Generic Rifater tablets

Background: Tuberculosis remains a leading cause of infectious disease mortality, with over 10 million new cases annually. The standard first-line regimen—isoniazid, rifampicin, pyrazinamide, and ethambutol—has dramatically improved survival, yet drug-induced micronutrient depletion, particularly zinc, is an underappreciated complication that may contribute to treatment-related morbidity. Ethambutol-induced optic neuropathy (EON) affects 1–5% of treated patients, and accumulating evidence implicates zinc chelation as its central mechanism. We hypothesize that anti-TB therapy creates a “multi-hit” zinc depletion state through convergent drug- and disease-mediated pathways. Methods: We conducted a systematic search of PubMed, Scopus, Web of Science, and Cochrane databases from 1944 (discovery of streptomycin) through March 2026. Search terms combined anti-TB drug names with zinc, copper, micronutrient, optic neuropathy, and visual loss. We included randomized controlled trials, cohort studies, case-control studies, case series, in vitro investigations, and animal models. PRISMA 2020 guidelines were followed. Risk of bias was assessed using the Newcastle–Ottawa Scale for observational studies and the Cochrane RoB 2.0 tool for trials. Results: From 2,847 initial records, 186 studies met inclusion criteria. Serum zinc was significantly lower in TB patients versus controls (pooled mean difference: −12.1 μmol/L; 95% CI: −14.5 to −9.7; I² = 68%). Ethambutol directly chelates zinc and copper in retinal ganglion cells via its metabolite EDBA, causing lysosomal membrane permeabilization and mitochondrial dysfunction. Isoniazid depletes pyridoxine, impairing zinc-dependent enzymatic cascades. Rifampicin induces CYP3A4 via PXR activation, accelerating retinol catabolism and functionally coupling zinc deficiency to vitamin A insufficiency through impaired retinol-binding protein synthesis. The zinc–vitamin A axis demonstrates a strong positive correlation (r = 0.86, p < 0.01) in TB cohorts. Zinc supplementation (50 mg elemental zinc/day) improved sputum conversion rates and reduced hepatotoxicity markers in three randomized trials. Conclusions: Anti-TB drugs collectively create a “multi-hit” zinc depletion syndrome that extends beyond simple ethambutol chelation. We propose a clinical algorithm for baseline zinc assessment, risk stratification, and prophylactic supplementation during TB therapy. Persistent visual loss despite ethambutol discontinuation should prompt evaluation of concurrent zinc depletion from isoniazid, rifampicin, and the underlying TB disease itself.

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BackgroundBased on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis.MethodsClo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries. Participants aged 18 years or older with pulmonary tuberculosis who were sputum smear positive for acid-fast bacilli or molecular tuberculosis assay positive (with Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid) were eligible for enrolment. Individuals with HIV infection with a CD4+ cell count ≥100 cells per mm3 could participate. Participants were randomly assigned in a 2:1 ratio (group 1: group 2) or a 2:1:1 ratio (group 1: group 2: group 3), depending on consent to participate in the intensive pharmacokinetic visits required in group 3, using a central web-based system with permuted blocks. The group 1 regimen included 8 weeks of rifapentine-isoniazid-pyrazinamide-ethambutol-clofazimine, with a 2-week 300 mg clofazimine loading dose, followed by 5 weeks of rifapentine-isoniazid-pyrazinamide-clofazimine (13 weeks total). The group 2 control regimen included 8 weeks of isoniazid-rifampicin-pyrazinamide-ethambutol followed by 18 weeks of rifampicin-isoniazid. Group 3 was identical to group 1 over the first 4 weeks of treatment, except that the regimen was administered without a clofazimine loading dose (100 mg daily); after 4 weeks of group 3 treatment, participants transitioned to local standard of care to complete treatment. Group 3 was designed to assess the effect of a 2-week loading dose on clofazimine pharmacokinetics. Randomisation was stratified by HIV status and advanced disease on chest radiograph. The primary efficacy endpoint was time to sputum culture-negative status by 12 weeks. The primary safety endpoint was the proportion of participants experiencing any grade 3 or worse adverse event over 65 weeks. The key secondary endpoint was unfavourable clinical or bacteriological outcomes by week 65. The efficacy analysis population contained participants assigned to groups 1 and 2 who were not late exclusions (no positive culture at screening, entry, or week 1, or if rifampicin resistance or isoniazid resistance was detected at screening or entry); the safety analysis population contained all randomly assigned participants who took at least one dose of treatment. The trial was registered with ClinicalTrials.gov ID: NCT04311502.Findings104 participants were randomly assigned to group 1 (n=58), group 2 (n=31), and group 3 (n=15). 82 (79%) were male and 74 (71%) had radiographically advanced disease; 30 (29%) were people with HIV. The trial was stopped early for lack of clinical efficacy. For the primary efficacy outcome, 49 (89%) of 55 group 1 participants and 28 (90%) of 31 group 2 participants had stable sputum culture conversion by week 12 (adjusted hazard ratio 1·21 [90% CI 0·82-1·79]; p=0·2089). Adverse events grade 3 or worse occurred in 26 (45%) of 58 group 1 participants and five (16%) of 31 group 2 participants (difference 30%, 90% CI 14-45; p=0·002). The cumulative probability of a week 65 unfavourable outcome was 52% (95% CI 37-69) in group 1 versus 27% (14-50) in group 2 (p=0·049).InterpretationAlthough the trial was stopped early, we found that a 3-month regimen containing clofazimine and rifapentine had 12-week culture conversion rates that did not differ statistically from the standard of care. The regimen was associated with an unacceptably high proportion of participants with unfavourable composite clinical outcomes and grade 3 or worse adverse events.FundingUS National Institutes of Health Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) and the National Institute of Allergy and Infectious Diseases.

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ObjectivesTo evaluate the safety and efficacy across rifapentine doses ranging from 10 to 20 mg/kg for pulmonary drug-susceptible tuberculosis population.MethodsThe stage 1 of this seamless phase 2/3 randomized controlled trial recruited enrolled adults with drug-susceptible tuberculosis at 16 sites in China between 1 February 2023 and 29 September 2024 (NCT05401071). Participants were randomly divided (1:1:1:1) to receive one of three 4-month regimens containing rifapentine 10, 15, or 20 mg/kg daily plus isoniazid, moxifloxacin, and pyrazinamide, or a standard 6-month regimen consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol. In the stage 1, the primary endpoint was the incidence of permanent regimen discontinuation for safety reasons by week 8. Key secondary endpoints included culture conversion before week 8, adverse events during treatment, and favourable outcomes at the end of treatment.ResultsA total of 400 participants underwent randomization in stage 1. The incidences of primary endpoint were 9.3% (9/97), 8.9% (9/101), and 14.6% (14/96) in the rifapentine 10, 15, and 20 mg/kg groups, and 3.0% (3/99) in the control group, respectively. Culture conversion before week 8 occurred in 73.8% (45/61), 84.8% (56/66), and 87.9% (51/58) of participants in the rifapentine 10, 15, and 20 mg/kg groups, and 78.0% (46/59) in the control group. Favourable outcomes at the end of treatment were similar across the groups: 81.4% (79/97) in the control group, 80.9% in the rifapentine 10 mg/kg group (relative risk [RR], 0.99; 95% CI, 0.87-1.14), 87.1% in the rifapentine 15 mg/kg group (RR, 1.07; 95% CI, 0.95-1.21), and 82.6% in the rifapentine 20 mg/kg group (RR, 1.01; 95% CI, 0.89-1.16).ConclusionsBoth rifapentine 15 and 20 mg/kg yielded higher culture conversion rates. However, safety-related discontinuation, particularly in the 20 mg/kg group, was more frequent, highlighting the need for careful benefit-risk assessment and enhanced safety monitoring.

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BackgroundCurrent combination antibiotic treatment for drug-susceptible tuberculosis (DS-TB) usually takes 6 months to complete. This long duration can compromise clinical outcomes. Although a 4-month regimen including an optimized dose of rifapentine plus moxifloxacin is non-inferior to standard therapy, rifapentine is hard to source globally and adoption of this regimen has been slow. This trial investigates the efficacy and safety of a 4-month DS-TB treatment including the more readily available rifamycin, rifampicin 35 mg/kg, with or without moxifloxacin 400 mg.MethodsThis multi-centre phase III randomized open-label clinical trial will be conducted across four African countries (Gabon, Malawi, Mozambique and Tanzania). A total of 414 newly diagnosed consenting adult participants will be block randomized, after stratification by chest radiograph cavitation, to two experimental and one control arm at a ratio of 1:1:1. The first experimental group will receive optimized dose rifampicin (35 mg/kg) with routine weight-banded doses of isoniazid, pyrazinamide, and ethambutol once daily for 4 months. The second experimental group will receive optimized dose rifampicin (35 mg/kg) and moxifloxacin 400 mg once daily alongside routine doses of isoniazid and pyrazinamide. The control group will receive 6-month standard of care therapy: rifampicin (10 mg/kg) plus weight-banded dose of isoniazid, pyrazinamide, and ethambutol for 2 months, followed by the same doses of rifampicin and isoniazid for 4 months. Participants will be followed until the allocation of efficacy (TB-free survival) and safety (proportion of severe adverse events) outcomes. Secondary outcomes will also include the evaluation of the Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) for microbiological treatment monitoring.DiscussionThis study will evaluate whether 4-month duration multi-drug treatment including an optimized dose of rifampicin with or without moxifloxacin has non-inferior efficacy and safety outcomes compared to standard of care DS-TB therapy in Africa.Trial registrationClinicalTrials.gov NCT05575518. Registered on 10th October 2022.

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BackgroundRifampicin-resistant tuberculosis (RR-TB) poses a great threat to global health. Increasing evidence of novel regimens in trial settings has risen, but the combinations of oral shorter regimens have not been optimised. An evaluation of the efficacy and safety of short-term regimens utilizing various drug combinations is essential across different settings.MethodsINSPIRE TB is a pragmatic, multicentre, randomised, controlled, non-inferiority open-label trial to evaluate novel regimens in pulmonary RR-TB patients of 16-75 years old with or without fluoroquinolone resistance. Before randomisation, an individualized assessment is conducted, considering drug susceptibility, contradictions, tolerance. Eligible participants are randomised based on fluoroquinolone susceptibility results from the Xpert MTB/XDR assay. Participants susceptible to fluoroquinolones are randomised to receive either one of seven different nine-month oral regimens or a nine-month standard-of-care regimen as the control. The experimental arms are five-drug regimens, each consisting of five agents selected from the following: bedaquiline, linezolid, a fluoroquinolone, cycloserine, clofazimine and pyrazinamide. Fluoroquinolone-resistant participants are randomised to either a 9-month oral regimen (bedaquiline, cycloserine, clofazimine, linezolid and pyrazinamide), or a 20-month conventional regimen as control in a 1:1 ratio. The primary outcome is the proportion of participants with a favourable outcome (two negative culture for Mycobacterium Tuberculosis, the latest sample collected between month 21 and 23) at 21 months after randomisation in the modified intention-to-treat population, measured in fluoroquinolone-susceptible and fluoroquinolone-resistant participants respectively. A sample size of 832 fluoroquinolone-susceptible RR-TB patients and 234 fluoroquinolone-resistant RR-TB patients afford 80% power to establish non-inferiority with a non-inferiority margin of 10% at a one-sided α level of 2.5%. The type I error will be controlled with a fixed-sequence approach.DiscussionIdentifying safer and effective short regimens remains an obstacle for drug-resistant tuberculosis and more treatment options are needed to benefit patients from different countries and settings to reduce disease burden. The INSPIRE TB study hopes to provide robust evidence on various options of safer and effective 9-month oral regimens for RR-TB in China.Trail registrationClinicalTrial.gov, NCT05081401. Registered on October 18, 2021; the record was lastupdated for study protocol version 6.0, on 06 April 2025.

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BackgroundCombined therapy with delamanid, bedaquiline, and quabodepistat (DBQ) showed potent early bactericidal activity and was well tolerated in a phase 2a, 14-day early bactericidal activity trial in participants with drug-susceptible pulmonary tuberculosis. This subsequent proof-of-concept trial evaluated the efficacy and safety of a 4-month, three-dose level regimen of DBQ in participants with drug-susceptible pulmonary tuberculosis compared with 6 months of the standard of care.MethodsThis open-label, randomised, proof-of-concept, non-inferiority, phase 2b/c trial was conducted at six clinical research sites in South Africa. Adults aged 18-65 years with newly diagnosed, drug-susceptible pulmonary tuberculosis were recruited by research sites from community tuberculosis clinics. Participants were randomly assigned (1:2:2:1) by balanced block randomisation (block size six) to receive oral delamanid (300 mg once a day) and bedaquiline (400 mg once a day for 2 weeks then 200 mg three times a week) plus quabodepistat at once-daily doses of 10 mg (DBQ10 group), 30 mg (DBQ30 group), or 90 mg (DBQ90 group) for 4 months; or 6 months of RHEZ (rifampicin, isoniazid, ethambutol, and pyrazinamide for 8 weeks followed by 18 weeks of rifampin and isoniazid). All drugs were administered orally. Masking procedures were not used, although microbiology laboratory staff were masked to treatment assignment. The primary endpoints were the proportion of participants reaching sputum culture conversion by the end of the treatment period in the modified intention-to-treat (mITT) analysis set and safety in the safety analysis set. Non-inferiority, with a margin of 12%, was assessed for the primary endpoint in the mITT analysis set, comparing the pooled DBQ group and the RHEZ group using a two-sided 80% CI. This study was registered at ClinicalTrials.gov, NCT05221502, and is complete.FindingsBetween April 12, 2022, and May 19, 2024, 306 individuals were screened, of whom 122 were enrolled and randomly assigned: 20 to the DBQ10 group, 42 to the DBQ30 group, 39 to the DBQ90 group, and 21 to the RHEZ group. 121 participants received at least one dose of study drug and comprised the mITT analysis set. At the end of the treatment period, the proportion of participants with sputum culture conversion was 100·0% (95% CI 83·2-100·0, all 20 participants) in the DBQ10 group, 92·9% (80·5-98·5, 39 of 42 participants) in the DBQ30 group, 97·4% (86·2-99·9, 37 of 38 participants) in the DBQ90 group, 96·0% (90·1-98·9, 96 of 100 participants) in the pooled DBQ group, and 100·0% (83·9-100·0, all 21 participants) in the RHEZ group. The comparison between the pooled DBQ group and the RHEZ group met non-inferiority for the primary endpoint (difference -4·0% [80% CI -7·4 to 3·4]). Adverse events were mostly mild to moderate, with no serious adverse events or discontinuations attributed to trial medications. Rates of adverse events of grade 3 or higher were 20% (four of 20 participants) in the DBQ10 group, 14% (six of 42 participants) in the DBQ30 group, 11% (four of 38 participants) in the DBQ90 group, and 5% (one of 21 participants) in the RHEZ group. One participant (in the DBQ90 group) died after worsening pulmonary tuberculosis with pneumonia, which was assessed as not related to study treatment. 105 (87%) of 121 participants had at least one treatment-emergent adverse event: 17 (85%) of 20 in the DBQ10 group, 37 (88%) of 42 in the DBQ30 group, 30 (79%) of 38 in the DBQ90 group, and all 21 (100%) participants in the RHEZ group. The most common treatment-emergent adverse events in the total population of 121 participants were upper respiratory tract infection (n=36, 30%), headache (n=24, 20%), and diarrhoea (n=12, 10%).InterpretationIn this proof-of-concept study, 4 months of DBQ showed a promising end-of-treatment non-inferiority signal versus 6 months of RHEZ and was generally well tolerated. Our results support further studies of quabodepistat as a potential component of new treatment-shortening regimens for tuberculosis.FundingOtsuka Pharmaceutical Development & Commercialization, with partial funding from the Gates Foundation.

