Current and emerging therapies for pulmonary tuberculosis in adults

Tuberculosis remains the biggest global killer from infectious causes, with an estimated 1.25 million deaths per year. The quadruple drug regimen of rifampicin, isoniazid, pyrazinamide, and ethambutol has been standard therapy for 40 years, with good outcomes in patients with drug susceptible tuberculosis who are able to tolerate the drug regimen. However, the frequency of adverse drug reactions and emergence of drug resistant tuberculosis has created demand for new treatment strategies: there is now a surge in novel tuberculosis agents and regimens entering human trials. For decades, drug resistant tuberculosis required at least 18 months of second line and third line combination treatments that included injectable agents. In 2022, in response to a growing body of trial evidence, the World Health Organization (WHO) introduced six month and nine month all oral regimens for pulmonary drug resistant tuberculosis in specific settings. These encompass agents in the bedaquiline-pretomanid-linezolid/moxifloxacin regimen, as well as repurposed and novel agents such as clofazimine and delamanid. In addition, a large number of novel antimicrobial and host directed treatments are progressing to late stage clinical trials for tuberculosis, raising the prospect of shorter, more efficacious, and better tolerated treatments. This review summarises the agents and regimens recommended in the latest consolidated WHO treatment guidelines for tuberculosis (2025), including a synopsis of the evidence base for their safety, efficacy, and cost effectiveness. It also outlines the antimicrobial and host directed treatments that have entered phase 2-4 clinical trials for pulmonary tuberculosis in adults.