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      Clinical standards for the dosing and management of TB drugs

      research-article
      1 , 2 , 3 , , 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 1 , 3 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 8 , 1 , 2 , 3 , 34 , 1 , 35 , 18 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 11 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 10 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 21
      The International Journal of Tuberculosis and Lung Disease
      International Union Against Tuberculosis and Lung Disease
      tuberculosis, pharmacokinetics, pharmacodynamics, adverse drug reaction, management, dosing

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          SUMMARY

          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.

          Translated abstract

          CONTEXTE :

          Une posologie optimale est importante afin de garantir une réponse adéquate au traitement, de prévenir le développement de résistances aux médicaments et de réduire la toxicité liée aux médicaments. L’objectif de ces normes cliniques est de donner des indications de « bonne pratique » en matière de posologie et de gestion des agents antituberculeux.

          MÉTHODES :

          Un panel de 57 experts internationaux spécialisés en microbiologie, pharmacologie et soins antituberculeux a été identifié ; 51 ont participé à un processus Delphi. Une échelle de Likert à 5 points a été utilisée pour noter les premières ébauches des normes. Le document final est fondé sur un large consensus puisqu’il a été approuvé par tous les participants.

          RÉSULTATS :

          Six normes cliniques ont été définies : Norme 1, définir la dose initiale la mieux adaptée au traitement de la TB ; Norme 2, identifier les patients potentiellement à risque d’exposition sous-optimale aux médicaments ; Norme 3, identifier les patients à risque de développer une toxicité liée aux médicaments et déterminer comment diminuer au mieux ce risque ; Norme 4, identifier les patients pouvant bénéficier d’un suivi thérapeutique pharmacologique (TDM) ; Norme 5, définir les informations et conseils à fournir aux patients placés sous traitement antituberculeux et Norme 6, enseigner les fondamentaux aux professionnels de santé. Les priorités de recherche ont également été définies, sur la base d’un consensus.

          CONCLUSION :

          Il s’agit des premières normes cliniques, fondées sur un consensus, en matière de posologie et de gestion des antituberculeux. Elles ont pour objectif d’orienter les cliniciens et les responsables de programme en matière de planification et de mise en place de mesures locales adéquates pour un traitement optimal centré sur le patient, afin d’améliorer la prise en charge.

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          Most cited references188

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          Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

          The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.
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            Bedaquiline, pretomanid and linezolid for treatment of extensively drug resistant, intolerant or non-responsive multidrug resistant pulmonary tuberculosis

            Background Patients with extensively drug resistant tuberculosis (TB) have limited treatment options with historically poor outcomes. We investigated treatment with 3 oral drugs, bedaquiline (B), pretomanid (Pa) and linezolid (L), (B-Pa-L), with TB bactericidal activity and little pre-existing resistance. Methods Nix-TB is an open label single arm study ongoing at three South African sites evaluating the safety and efficacy of B-Pa-L for 26 weeks for extensively drug-resistant TB or treatment intolerant /non-responsive multidrug-resistant TB. We present the efficacy and safety outcomes for all 109 patients enrolled in the trial followed to the predefined primary endpoint, six months after the end of treatment. Results In the intent to treat analysis, 98 patients (90%), (95% CI 82.7-94.9%) had a favourable outcome at 6 months after the end of treatment. Six patients died during the early stages of treatment, one withdrew during treatment, one died during follow-up without evidence of relapse, one relapsed, one relapsed and subsequently died during follow up and one was lost to follow-up. The expected linezolid toxicities of peripheral neuropathy (experienced by 81% of patients) and myelosuppression (48%), while common, were manageable, often requiring reductions of dose and/or interruptions in linezolid. Conclusions These results suggest that B-Pa-L is a viable option for tuberculosis patients with highly resistant forms of TB, provided adequate safety management is available. Trial registration: ClinicalTrials.gov Identifier: NCT02333799 Sponsor: Global Alliance for TB Drug Development (TB Alliance)
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              Developmental pharmacology--drug disposition, action, and therapy in infants and children.

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                Author and article information

