RESUMEN
In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).
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Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/farmacocinética , Rifampin/administración & dosificación , Rifampin/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Antibióticos Antituberculosos/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Etambutol/uso terapéutico , Femenino , Humanos , Isoniazida/uso terapéutico , Masculino , Mycobacterium tuberculosis/efectos de los fármacos , Pirazinamida/uso terapéutico , Rifampin/efectos adversos , Resultado del Tratamiento , Tuberculosis Pulmonar/mortalidadRESUMEN
Mycobacterium bovis has a wide host range causing TB in animals, both in wildlife and cattle (bovine TB bTB), and in humans (zoonotic TB zTB). The real burden of bovine and zoonotic TB (b/zTB) remains unknown due to diagnostic challenges. Although progress has been made to reduce the burden of TB, b/zTB has been neglected in low- and middle-income countries (LMICs) with little improvement in prevention, diagnosis or treatment. Using Tanzania as a case study, because of its high TB burden, large wildlife diversity and wide reliance on livestock, we developed an approach to comprehensively estimate the burden and implement multidisciplinary actions against b/zTB. We performed a review of the literature on b/zTB, but there is a lack of available data on the b/zTB burden in Tanzania and, notably, on epidemiological indicators other than incidence. We propose a five-action programme to address b/zTB in Tanzania, and we believe our proposed approach could benefit other LMICs as it operates by implementing and strengthening surveillance and health delivery. The resulting knowledge and system organisation could further prevent and mitigate the effects of such conditions on human and animal health, livestock production, population livelihood and the economy.
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Zoonosis Bacterianas , Mycobacterium bovis , Tuberculosis , Animales , Bovinos , Humanos , Tanzanía/epidemiología , Tuberculosis/epidemiologíaRESUMEN
BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).
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Oxazolidinonas , Tuberculosis Pulmonar , Adulto , Humanos , Moxifloxacino/efectos adversos , Linezolid , Quimioterapia Combinada , Antituberculosos , Oxazolidinonas/efectos adversos , Tuberculosis Pulmonar/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hipersensibilidad , Tuberculosis , Humanos , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Personal de SaludRESUMEN
BACKGROUND: There are only limited data from resource-limited settings available on the prevalence of non-communicable diseases and associated risk factors of tuberculosis patients. This study investigated non-communicable disease co-morbidity in tuberculosis patients from Moyen Ogooué Province, Gabon. METHODS: All patients aged 18 years or older consulting for tuberculosis (TB) symptoms in Gabon's Moyen Ogooué province and neighbouring provinces from November 2018 to November 2020 were screened for diabetes mellitus, hypertension, and risk factors thereof (obesity, dyslipidaemia, smoking and alcohol consumption). Logistic regression was performed to identify factors associated with TB-diabetes and TB-hypertension co-morbidities. FINDINGS: Of 583 patients included, 227 (39%) were diagnosed with tuberculosis. In tuberculosis-confirmed patients, the prevalences of hypertension and diabetes were 16·3% and 12·8%, respectively. The prevalence of diabetes was twice as high in tuberculosis patients compared to non-tuberculosis patients. Factors independently associated with hypertension-tuberculosis co-morbidity were age >55 years (aOR=8·5, 95% CI 2·43, 32·6), age 45-54 years (aOR=4.9, 95%CI 1.3-19.8), and moderate alcohol consumption (aOR=2·4; 95% CI 1·02- 5·9), respectively. For diabetes-tuberculosis co-morbidity, age >55 years was positively (aOR=9·13; 95% CI 2·4-39·15), and moderate alcohol consumption inversely associated (aOR=0·26, 95% CI 0·08- 0·73). One-hundred-and-four (46%) of the tuberculosis patients had at least either dyslipidaemia, hypertension, diabetes, or obesity with a majority of newly-diagnosed hypertension and diabetes. INTERPRETATION: Integration of screening of non-communicable diseases and their risk factors during TB assessment for early diagnosis, treatment initiation and chronic care management for better health outcomes should be implemented in all tuberculosis healthcare facilities. FUNDING: This study was supported by WHO AFRO/TDR/EDCTP (2019/893,805) and Deutsches Zentrum für Infektiologie (DZIF/ TTU 02.812).
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BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.
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Antituberculosos , Monitoreo de Drogas , Tuberculosis , Humanos , Atención al Paciente , Estándares de Referencia , Tuberculosis/tratamiento farmacológico , Antituberculosos/administración & dosificaciónRESUMEN
BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants.RESULTS: Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION: These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.
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Tuberculosis Pulmonar , Adulto , Niño , Humanos , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiologíaRESUMEN
BACKGROUND: Post-TB lung disease (PTLD) is an important but under-recognised chronic respiratory disease in high TB burden settings such as Tanzania.METHODS: This was a cross-sectional survey of adults within 2 years of completion of TB treatment in Kilimanjaro, Tanzania. Data were collected using questionnaires (symptoms and exposures), spirometry and chest radiographs to assess outcome measures, which were correlated with daily life exposures, including environment and diet.RESULTS: Of the 219 participants enrolled (mean age: 45 years ± 10; 193 88% males), 98 (45%) reported chronic respiratory symptoms; 46 (22%) had received treatment for TB two or more times; and HIV prevalence was 35 (16%). Spirometric abnormalities were observed in 146 (67%). Chest X-ray abnormalities occurred in 177 (86%). A diagnosis of PTLD was made in 200 (91%), and half had clinically relevant PTLD. The prevalence of mMRC ≥Grade 3 chronic bronchitis and dyspnoea was respectively 11% and 26%. Older age, multiple episodes of TB and poverty indicators were linked with clinically relevant PTLD.CONCLUSIONS: We found a substantial burden of PTLD in adults who had recently completed TB treatment in Tanzania. There is a pressing need to identify effective approaches for both the prevention and management of this disease.
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Enfermedades Pulmonares , Tuberculosis , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Transversales , Enfermedades Pulmonares/epidemiología , Prevalencia , Espirometría , Tanzanía/epidemiología , Tuberculosis/epidemiologíaRESUMEN
BACKGROUND: Persistent respiratory symptoms and lung function deficits are common after patients with TB. We aimed to define the burden of post-TB lung disease (PTLD) and assess associations between symptoms and impairment in two high TB incidence communities.METHODS: This was a cross-sectional survey of adults in Cape Town, South Africa who completed TB treatment 1-5 years previously. Questionnaires, spirometry and 6-minute walking distance (6MWD) were used to assess relationships between outcome measures and associated factors.RESULTS: Of the 145 participants recruited (mean age: 42 years, range: 18-75; 55 [38%] women), 55 (38%) had airflow obstruction and 84 (58%) had low forced vital capacity (FVC); the mean 6MWD was 463 m (range: 240-723). Respiratory symptoms were common: chronic cough (n = 27, 19%), wheeze (n = 61, 42%) and dyspnoea (modified MRC dyspnoea score 3 or 4: n = 36, 25%). There was poor correlation between FVC or obstruction and 6MWD. Only low body mass index showed consistent association with outcomes on multivariable analyses. Only 19 (13%) participants had a diagnosis of respiratory disease, and 16 (11%) currently received inhalers.CONCLUSION: There was substantial burden of symptoms and physiological impairment in this "cured" population, but poor correlation between objective outcome measures, highlighting deficits in our understanding of PTLD.
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Pulmón , Enfermedad Pulmonar Obstructiva Crónica , Tuberculosis , Adulto , Femenino , Humanos , Estudios Transversales , Volumen Espiratorio Forzado , Sudáfrica/epidemiología , Espirometría , Capacidad Vital , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.
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Enfermedades Pulmonares , Calidad de Vida , Tuberculosis , Humanos , Consenso , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/terapia , Tuberculosis/complicacionesRESUMEN
Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less well studied. A systematic search of MEDLINE/Pubmed and the Cochrane Central Register of Controlled Trials up to 31 March 2018 was conducted for articles describing drug concentrations of first-line TB drugs and treatment outcome in adult patients with drug-susceptible TB. The search identified 3073 unique publication abstracts, which were reviewed for suitability: 21 articles were acceptable for inclusion in the qualitative analysis comprising 13 prospective observational cohorts, 4 retrospective observational cohorts, 1 case-control study and 3 randomised controlled trials. Data for meta-analysis were available for 15 studies, 13 studies of rifampicin (RMP), 10 of isoniazid (INH), 8 of pyrazinamide (PZA) and 4 of ethambutol (EMB). This meta-analysis revealed that low PZA concentration appears to increase the risk of poor outcomes (8 studies, n = 2727; RR 1.73, 95%CI 1.10-2.72), low RMP concentrations may slightly increase the risk of poor outcomes (13 studies, n = 2753; RR 1.40, 95%CI 0.91-2.16), whereas low concentrations of INH (10 studies, n = 2640; RR 1.32, 95%CI 0.66-2.63) and EMB (4 studies, n = 551; RR 1.12, 95%CI 0.41-3.05) appear to make no difference to treatment outcome. There was no significant publication bias or between-study heterogeneity in any of the analyses. The potential clinical impact of low concentrations of PZA and RMP warrants further evaluation. Also, comprehensive assessments of the complex pharmacokinetic-pharmacodynamic relationships in the treatment of TB are urgently needed.
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Preparaciones Farmacéuticas , Tuberculosis , Adulto , Antituberculosos/uso terapéutico , Estudios de Casos y Controles , Humanos , Isoniazida , Estudios Observacionales como Asunto , Pirazinamida , Estudios Retrospectivos , Resultado del Tratamiento , Tuberculosis/tratamiento farmacológicoRESUMEN
ALTHOUGH CURABLE, TB frequently leaves the individual with chronic physical and psycho-social impairment, but these consequences have been largely neglected. The 1st International Post-Tuberculosis Symposium (Stellenbosch, South Africa) was held to discuss priorities and gaps in addressing this issue. A barrier to progress has been the varied terminology and nomenclature, so the Delphi process was used to achieve consensus on definitions. Lack of sufficient evidence hampered definitive recommendations in most domains, including prevention and treatment of post-TB lung disease (PTLD), but the discussions clarified the research needed. A consensus was reached on a toolkit for future PTLD measurement and on PTLD patterns to be considered. The importance of extra-pulmonary consequences and progressive impairment throughout the life-course was identified, including TB recurrence and increased mortality. Patient advocates emphasised the need to address the psychological and social impacts post TB and called for clinical guidance. More generally, there is an urgent need for increased awareness and research into post-TB complications.