Tuberculosis is a leading cause of morbidity and mortality worldwide. Current TB treatments are inadequate, requiring patients closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated. These concerns are greatly magnified in rifampicin-resistant (RIF-R) TB, an urgent global and EU public health priority. WHO estimates that only 54% of patients who began RIF-R TB treatment in 2016 were cured. In addition to these well-recognized shortcomings, current TB treatments, particularly those for RIF-R TB, leave a majority of cured patients with permanent, clinically significant lung impairment and radiographic evidence of bronchiectasis and fibrosis. This project will determine if two adjunctive host-directed therapies (HDTs) can prevent these poor outcomes. 330 patients with RIF-R TB and baseline risk factors for poor outcome will be enrolled in a randomized, controlled, 3-armed multi-centre trial, with clinical sites in Romania, Moldova, Georgia, Mozambique, and South Africa. All patients will receive standard multidrug therapy according to national guidelines. Those patients randomized to the experimental arms will in addition receive either CC-11050 or metformin. These selected HDT candidates represent 2 complementary HDT strategies: reducing inflammation vs inducing host cell anti-microbial activity, respectively. Both candidates are supported by data from preclinical and clinical studies. Co-primary efficacy endpoints will examine effects on lung function (measured by spirometry) and infection (measured as time to stable sputum culture conversion). A sub-study will examine quantitative change in lung radiodensity by CT scan. If successful, this ground-breaking project will increase Europe’s capacity to control RIF-R-TB by developing new treatments that increase the likelihood of cure and reduce the risk of life-long disability.

In the 2024 updated Bacterial Priority Pathogen list of WHO, Mycobacterium tuberculosis (TB) is a critical priority pathogen, emphasizing the urgent need for action. Rifampicin resistant-tuberculosis (Rr-TB) is estimated to cause 13% of antimicrobial resistance-attributable deaths globally and is driven by both ongoing resistance acquisition and person-to-person transmission. Bedaquiline (BDQ), a new drug, is strongly recommended for Rr-TB treatment since 2018. In this very short time, BDQ resistance has proliferated significantly. For Rr-TB at risk of/with BDQ resistance (BDQr/Rr-TB) there is no evidence-based regimen. The current practice, with continued failing regimens, imperils the potency of the remaining Rr-TB drug arsenal. Tuberculosis Antimicrobial Stewardship Program (TASP) aims to rapidly reduce bacillary load in patients at risk/with BDQr/Rr-TB by using an empirical highly bactericidal intensive phase (for those at risk) followed by drug-susceptibility testing (DST)-informed artificial intelligence (AI)-aided Treatment Recommender's regimen composition. 125 participants at risk/with BDQr/Rr-TB will be enrolled in Nigeria, Mozambique and South Africa. Baseline and acquired resistance will be monitored and a novel, fast and quantitative phenotypic method (thin layer agar), with little infrastructural requirements, will be evaluated in TASP’s high burden, limited resource settings through decentralized implementation. Additionally, TASP will improve environmental control with co-designed, portable air cleaners, built sourcing low-cost materials from the local market. Filter waste products will be used for resistance surveillance and compared to conventional bio-aerosol samplers. The anticipated impact of TASP is a cost-effective TB antimicrobial stewardship programme that reduces further resistance development and salvages the current all-oral BDQ regimens for the future.