                Journal
                Int J Tuberc Lung Dis
                Int J Tuberc Lung Dis
                jtld
                The International Journal of Tuberculosis and Lung Disease
                International Union Against Tuberculosis and Lung Disease
                1027-3719
                1815-7920
                June 2022
                1 June 2022
                : 26
                : 6
                : 483-499
                Affiliations
                [1 ]Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, NSW, Australia
                [2 ]School of Pharmacy, The University of Sydney Faculty of Medicine and Health, Sydney, NSW, Australia
                [3 ]Westmead Hospital, Sydney, NSW, Australia
                [4 ]Department of Clinical Pharmacology and Toxicology, St Vincent’s Hospital, Sydney, NSW, Australia
                [5 ]St Vincent’s Clinical Campus, University of NSW, Kensington, NSW, Australia
                [6 ]Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Solna, Sweden
                [7 ]Department of Infectious Diseases Karolinska University Hospital, Solna, Sweden
                [8 ]Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg, South Africa
                [9 ]Department of Pediatrics, University of Wisconsin, Madison, WI
                [10 ]Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
                [11 ]Department of Pharmacy, Radboud Institute for Health Sciences & Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
                [12 ]University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands
                [13 ]University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands
                [14 ]Educational Institution “Grodno State Medical University”, Grodno, Belarus
                [15 ]Asian Harm Reduction Network (AHRN) and Medical Action Myanmar (MAM) in Yangon, Myanmar
                [16 ]Belgian Scientific Institute for Public Health (Belgian Lung and Tuberculosis Association), Brussels, Belgium
                [17 ] Indian Council of Medical Research-National Institute for Research in Tuberculosis-International Center for Excellence in Research, Chennai, India
                [18 ]Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
                [19 ]Department of Public Health TB Control, Metropolitan Public Health Services, The Hague, The Netherlands
                [20 ]Laboratório de Inovações em Terapias, Ensino e Bioprodutos (LITEB), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
                [21 ]Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Tradate, Italy
                [22 ]Department of Medicine, Therapeutics and Dermatology, Kenyatta University, Nairobi, Kenya
                [23 ]Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
                [24 ]Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
                [25 ]Parramatta Chest Clinic, Parramatta, NSW, Australia
                [26 ]Public Health Consulting Group, Lugano, Switzerland
                [27 ]Reference Center Hélio Fraga, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
                [28 ]Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
                [29 ]Centre for Lung Infection and Immunity, Department of Medicine, Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa
                [30 ]University of Cape Town Lung Institute & South African MRC Centre for the Study of Antimicrobial Resistance, Cape Town, South Africa
                [31 ]Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK
                [32 ]Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
                [33 ]Woolcock Institute of Medical Research, Glebe, NSW, Australia
                [34 ]Department of Genetics, University of Cambridge, Cambridge, UK
                [35 ]Department of Infectious Diseases and Microbiology, The Children’s Hospital at Westmead, Westmead, NSW, Australia
                [36 ]Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
                [37 ]Clínica de Tuberculosis, Instituto Nacional de Enfermedades Respiratorias, Ciudad de México, Mexico
                [38 ]Division of Paediatric Respirology, Department of Child Health, Faculty of Medicine, Universitas Padjadjaran, Hasan Sadikin Hospital, Bandung, Indonesia
                [39 ]Infectious Disease Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
                [40 ]Institute for Health Innovation & Technology (iHealthtech), National University of Singapore, Singapore
                [41 ]Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore
                [42 ]German Central Committee against Tuberculosis (DZK), Berlin, Germany
                [43 ]Infectious Disease Pharmacokinetics Laboratory, Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA
                [44 ]Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
                [45 ]TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
                [46 ]Department of Biomedical Sciences, Division of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
                [47 ]Division of Respirology and Critical Care, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
                [48 ]Department of Bioengineering and Therapeutic Sciences, Division of Pulmonary and Critical Care Medicine, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, USA
                [49 ]Department of TB & Respiratory Diseases, National Institute of TB & Respiratory Diseases, New Delhi, India
                [50 ]Department of Pharmacy, Uppsala University, Uppsala, Sweden
                [51 ]The Republican Research and Practical Centre for Pulmonology and TB, Minsk, Belarus
                [52 ]National Institute for Public Health and the Environment, TB Reference Laboratory (RIVM), Bilthoven, The Netherlands
                [53 ]Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, USA
                [54 ]Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
                [55 ]Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
                [56 ]Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
                [57 ]P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India
                [58 ]National Drug Information and Adverse Drug Reaction Monitoring Centre, Hanoi University of Pharmacy, Hanoi, Vietnam
                [59 ]Department of Infectious Diseases, National Medical Center for Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
                [60 ]Kilimanjaro Christian Medical University College, Moshi, United Republic of Tanzania
                [61 ]Kibong’oto Infectious Diseases Hospital, Sanya Juu, Siha, Kilimanjaro, United Republic of Tanzania
                [62 ]Department of Infectious Diseases, Linköping University Hospital, Linköping, Sweden
                [63 ]Institute of Biomedical and Clinical Sciences, Division of Infection and Inflammation, Linköping University, Linköping, Sweden
                [64 ]Department of Infectious Diseases, Kalmar County Hospital, Kalmar, Linköping University, Linköping, Sweden
                Author notes
                [*]

                JWCA and SLS contributed equally, JWCA, SLS, LDF, AGP, SKH, SGM, TS and GBM comprise the core writing team

                Correspondence to: Jan-Willem Alffenaar, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Pharmacy Building (A15), Camperdown, NSW, 2006, Australia. e-mail: johannes.alffenaar@ 123456sydney.edu.au
                Article
                i1815-7920-26-6-483
                10.5588/ijtld.22.0188
                9165737
                35650702
                ccb010a7-115d-4005-91c0-853c3d880333
                © 2022 The Union

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 April 2022
                : 4 April 2022
                Page count
                Pages: 18
                Categories
                Clinical Standard Series

                tuberculosis,pharmacokinetics,pharmacodynamics,adverse drug reaction,management,dosing

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