Optimizing combination therapy against drug resistance Mycobacterium tuberculosis: a modelling study

Despite the prevalence of co-infection with drug-sensitive and drug-resistant Mycobacterium tuberculosis strains within a single host, the implications of such dual infections remain poorly understood. In this study, we develop a comprehensive within-host model that incorporates both bacterial strains, their mutation dynamics, and cross-reactive immune responses. We analyze the basic reproduction number ( R0 ) and identify its dependence on key parameters, finding that R0 is strongly influenced by the adaptive immune response rate, bacterial fitness cost, and macrophage engulfment rates. Our bifurcation analysis reveals the presence of a backward bifurcation at R0=1 , indicating complex threshold dynamics. Utilizing optimal control theory, we evaluate treatment strategies and demonstrate that a combination therapy with at least 85% efficacy against both strains can effectively control the infection. These findings deepen our understanding of host-pathogen interactions in tuberculosis and provide valuable insights for the development of more effective anti-tuberculosis therapies.