title: New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects.
abstract: About 1·3 million people died of tuberculosis in 2012, despite availability of effective drug treatment. Barriers to improvements in outcomes include long treatment duration (resulting in poor patient adherence and loss of patients to follow-up), complex regimens that involve expensive and toxic drugs, toxic effects when given with antiretroviral therapy, and multidrug resistance. After 50 years of no antituberculosis drug development, a promising pipeline is emerging through the repurposing of old drugs, re-engineering of existing antibacterial compounds, and discovery of new compounds. A range of novel antituberculosis drugs are in preclinical development, several phase 2 and 3 trials are underway, and use of adjunct therapies is being explored for drug-sensitive and drug-resistant tuberculosis. Historical advances include approval of two new drugs, delamanid and bedaquiline. Combinations of new and existing drugs are being assessed to shorten the duration of therapy and to treat multidrug-resistant tuberculosis. There has also been progress in development of new antituberculosis drugs that are active against dormant or persister populations of Mycobacterium tuberculosis. In this Review, we discuss recent advances in antituberculosis drug discovery and development, clinical trial designs, laboratory methods, and adjunct host-directed therapies, and we provide an update of phase 3 trials of various fluoroquinolones (RIFAQUIN, NIRT, OFLOTUB, and REMoxTB). We also emphasise the need to engage the community in design, implementation, and uptake of research, to increase international cooperation between drug developers and health-care providers adopting new regimens.
authors.affiliation: Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK; University College London Hospitals NHS Foundation Trust, London, UK. Electronic address: a.zumla@ucl.ac.uk.
authors.forename: Alimuddin I
authors.initials: AI
authors.lastname: Zumla
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gillespie
authors.affiliation: Department for Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany; German Centre for Infection Research, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Patrick P J
authors.initials: PP
authors.lastname: Philips
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, EPFLSV/GHI/UPCOL, Lausanne, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Abubakar
authors.affiliation: Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McHugh
authors.affiliation: Henry M Jackson Foundation-Division of AIDS, TB Clinical Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Schito
authors.affiliation: Centre for Allogeneic Stem Cell Transplantation, Therapeutic Immunology Division, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nunn
mesh_terms: D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D004359:Drug Therapy, Combination; D006801:Humans; D007167:Immunotherapy; D055118:Medication Adherence; D012107:Research Design; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000628:therapy
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers