Current and emerging therapies for pulmonary tuberculosis in adults

Introduction Tuberculosis (TB) remains the leading cause of death from infectious diseases globally, with an estimated 1.25 million deaths in 2023. 1 The World Health Organization (WHO) estimates around 10 million new cases each year, with the greatest burden in low income and middle income countries, and one quarter of these patients will go undiagnosed. The covid-19 pandemic was responsible for a global fall in diagnoses in 2020, with a rebound in cases now reported in many countries.2 The UK is still considered a low incidence country for TB (defined as <10 cases per 100 000 people) but the downward trend in case numbers has stagnated in the past decade.3 Three important trends are changing the practice of TB medicine. Firstly, the scientific understanding of Mycobacterium tuberculosis (M tuberculosis) infection and disease is improving: traditional dichotomous categories of TB into so-called active disease and latent disease is being replaced by a disease spectrum of inactive presence of controlled bacilli, to subclinical disease, to clinically detectable disease of graduated severity.4 This nuanced understanding shapes decisions regarding timing, regimen, and duration of treatment.Secondly, cases of drug resistance and intolerances are rising: since 2021 around 10% of people with TB confirmed by culture testing in the UK have exhibited resistance to at least one of the four first line antibiotics,5 with global estimations of 400 000 new multidrug resistant TB cases per year.1 WHO has revised the definition of multidrug resistant TB several times, with five categories of resistance now recognised (box 1).Box 1Five categories of drug resistant tuberculosis recognised by the World Health Organization Isoniazid resistant (HR) tuberculosisRifampicin resistant (RR) tuberculosisMultidrug resistant (MDR) tuberculosis: resistant to both isoniazid and rifampicinPre-extensively drug-resistant (pre-XDR) tuberculosis: resistant to rifampicin and a fluoroquinoloneExtensively drug-resistant (XDR) tuberculosis: resistant to rifampicin, plus any fluoroquinolone, plus at least one further priority group A drug (bedaquiline or linezolid)16 Thirdly, advances in therapeutics research have led to many new treatments reaching late stage clinical trials, comprising novel agents and repurposed drugs, as well as variable combinations, doses, and chemical modifications of established agents. In addition, host directed treatments that target and enhance immune clearance raise the prospect of adjunct treatments used to shorten existing drug regimens. Much of this progress can be attributed to consolidation of resources by national and international bodies (eg, WHO, the TB Alliance, and the StopTB Partnership) and many other humanitarian, academic, and political partners. Although this work focuses on current and emerging pharmacological strategies, endeavours by these organisations to improve TB management encompass many aspects of patient health and population health beyond drugs.Sources and selection criteria TB is an ancient affliction with a worldwide spread and a correspondingly vast literature base: a search for “tuberculosis” on PubMed returns more than 1000 articles published per year since 1946, with around 10 000 published per year in the last five years alone. We sought to condense the latest evidence for clinicians on current and emerging treatment strategies for pulmonary TB in adults. Between January and July 2025, we identified articles using PubMed and by manually searching international and national guidelines. For PubMed, we searched using terms “tuberculosis” and “clinical trial” with the terms “antimicrobial” or “host-directed.” We prioritised more recent articles (published within the past 10 years) focused on pharmacological treatment strategies, including clinical trials (phases 2-4), systematic reviews, and meta-narratives. We excluded case reports, small case series, and articles not published in English. For host directed treatments, we included interventions for active tuberculosis only and excluded data on preventative therapies such as vaccines. For data on trials and emerging treatment strategies, we searched ClinicalTrials.gov using the term “tuberculosis,” with filters for “interventional” and “adult.” Seminal trials that have influenced WHO guidelines have been summarised in detail in a supplementary table ( online supplemental Table S1). We limited our scope to non-pregnant adults with pulmonary TB, and discussion on the evidence gap for current and emerging TB treatments for other populations (eg, children, women who are breast feeding, and pregnant women) and extrapulmonary disease is discussed later in the article.SP110.1136/bmjmed-2025-001836.supp1Supplementary data Current treatments for drug sensitive TB Standard treatment for drug sensitive TB Globally, over 96% of new pulmonary TB cases are drug sensitive, meaning they are susceptible to the four drugs widely used as standard combination treatment since the 1980s 6 7: rifampicin, isoniazid, pyrazinamide, and ethambutol. These drugs are currently available as a single tablet and in liquid form (except for ethambutol), as well as fixed dose combinations. Parenteral forms are available for rifampicin and isoniazid. Treatment outcomes are favourable for patients who complete the recommended six month course (two months of rifampicin, isoniazid, pyrazinamide, and ethambutol and four months of isoniazid and rifampicin, or 2HRZE/4HR), with cure rates now consistently above 85% globally.1 This has been partly helped by the wider use of fixed dose combinations which reduces the number of pills required for treatment, prescribing errors, and drug supply inefficacies. Nevertheless, grade 3-4 adverse drug reactions are common, affecting up to 10% of participants in clinical trials, highlighting the need for safer and shorter regimens.8 Important clinical considerations for agents used in the 2HRZE/4HR regimen are summarised in table 1.Table 1Core characteristics of drugs in the World Health Organization (WHO) recommended guidelines for standard treatment of drug senstitive tuberculosisDrugMechanism of actionMechanism of resistanceCommon or important side effectsDrug interactionsRifampicinInhibits DNA transcription by binding to the bacterial RNA polymerase β-subunit, encoded by the rpoB gene in Mycobacterium tuberculosis 76 Mutations arise in the rpoB gene that modify the binding site and induce resistance, typically following rifampicin exposure.Occurs in 3.2% of new TB cases (95% CI 2.5% to 3.8%) and 16% of previously treated cases (9.0% to 24.0%)1. Gastrointestinal upsetOrange discolouration of bodily fluidsHepatotoxicity (less than 5% and typically manifests with liver enzyme transaminitis)77 Potent inducer of cytochrome P450 enzymes (especially CYP3A4)It can reduce plasma concentrations of oral contraceptives, corticosteroids, anticoagulants, anticonvulsants and antiretrovirals (especially