Young Adult

Multidrug-resistant tuberculosis (MDR-TB) has become a worldwide problem and a major public health concern. The mechanisms of resistance are fairly well characterized for most agents, but MDR limits the therapeutic usefulness of both new and classical medicines against TB. Ethionamide (ETA) is a thioamide antibiotic and one of the most widely used drugs as second line agent for the treatment of MDR-TB. Over the years, some studies have emerged to improve the bioavailability of this drug and of its active metabolites. However, inactive metabolites of ETA are still a major drawback in its application against TB. Porous silicon (PSi) materials can be applied to improve the dissolution behavior of poorly water-soluble compounds and to overcome toxicity and other drug-related problems in oral delivery. In the present work, we have loaded ETA into thermally carbonized-PSi (TCPSi) microparticles and studied the solubility, toxicity, permeability, and metabolic profiles of the PSi-loaded drug. The solubility and permeability of ETA was clearly enhanced after loaded into TCPSi particles at different pH-values. ETA was in general toxic at concentrations above 0.50mM to HepG2, Caco-2, and RAW macrophage cells, but the toxicity was drastically reduced when the drug was loaded into the microparticles. ETA showed a fast metabolization process in the presence of the TCPSi particles. In addition, new thiolated metabolites were identified from incubation of ETA-loaded PSi with HepG2 liver cells, which opens new perspectives toward both the understanding of ETA metabolism and the development of novel ETA-based systems with improved efficacy against MDR-TB.

Topics: Adenosine Triphosphate; Antitubercular Agents; Caco-2 Cells; Cell Line, Tumor; Cell Survival; Drug Carriers; Ethionamide; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Macrophages; Particle Size; Permeability; Porosity; Silicon; Solubility; Tuberculosis, Multidrug-Resistant

A 28-year-old woman without any history of prior antituberculosis treatment presented with cervical lymphadenopathy and a cold abscess near medial end of clavicle of 5 months duration. Pus culture and sensitivity revealed Mycobacterium tuberculosis resistant to rifampicin and isoniazid. Thus she was diagnosed as a case of primary multidrug-resistant tuberculosis and treated with second line drugs according to culture susceptibility pattern. On completion of therapy, patent showed good clinical response. This case highlights the observation that even extra-pulmonary primary multidrug-resistant tuberculosis can be successfully treated with currently available second line drugs.

Topics: Adult; Antitubercular Agents; Clarithromycin; Clofazimine; Cycloserine; Diagnosis, Differential; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; HIV Seronegativity; Humans; Isoniazid; Kanamycin; Ofloxacin; Pyrazinamide; Rifampin; Tuberculosis, Lymph Node; Tuberculosis, Multidrug-Resistant

Drug susceptibility pattern of standard Mycobacterium tuberculosis strain H 37 Rv showed discrepancy in minimum inhibitory concentration method for ethionamide and consistent results were obtained for the other second line drugs namely, kanamycin and ofloxacin. It is, therefore, necessary to revisit the susceptibility testing method for ethionamide for effective clinical management of patients with drug resistant tuberculosis.

Topics: Drug Resistance, Microbial; Ethionamide; Humans; Kanamycin; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Tuberculosis, Multidrug-Resistant

Sustained release nanoformulations of second line anti-tubercular drugs can help in reducing their dosing frequency and improve patient's compliance in multi-drug resistant tuberculosis (MDR TB). The objective of the current study was to investigate the pharmacokinetics and tissues distribution of ethionamide encapsulated in poly (DL-lactide-co-glycolide) (PLGA) nanoparticles. The drug loaded nanoparticles were 286 ± 26 nm in size with narrow size distribution, and zeta-potential was -13 ± 2.5 mV. The drug encapsulation efficiency and loading capacity were 35.2 ± 3.1%w/w and 38.6 ± 2.3%w/w, respectively. Ethionamide-loaded nanoparticles were administered orally to mice at two different doses and the control group received free (unencapsulated) ethionamide. Ethionamide-loaded PLGA nanoparticles produced sustained release of ethionamide for 6 days in plasma against 6 h for free ethionamide. The Ethionamide was detected in organs (lung, liver, and spleen) for up to 5-7 days in the case of encapsulated ethionamide, whereas free ethionamide was cleared within 12 h. Ethionamide-loaded PLGA nanoparticles exhibited significant improvement in pharmacokinetic parameters, i.e. C(max), t(max), AUC₀₋∞, AUMC₀₋∞, and MRT of encapsulated ethionamide as compared with free ethionamide. Drug in nanoparticles also exhibited a dose proportional increase in the AUC₀₋∞ values. The pharmacodynamic parameters such as AUC₀₋₂₄/MIC, C(max)/MIC, and Time > MIC were also improved. PLGA nanoparticles of ethionamide have great potential in reducing dosing frequency of ethionamide in treatment of MDR TB.

Topics: Administration, Oral; Animals; Chemistry, Pharmaceutical; Delayed-Action Preparations; Ethionamide; Female; Lactic Acid; Male; Mice; Nanocapsules; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Tissue Distribution; Tuberculosis, Multidrug-Resistant

Ethionamide (ETH) needs to be activated by the mono-oxygenase EthA, which is regulated by EthR, in order to be active against Mycobacterium tuberculosis. The activated drug targets the enzyme InhA, which is involved in cell wall biosynthesis. Resistance to ETH has been reported to result from various mechanisms, including mutations altering EthA/EthR, InhA and its promoter, the NADH dehydrogenase encoded by ndh, and the MshA enzyme, involved in mycothiol biosynthesis. We searched for such mutations in 87 clinical isolates: 47 ETH-resistant (ETH(r)) isolates, 24 ETH-susceptible (ETH(s)) isolates, and 16 isolates susceptible to ETH but displaying an intermediate proportion of resistant cells (ETH(Sip); defined as ≥1% but <10% resistant cells). In 81% (38/47) of the ETH(r) isolates, we found mutations in ethA, ethR, or inhA or its promoter, which mostly corresponded to new alterations in ethA and ethR. The 9 ETH(r) isolates without a mutation in these three genes (9/47, 19%) had no mutation in ndh, and a single isolate had a mutation in mshA. Of the 16 ETH(Sip) isolates, 7 had a mutation in ethA, 8 had no detectable mutation, and 1 had a mutation in mshA. Finally, of the 24 ETH(s) isolates, 23 had no mutation in the studied genes and 1 displayed a yet unknown mutation in the inhA promoter. Globally, the mechanism of resistance to ETH remained unknown for 19% of the ETH(r) isolates, highlighting the complexity of the mechanisms of ETH resistance in M. tuberculosis.

Topics: Antitubercular Agents; Ethionamide; Humans; Molecular Sequence Data; Mycobacterium tuberculosis; Polymerase Chain Reaction; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant

Topics: Adult; Aged; Aged, 80 and over; Aminosalicylic Acid; Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Ethionamide; Female; Fluoroquinolones; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Ofloxacin; Rifabutin; Rifampin; Streptomycin; Taiwan; Tuberculosis, Multidrug-Resistant

To achieve prolonged drug release for the treatment of multidrug resistant tuberculosis and to improve the patient compliance, ethionamide loaded PLGA nanoparticles were developed.. They were developed by solvent evaporation method and optimized. The optimized formulation was subjected to various physico-chemical characterization, in vitro release studies and in vivo tolerability study.. There was no significant drug-polymer interaction and drug was encapsulated as crystalline form in nanoparticles. In vitro release was sustained up to 15 days in various media. Ethionamide loaded nanoparticles in mice did not reveal any statistically significant treatment related effects on body weight gain and clinical signs. Likewise, no treatment-related toxic effect was found in hematology, clinical chemistry and histopathology. Our results indicate the development of an orally effective safe formulation of ethionamide with sustained release property.. Hence, ethionamide loaded nanoparticles offer excellent potential for further preclinical and clinical studies.

