A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic ...effects.
In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels.
Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval CI, -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events.
The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).
Tuberculosis preventive treatment (TPT) is an essential component for TB elimination. In order to be successfully implemented on a large scale, TPT needs to be safe, affordable and widely available ...in all settings. Short TPT regimens, that are less burdensome than longer regimens, to patients and health systems, are needed. Doses of rifampin higher than the standard 10mg/kg/day were tolerated in studies to reduce duration of treatment for tuberculosis disease (TBD). The objective of this trial is to test the safety of high dose rifampin monotherapy to shorten the duration of the currently recommended TPT of 4 months rifampin.
This is a phase 2b, randomised, controlled, parallel group, superiority, partially-blind trial. Primary outcomes are completion of treatment (as a proxy measure of tolerability) and safety. The two experimental arms comprise 60 days of (i) 20mg/kg/day or (ii) 30mg/kg/day rifampin; the control arm comprises 120 days of 10mg/kg/day rifampin as TPT. Participants are adults and children 10 years or older, eligible for TPT. Completion is the primary outcome, measured by pill count and is defined as taking minimum of 80% of treatment in 120% of allowed time; it will be tested for superiority by logistic regression. Safety outcome comprises proportion of grade 3-5 adverse events and grade 1-2 rash, adjudicated related to study drug, and resulting in permanent drug discontinuation; compared for non-inferiority between each of the two high dose arms and the standard arm, using Poisson regression. A sample size of 1,359 participants will give 80% power to detect a 10% difference in completion rates and a 1% difference in the safety outcome. The study is conducted in Canada, Indonesia and Vietnam. Enrolment is ongoing at all sites.
Approvals from a local research ethics board (REB) have been obtained at all participating sites and by the trial coordinating centre. Approval has been given by drug regulatory agencies in Canada and Indonesia and by Ministry of Health in Vietnam; participants give written informed consent before participation. All data collected are non-nominal. Primary results will be submitted for publication in a peer-reviewed journal when all participants have completed treatment; results of secondary outcomes will be submitted for publication at the end of study; all sites will receive the final data of participants from their sites.
Trial registered in ClinicalTrials.gov (Identifier: NCT03988933). Coordinating center is the study team working at McGill University Health Center-Research Institute (MUHC-RI); sponsor is the MUHC-RI; funding has been granted by Canadian Institute of Health Research (FDN-143350).
Neuroradiological abnormalities in tuberculous meningitis (TBM) are common, but the exact relationship with clinical and inflammatory markers has not been well established. We performed magnetic ...resonance imaging (MRI) at baseline and after two months treatment to characterise neuroradiological patterns in a prospective cohort of adult TBM patients in Indonesia. We included 48 TBM patients (median age 30, 52% female, 8% HIV-infected), most of whom had grade II (90%), bacteriologically confirmed (71%) disease, without antituberculotic resistance. Most patients had more than one brain lesion (83%); baseline MRIs showed meningeal enhancement (89%), tuberculomas (77%), brain infarction (60%) and hydrocephalus (56%). We also performed an exploratory analysis associating MRI findings to clinical parameters, response to treatment, paradoxical reactions and survival. The presence of multiple brain lesion was associated with a lower Glasgow Coma Scale and more pronounced motor, lung, and CSF abnormalities (p-value <0.05). After two months, 33/37 patients (89%) showed worsening of MRI findings, mostly consisting of new or enlarged tuberculomas. Baseline and follow-up MRI findings and paradoxical responses showed no association with six-month mortality. Severe TBM is characterized by extensive MRI abnormalities at baseline, and frequent radiological worsening during treatment.
Summary Background Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens ...containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. Methods In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01158755. Findings 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC0–6 ; 78·7 mg.h/L 95% CI 71·0–87·3 vs 26·0 mg.h/L 19·0–35·6), maximum plasma concentrations (Cmax ; 22·1 mg/L 19·9–24·6 vs 6·3 mg/L 4·9–8·3), and concentrations in cerebrospinal fluid (0·60 mg/L 0·46–0·78 vs 0·21 mg/L 0·16–0·27). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC0–6 (31·5 mg.h/L 24·1–41·1 vs 15·1 mg.h/L 12·8–17·7), Cmax (7·4 mg/L 5·6–9·6 vs 3·9 mg/L 3·2–4·8), and drug concentrations in the cerebrospinal fluid (2·43 mg/L 1·81–3·27 vs 1·52 mg/L 1·28–1·82). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten 35% vs 20 65%), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20–0·91; p=0·03). Interpretation These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Funding Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.
Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted ...metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism.
We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins.
CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio HR = 1.16, 95% confidence interval CI = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis.
TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy.
This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).
