AMERICAN THORACIC SOCIETY DOCUMENTS Treatment of Drug-Resistant Tuberculosis An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline Payam Nahid, Sundari R. Mase, Giovanni Battista Migliori, Giovanni Sotgiu, Graham H. Bothamley, Jan L. Brozek, Adithya Cattamanchi, J. Peter Cegielski, Lisa Chen, Charles L. Daley, Tracy L. Dalton, Raquel Duarte, Federica Fregonese, C. Robert Horsburgh, Jr., Faiz Ahmad Khan, Fayez Kheir, Zhiyi Lan, Alfred Lardizabal, Michael Lauzardo, Joan M. Mangan, Suzanne M. Marks, Lindsay McKenna, Dick Menzies, Carole D. Mitnick, Diana M. Nilsen, Farah Parvez, Charles A. Peloquin, Ann Raftery, H. Simon Schaaf, Neha S. Shah, Jeffrey R. Starke, John W. Wilson, Jonathan M. Wortham, Terence Chorba, and Barbara Seaworth; on behalf of the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America THIS OFFICIAL CLINICAL PRACTICE GUIDELINE WAS APPROVED BY THE AMERICAN THORACIC SOCIETY, THE EUROPEAN RESPIRATORY SOCIETY, AND THE INFECTIOUS DISEASES SOCIETY OF AMERICA SEPTEMBER 2019, AND WAS CLEARED BY THE U.S. CENTERS FOR DISEASE CONTROL AND PREVENTION SEPTEMBER 2019 Background: The American Thoracic Society, U.S. Centers for was judged to be very low, because the data came Disease Control and Prevention, European Respiratory Society, and from observational studies with significant loss to follow-up Infectious Diseases Society of America jointly sponsored this new and imbalance in background regimens between comparator practice guideline on the treatment of drug-resistant tuberculosis groups. Good practices in the management of MDR-TB are (DR-TB). The document includes recommendations on the described. On the basis of the evidence review, a clinical strategy treatment of multidrug-resistant TB (MDR-TB) as well as tool for building a treatment regimen for MDR-TB is also isoniazid-resistant but rifampin-susceptible TB. provided. Methods: Published systematic reviews, meta-analyses, and a new Conclusions: New recommendations are made for the choice and individual patient data meta-analysis from 12,030 patients, in 50 number of drugs in a regimen, the duration of intensive and studies, across 25 countries with confirmed pulmonary rifampin- continuation phases, and the role of injectable drugs for MDR-TB. resistant TB were used for this guideline. Meta-analytic approaches On the basis of these recommendations, an effective all-oral included propensity score matching to reduce confounding. Each regimen for MDR-TB can be assembled. Recommendations are also recommendation was discussed by an expert committee, screened for provided on the role of surgery in treatment of MDR-TB and for conflicts of interest, according to the Grading of Recommendations, treatment of contacts exposed to MDR-TB and treatment of Assessment, Development, and Evaluation (GRADE) methodology. isoniazid-resistant TB. Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 Keywords: MDR-TB; tuberculosis; duration of treatment; drug GRADE-based recommendations. Certainty in the evidence treatment; treatment monitoring ORCID IDs: 0000-0003-2811-1311 (P.N.); 0000-0001-5363-0637 (S.R.M.); 0000-0002-2597-574X (G.B.M.); 0000-0002-1600-4474 (G.S.); 0000-0002-7092-8547 (G.H.B.); 0000-0002-3122-0773 (J.B.); 0000-0002-6553-2601 (A.C.); 0000-0001-6804-0111 (L.C.); 0000-0003-3324-926X (C.L.D.); 0000-0001-6838-7895 (C.R.H.); 0000-0003-0473-8734 (F.A.K.); 0000-0002-4192-5080 (F.K.); 0000-0001-5519-2474 (Z.L.); 0000-0003-3273-1097 (A.L.); 0000-0002-7096-4185 (M.L.); 0000-0001-6770-086X (J.M.M.); 0000-0003-3024-1940 (S.M.M.); 0000-0002-4703-0835 (L.M.); 0000-0002-3455-658X (C.D.M.); 0000-0003-1211-5043 (F.P.); 0000-0001-9002-7052 (C.A.P.); 0000-0001-5755-4133 (H.S.S.); 0000-0001-7722-0958 (T.C.); 0000-0003-2922-4940 (B.S.). Supported by the American Thoracic Society, the United States Centers for Disease Control and Prevention, the European Respiratory Society, and the Infectious Diseases Society of America. An Executive Summary of this document is available at http://www.atsjournals.org/doi/suppl/10.1164/rccm.201909-1874ST. You may print one copy of this document at no charge. However, if you require more than one copy, you must place a reprint order. Domestic reprint orders: [email protected]; international reprint orders: [email protected]. Correspondence and requests for reprints should be addressed to Payam Nahid, M.D., M.P.H, Zuckerberg San Francisco General Hospital, Division of Pulmonary and Critical Care Medicine, UCSF Center for Tuberculosis, 1001 Potrero Avenue, Building 5, Room 5K1, San Francisco, CA 94110. E-mail: [email protected]. This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org. Am J Respir Crit Care Med Vol 200, Iss 10, pp e93–e142, Nov 15, 2019 Copyright © 2019 by the American Thoracic Society DOI: 10.1164/rccm.201909-1874ST Internet address: www.atsjournals.org American Thoracic Society Documents e93 AMERICAN THORACIC SOCIETY DOCUMENTS Contents Ethionamide and Prothionamide Additional Considerations Overview Fluoroquinolones: Levofloxacin, Conclusions Summary of Good Practices Moxifloxacin, Ciprofloxacin, and Research Needs Summary of Recommendations Ofloxacin Treatment of Isoniazid-Resistant TB Introduction Injectables: Amikacin, Summary of the Evidence Good Practices for Treating DR-TB Capreomycin, Kanamycin, and Benefits Diagnosing TB and Identification Streptomycin Harms of Drug Resistance Linezolid Additional Considerations Treatment and Monitoring of DR- Macrolides: Azithromycin and Conclusions TB Clarithromycin Research Needs Infection Control and DR-TB p-Aminosalicylic Acid Treatment of MDR-TB in Special Case Management for DR-TB Pyrazinamide Situations Treatment of MDR-TB, Number of Building a Treatment Regimen for HIV Infection Drugs, and Duration of Treatment MDR-TB Children Phases Role of Therapeutic Drug Monitoring in Pregnant Women Number of Drugs in the Regimen Treatment of MDR-TB Treatment of Contacts Exposed to Duration of Intensive and Shorter-Course, Standardized, 9- to MDR-TB Continuation Phases in Treating 12-Month Regimen for MDR-TB Summary of the Evidence MDR-TB Summary of the Evidence Benefits Drugs and Drug Classes Benefits Harms Amoxicillin/Clavulanate Harms Additional Considerations Bedaquiline Additional Considerations Conclusions Carbapenems with Clavulanic Conclusions Research Needs Acid Research Needs Summary of Key Differences Clofazimine Role of Surgery in MDR-TB between ATS/CDC/ERS/IDSA and Cycloserine Summary of the Evidence WHO 2019 Consolidated Guidelines Delamanid Benefits on Drug-Resistant Tuberculosis Ethambutol Harms Treatment Overview options associated with improved outcomes treatment of a specific limited population of (i.e., greater treatment success, fewer adults with pulmonary extensively drug- Treatment of tuberculosis (TB), regardless adverse events, and fewer deaths) and in the resistant (XDR-TB) or treatment-intolerant of the results of drug susceptibility testing context of individual patient values and or nonresponsive MDR-TB; however, the (DST), is focused on both curing the preferences. Worthy of emphasis, the preparation and completion of these individual patient and minimizing the committee recommends that only drugs to guidelines predated this approval (2). For transmission of Mycobacterium tuberculosis which the patient’s M. tuberculosis isolate each drug or drug class, the following to other persons. Thus, effective treatment has documented, or high likelihood of, Population, Intervention, Comparator, and of TB has benefits for both the individual susceptibility be included in an effective Outcomes (PICO) question was addressed: patient and the community in which the treatment regimen, noted as an ungraded In patients with MDR-TB, are outcomes patient resides. However, notable good practice statement, and consistent safely improved when regimens include the complexities need to be addressed to with ongoing stewardship efforts for the following individual drugs or drug classes successfully treat disease resulting from optimal use of antibiotics (1). Drugs known compared with regimens that do not drug-resistant M. tuberculosis isolates to be ineffective on the basis of in vitro include them? compared with treatment of drug- growth-based or molecular DST should The recommendations in this practice susceptible TB disease, including additional not be used. The following alphabetically guideline were supported by scientific molecular and phenotypic diagnostic tests listed drugs and drug classes were evidence, including results of a propensity to determine drug susceptibility; the use of considered for inclusion in treatment score (PS)-matched individual patient data second-line drugs, which have toxicities regimens: amoxicillin/clavulanate, meta-analyses (IPDMA) conducted using a that increase harms that must be balanced bedaquiline, carbapenem with database of more than 12,000 patient with their benefits; and prolonged clavulanic acid, clofazimine, cycloserine, records from 25 countries in support of treatment durations. The new delamanid, ethambutol, ethionamide, these guidelines (see APPENDIX A: recommendations provided in this fluoroquinolones, injectable agents, METHODOLOGY in the online supplement) (3). guideline are for the treatment of linezolid, macrolides, p-aminosalicylic acid, We used the Grading of Recommendations, drug-resistant TB (DR-TB), including and pyrazinamide. Of