Topics: Animals; Antitubercular Agents; Delayed-Action Preparations; Ethionamide; Female; Humans; Lactic Acid; Male; Mice; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Spectroscopy, Fourier Transform Infrared; Tuberculosis, Multidrug-Resistant

Nucleotide sequences of genes conferring isoniazid resistance (katG, inhA, oxyR-ahpC and ndh) and ethionamide resistance (ethA) in 160 drug-resistant Mycobacterium tuberculosis clinical isolates from Thailand were analysed. Mutations in the katG gene were found in 129 isolates, predominantly at codon 315, which was mutated in 127 isolates. Twenty-two isolates had mutations in the inhA promoter and coding region. Mutations in the oxyR-ahpC intergenic region and in ndh were detected in four and one isolate(s), respectively. Of 24 ethionamide-resistant isolates, 13 had mutations in the ethA gene. However, these mutations were dispersed along the entire gene, with no codon predominating significantly.

Topics: Antitubercular Agents; Bacterial Proteins; Catalase; Drug Resistance, Multiple, Bacterial; Ethionamide; Genotype; Isoniazid; Mycobacterium tuberculosis; Sequence Analysis; Thailand; Tuberculosis, Multidrug-Resistant

To evaluate the frequency of drug resistance profiles of multidrug resistant tuberculosis (MDR-TB) isolates of pulmonary tuberculosis patients, against both the first and the second line drugs.. An observational study.. The multidrug resistant tuberculosis (MDR-TB) ward of Ojha Institute of Chest Diseases (OICD), Karachi, from 1996 to 2006.. Culture proven MDR-TB cases (resistant to both isoniazid and Rifampicin) were retrospectively reviewed. Susceptibility testing was performed at the clinical laboratory of the Aga Khan University. Sensitivity against both first and second line anti-tuberculosis drugs was done. Susceptibility testing was performed using Agar proportion method on enriched middle brook 7H10 medium (BBL) for Rifampicin, Isoniazid, Streptomycin, Ethambutol, Ethionamide, Capreomycin and Ciprofloxacin. Pyrazinamide sensitivity was carried out using the BACTEC 7H12 medium. During the study period MTB H37Rv was used as control.. Out of total 577 patients, all were resistant to both Rifampicin and Isoniazid (INH). 56.5% isolates were resistant to all five first line drugs. Resistances against other first line drugs was 76.60% for Pyrazinamide, 73% for Ethambutol and 68.11% for Streptomycin. Five hundred and ten (88%) cases were MDR plus resistant to one more first line drug. Forty (07%) isolates were MDR plus Quinolone-resistant. They were sensitive to Capreomycin but sensitivity against Amikacin and Kanamycin were not tested.. There were high resistance rates in MDR-TB to remaining first line and second line drugs. Continuous monitoring of drug resistance pattern especially of MDR isolates and treatment in specialized centers is a crucial need for future TB control in Pakistan.

Topics: Adult; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Female; Humans; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pakistan; Pyrazinamide; Retrospective Studies; Risk Factors; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Three centres for the treatment of multidrug-resistant tuberculosis (MDR-TB) in Istanbul, Turkey: Heybeliada Centre for Chest Diseases and Thoracic Surgery, Süreyyapaşa Centre for Chest Diseases and Thoracic Surgery and Yedikule Centre for Chest Diseases and Thoracic Surgery.. To evaluate the presence of ethionamide (ETH) resistance and its effect on time to sputum smear negativity in MDR-TB patients who had not previously received second-line anti-tuberculosis drugs.. Drug susceptibility testing for isoniazid (INH), rifampicin (RMP), ethambutol, streptomycin and ETH was performed on 50 patients treated between August 2004 and May 2005. Indirect agar proportion and BACTEC methods were used to determine ETH susceptibility.. Of the patients who were resistant to at least INH and RMP, 11 (22%) (three [27.3%] new and eight [72.7%] retreatment) were resistant to ETH with the BACTEC method. Of 18 new patients, three (16.6%) were ETH-resistant using the BACTEC method compared to 8/32 (25%) retreatment patients. The mean time to smear negativity was 75.2 days in ETH-resistant patients and 50 days in susceptible patients (P < 0.05). Both ETH-resistant and -susceptible groups were homogeneous for factors that may have a possible effect on time to conversion.. Not only ETH resistance but also age and radiologically advanced disease adversely affected time to sputum conversion.

Topics: Adolescent; Adult; Agar; Antitubercular Agents; Chi-Square Distribution; Child; Ethambutol; Ethionamide; Humans; Isoniazid; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Radiometry; Regression Analysis; Rifampin; Sputum; Streptomycin; Tuberculosis, Multidrug-Resistant; Turkey

Limited information about the prevalence of drug-resistant tuberculosis (TB) has been reported from India, the country with the world's highest burden of TB. We conducted a representative state-wide survey in the state of Gujarat (2005 population: 56 million).. Mycobacterium tuberculosis isolates from a representative sample of new and previously treated smear-positive pulmonary TB (PTB) cases were subjected to drug susceptibility testing (DST) against first-line drugs at a World Health Organization supranational reference laboratory. Isolates found to have at least both isoniazid (INH) and rifampicin (RMP) resistance (i.e., multidrug-resistant TB [MDR-TB]) were subjected to second-line DST.. Of 1571 isolates from new patients, 1236 (78.7%) were susceptible to all first-line drugs, 173 (11%) had any INH resistance and MDR-TB was found in 37 (2.4%, 95%CI 1.6-3.1). Of 1047 isolates from previously treated patients, 564 (54%) were susceptible to all first-line drugs, 387 (37%) had any INH resistance and MDR-TB was found in 182 (17.4%, 95%CI 15.0-19.7%). Among 216 MDR-TB isolates, 52 (24%) were ofloxacin (OFX) resistant; seven cases of extensively drug-resistant TB (XDR-TB) were found, all of whom were previously treated cases.. MDR-TB prevalence remains low among new TB patients in Gujarat, but is more common among previously treated patients. Among MDR-TB isolates, the alarmingly high prevalence of OFX resistance may threaten the success of the expanding efforts to treat and control MDR-TB.

Topics: Antitubercular Agents; Bacteriological Techniques; Colony Count, Microbial; Drug Resistance, Multiple, Bacterial; Ethionamide; Extensively Drug-Resistant Tuberculosis; Female; Humans; India; Isoniazid; Kanamycin; Male; Microscopy, Fluorescence; Mycobacterium tuberculosis; Ofloxacin; Population Surveillance; Prevalence; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant

Ethionamide (ETH) is a structural analogue of isoniazid (INH). Both are pro-drugs requiring activation by separate and common enzyme pathways, which could lead to co- and/or cross-resistance.. To characterise paediatric INH-resistant mycobacterial isolates to investigate the presence of ETH resistance and mutations in the katG gene and the inhA promoter region.. Forty-five INH-resistant and 19 INH-susceptible Mycobacterium tuberculosis control isolates from children from the Western Cape Province, South Africa, were analysed to quantify INH minimal inhibitory concentration, test for ETH resistance and investigate mutations in the katG gene and/or inhA promoter region.. Among 45 INH-resistant children, ETH resistance was present in 19 of 39 (49%). An inhA promoter mutation was identified in 15 (33.3%); 12/14 (86%) of these isolates were also ETH-resistant. Of the 21 isolates with a katG mutation, six (29%) were ETH-resistant. No isolate had both katG and inhA promoter mutations. Nine (20%) isolates had neither inhA promoter nor katG mutations. Of 15 isolates with inhA promoter mutation, 14 (93%) displayed low- or intermediate-level INH resistance. Among the 19 INH-susceptible isolates, ETH resistance was present in 1/18 (6%) and none showed inhA or katG gene mutations.. We found a high level of cross- and co-resistance with ETH among INH-resistant M. tuberculosis isolates from children in this geographic area.

Topics: Antitubercular Agents; Bacterial Proteins; Case-Control Studies; Catalase; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Ethionamide; Genotype; Humans; Infant; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Phenotype; Promoter Regions, Genetic; Prospective Studies; South Africa; Treatment Failure; Tuberculosis, Multidrug-Resistant

Spontaneous mutants of Mycobacterium tuberculosis that were resistant to the anti-tuberculosis drugs ethionamide and isoniazid were isolated and found to map to mshA, a gene encoding the first enzyme involved in the biosynthesis of mycothiol, a major low-molecular-weight thiol in M. tuberculosis. Seven independent missense or frameshift mutations within mshA were identified and characterized. Precise null deletion mutations of the mshA gene were generated by specialized transduction in three different strains of M. tuberculosis. The mshA deletion mutants were defective in mycothiol biosynthesis, were only ethionamide-resistant and required catalase to grow. Biochemical studies suggested that the mechanism of ethionamide resistance in mshA mutants was likely due to a defect in ethionamide activation. In vivo, a mycothiol-deficient strain grew normally in immunodeficient mice, but was slightly defective for growth in immunocompetent mice. Mutations in mshA demonstrate the non-essentiality of mycothiol for growth in vitro and in vivo, and provide a novel mechanism of ethionamide resistance in M. tuberculosis.