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A 73-year-old man from the Philippines with Type 2 diabetes mellitus and end-stage renal disease on peritoneal dialysis developed peritonitis. The infection was refractory to empiric therapy, and the pathogen was identified as Mycobacterium tuberculosis, when 4 weeks after collection, a preliminary positive AFB culture underwent PCR testing. He did not initially tolerate a regimen of isoniazid, rifampin, pyrazinamide, and ethambutol but temporarily tolerated rifabutin, levofloxacin, and ethambutol and ultimately tolerated a regimen of levofloxacin, ethambutol, and pyrazinamide. This case highlights the diagnostic and treatment challenges of peritonitis due to tuberculosis, emphasizing the importance of including tuberculosis in the differential diagnosis. Given the severity and the limited current understanding, further research is needed to guide effective management and improve outcomes.

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AimsThis study aims to report three cases of maternal-fetal transmission of tuberculosis in premature infants, systematically analyze their clinical characteristics, diagnostic processes, and treatment outcomes, explore the core role of the multidisciplinary team (MDT) in optimizing diagnosis and treatment, and provide an evidence-based basis for early identification, precise diagnosis, and effective therapy to reduce high mortality rates and enhance clinical management levels.MethodsThrough retrospective case reports combined with a literature review, three cases of maternal-fetal transmission of tuberculosis in extremely premature twins and a premature infant were reported. Integration of maternal history, placental pathology assessment (such as acid-fast staining positive bacilli and Mycobacterium tuberculosis qPCR detection), imaging examinations (such as chest x-ray and CT), etiological tests (such as NGS), and fundus examination results. Treatment adopted individualized anti-tuberculosis regimens (isoniazid 10-15 mg/kg/d, rifampicin 15-20 mg/kg/d, pyrazinamide 20-30 mg/kg/d), collaboratively developed by MDT (neonatology, infectious diseases, pharmacists, and ophthalmology experts), combined with supportive therapies (such as mechanical ventilation, blood transfusion, and nutritional support). Follow-up evaluated growth and neurodevelopmental outcomes.ResultsThis study reported three cases of maternal-fetal transmission of tuberculosis, involving extremely premature twins at 27+4 weeks (birth weights 890 g and 880 g) and one premature infant at 34+1 weeks. The twins' mother had a history of tuberculosis of the uterus or uterine TB, fever during pregnancy, and postpartum confirmed tuberculosis (positive placental pathology and NGS); infants presented with respiratory distress and fever. Diagnostic basis included maternal history, placental pathology, NGS detection of Mycobacterium, and fundus examination (retinal white spot changes). Under MDT collaboration, anti-tuberculosis treatment (isoniazid, rifampicin, pyrazinamide) and supportive therapy controlled the infection. The older twin (male) was hospitalized for 93 days, weight reached 3,670 g, and at follow-up to corrected age of 4.5 months, weight increased to 7.44 kg, length 59 cm; the younger twin (female) hospitalized for 60 days, weight 2,170 g, follow-up to corrected age of 4.5 months, weight 6.62 kg, length 54 cm. The twins had normal growth and development, no permanent visual impairment. The premature infant case was similar with good prognosis.ConclusionThe diagnosis of maternal-fetal transmission of tuberculosis in extremely premature and premature infants is highly challenging due to the lack of specific symptoms, often misdiagnosed as sepsis or respiratory distress syndrome (RDS). This study observed through three cases that integrating chest imaging, etiological tests (such as NGS), placental pathology assessment, and fundus screening (such as retinal white spot changes) aids in early diagnosis. MDT collaboration in developing individualized anti-tuberculosis treatment plans (including isoniazid, rifampicin, and pyrazinamide) supplemented with supportive therapy effectively improves infant prognosis, with normal weight gain post-discharge, good development, and no permanent visual damage. Strengthening prenatal screening and monitoring for high-risk pregnant women helps prevent such cases. In the future, multicenter studies should further optimize diagnostic criteria and treatment strategies to reduce mortality and improve neonatal quality of life.

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