protease inhibitors and NNRTIs)IsoniazidA prodrug, converted by the mycobacterial enzyme KatG into the active form which then inhibits the synthesis of mycolic acids required for cell wall stability78 Mutations in the inhA promoter, katG, kasA and/or ndh genes,Occurs in estimated 6-8% new cases and 9-13% previously treated TB cases78 Hepatotoxicity (up to 2% cases in monotherapy, with increased risk associated with age >35 years, alcohol use, and pre-existing liver disease)79 Peripheral neuropathy (less than 1%) because of vitamin B6 antagonism by drug metabolites, for which supplementary vitamin B6 is usually co-prescribed Inhibits cytochrome P450 enzymes (particularly CYP2C19 and CYP3A4) which can increase plasma levels of some anticonvulsants and anticoagulantsPyrazinamideA prodrug that is intracellularly converted to the active form and binds to aspartate decarboxylase to inhibit biosynthesis of bacterial coenzyme A, inhibiting several downstream processes involved in energy production and ribosomal regulation80 Mutations in the pncA gene that encodes the enzyme that converts the prodrug to the active form81.Occurs in estimated one in six incident TB cases and more than half of all multidrug resistant TB cases globally82 Drug induced liver injury in up to 10% of casesHyperuricaemia and gout Increased risk of drug induced liver injury if taken with alcohol, statins, methotrexate, tetracyclines, azole, or echinocandin antifungalsEthambutolBinds to the enzyme arabinosyl transferase (encoded by embB) and blocks arabinogalactan polymerisation, which is essential for the mycolic acid cell wall stability83 Mutations in the embCAB locus encompassing three contiguous genes embC, embA, and embB 84 Occurs in 1% and 14% of cases with regional variation85–87 Ocular neuritis (in 1-6% of patients presenting with reduced visual acuity and/or red-green colour blindness)Peripheral neuropathy Increased risk of optic neuropathy when taken with isoniazidCI, confidence interval.Shorter treatment regimens for drug sensitive TB Attempts to find a four month regimen to match the efficacy and safety of the rifampicin, isoniazid, pyrazinamide, and ethambutol regimen for drug sensitive TB for adults have proven challenging. 6 Of four phase 3 trials reported to date, only one (TBTC Study 31) has demonstrated non-inferiority in TB disease-free survival at 12 months for a four month course of rifapentine, isoniazid, and moxifloxacin, with two months of pyrazinamide, against 2HRZE/4HR (84.5% v 85.4%)9, which found a modest increase in grade 3–4 adverse drug reactions in the four month treatment group compared with standard treatment (risk ratio 1.01, 95% confidence interval (CI) 1 to 1.02). A 2019 Cochrane review found that treatment success and adverse drug reactions were similar for four month and six month regimens for drug sensitive TB, but that the four month regimens carried higher risk of relapse.10 Nevertheless, WHO has incorporated the regimen as a conditional recommendation for certain patient groups dependent on resources, equity, and feasibility.6 High dose rifampicin in drug sensitive TB The standard dose of rifampicin in drug sensitive TB is 10 mg/kg, chosen in the 1960s owing to cost and hepatotoxicity concerns. 11 Preclinical studies confirm that rifampicin exerts a dose responsive, concentration dependent antimycobacterial effect.12 To date, at least eight trials have tested rifampicin dosages between 20-35 mg/kg in drug sensitive pulmonary TB,13 with other studies testing higher doses (40 mg/kg) in meningeal TB.14 A systematic review of 19 studies found higher rifampicin doses were not superior to standard dosing in rates of treatment success.13 However, all cause mortality and serious adverse events (eg, drug induced liver injury) were observed at dosages >20 mg/kg, although the evidence was uncertain and no correlation between dose and response was seen.Current treatments for drug resistant TB WHO released its first guidelines on the management of drug resistant TB in 1996, with several subsequent revisions: in 2005, the category of extensively drug resistant TB was introduced, initially referring to TB resistant to isoniazid, rifampicin, and at least three of the six main classes of second line drugs (aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine and p-aminosalicylic acid). In 2006, the definition of extensively drug resistant TB was revised to TB resistant to rifampicin, isoniazid, fluoroquinolones, and at least one of three second line injectable drugs (capreomycin, kanamycin, and amikacin).15 Since 2021, WHO has recognised five categories of drug resistant TB6 (box 1).Until 2018, WHO recommendations for drug resistant TB comprised 18 months of five or more drugs, including an injectable agent, which required protracted hospital admission with attendant toxicity risks. The management of drug resistant TB has since been revolutionised by the introduction of all oral TB drug regimens.1 These regimens are shorter (6-9 months), have greater efficacy and tolerability, and require shorter hospital admissions, leading to improved adherence and treatment outcomes for patients.16 Nevertheless, the limited evidence base and selective criteria for these shorter regimens mean the longer courses remain commonly used.WHO now recommends three strategies for treating pulmonary drug resistant TB using regimens selected from more than fifteen individual agents (table 2).6 The first strategy comprises six month all oral regimens for multidrug resistant/rifampicin resistant TB or pre-extensively drug resistant TB. The second comprises nine month all oral regimens for multidrug resistant/rifampicin resistant TB in the absence of fluoroquinolone resistance. The third comprises regimens of 18-20 months that may include an injectable agent. The key factors that define regimen choice include patient age, coexisting long term conditions, drug resistance profile (and that of close contacts), earlier exposure to TB medicines, the extent of pulmonary TB, and the presence of extrapulmonary TB.Table 2Core characteristics of additional drugs in the guidelines recommended by the World Health Organization for drug resistant tuberculosisAgentProposed mechanism of actionCommon and/or important side effectsMonitoring required Agents in the short (6-9 month) all oral regimens BedaquilineDisrupts cellular energy production by inhibiting the mycobacterial ATP synthase88 QTc prolongationLFT derangementHeadachesECGLFTs, U&E, Calcium, magnesiumPretomanidInhibits the biosynthesis of mycolic acid in the bacterial cell wall89 Peripheral and optic neuropathyQTc prolongationMyelosuppressionTransaminitisECGFBC, LFTs, U&E, Calcium, magnesiumVisual acuity & colour discriminationLinezolidInhibits bacterial protein synthesis by binding to the 70S initiation complex of the ribosome90 MyelosuppressionPeripheral neuropathyOptic neuropathyFBCVisual acuityColour discrimination Fluoroquinolones Moxifloxacin Levofloxacin Inhibits bacterial DNA replication by