Topics: Amino Acid Sequence; Animals; Antitubercular Agents; Bacterial Proteins; Catalase; Corynebacterium glutamicum; Cysteine; Drug Resistance, Bacterial; Ethionamide; Glycopeptides; Glycosyltransferases; Humans; Inositol; Isoniazid; Mice; Mice, Inbred C57BL; Mice, SCID; Microbial Sensitivity Tests; Mixed Function Oxygenases; Molecular Sequence Data; Mycobacterium Infections; Mycobacterium tuberculosis; Sequence Alignment; Sequence Deletion; Tuberculosis, Multidrug-Resistant

Multidrug-resistant tuberculosis (MDR-TB) has become a therapeutic problem in many parts of the world, necessitating the inclusion of second-line anti-tuberculosis drugs in specific treatment regimens.. We studied the susceptibility of 69 MDR Mycobacterium tuberculosis isolates from Rwanda to second-line drugs by the BACTEC 460 method.. The results showed that 62 (89.9%) were resistant to rifabutin while a low rate (4.3%) of resistance was registered for ofloxacin; there was one case (1.4%) of resistance each for para-aminosalicylic acid, kanamycin, ethionamide, and clarithromycin.. This information is important for devising an appropriate treatment regimen for MDR-TB patients in order to stop the spread of MDR strains and contain the acquisition of additional drug resistance in Rwanda.

Topics: Adult; Aminosalicylic Acids; Anti-Bacterial Agents; Antitubercular Agents; Clarithromycin; Drug Resistance, Multiple, Bacterial; Ethionamide; Female; Humans; Kanamycin; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Rwanda; Tuberculosis, Multidrug-Resistant

To identify recent trends in, and factors associated with, resistance to antituberculosis drugs in England, Wales, and Northern Ireland.. Cohort of tuberculosis cases reported to the enhanced tuberculosis surveillance system matched to data on drug susceptibility and national strain typing data.. England, Wales, and Northern Ireland 1998-2005.. Unadjusted and adjusted odds ratios for drug resistance and associated factors. Proportion of multidrug resistant tuberculosis cases clustered.. 28 620 culture confirmed cases were available for analysis. The proportion of cases resistant to isoniazid increased from 5% to 7%. Rifampicin resistance increased from 1.0% to 1.2% and multidrug resistance from 0.8% to 0.9%. Ethambutol and pyrazinamide resistance remained stable at around 0.4% and 0.6%, respectively. Regression analyses showed a significant increase in isoniazid resistance outside London (odds ratio 1.04, 95% confidence interval 1.01 to 1.07, a year, associated with changes in age (0.98, 0.98 to 0.99, a year), place of birth (1.49, 1.16 to 1.92), and ethnicity (P<0.05). In London, the rise (1.05, 1.02 to 1.08, a year) was related mainly to an ongoing outbreak. Increases in rifampicin resistance (1.06, 1.01 to 1.11, a year) and multidrug resistance (1.06, 1.00 to 1.12, a year) were small. A fifth of patients with multidrug resistant tuberculosis in 2004-5 had indistinguishable strain types, and one case was identified as extensively drug resistant.. The rise in isoniazid resistance reflects increasing numbers of patients from sub-Saharan Africa and the Indian subcontinent, who might have acquired resistance abroad, and inadequate control of transmission in London. The observed increases highlight the need for early case detection, rapid testing of susceptibility to drugs, and improved treatment completion.

Topics: Adult; Aminosalicylic Acid; Antitubercular Agents; Disease Susceptibility; Epidemiologic Methods; Ethionamide; Female; Humans; Isoniazid; Male; Middle Aged; Tuberculosis, Multidrug-Resistant; United Kingdom

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

The value of susceptibility tests in guiding antituberculous therapy with second-line drugs remains controversial. We reanalyzed three reports regarding the relationship between in vitro susceptibility of Mycobacterium tuberculosis and the clinical outcome of in-patients treated with these drugs at the Muñiz Hospital, Buenos Aires, during the sixties. These patients had been irregularly treated with a standard regimen consisting of isoniazid, streptomycin and PAS; they developed resistance to at least the first two drugs and persisted culture-positive. Susceptibility testing to ethionamide, cycloserine and kanamycin were performed by the proportion method on Löwenstein Jensen medium. Some level of resistance was detected among isolates from patients not previously treated with these drugs, that could be due to cross resistance with previously administered first line structural analogs. However, the studies evidenced significant association between resistance to ethionamide and cycloserine and prior treatment with these drugs. Increased resistance to all three drugs was detected within the first three months of treatment. In vitro resistance to ethionamide emerged earlier and was the most frequent followed by resistance to cycloserine and kanamycin. The low frequency of resistance to kanamycin could be related to the low dosage of this drug used at that time. Simultaneous resistance to the three agents, but not to two or one drug, appeared to be a marker of treatment failure. An apparent reversion of drug resistance was observed in near 6% of patients, for whom susceptibility tests were repeated on subsequent isolates, indicating this percentage of inconsistency in reproducibility of test results.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Argentina; Clinical Trials as Topic; Cycloserine; Drug Therapy, Combination; Ethionamide; Evidence-Based Medicine; Follow-Up Studies; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To review the outcome for MDR-TB treatment among potential migrants from Vietnam.. All cases of documented MDR-TB treated by the International Organization of Migration (IOM) in Vietnam from 1989 to 2000 were reviewed.. MDR-TB was defined as isoniazid- and rifampicin-resistant Mycobacterium tuberculosis. All cases of TB treated by the IOM and recorded in the computerised database were reviewed to identify MDR-TB cases. Demographics, chest radiograph results, drug resistance, drug use and dosage, duration of treatment, and outcome were analysed.. Forty-four cases of MDR-TB were identified. Treatment consisted of ambulatory directly observed treatment with an 8-drug protocol: isoniazid, rifampicin, pyrazinamide, ethambutol, capreomycin, ethionamide, ofloxacin and cycloserine. This initial protocol was modified due to drug availability or drug intolerance. Patients were treated with a median of 8 drugs (range 6-12). Mean duration of treatment for MDR-TB was 23.0 (SD+/-11.4) months. Thirty-eight (86%) patients were cured and emigrated, one failed treatment (2%), three were lost to follow-up (7%) and two died (4%).. Treatment for MDR-TB provided by the IOM was effective in preparing a low-income population for migration.

Topics: Capreomycin; Cycloserine; Drug Therapy, Combination; Emigration and Immigration; Ethambutol; Ethionamide; Female; Humans; Isoniazid; Male; Middle Aged; Ofloxacin; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Vietnam

Topics: Antitubercular Agents; Ethionamide; Female; Humans; Hypothyroidism; Middle Aged; Tuberculosis, Multidrug-Resistant

Tentative standards for testing MICs for Mycobacterium tuberculosis include agar dilution and the BACTEC method. However, the conventional agar dilution method requires 3-5 weeks to complete; whereas BACTEC, although a rapid test, involves the use of radioisotopes. In contrast, the MGIT 960 system uses a fluorescence quenching based oxygen sensor that can be read automatically. This system is not only robust, safe and simple, but has been validated for susceptibility tests of first-line antituberculous agents.. We evaluated 46 clinical strains of M. tuberculosis isolated from patients admitted to Kaohsiung Veterans General Hospital. Testing of MICs of ciprofloxacin and ethionamide was carried out by MGIT 960 and compared with the agar dilution method.. Good agreement was found between MGIT 960 and agar dilution. The greatest concordance between the agar dilution and MGIT assay at +/-1 and +/-2 dilution was 80.4% and 97.8% for ciprofloxacin, and 82.6% and 93.5% for ethionamide, respectively.. MGIT 960 was found to be comparable to the current NCCLS standard method, agar dilution, and has the advantage of being rapid (obtaining results within 5-17 days, average 8.9 days) and easy to achieve standardization.

Topics: Antitubercular Agents; Ciprofloxacin; Drug Resistance, Microbial; Ethionamide; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant

To determine the trend in changes in susceptibility of Mycobacterium tuberculosis strains, including to second-line drugs, from patients with a history of previous anti-tuberculosis (TB) treatment in a 'DOTS-Plus' programme.. A retrospective survey of centralised M. tuberculosis laboratory records of all culture-positive cases over an 8-year period. The drug susceptibility of the isolates was determined using the absolute concentration method. Isolates obtained from patients with a history of previous treatment were further analysed for trends of changes in susceptibility to first- and second-line drugs.. Of 1921 patients with a previous history of treatment and positive cultures, 1425 (74.2%) had isolates susceptible to all four first-line drugs, while 176 (9.2%) were multidrug-resistant (MDR-TB). For the MDR-TB group, 101 (57.4%) isolates were sensitive to all second-line drugs, while 30 (17.0%) were resistant to three or more second-line drugs.. In a DOTS-Plus programme environment where there is strict control on use of second-line drugs, the prevalence of MDR-TB is low amongst retreatment cases and the prudent use of second-line drugs in a population with well functioning DOTS-Plus programme does not generate super-resistant strains. In circumstances where most retreatment strains are still susceptible and good laboratory support for detection of MDR cases is available, retreatment using first-line drugs is feasible.

Topics: Amikacin; Anti-Bacterial Agents; Antitubercular Agents; Communicable Disease Control; Cycloserine; Directly Observed Therapy; Drug Combinations; Ethionamide; Hong Kong; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Population Surveillance; Program Evaluation; Recurrence; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

An Argentinean reference hospital specialising in infectious diseases.. To assess the outcomes of all human immunodeficiency virus (HIV) negative multidrug-resistant tuberculosis (MDR-TB) patients referred to or diagnosed at Hospital Muñiz.. Clinical study for the period 1996-1999, with follow-up until June 2002.. One hundred and forty-one adult patients (52.5% female) with resistance to two to seven drugs were studied. Fifty patients (35.5%) had not been treated previously. The most frequently used second-line drugs were 5-F-quinolones, cycloserine and ethionamide in susceptibility based individually tailored three- to five-drug regimens. Hospital admission was associated with treatment success. Forty-five episodes of severe toxicity occurred. Treatment was successful in 51.8% of cases, but follow-up of 73 patients yielded 11.9% relapse. The mortality rate was 19.1% and default was 19.9%. Logistic regression analysis was statistically significant for treatment success in relation to patient admission, residence and resistance pattern.. The burden of MDR-TB in this setting--prolonged infection, treatment cost and difficulties, low rates of cure and treatment adherence and high rates of fatality and relapse--can be improved by strengthening TB control programme activities and fighting against poverty and HIV/AIDS.

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Argentina; Cycloserine; Drug Combinations; Ethionamide; Female; Follow-Up Studies; HIV Seronegativity; Hospitalization; Hospitals, Special; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prognosis; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The activity of moxifloxacin was enhanced by the addition of ethionamide but not by that of cycloserine, thiacetazone, capreomycin, para-aminosalicylic acid, or linezolid in BALB/c mice infected with a strain of Mycobacterium tuberculosis resistant to isoniazid, rifampin, and six other drugs. These observations are important for the therapy of multidrug-resistant tuberculosis.

Topics: Animals; Anti-Bacterial Agents; Aza Compounds; Drug Therapy, Combination; Ethionamide; Fluoroquinolones; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Tuberculosis, Multidrug-Resistant

We report a chronic case of pulmonary tuberculosis in a Malagasy citizen from Antsohihy (West of Madagascar), who was infected with a multi-drug resistant Mycobacterium bovis strain. This is the first case reported of the isolation of such a strain in Madagascar.

Topics: Amikacin; Antitubercular Agents; Capreomycin; Chronic Disease; Ciprofloxacin; Cough; DNA, Bacterial; Drug Therapy, Combination; Ethionamide; Humans; Kanamycin; Madagascar; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium bovis; Ofloxacin; Patient Compliance; Polymorphism, Restriction Fragment Length; Sputum; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The single base change at the 94th codon of inhA has been referred to as the event that confers resistance on the drugs isoniazid (INH) and ethionamide (ETH) in Mycobacterium smegmatis and M. bovis. From this observation, it has been anticipated that some of the INH-resistant clinical isolates of M. tuberculosis would carry missense mutations in the same region of the gene. However, few polymorphisms have been identified in this region among INH-resistant isolates.. To understand the molecular basis for M. tuberculosis resistance to INH and ETH.. The sequence polymorphism at the 94th codon of inhA among M. tuberculosis isolates from Korea was analyzed by polymerase chain reaction (PCR) cloning and sequence analysis.. No nucleotide change at the 94th codon of inhA was detected in any of the 24 INH-resistant isolates analyzed in this study. On the other hand, a point mutation was found exclusively at the regulatory region flanking a putative ribosome-binding site of the inhA locus in 14 isolates. Interestingly, all the mutations were of the same kind, which substitutes C to T. Among 14 isolates, 12 were resistant to INH as well as to ETH, while two were resistant to INH only.. It seems that mutations previously found at the 94th codon of inhA have no particular relationship with the mechanism involved in the resistance of M. tuberculosis to INH and/or ETH. On the other hand, the resistance mechanism of M. tuberculosis to INH/ETH may involve an altered level of InhA, an expression which may have been influenced by the sequence change in the regulatory region of the inhA locus.

Topics: Antitubercular Agents; Base Sequence; Drug Resistance, Multiple; Ethionamide; Humans; Isoniazid; Korea; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Genetic; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Central Nervous System Infections; Dexamethasone; Drug Therapy, Combination; Ethionamide; Glucocorticoids; Humans; Immunocompetence; Infant; Isoniazid; Male; Prednisolone; Pyrazinamide; Rifampin; Streptomycin; Treatment Failure; Tuberculoma; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Multidrug-Resistant

Topics: Adult; Antitubercular Agents; Ciprofloxacin; Cycloserine; Drug Monitoring; Drug Resistance, Microbial; Drug Resistance, Multiple; Ethionamide; Humans; Ofloxacin; Tuberculosis, Multidrug-Resistant

Tuberculosis-control programmes are compromised by the increased frequency of multidrug-resistant strains of Mycobacterium tuberculosis. We used the polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis techniques to establish the molecular basis of resistance in 37 drug-resistant isolates of M tuberculosis, and correlated these findings with clinical and antibiotic-sensitivity data. Resistance to isoniazid was found in 36 strains, 16 of which were also resistant to ethionamide. Of the 36 isoniazid-resistant strains, 23 had mutations in the katG gene, and 5 of these also had mutations in the inhA gene. A further 5 strains had alterations in the inhA locus without the katG gene being mutated. Rifampicin resistance was less frequent (13 strains) and usually associated with isoniazid resistance (11 of 13 strains). Mutations in the rpoB gene were detected for all these rifampicin-resistant isolates. Mutations in the rpsL and rrs genes, associated with streptomycin resistance, were found in 13 of 25 and 2 of 25 streptomycin-resistant strains, respectively. The same chromosomal mutations, or combinations of mutations, were found in strains displaying single or multidrug resistance, from cases of both primary and secondary resistance, and from patients infected with human immunodeficiency virus. Thus, multidrug resistance is not due to a novel mechanism and tuberculosis chemotherapy is not subject to a new threat.

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Resistance, Microbial; Ethionamide; Female; Genes, Bacterial; Humans; Isoniazid; Male; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant

Topics: Adolescent; Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Cycloserine; Drug Resistance; Drug Resistance, Microbial; Drug Therapy; Ethionamide; Hepatomegaly; Isoniazid; Kanamycin; Liver Function Tests; Pharmacology; Pyrazinamide; Toxicology; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Viomycin

Topics: Drug Therapy; Ethionamide; Toxicology; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Cycloserine; Drug Resistance; Drug Resistance, Microbial; Drug Therapy; Ethambutol; Ethionamide; Geriatrics; Hospitals, State; Isoniazid; Kanamycin; Pyrazinamide; Streptomycin; Toxicology; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Viomycin

Topics: Drug Resistance; Drug Resistance, Microbial; Ethionamide; Humans; Isoniazid; Pyrazinamide; Streptomycin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary