Nafees Ahmad1, Shama D Ahuja2, Onno W Akkerman3, Jan-Willem C Alffenaar4, Laura F Anderson5, Parvaneh Baghaei6, Didi Bang7, Pennan M Barry8, Mayara L Bastos9, Digamber Behera10, Andrea Benedetti11, Gregory P Bisson12, Martin J Boeree13, Maryline Bonnet14, Sarah K Brode15, James C M Brust16, Ying Cai17, Eric Caumes18, J Peter Cegielski19, Rosella Centis20, Pei-Chun Chan21, Edward D Chan22, Kwok-Chiu Chang23, Macarthur Charles24, Andra Cirule25, Margareth Pretti Dalcolmo26, Lia D'Ambrosio27, Gerard de Vries28, Keertan Dheda29, Aliasgar Esmail29, Jennifer Flood8, Gregory J Fox30, Mathilde Fréchet-Jachym31, Geisa Fregona32, Regina Gayoso26, Medea Gegia5, Maria Tarcela Gler33, Sue Gu34, Lorenzo Guglielmetti35, Timothy H Holtz19, Jennifer Hughes36, Petros Isaakidis37, Leah Jarlsberg38, Russell R Kempker39, Salmaan Keshavjee40, Faiz Ahmad Khan11, Maia Kipiani41, Serena P Koenig42, Won-Jung Koh43, Afranio Kritski44, Liga Kuksa45, Charlotte L Kvasnovsky46, Nakwon Kwak47, Zhiyi Lan11, Christoph Lange48, Rafael Laniado-Laborín49, Myungsun Lee50, Vaira Leimane25, Chi-Chiu Leung23, Eric Chung-Ching Leung23, Pei Zhi Li11, Phil Lowenthal8, Ethel L Maciel32, Suzanne M Marks51, Sundari Mase52, Lawrence Mbuagbaw53, Giovanni B Migliori20, Vladimir Milanov54, Ann C Miller55, Carole D Mitnick55, Chawangwa Modongo56, Erika Mohr36, Ignacio Monedero57, Payam Nahid38, Norbert Ndjeka58, Max R O'Donnell59, Nesri Padayatchi60, Domingo Palmero61, Jean William Pape62, Laura J Podewils19, Ian Reynolds34, Vija Riekstina25, Jérôme Robert63, Maria Rodriguez64, Barbara Seaworth65, Kwonjune J Seung66, Kathryn Schnippel67, Tae Sun Shim68, Rupak Singla69, Sarah E Smith19, Giovanni Sotgiu70, Ganzaya Sukhbaatar71, Payam Tabarsi6, Simon Tiberi72, Anete Trajman73, Lisa Trieu2, Zarir F Udwadia74, Tjip S van der Werf75, Nicolas Veziris63, Piret Viiklepp76, Stalz Charles Vilbrun77, Kathleen Walsh77, Janice Westenhouse8, Wing-Wai Yew78, Jae-Joon Yim47, Nicola M Zetola56, Matteo Zignol5, Dick Menzies79. 1. Faculty of Pharmacy and Health Sciences, University of Baluchistan, Quetta, Pakistan. 2. Bureau of Tuberculosis Control, New York City Department of Health and Mental Hygiene, NY, USA. 3. Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands; Tuberculosis Centre Beatrixoord, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands. 4. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands. 5. Global Tuberculosis Program, World Health Organization, Geneva, Switzerland. 6. Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 7. Statens Serum Institut, Copenhagen, Denmark. 8. Tuberculosis Control Branch, Division of Communicable Disease Control, Center for Infectious Diseases, California Department of Public Health, CA, USA. 9. Social Medicine Institute, Epidemiology Department, State University of Rio de Janeiro, Rio de Janeiro, Brazil. 10. Department of Pulmonary Medicine, World Health Organization Collaborating Centre for Research & Capacity Building in Chronic Respiratory Diseases, Chandigarh, India; Postgraduate Institute of Medical Education & Research, Chandigarh, India. 11. Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, QC, Canada. 12. University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. 13. Department of Pulmonary Diseases, Radboud University Medicale Centre Nijmegen and Dekkerswald Radboudumc Groesbeek, Netherlands. 14. Epicentre MSF, Paris, France; Institut de Recherche pour le Développement UM233, INSERM U1175, Université de Montpellier, Montpellier, France. 15. Department of Medicine, Division of Respirology, University of Toronto, West Park Healthcare Centre, University Health Network, and Sinai Health System, Toronto, ON, Canada. 16. Division of General Internal Medicine and Division of Infectious Diseases, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA. 17. Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, MD, USA. 18. AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France. 19. Division of Global HIV and TB, Centers for Disease Control and Prevention, Atlanta, GA, USA. 20. World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Maugeri Care and Research Institute, Tradate, Italy. 21. Division of Chronic Infectious Diseases, Taiwan Centers for Disease Control, Taipei, Taiwan. 22. Department of Medicine, University of Colorado Denver, Aurora, CO, USA; Department of Medicine, National Jewish Health, Denver, CO, USA; VA Medical Center, Denver, CO, USA. 23. Department of Health, Tuberculosis and Chest Service, Centre for Health Protection, Hong Kong Special Administrative Region, China. 24. Centers for Disease Control and Prevention, Haiti Country Office, Port-au-Prince, Haiti. 25. Centre of TB and Lung Diseases, Riga East University Hospital, Riga, Latvia. 26. Centro de Referência Helio Fraga, Fiocruz, Brazil. 27. World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Maugeri Care and Research Institute, Tradate, Italy; Public Health Consulting Group, Lugano, Switzerland. 28. Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands; KNCV Tuberculosis Foundation, The Hague, Netherlands. 29. Centre for Lung Infection and Immunity, Department of Medicine & UCT Lung Institute, University of Cape Town, Cape Town, South Africa. 30. Sydney Medical School, University of Sydney, NSW, Australia. 31. Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France. 32. University Federal of Espirito Santo, Vitória, Brazil. 33. Tropical Disease Foundation, Manila, Philippines. 34. Department of Medicine, University of Colorado Denver, Aurora, CO, USA. 35. AP-HP, Laboratoire de Bactériologie-Hygiène, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France; Sorbonne Université, Centre d'Immunologie et des Maladies Infectieuses (CIMI; INSERM U1135/UMRS CR7/CNRS ERL 8255), Bactériologie, Faculté de Médecine Sorbonne Université, Paris, France; Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France. 36. Médecins Sans Frontières, Khayelitsha, South Africa. 37. Médecins Sans Frontières, Mumbai, India. 38. Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA, USA. 39. Emory University School of Medicine, Division of Infectious Diseases, Atlanta, GA, USA. 40. Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA; Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA. 41. National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia. 42. Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti. 43. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 44. Academic Tuberculosis Program, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 45. Department of MDR TB, Riga East University Hospital, Riga, Latvia. 46. Division of Pediatric Surgery, Cohen Children's Medical Center, Hofstra Northwell School of Medicine, New Hyde Park, NY, USA. 47. Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul, South Korea. 48. Division of Clinical Infectious Diseases, Research Center Borstel, Germany; German Center for Infection Research, Clinical Tuberculosis Unit, Borstel, Germany; International Health/Infectious Diseases, University of Luebeck, Luebeck, Germany; Department of Medicine, Karolinska Institute, Stockholm, Sweden. 49. Tuberculosis Clinic and Laboratory, Tijuana General Hospital, Tijuana, Mexico. 50. Clinical Research Section, International Tuberculosis Research Centre, Seoul, South Korea. 51. Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA. 52. Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA; Regional WHO Office, New Delhi, India. 53. Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada. 54. Medical Faculty, Medical University-Sofia, University Hospital for Respiratory Diseases "St. Sofia", Sofia, Bulgaria. 55. Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA. 56. Botswana-UPenn Partnership, Gaborone, Botswana. 57. TB-HIV Department, International Union against Tuberculosis and Lung Diseases, Paris, France. 58. National TB Programme, South African National Department of Health, Pretoria, South Africa. 59. Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. 60. CAPRISA, MRC TB-HIV Treatment and Pathogenesis Research Unit, Durban, South Africa. 61. Pulmonology Division, Municipal Hospital F J Munĩz, Buenos Aires, Argentina. 62. Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti; Center for Global Health, Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 63. AP-HP, Laboratoire de Bactériologie-Hygiène, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France; Sorbonne Université, Centre d'Immunologie et des Maladies Infectieuses (CIMI; INSERM U1135/UMRS CR7/CNRS ERL 8255), Bactériologie, Faculté de Médecine Sorbonne Université, Paris, France. 64. National Tuberculosis Control Program, Dominican Republic. 65. Heartland National TB Center, University of Texas Health Science Center at Tyler, Tyler, TX, USA. 66. Partners In Health, Boston, MA, USA. 67. Faculty of Health Sciences, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. 68. Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Seoul, South Korea. 69. National Institute of Tuberculosis & Respiratory Diseases, New Delhi, India. 70. Department of Medical, Surgical and Experimental Sciences, Clinical Epidemiology and Medical Statistics Unit, University of Sassari, Sassari, Italy. 71. Ministry of Health of Mongolia, Mongolia. 72. Royal London Hospital, Barts Health NHS Trust, London, UK; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 73. Social Medicine Institute, Epidemiology Department, State University of Rio de Janeiro, Rio de Janeiro, Brazil; Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, QC, Canada; Academic Tuberculosis Program, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 74. Hinduja Hospital & Research Center, Mumbai, India. 75. Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands; Department of Internal Medicine/Infectious Diseases, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands. 76. Estonian Tuberculosis Registry, National Institute for Health Development, Tallinn, Estonia. 77. Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti. 78. Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. 79. Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, QC, Canada. Electronic address: dick.menzies@mcgill.ca.
Abstract
BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
Authors: Ahmed A Abulfathi; Peter R Donald; Kim Adams; Elin M Svensson; Andreas H Diacon; Helmuth Reuter Journal: Br J Clin Pharmacol Date: 2020-06-21 Impact factor: 4.335
Authors: Francesca Conradie; Andreas H Diacon; Nosipho Ngubane; Pauline Howell; Daniel Everitt; Angela M Crook; Carl M Mendel; Erica Egizi; Joanna Moreira; Juliano Timm; Timothy D McHugh; Genevieve H Wills; Anna Bateson; Robert Hunt; Christo Van Niekerk; Mengchun Li; Morounfolu Olugbosi; Melvin Spigelman Journal: N Engl J Med Date: 2020-03-05 Impact factor: 91.245
Authors: Mohammad H Al-Shaer; Anne-Grete Märtson; Wael A Alghamdi; Abdullah Alsultan; Guohua An; Shahriar Ahmed; Yosra Alkabab; Sayera Banu; Eric R Houpt; David Ashkin; David E Griffith; J Peter Cegielski; Scott K Heysell; Charles A Peloquin Journal: Antimicrob Agents Chemother Date: 2020-08-20 Impact factor: 5.191