binding DNA gyrase33 QTc prolongationNeuromuscular effectsAneurysmal ruptureECGFBC, U&E, LFTsBlood glucoseClofaziminePromotes bacterial killing through reactive oxygen species release91 QTc prolongationBrownish skin discolouration; dry skin; itchGastrointestinal upsetECGDelamanidInhibits the biosynthesis of mycolic acid in the bacterial cell wall92 Limited dataQTc prolongationCytopeniasECG (monthly)Serum albumin, U&E, calcium and magnesium Agents also used in the longer individualised regimens CycloserineTerizidoneInhibits formation of cell wall by binds to alanine racemase and D-alanine ligase93 Neuropsychiatric effectsSudden congestive cardiac failureTDM (trough and peaks) Beta lactams Co-amoxiclav Meropenem Imipenem-cilastatin Inhibits PBPs involved in the synthesis of the peptidoglycan cell wall41 Penicillin hypersensitivityGastrointestinal upsetAntibiotic-associated colitisNo specific monitoring Aminoglycosides Amikacin Streptomycin Inhibits bacterial protein synthesis by binding to 30S subunit of the ribosome94 NephrotoxicityOtotoxicityElectrolyte disturbanceTDM (trough and peaks)Renal functionEthionamideProthionamideInhibits fatty acid elongation in mycolic acid production by binding the enzyme InhA95 Gastrointestinal upset and anorexiaTransient LFT derangementNeuropsychiatric effectsTFTs every three months (monthly if taken with p-aminosalicylic acid)Blood glucose p-aminosalicylic acidInhibits M tuberculosis folate production by binding dihydropteroate synthase96 Hypersensitivity reaction (rash and fever)Haemolysis in G6PD deficiencyCytopeniasTFTs every three months (monthly if taken with prothionamide)LFTs, liver function testsECG, electrocardiogram; FBC, full blood count; PAS, p-aminosalicylic acid; PBPs, penicillin-binding proteins; TDM, therapeutic drug monitoring; TFTs, thyroid function tests; U&E, urea and electrolytes.The six month regimens: BPaL, BPaLM, and BDLLfxC The six month all oral treatment regimen was introduced to WHO guidelines in 2022. Box 2 shows a summary timeline for individual agent approval. The first line regimen comprises bedaquiline-pretomanid-linezolid (BPaL) for pre-extensively resistant TB, plus moxifloxacin (BPaLM) in multidrug resistant/rifampicin resistant TB.17 Clofazimine can be exchanged for moxifloxacin (BPaLC), which may be useful for multidrug resistant/rifampicin resistant TB complicated by fluoroquinolone resistance or intolerance. BPaLC appears to be superior to the longer regimens (9-18 months), but there is currently insufficient evidence to recommend BPaLC over BPaL, and therefore BPaLC is not recommended by WHO.6 Box 2Licensing timeline for agents in six month regimens for multidrug resistant tuberculosis Bedaquiline 2012: US Food and Drug Administration (FDA) approval2013: World Health Organization (WHO) recommendation2014: European Medicines Agency (EMA) approval2015: NHS England commissionedPretomanid 2019: US FDA approval2020: EMA approval2013: WHO recommendation2024: NHS England commissionedLinezolid 2018: WHO recommendation2019: US FDA and EMA approval2024: NHS England commissionedMoxifloxacin 2022: WHO recommendation2024: NHS England commissionedNot yet approved by FDA or EMAClofazamine 2018: WHO recommendationNot yet approved by FDA or EMADelamanid 2014: WHO recommendation and EMA approval2015: NHS England commissionedThese regimens are recommended for people older than 14 years, including for people with HIV, and in extrapulmonary TB except for central nervous system, osteoarticular, or disseminated disease. Pregnant women and breastfeeding women are currently excluded (because of lack of safety data for pretomanid), as are patients who have been exposed to more than one month's treatment comprising any of the agents, unless mycobacterial isolates are confirmed to be susceptible to the drugs in the regimen.An alternative six month regimen, which can be used in multidrug resistant/RR TB and pre-extensively drug resistant TB in patients of all ages (including children and pregnant/breastfeeding women), comprises bedaquiline-delamanid-linezolid-levofloxacin-clofazimine (BDLLfxC). Data from the BEAT Tuberculosis trial indicated this regimen had similar rates of cure, treatment completion, and grade 3-4 adverse drug reactions to regimens of more than nine months in treating cases of rifampicin resistant TB.18 However, the trial report has yet to be peer reviewed (as of January 2026) and the regimen's broad use may be limited by the high cost of delamanid. Delamanid has otherwise performed well in observational studies, with pooled treatment success rate for regimens containing delamanid around 81%.19 Efficacy, safety, and cost effectiveness of BPaL based regimens To date, at least 10 trials have demonstrated efficacy and safety of agents in the BPaLM regimens ( online supplemental table S1). The Nix-TB trial (2015-2020) was a single group study (n=109) that found BPaL had favourable outcomes of 90% (95% CI 83-95%) in patients with multidrug resistant and extensively drug resistant TB, defined as sustained sputum culture conversion or avoidance of treatment failure, retreatment or TB related death.20 However, full dose linezolid (1200 mg daily) was associated with haematological and neurological adverse drug reactions in 85% of participants, prompting dose reductions in subsequent studies. The ZeNix study (2017-22) was a phase 3 trial21 (n=181) that randomised patients with multidrug resistant, pre-extensively drug resistant, or extensively drug resistant TB to receive BPAL with variable linezolid doses.21 BPaL again demonstrated high rates of favourable outcomes in patients with multidrug resistant TB, pre-extensively drug resistant TB, or extensively drug resistant TB (84–93% patients reported favourable outcomes), defined similarly as for Nix-TB, with reduced dose linezolid (600 mg daily) resulting in fewer adverse drug reactions. The TB-PRACTEAL study (2017-22) was a phase 2/3 non-inferiority trial (n=552) that22 compared 24 week courses of BPaL, BPaLM, or BPALC versus standard of care (9-20 month regimens) in patients with rifampicin resistant TB.22 All three BPaL based regimens had higher culture conversion rates after 12 weeks (81%, 88, and 87%, respectively v 79% of control) and at 72 weeks with absence of treatment failure or death (86%, 88%, and 77%, respectively v 59% of control) and fewer adverse drug reactions of grade 3 or higher (25%, 23%, 32%, respectively v 50% of control). However, these differences were less pronounced in the per protocol analysis (which included patients who discontinued therapy early), suggesting that standard care was as efficacious when tolerated.Subsequently, retrospective studies have reported favourable outcomes for BPaL from both high income and low income settings.23–25 Meta-analyses confirm the regimen is well tolerated at lower doses of linezolid (600 mg daily) and carries a low frequency of relapse (2%, 95% CI 1% to 3%). Resistance acquired during treatment is uncommon.26–28 In more than 1000 patients, bedaquiline and pretomanid resistance developed in only three patients, of whom two had poor adherence to treatment, and there were no cases of acquired linezolid resistance.26 Despite this, bedaquiline and linezolid resistance are increasingly recognised among patients with pre-extensively drug resistant TB or extensively drug resistant TB. In a recent European retrospective cohort study, 188 patients with extensively drug resistant TB showed high rates of resistance to bedaquiline (48%), linezolid (32%), or both (18%).29 Only 40% of treated patients with extensively drug resistant TB attained treatment success, defined by achieving clinical cure and/or completion of treatment without evidence of failure. Death and treatment failure correlated with resistance to one or both agents, as did treatment in an upper-middle income country compared with a high income country. Access to reliable drug susceptibility testing for bedaquiline and linezolid is commonly cited a primary obstacle to their effective use, which is particularly important for poorer socioeconomic regions where extensively drug resistant TB is most prevalent.Economic evaluations suggest a favourable cost effectiveness for BPaL.30–32 For multidrug resistant/rifampicin resistant, pre-extensively drug resistant, and extensively drug resistant TB, the cost per patient for BPaL was consistently lower than standard of care in several high incidence, low income countries. The case for BPaL use is stronger in high burden settings of pre-extensively drug resistant and extensively drug resistant TB, where there is greater justification and experience of validated drug susceptibility testing for BPaL agents. For this reason, BPaL cost savings are less pronounced in some low burden, high income settings due to delays in receiving susceptibility results which leads to prolonged hospital admission and isolation.24 Moxifloxacin was recommended by WHO in 2022 following the REMoxTB and RIFAQUIN trials where it was shown to have comparable efficacy (bacteriological cure with no relapse within one year of therapy completion) and safety (rate of grade 3-4 adverse drug reactions) when substituted for isoniazid and/or ethambutol for drug sensitive TB for the first four months.33 It also demonstrated higher rate of early culture conversion in combination with bedaquiline, pretomanid, and pyrazinamide against rifampicin resistant TB in the NC-005 trial.34 The nine month all oral regimens The nine month regimens are recommended for patients with multidrug resistant/rifampicin resistant TB in whom resistance to fluoroquinolones has been excluded and without extensive or severe extrapulmonary involvement. 17 In contrast to the six month course, children, pregnant women, and breastfeeding women can be treated with the nine month regimen. The main nine month regimen consists of bedaquiline (first six months only) with four months of levofloxacin/moxifloxacin-clofazimine-ethambutol-pyrazinamide-isoniazid-ethionamide, followed by five months of levofloxacin/moxifloxacin-clofazimine-ethambutol-pyrazinamide. Some modifications are permitted, including a two month extension in the absence of culture conversion at month four, and the replacement of four months of ethionamide with two months of linezolid. The characteristics of these individual agents (mechanism of action, adverse drug reactions, and recommended monitoring) are summarised in tables 1 and 2.Modified versions of this nine month all oral regimen are also recognised by WHO, which are still recommended in preference to longer (>18 month long) regimens.6 These regimens were investigated in the endTB trial35 and are based on a backbone of bedaquiline-linezolid-pyrazinamide, with additional agents including a fluoroquinolone (levofloxacin/moxifloxacin), clofazimine and/or delamanid. In order of WHO preference: bedaquiline-linezolid-moxifloxacin-pyrazinamide (BLMZ), bedaquiline-linezolid-levofloxacin-clofazimine-pyrazinamide (BLLfxCZ), and bedaquiline-delamanid-linezolid-levofloxacin-pyrazinamide (BDLLfxZ). In the event of fluoroquinolone resistance, WHO also recognise a regimen of bedaquiline-delamanid-linezolid-clofazimine (BDLC).WHO recommends against modified nine month regimens that substitute bedaquiline for delamanid, as trial data reported variable levels of treatment success, deaths, and drug resistance.6 Efficacy, safety, and cost effectiveness of nine month regimens A large phase 3 trial (ChiCTR2000029012, n=264) randomised patients with pulmonary multidrug resistant/rifampicin resistant TB to receive either a nine month oral regimen bedaquiline-linezolid-levofloxacin-clofazimine-cycloserine or 18 month standard of care regimens. 36 Rates of treatment success were higher in the nine month group (83.5%) than the 18 month group (77.6%), with similar numbers of patients reporting grade 3-4 adverse events (34% and 42%, respectively). However, the endTB-Q trial studied the BDLC regimen in six month or nine month courses (dependent on extent of disease and persistent of culture positivity), compared with longer regimens recommended by WHO in adults with pre-extensively drug resistant TB.37 Patients with limited disease who received BDLC for six months had similar outcomes to longer regimens, but a nine month course of BDLC was not non-inferior to standard care for extensive disease (87% v 89% achieved bacteriological, radiological, and clinical resolution of disease). Rates of grade 3-4 adverse events were similar (68% v 73%). These findings support a personalised approach in regimen selection for pre-extensively drug resistant TB, favouring longer courses for patients with greater disease severity or delayed culture conversion.Retrospective studies show that nine month regimens containing bedaquiline had favourable outcomes compared with longer regimens containing oral and injectable agents. In one large study, the nine month oral regimen performed better than regimens containing injectable agents in rates of treatment success (by 14%, 95% CI 8% to 20%) and disease-free survival (by 2%, 0% to 5%) at 24 month follow-up.38 The cost effectiveness of bedaquiline outside of BPaL regimens is dependent on setting. Although bedaquiline is expensive (estimated to cost £18 700 (€21 648; $24 836) for six months), in the UK these costs are almost entirely offset by reductions in costs associated with inpatient stays through avoiding injectable agents.39 However, the case for cost effectiveness is not as strong in resource poor settings. For low income and middle income countries, a six month oral regimen containing bedaquiline was only as cost effective as a standard nine month regimen if it also included an eight week induction phase with an injectable agent.40 Longer individualised regimens WHO continue to recommend longer individualised regimens for patients with multidrug resistant/rifampicin resistant TB who are not eligible for, or had no favourable treatment outcome using, the shorter all oral regimens, as well as for patients with pre-extensively drug resistant or extensively drug resistant TB and intolerance to key components of the shorter all oral regimens. These individualised regimens require at least four drugs chosen from a hierarchical grouping of second line TB medicines ( table 3), based on clinician consideration of the drug resistance profile and the patient's medical history.Table 3Drug combinations in longer regimens recommended by the World Health Organization for drug resistant tuberculosisPriority drug groupsTuberculosis drugAbbreviationGroup A: include all three drugsLevofloxacin or moxifloxacinLfx or MBedaquilineBLinezolidLGroup B: add one or both drugsClofazimineCCycloserine or terizidoneCS or TrdGroup C: add to complete the regimen and when drugs from groups A and B cannot be used either because of drug resistance, toxicity, or tolerabilityEthambutolEDelamanidDPyrazinamideZImipenem-cilastatin or meropenemwith amoxicillin/clavulanateIpm-Cln or MpmAMCAmikacin (or streptomycin)Am (S)Ethionamide or prothionamideEto or Pto p-aminosalicylic acidPASTB, tuberculosis.The evidence base for these regimens is oflow quality at best, relying primarily on meta-analysis of individual patient data captured in observational studies following an open call by WHO in 2018. The total treatment duration for these regimens are typically 18-20 months, with a recommended duration of 15-17 months after sputum culture conversation and/or consideration of other factors to determine patient response to treatment.6 Emerging pathogen directed strategies in tuberculosis WHO launched their TB Trials Tracker in June 2023 to support research and development into TB treatments. This digital platform monitors global progress on novel drug candidates and combinations, and alternative routes for existing agents (such as inhaled clofazimine, NCT06418711). These are primarily pathogen directed approaches, which typically act by targeting one of three sites: the mycobacterial cell wall, cellular energy production, or transcription and translation (figure 1). The characteristics and latest findings for pathogen directed treatments that have been investigated in phase 2/3 trials for pulmonary TB are summarised in figure 1 and table 4.Figure 1Mechanism of action behind current and emerging (phase 2-4 trials) pathogen directed treatments for tuberculosisTable 4Summary of pathogen directed treatment candidates for adults with pulmonary tuberculosis (TB) in phase 2/3 trials with known status and/or outcomeAgentMechanism of actionReference/Study IDDesignStatusBeta lactamsInhibiting penicillin-binding proteins (PBPs) involved in the synthesis of peptidoglycan, a vital component of the Mycobacterium tuberculosis cell wall41 NCT03174184 (Amoxicillin/clavulanic acid with meropenem)Phase 2Completed; results published NCT04629378 (Amoxicillin/clavulanic acid with meropenem)Phase 2Completed; results awaitedNCT05896930 (Amoxicillin/clavulanic acid and meropenem or ertapenem)Phase 2Completed; results awaitedNCT02381470 (Amoxicillin/clavulanic acid and faropenem or cefadroxil)Phase 2Completed; results awaitedNCT02349841 (Amoxicillin/clavulanic acid and faropenem or meropenem)Phase 2Completed; results awaitedNCT05388448 (Sanfetrinem cilexetil)Phase 2Completed; results awaitedOxazolidinonesDelpazolidSutezolid Inhibits protein synthesis by binding to the 50S ribosomal subunit90 NCT02836483 (Delpazolid)Phase 2Completed; results publishedNCT04550832 (Delpazolid)Phase 2Completed; results publishedNCT03959566 (Sutezolid)Phase 2Completed; results publishedNCT05686356 (Sutezolid)Phase 2/3RecruitingNCT06192160 (Sutezolid)Phase 2RecruitingGanfeborole (GSK-3036656)Orally active leucyl-tRNA synthetase (LeuRS) inhibitor that disrupts protein synthesis in Mycobacterium tuberculosis49 NCT03557281 (GSK306656)Phase 2Completed; results publishedNCT06114628 (BTZ-043 and GSK306656)Phase 2RecruitingNovel diarylquinolinesInhibits mycobacterial ATP synthase (F-ATPase), disrupting proton flow across the bacterial membrane97 NCT06058299 (TBAJ-876)Phase 2Active, not recruitingDecaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1) inhibitorsBTZ-043Quabodepistat (OPC-167832)TBA-7371Pyrifazimine (TBI-166) Targets DprE1, an enzyme involved in the biosynthesis of mycobacterial cell wall components)48 NCT04044001 (BTZ-043)Phase 1/2Completed; results publishedNCT06114628 (BTZ-043 and GSK306656)Phase 2RecruitingNCT03678688 (Quabodepistat)Phase 2Completed; results publishedNCT05221502 (Quabodepistat)Phase 2Completed; results awaitedNCT04176250 (TBA-7371)Phase 2Completed; results awaitedNCT04670120 (Pyrifazimine)Phase 2Active, not recruitingBVL-GSK098 (Alpibectir)Inhibits bacterial repressors that regulate bioactivation of ethionamide98 NCT05473195 (Alpibectir plus ethionamide)Phase 2Completed; results awaitedTelacebec (Q203)Inhibits the mycobacterial Cytochrome BC1 Complex, impairing energy production50 NCT01218217Phase 2Completed; results publishedNCT03563599Phase 2Completed; results publishedSQ109 Inhibits MmpL3, a membrane transporter that exports precursor molecules in mycobacterial cell wall synthesisDisrupts the proton motive force and impairs energy metabolism51 52 NCT01785186Phase 2Completed; results publishedSudapyridine (WX-081)Inhibits mycobacterial ATP synthase, and disrupts bacterial energy production53 NCT04608955Phase 2Completed; results awaitedBeta lactams The COMRAD phase 2 trial compared several doses of meropenem in combination with co-amoxiclav and rifampicin in patients with pulmonary TB ( NCT03174184).41 Highest doses of meropenem did improve bacterial clearance, but all doses were poorly tolerated due to gastrointestinal/biliary adverse drug reactions. A further five phase 2 trials investigating carbapenems with or without co-amoxiclav have now completed with results awaited (table 4). The need for intravenous administration remains a limitation for carbapenem therapy.Oxazolidinones Delpazolid, a novel oxazolidinone, has been substituted for linezolid in combination therapy in phase 2 trials for pulmonary TB where it performed well and appears to be better tolerated than linezolid ( NCT02836483; NCT04550832).42 43 Similarly, sutezolid was found to efficacious and well tolerated in combination with bedaquiline-delamanid-moxifloxacin in adults with pulmonary drug sensitive TB (NCT03959566).44 Sutezolid remains under investigation in two active phase 2/3 trials (NCT05686356; NCT06192160). Contezolid is another novel oxazolidinone that has demonstrated early bactericidal activity against M tuberculosis in several small clinical cohort studies in China.45 46 There is early preclinical and clinical evidence that cortezolid causes less myelosuppression than linezolid, though it has yet to enter phase 2/3 trials.47 Decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1) inhibitors The phase 1/2 PanACEA-BTZ-043-02 trial examined BTZ-043, the novel DprE1 inhibitor in combination with standard therapy for pulmonary drug sensitive TB, finding it to have favourable safety profile and early bactericidal activity in sputum ( NCT04044001).48 The subsequent multi-arm phase 2 PARADIGM4TB trial (n=2500), which is currently recruiting, will compare BTZ-043 in various combinations of regimens that contain bedaquiline with standard therapy for drug sensitive TB (NCT06114628). This trial will assess the effect on sputum culture conversion at 12 weeks and favourable outcome (culture negative without treatment failure or relapse) at 48 weeks. Quabodepistat (formerly known as OPC-167832) is another DprE1 inhibitor that has demonstrated safety and early bactericidal efficacy in combination with bedaquiline or delamanid, compared with standard therapy, for drug sensitive TB in a phase 2/3 trial (NCT03678688). Quabodepistat has now entered a phase 2 trial (n=112) testing similar combination regimens for a four month duration with results awaited (NCT05221502). Other DpRE1 inhibitors, such as TBA-7371 (NCT04176250) and TBI-166 (NCT04670120), are being tested in phase 2 trials, with results anticipated.Other emerging pathogen directed candidates Ganfeborole (GSK3036656) is a new benzoxaborole that was studied in a phase 2 trial (n=76) comparing graduated doses of ganfeborole against HRZE for the first 14 days of therapy, measuring effect on bacterial counts in sputum and PET (positron emission tomography)/CT (computed tomography) lung changes ( NCT03557281).49 The drug was well tolerated and demonstrated early bactericidal activity, particularly at higher dosages, and is now included in various combination therapies in the ongoing PARADIGM4TB trial (NCT06114628).TBAJ-876 is a diarylquinoline derivative currently under investigation in a phase 2 trial (n=309), in which it is substituting for bedaquiline in a BPaL regimen in comparison with standard BPaL or HRZE for pulmonary drug sensitive TB (NCT06058299). This trial will assess the effect of TBAJ-876 on sputum culture conversion at eight weeks and favourable outcome after 26 weeks.BVL-GSK098 (alpibectir) enhances the activity of ethionamide by inhibiting repressors of molecules that activate ethionamide in vivo, which lowers the oral dose of ethionamide required to achieve therapeutic effect, improving efficacy while reducing side effects. The safety and effect on sputum bacterial burden of the drug in the first seven days, in combination with ethionamide or isoniazid, is being studied in a phase 2 trial that has recently completed with results awaited (NCT05473195).Telacebec (Q203) is another novel first-in-class drug which has come through a phase 2 clinical trial (NCT 03563599). In this study, 60 participants were randomised to receive various doses of telacebec or HRZE for the first 14 days of therapy. Telacebec was well tolerated, safe, and, at higher doses, resulted in lower sputum bacterial burden than standard therapy at day 14.50 SQ109 is a small molecule that has been studied in two phase 2 trials, in combination with rifampicin at standard and high doses. Although safe and well-tolerated in both trials, SQ109 did not reduce bacterial burden in sputum at 14 days, nor improve culture conversion rates by 12 weeks.51 52 Sudapyridine (WX-081) is a chemically modified compound based on the structure of bedaquiline, developed in search of a quinoline drug with a better cardiovascular side effect profile.53 It is currently being tested in a phase 2 trial (n=99) in comparison to bedaquiline and standard therapy for drug sensitive TB for the first 14 days (NCT04608955). This study will measure sputum bacterial burden at day 14, as well as effect on QT interval.Long acting injectable agents Long acting injectable formulations of established and new TB drugs could simplify dosing, improve adherence, and expand options for both TB treatment and preventative treatment. 54 Preclinical and modelling data suggest that rifapentine and rifabutin are suitable candidates for depot or long acting injectable formulations owing to their pharmacological and physicochemical characteristics.55 Similarly, long acting formulations of bedaquiline have demonstrated favourable pharmacokinetics and efficacy in animal studies.56 The findings indicate that sustained release formulations could help overcome one of the major challenges in TB treatment: prolonged daily or weekly dosing, which often leads to poor compliance to treatment and treatment failure/drug resistance. Currently, no long acting injectable TB drug is approved for clinical use, with some strategies at the preclinical and early translational stage. A phase 1 trial of a long acting injectable bedaquiline formulation has been initiated in healthy volunteers (EU Clinical Trial No 2023-508810-41-00).Emerging host directed treatments Host directed treatments modulate immune function to enhance immune cell clearance, suppress excessive inflammation or improve the efficacy of antimicrobial treatment ( figure 2). For TB, the anticipated benefits of host directed therapies are to shorten antimicrobial courses and enhance their efficacy, but their anti-inflammatory properties may also be useful in attenuating lung disease that develops after treatment. Many host directed treatment trials therefore incorporate endpoints to measure functional lung activity (forced expiratory volume in one second (FEV1)) and radiological evidence of sequelae (cavity size). Although some prospective host directed treatments have progressed to late phase trials, the data have not matured sufficiently for any to enter WHO recommendations. For some host directed treatments, such as mammalian target of rapamycin (mTOR) inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and mesenchymal stromal cells, theoretical safety concerns remain over modulating the innate immunity and cell mediated immunity that are required for effective control and clearance of intracellular M tuberculosis.57 58 We summarise the latest findings and characteristics of host directed treatments and/or adjunctive therapies that have been investigated in phase 2/3 trials for pulmonary TB below and in table 5.Figure 2Mechanism of action behind emerging (phase 2-4 trials) host directed treatments for tuberculosis. MMP=matrix metalloprotease; mTOR=mammalian target of rapamycin; NSAID=non-steroidal anti-inflammatory drug; ROS=reactive oxygen speciesTable 5Summary of host directed treatment candidates for adults with pulmonary tuberculosis in phase 2-4 trials with known status and/or outcome Agent Proposed mechanism of action Study ID Design Status AuranofinBinds to bacterial thioredoxin reductase and promotes accumulation of free radical oxygen species inside the bacilli59 NCT02968927Phase 2Completed; results publishedCC-11050Type four phosphodiesterase inhibitor which increases intracellular cAMP and suppresses inflammation59 NCT02968927Phase 2Completed; results publishedEverolimusmTOR inhibitor which induces autophagy and promotes intracellular bacterial clearance59 NCT02968927Phase 2Completed; results publishedDoxycyclineInhibiting matrix metalloproteinases (MMPs) enzymes that break down the extracellular matrix and potentially some direct antibacterial effects against M tuberculosis 64 NCT02774993Phase 2Completed; results publishedNCT05473520Phase 3Recruiting N-acetylcysteine (NAC)Exhibits potential anti-tuberculosis effects by acting as a glutathione precursor, reducing oxidative stress, and potentially having direct antimicrobial activity against M tuberculosis 65 66 NCT03702738Phase 2Completed; results publishedNCT03281226Phase 2Completed; results publishedNCT05686356Phase 3Active, not recruitingNCT06909799Phase 3RecruitingNSAIDSInhibits cyclooxygenase (COX), an enzyme involved in prostaglandin production, thereby reducing inflammation and potentially enhancing the efficacy of other TB drugs67 NCT02781909(ibuprofen)Phase 2Completed; results published NCT04575519 (ibuprofen and aspirin)Phase 2RecruitingRecombinant interleukin 2Promotes proliferation, differentiation and activity of lymphocytes against M tuberculosis 70 NCT03069534Phase 2Completed; results publishedNCT04766307Phase 4RecruitingStatinsPromotes phagosome maturation and autophagy, modulates immune responses, enhances the activity of first line TB drugs, and reduces the M tuberculosis burden in macrophages68 69 NCT04504851(rosuvastatin)Phase 2Completed; results published NCT03456102 (pravastatin)Phase 2Completed; results awaited NCT04147286 (atorvastatin)Phase 2/3Recruiting NCT04721795 (atorvastatin)Phase 2Completed; results publishedVitamins A and DPromotes immune cell function and production of host protective antimicrobial peptides60 61 62 NCT00057434(vitamin A)Phase 3Completed; results published NCT00419068 (vitamin D3)Phase 3 Completed; results published NCT02968927 (vitamin D2)Phase 2Completed; results published NCT00311298 (micronutrients)Phase 3Completed; results published NCT01130311 (vitamin D3)Phase 3Completed; results published NCT00677339 (vitamin D3)Phase 3Completed; results published NCT02169570 (vitamin D3)Phase 4 Completed; results awaited NCT02464683 (vitamin D3)Phase 4 Completed; results awaited NCT00366470 (vitamin D3)Phase 3Completed; results published NCT01580007 (vitamin D3 and phenylbutyrate)Phase 2Completed; results published NCT01698476 (vitamin D3 and phenylbutyrate)Phase 2Completed; results publishedThe TB Host Directed Therapy (TBHDT) trial was an open label, phase 2 trial that randomised 200 participants with drug sensitive TB to receive standard treatment with one of four adjunctive host directed treatments59: CC-11050 (type four phosphodiesterase inhibitor), everolimus (mTOR inhibitor), auranofin (a gold salt), or ergocalciferol (vitamin D2). The primary end point was safety and tolerability at day 210, with secondary end points including sputum culture conversion and pulmonary function. CC-11050 and everolimus were found to be safe and increased recovery of FEV1, with mean improvement above control group of 6.30% (P=0.048) and 6.56% (P=0.044), respectively. By contrast, no improvement in pulmonary function was observed in patients receiving vitamin D2 or auranofin.Vitamins and micronutrients Clinical studies for vitamin and dietary supplements in TB have largely been disappointing. An early phase 3 trial (n=1140) found that vitamin A supplements did not affect mortality in patients with HIV and pulmonary TB compared with placebo ( NCT00057434).60 Later, a phase 3 trial randomised 126 participants to receive standard therapy for drug sensitive TB with or without high dose vitamin D3.61 There was no significant difference in time to sputum culture conversion, except in participants with a vitamin D receptor polymorphism (the homozygote recessive tt genotype). Since then, vitamin D has been tested in at least nine phase 2-4 trials in adults with pulmonary TB (table 5). A recent meta-analysis found that vitamin D has no effect on sputum culture conversion, except in pulmonary multidrug resistant TB.62 Antimicrobials with host directed activity Azithromycin was studied as an adjunct treatment to standard of care in a small phase 2 study (n=28) in adults with pulmonary drug sensitive TB ( NCT03160638).63 Azithromycin was well tolerated and reduced blood biomarker levels of TB disease, as well as sputum neutrophil counts and neutrophil elastase. Doxy-TB is a phase 3 randomised controlled trial investigating oral doxycycline versus placebo as an adjunct to drug sensitive TB (NCT05473520). It follows a phase 2 study in which doxycycline reduced sputum concentration of matrix metalloproteases and the size of pulmonary cavities (NCT02774993).64 This phase 3 study will assess similar measures, plus its effect on FEV1. N-acetylcysteineThe NAC-TB trial was a phase 2 trial that investigated N-acetylcysteine in assisting sputum conversion in patients with drug sensitive TB (NCT03702738).65 Although participants who received N-acetylcysteine had improved pulmonary function and higher blood levels of glutathione, there were no differences in sputum conversion. A similar finding of raised glutathione levels was observed in a contemporaneous study, that assessed N-acetylcysteine in patients with TB and HIV co-infection (NCT03281226).66 Two larger trials have followed the NAC-TB study: the phase 3 PanTB-HM study (n=352) will test the efficacy and safety of N-acetylcysteine when added to a regimen of bedaquiline, pretomanid, and sutezolid, a new oxazolidinone (NCT05686356). The other is the NAC-PTBL study (n=242) which will assess the effect of adding N-acetylcysteine to standard treatment on pulmonary function at month 12, after completion of TB therapy (NCT06909799).Non-steroidal anti-inflammatory drugs The NSAIDS-XDR-TB trial, completed in 2019 with results recently posted on medRxiv ( NCT02781909),67 was a small, phase 2 trial (n=24) that tested the non-steroidal anti-inflammatory drug ibuprofen as an adjunct to standard treatment for extensively drug resistant TB. The trial measured rates of sputum culture conversion and chest x ray image changes at six months. Despite no significant differences between groups in these primary outcomes, ibuprofen was found to be safe and resulted in reduced plasma levels of pro-inflammatory cytokines. The SMA-TB trial is currently recruiting to investigate aspirin and ibuprofen as adjuncts to standard of care in drug sensitive and multidrug resistant TB (NCT04575519). This trial will measure time to sustained sputum culture conversion and clinical improvement using the TB score, a composite measure of self reported symptoms and clinical signs.Statins The ROSETTE trial (n=154) randomised participants with drug sensitive TB to receive standard treatment with or without rosuvastatin ( NCT04504851).68 Rosuvastatin was safe but did not improve rates of sputum culture conversion. The StAT-TB study, a phase 2 trial (n=16) that completed in 2022 with peer reviewed results awaited, investigated the safety of adjunctive pravastatin with secondary outcomes examining effects on sputum culture conversion and pulmonary function tests. The phase 2/3 ATORTUB trial recently found that atorvastatin, as an adjunct to standard treatment, improved rates of sputum culture conversion and reduced chest x ray severity score.69 The StatinTB trial is currently recruiting and will randomise 220 participants in a phase 2/3 trial to receive standard treatment plus atorvastatin versus placebo (NCT04147286). The primary outcome will be level of pulmonary metabolic activity seen on PET/CT imaging.Recombinant interleukin 2 Patients with multidrug resistant TB were randomised to receive standard therapy with or without subcutaneous courses of recombinant interleukin 2 ( NCT03069534).70 Treatment was found to be safe and the rate of sputum culture conversion was higher in the treatment group (74% v 59%, P<0.05) as was sustained cure at 24 months (56% v 36%, P<0.01). This has been followed by a phase 4 study currently looking at effect of adjunctive interleukin 2 on culture conversion and infectious relapse (NCT04766307).Questions for future research The upsurge in novel TB treatment strategies has produced large amounts of clinical data, although limitations around trial design has meant these data tend to underrepresent special populations, particularly children, breastfeeding women, and pregnant women, patients with TB and HIV, and patients with extrapulmonary TB.Children The international phase 3 SHINE trial found a four month regimen of 2 months isoniazid-rifampicin-pyrazinamide+/-ethambutol, followed by 2 months isoniazid-rifampicin (2HRZ(E)/2HR) was non-inferior to standard six month regimen in children aged 3 months to 16 years with non-severe, drug sensitive TB. 71 The four month regimen has now been adapted by WHO for children with uncomplicated disease.6 An alternative four month isoniazid-rifapentine-moxifloxacin-pyrazinamide regimen is also available for children older than 12 years who weigh more than 40 kg. In cases of multidrug resistant/rifampicin resistant TB, there are conditional recommendations to use bedaquiline, delamanid, fluoroquinolones, clofazimine, and cycloserine, as well as ethionamide/prothionamide and p-aminosalicylic acid. Aminoglycosides should be avoided and there is insufficient evidence to recommend pretomanid in children younger than 14 years. This allows the use of modified six month and nine month BLMZ, BLLfxCZ, and BDLLfxZ regimens. Research priorities for TB treatments for children include identifying safe and efficacious agents, including tolerable dosages, formulations, and combinations for children younger than 14, who weigh less than 40 kg (commonly through malnutrition) and have extrapulmonary or severe TB.People who are breastfeeding or pregnant Human safety data for emerging TB treatments in breastfeeding, pregnant, and postpartum women are lacking because of the exclusion of these groups from major trials (including ZeNix, TB-PRACTECAL, and endTB trials). Although preclinical data on use of pretomanid in breastfeeding women and pregnant women suggest no harmful effects to the patient, human data are insufficient to recommend its use. This population is excluded from regimens recommended by WHO, including the four month drug sensitive TB regimen and the six month BPaL/M regimens. However, the inclusion of breastfeeding women and pregnant women in the BEAT Tuberculosis trial 18 allowed for conditional recommendations for the six month BDLLfxC and nine month BLMZ, BLLfxCZ, and BDLLfxZ regimens, which are offered in preference to the individualised longer regimens. Recent estimations suggest annual global TB incidence includes 239 500 pregnant women (95% CI 216 300 to 262 800) and 97 600 postpartum women (90 100 to 105 200),72 highlighting the need to include these patients in future trial design.People with HIV New diagnoses of TB/HIV co-infection have fallen markedly in the past 20 years, with global incidence currently around 660 000 (95% CI 590 000 to 740 000). 73 However, co-infection of HIV and TB still accounts for disproportionately higher mortality, with 24% of these patients dying compared with 11% of people with TB alone.6 73 74 Treatment decisions for people with TB/HIV co-infection revolve around CD4 count and the initiation and maintenance of effective antiretroviral treatment.6 Considerations include interactions between rifamycins and protease inhibitors, bedaquiline/delamanid/clofazimine and efavirenz, and possibly between BDLLfxC agents and integrase inhibitors, which have not been extensively studied. Adults with HIV must have a CD4 count >100 cells/mm3 to be eligible for four month regimens. Children with HIV and drug sensitive TB are eligible for four month regimen irrespective of CD4 count, but ethambutol must be included in the regimen for the first two months. Research priorities for children with HIV requiring TB treatment include dosage adjustments in anticipated drug interactions (which has been done for rifampicin and dolutegravir) and long term outcomes in patients treated with shorter regimens. In addition, host directed treatments are being pursued that may enhance immune response against HIV and TB, without causing immune suppression which could be harmful to the patient.75 Extrapulmonary disease Extrapulmonary cases represent around 15% of the global TB burden but are often clinically severe. 1 WHO continue to recommend longer treatment duration (9-12 months) of standard therapy for drug sensitive, disseminated, meningeal, or osteoarticular TB. Patients with extrapulmonary TB were not included in the ZeNix and TB-PRACTECAL trials and are therefore are ineligible for the six month oral regimens in multidrug resistant/rifampicin resistant TB cases, requiring a longer individualised course which is associated with poor outcomes.29 This represents an important research priority and trials are currently underway to test these agents against extrapulmonary TB, including meningitis and osteoarticular disease (NCT05040126, NCT07227779, NCT04021121, NCT06811012).Conclusion After decades of modest progress in TB therapeutics, novel agents and drug combinations are increasingly entering and completing clinical trials. Some of these have already demonstrated sufficient safety and efficacy to merit WHO endorsement and all oral six month and nine month regimens are anticipated to improve patient outcomes in cases of drug resistant TB. Further work is needed to expand the criteria for these novel treatment strategies for underserved patient populations, to shorten total course duration, and to identify safe adjunctive treatments.Questions for future research Are four month regimens that are safe and efficacious in adults with tuberculosis available?Can new strategies against tuberculosis be shown to be safe and efficacious in children younger than 14 years and in people who are breastfeeding or pregnant?Can the six month and nine month regimens be given to people with extrapulmonary tuberculosis safely?How could long acting injectable agents transform tuberculosis management?Can host directed treatments reduce dependence on antimicrobials and shorten tuberculosis drug courses?