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The New England Journal of Medicine Mar 2023Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear.
METHODS
In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points.
RESULTS
Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups.
CONCLUSIONS
A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).
Topics: Humans; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Isoniazid; Linezolid; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Diarylquinolines
PubMed: 36808186
DOI: 10.1056/NEJMoa2212537 -
Drug Metabolism and Disposition: the... Aug 2021Pyrazinamide (PZA) is an important component of a standard combination therapy against tuberculosis. However, PZA is hepatotoxic, and the underlying mechanisms are... (Review)
Review
Pyrazinamide (PZA) is an important component of a standard combination therapy against tuberculosis. However, PZA is hepatotoxic, and the underlying mechanisms are poorly understood. Biotransformation of PZA in the liver was primarily suggested behind its hepatoxicity. This review summarizes the knowledge of the key enzymes involved in PZA metabolism and discusses their contributions to PZA hepatotoxicity. SIGNIFICANCE STATEMENT: This review outlines the current understanding of PZA metabolism and hepatotoxicity. This work also highlights the gaps in this field, which can be used to guide the future studies on PZA-induced liver injury.
Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Liver; Pyrazinamide; Tuberculosis
PubMed: 34074731
DOI: 10.1124/dmd.121.000389 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Dec 2022Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the... (Review)
Review
Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including mutations in isoniazid resistance, mutations in rifampin resistance, mutations in pyrazinamide resistance, and mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.
Topics: Humans; Pyrazinamide; Isoniazid; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Mycobacterium tuberculosis; Tuberculosis; Rifampin; Mutation; Drug Resistance, Multiple, Bacterial
PubMed: 36915970
DOI: 10.3724/zdxbyxb-2022-0454 -
Annals of Internal Medicine Aug 2017Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.
PURPOSE
To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.
DATA SOURCES
PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.
STUDY SELECTION
Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).
DATA EXTRACTION
2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.
DATA SYNTHESIS
The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.
LIMITATION
Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.
CONCLUSION
Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.
PRIMARY FUNDING SOURCE
U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).
Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Drug Combinations; Humans; Isoniazid; Latent Tuberculosis; Network Meta-Analysis; Pyrazinamide; Rifampin
PubMed: 28761946
DOI: 10.7326/M17-0609 -
Clinical Pharmacokinetics Sep 2019The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with... (Review)
Review
The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (C) > 8.2 μg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin C is required for severe forms TB such as TB meningitis, with C ≥ 22 μg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC) ≥ 70 μg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C/MIC (minimum inhibitory concentration) and AUC/MIC.
Topics: Administration, Oral; Adult; Antibiotics, Antitubercular; Biological Variation, Population; Comorbidity; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mortality; Pharmacogenetics; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 31049868
DOI: 10.1007/s40262-019-00764-2 -
Lancet (London, England) Oct 2022With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We... (Randomized Controlled Trial)
Randomized Controlled Trial
9 months of delamanid, linezolid, levofloxacin, and pyrazinamide versus conventional therapy for treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-END): a multicentre, randomised, open-label phase 2/3 non-inferiority trial in South Korea.
BACKGROUND
With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We aimed to investigate whether a new all-oral regimen was non-inferior to the conventional regimen including second-line anti-tuberculosis drugs for 20-24 months in the treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis.
METHODS
In this multicentre, randomised, open-label phase 2/3 non-inferiority trial, we enrolled men and women aged 19-85 years with multidrug-resistant tuberculosis confirmed by phenotypic or genotypic drug susceptibility tests or rifampicin-resistant tuberculosis by genotypic tests at 12 participating hospitals throughout South Korea. Participants with fluoroquinolone-resistant multidrug-resistant tuberculosis were excluded. Participants were randomly assigned (1:1) to two groups using a block randomisation, stratified by the presence of diabetes and cavitation on baseline chest radiographs. The investigational group received delamanid, linezolid, levofloxacin, and pyrazinamide for 9 months, and the control group received a conventional 20-24-month regimen, according to the 2014 WHO guidelines. The primary outcome was the treatment success rate at 24 months after treatment initiation in the modified intention-to-treat population and the per-protocol population. Participants who were "cured" and "treatment completed" were defined as treatment success following the 2014 WHO guidelines. Non-inferiority was confirmed if the lower limit of a 97·5% one-sided CI of the difference between the groups was greater than -10%. Safety data were collected for 24 months in participants who received a predefined regimen at least once. This study is registered with ClinicalTrials.gov, NCT02619994.
FINDINGS
Between March 4, 2016, and Sept 14, 2019, 214 participants were enrolled, 168 (78·5%) of whom were included in the modified intention-to-treat population. At 24 months after treatment initiation, 60 (70·6%) of 85 participants in the control group had treatment success, as did 54 (75·0%) of 72 participants in the shorter-regimen group (between-group difference 4·4% [97·5% one-sided CI -9·5% to ∞]), satisfying the predefined non-inferiority margin. No difference in safety outcomes was identified between the control group and the shorter-regimen group.
INTERPRETATION
9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis.
FUNDING
Korea Disease Control and Prevention Agency, South Korea.
Topics: Male; Female; Humans; Pyrazinamide; Linezolid; Levofloxacin; Fluoroquinolones; Drug Therapy, Combination; Tuberculosis, Multidrug-Resistant; Antitubercular Agents; Treatment Outcome
PubMed: 36522208
DOI: 10.1016/S0140-6736(22)01883-9 -
PloS One 2022Mycobacterium tuberculosis strains with phenotypically susceptible rpoB mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug...
INTRODUCTION
Mycobacterium tuberculosis strains with phenotypically susceptible rpoB mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug resistance testing for tuberculosis. Whilst rifampicin resistance is known to be associated with resistance to other rifamycins (rifapentine and rifabutin) as well as isoniazid and pyrazinamide, rifampicin discordant strains have shown high rates of susceptibility to isoniazid and rifabutin. However, pyrazinamide susceptibly testing results have not been reported.
MATERIALS AND METHODS
We evaluated pyrazinamide resistance in 80 rifampicin discordant and 25 rifampicin and isoniazid susceptible isolates from KwaZulu-Natal in South Africa using Mycobacteria Growth Indicator Tube method and sequencing of the pncA. We also compared susceptibility of pyrazinamide with that of isoniazid.
RESULTS
Pyrazinamide resistance was found in 6/80 (7.5%) rifampicin discordant isolates. All pyrazinamide resistant isolates were also resistant to isoniazid and pyrazinamide resistance was found to be associated with isoniazid resistance. No pyrazinamide resistance was found among the isoniazid susceptible isolates.
CONCLUSION
Given the low prevalence of pyrazinamide resistance in rifampicin discordant TB, this anti-TB drug still has a significant role in the treatment of these patients. Performing pyrazinamide susceptibility testing remains a challenge, our findings show that isoniazid susceptible isolates are unlikely to be resistant to pyrazinamide among the discordant TB isolates.
Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Rifabutin; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 36129921
DOI: 10.1371/journal.pone.0274688 -
Indian Journal of Pediatrics May 2019Determining the optimal dosages of isoniazid, rifampicin, pyrazinamide and ethambutol in children is necessary to obtain therapeutic serum concentrations of these drugs.... (Review)
Review
Determining the optimal dosages of isoniazid, rifampicin, pyrazinamide and ethambutol in children is necessary to obtain therapeutic serum concentrations of these drugs. Revised dosages have improved the exposure of 1st line anti-tubercular drugs to some extent; there is still scope for modification of the dosages to achieve exposures which can lead to favourable outcome of the disease. High dose of rifampicin is being investigated in clinical trials in adults with some benefit; studies are required in children. Inter-individual pharmacokinetic variability and the effect of age, nutritional status, Human immunodeficiency virus (HIV) infection, acetylator genotype may need to be accounted for in striving for the dosages best suited for an individual.
Topics: Age Factors; Antitubercular Agents; Child; Drug Overdose; Ethambutol; Food; Genotype; HIV Infections; Humans; Isoniazid; Malnutrition; Nutritional Status; Polymorphism, Genetic; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis
PubMed: 30915644
DOI: 10.1007/s12098-019-02911-w -
Microbiology and Molecular Biology... May 2020Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months... (Review)
Review
Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months and reduce disease relapse rates, PZA is considered an irreplaceable component of standard first-line short-course therapy for drug-susceptible TB and second-line treatment regimens for multidrug-resistant TB. Despite over 60 years of research on PZA and its crucial role in current and future TB treatment regimens, the mode of action of this unique drug remains unclear. Defining the mode of action for PZA will open new avenues for rational design of novel therapeutic approaches for the treatment of TB. In this review, we discuss the four prevailing models for PZA action, recent developments in modulation of PZA susceptibility and resistance, and outlooks for future research and drug development.
Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Development; Drug Resistance, Multiple, Bacterial; Humans; Mice; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 32132245
DOI: 10.1128/MMBR.00070-19 -
Innere Medizin (Heidelberg, Germany) Jul 2023Never before have so many people around the world been simultaneously affected by tuberculosis. Tuberculosis is the leading cause of death from a bacterial infectious... (Review)
Review
Never before have so many people around the world been simultaneously affected by tuberculosis. Tuberculosis is the leading cause of death from a bacterial infectious disease worldwide. The World Health Organization's ambitious goal from 2014 of achieving global elimination of tuberculosis does not seem realistic, but on current trends, tuberculosis could be eliminated in the European Union by 2040. Since the beginning of 2022, there have been more innovations for the treatment of tuberculosis than in no other comparable time period before. One month of rifapentine and isoniazid is effective in treating latent tuberculosis infection. However, rifapentine is licensed in the USA but not in the EU and must be imported for individual cases. The duration of the standard treatment for tuberculosis can be shortened to four months but this treatment regimen is also based on rifapentine, in addition to isoniazid, pyrazinamide, and moxifloxacin. The approval of rifapentine in Europe is a much-needed step towards shortening the treatment of tuberculosis. With new drugs an even shorter standard treatment of only 2 months is possible. The treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR-/RR-TB) has been shortened to six months, the same length as the standard treatment available in Germany. The combination of bedaquiline, pretomanid, linezolid ± moxifloxacin, cured around 90% of affected patients were cured in studies with a treatment duration of six months. With 19 drugs in clinical trials, the treatment of tuberculosis is expected to continue to improve rapidly in the coming years.
Topics: Humans; Antitubercular Agents; Isoniazid; Moxifloxacin; Tuberculosis; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 37316702
DOI: 10.1007/s00108-023-01523-z