The World Health Organization (WHO) stated that ensuring access to effective and optimal treatment is a key component to eradicate tuberculosis (TB) through the End TB Strategy. Personalized medicine ...that depends on the genetic profile of an individual is one way to optimize treatment. It is necessary because of diverse drug responses related to the variation in human DNA, such as single-nucleotide polymorphisms (SNPs). Ethambutol (EMB) is a drug widely used as the treatment for
(Mtb) and/non-tuberculous mycobacteria and has become a potential supplementary agent for a treatment regimen of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. In human genetic polymorphism studies of anti-tuberculosis, the majority focus on rifampicin or isoniazid, which discuss polymorphisms related to their toxicity. Whereas there are few studies on EMB, the incidence of EMB toxicity is lower than that of other first-line anti-TB drugs. To facilitate personalized medicine practice, this article summarizes the genetic polymorphisms associated with alterations in the pharmacokinetic profile, resistance incidence, and susceptibility to EMB toxicity. This study includes 131 total human studies from 17 articles, but only eight studies that held in the low-middle income country (LMIC), while the rest is research conducted in developed countries with high incomes. Personalized medicine practices are highly recommended to maintain and obtain the optimal therapeutic effect of EMB.
Multidrug-resistant tuberculosis (MDR-TB) is caused by an organism that is resistant to both rifampicin and isoniazid. Extensively drug-resistant TB, a rare type of MDR-TB, is caused by an organism ...that is resistant to quinolone and one of group A TB drugs (i.e., linezolid and bedaquiline). In 2018, the World Health Organization revised the groupings of TB medicines and reclassified linezolid as a group A drug for the treatment of MDR-TB. Linezolid is a synthetic antimicrobial agent in the oxazolidinone class. Although linezolid has a good efficacy, it can cause substantial adverse events, especially hematologic toxicity. In both TB infection and linezolid mechanism of action, mitochondrial dysfunction plays an important role. In this concise review, characteristics of linezolid as an anti-TB drug are summarized, including its efficacy, pathogenesis of hematologic toxicity highlighting mitochondrial dysfunction, and the monitoring and management of hematologic toxicity.
Volumetric absorptive microsampling (VAMS) is the newest and most promising sample-collection technique for quantitatively analyzing drugs, especially for routine therapeutic drug monitoring (TDM) ...and pharmacokinetic studies. This technique uses an absorbent white tip to absorb a fixed volume of a sample (10–50 µL) within a few seconds (2–4 s), is more flexible, practical, and more straightforward to be applied in the field, and is probably more cost-effective than conventional venous sampling (CVS). After optimization and validation of an analytical method of a drug taken by VAMS, a clinical validation study is needed to show that the results by VAMS can substitute what is gained from CVS and to justify implementation in routine practice. This narrative review aimed to assess and present studies about optimization and analytical validation of assays for drugs taken by VAMS, considering their physicochemical drug properties, extraction conditions, validation results, and studies on clinical validation of VAMS compared to CVS. The review revealed that the bio-analysis of many drugs taken with the VAMS technique was optimized and validated. However, only a few clinical validation studies have been performed so far. All drugs that underwent a clinical validation study demonstrated good agreement between the two techniques (VAMS and CVS), but only by Bland–Altman analysis. Only for tacrolimus and mycophenolic acid were three measurements of agreement evaluated. Therefore, VAMS can be considered an alternative to CVS in routine practice, especially for tacrolimus and mycophenolic acid. Still, more extensive clinical validation studies need to be performed for other drugs.
No gold standard diagnostic test exists for latent tuberculosis infection (LTBI). The intra-dermal tuberculin skin test (TST) has known limitations and Interferon-gamma release assays (IGRA) have ...been developed as an alternative. We aimed to assess agreement between IGRA and TST, and risk factors for test positivity, in Indonesian healthcare students.
Medical and nursing students starting their clinical training were screened using IGRA and TST. Agreement between the two tests was measured using Cohen's Kappa coefficient. Logistic regression was used to identify factors associated with test positivity.
Of 266 students, 43 (16.2%) were IGRA positive and 85 (31.9%) TST positive. Agreement between the two tests was 74.7% (kappa 0.33, 95% CI 0.21-0.45, P<0.0001). Students who had direct contact with family or friends with TB were less likely to be test positive using IGRA (AOR 0.18, 95% CI 0.05-0.64) and using TST (AOR 0.51, 95% CI 0.26-0.99).
Test positivity for LTBI was lower when measured by IGRA than by TST, with poor agreement between the two tests. Known close TB contact was unexpectedly negatively associated with positivity by either test. Longitudinal studies may be required to help determine the best test for LTBI in healthcare students in Indonesia.
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