Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care.
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 (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 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 AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (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.
Modeling early bactericidal activity in murine tuberculosis provides insights into the activity of isoniazid and pyrazinamide.
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 8 years ago
Standard tuberculosis (TB) treatment includes an initial regimen containing drugs that are both rapidly bactericidal (isoniazid) and sterilizing (rifampin and pyrazinamide), and ethambutol to help prevent the emergence of drug resistance. Antagonism between isoniazid and pyrazinamide has been demonstrated in a TB treatment mouse model. Because isoniazid’s bactericidal activity is greatest during the initial two treatment days, we hypothesized that removing isoniazid after the second day would increase the effectiveness of the standard regimen. To test this hypothesis, we developed a mouse model to measure the early bactericidal activity (EBA) of drug regimens designed to analyze the essentiality of both isoniazid and pyrazinamide during the first 14 d of therapy. Our results clearly indicate that discontinuation of isoniazid after the second day of treatment increases the EBA of standard therapy in the mouse model, whereas omitting pyrazinamide during the first 14 d was detrimental. Substitution of moxifloxacin for isoniazid on day 3 did not increase the EBA compared with only removing isoniazid after day 2. Our data show that a mouse model can be used to analyze the EBA of TB drugs, and our findings support pursuing clinical trials to evaluate the possible benefit of removing isoniazid after the first 2 treatment days.
Early detection of Mycobacterium tuberculosis complex (MTBC) and markers conveying drug resistance can have a beneficial impact on preventive public-health actions. We describe a new molecular point-of-care (POC) system - Genedrive®- based on a simple sample preparation combined with PCR to provide detection of MTBC and a simultaneous detection of mutation markers in the rpoB gene directly from raw sputa. Hybridization probes were used to report the presence of the key mutations in codons 516, 526, and 531 of the rpoB gene. Sensitivity MTBC and rpoB detection from sputa was assessed using model sputa spiked with known numbers of bacteria prepared from liquid cultures of Mycobacterium tuberculosis. The overall sensitivity was 90.8% (95% CI: 81, 96.5) for MTBC detection and 72.3% (95% CI: 59.8, 82.7) for rpoB detection. For samples ≥1,000 CFU/mL sensitivity was 100% for MTBC and 85.7% for rpoB detection while for samples containing ≤100 CFU/mL was 86.4% and 65.9% for MTBC and rpoB detections, respectively. Specificity was shown to be 100% (95% CI: 83.2, 100) for both MTBC and rpoB. Clinical sputum samples were processed using the same protocol and showed good concordance with data generated from the model. Tuberculosis infected subjects with smear samples assessed as scanty or negative were detectable by the Genedrive®. In these paubacillary patients, the performance of Genedrive® was comparable to GeneXpert®. The characteristics of Genedrive® platform make it particularly useful for MTBC detection and rifampicin resistance in low resource setting and reduce the burden of tuberculosis disease.
Prompt administration of antibiotics, adjunctive steroid therapy, and optimization of antibiotic delivery to cerebrospinal fluid (CSF) are factors associated with improved outcome of patients hospitalized for acute bacterial meningitis (ABM). However, the impact of a bundle of these procedures has not been reported.
To the Editor: New treatments are needed to combat the worldwide increase in resistance to antituberculosis drugs.(1) The outlook for patients with tuberculosis who do not show a response to the key agents used in treatment - isoniazid, rifampin, fluoroquinolones, and aminoglycosides - is grim and reminiscent of the plight of patients with cancer in the era before chemotherapy.(2) New agents are emerging, but the obligatory evaluation of their safety and efficacy in combination with other antituberculosis and antiretroviral agents slows the pace of progress. Repurposing or combining commercially available products may offer a faster track to new antituberculosis regimens. . . .
Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.
Rapid diagnosis of drug-resistant tuberculosis is important in determining proper management. This letter reports on limitations of the Xpert MTB/RIF assay in determining rifampin resistance in tuberculosis isolates in Swaziland.
Tuberculous meningitis, the most destructive form of tuberculosis, continues to be associated with considerable mortality and morbidity; among children, it is the major cause of death resulting from tuberculosis. The consequences of tuberculous meningitis are yet again clearly shown in the article by Heemskerk et al. in this issue of the Journal.(1) This randomized, controlled study of tuberculous meningitis in Vietnamese adults, probably the largest ever undertaken, was carefully planned and executed and evaluated an intensified regimen that included both a higher dose of oral rifampin than the standard dose (15 mg per kilogram of body weight vs. 10 . . .
Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes.