Background: The single antibiotic drug monotherapies have been used by clinicians in medical treatments of various infectious diseases including tuberculosis (TB); however, World Health Organization accredited the rise of antimicrobial resistant bacterial pathogens, is a major global health crisis. As a result, a widely promising strategy known as antibiotic drug combination therapies have been designed to combat the evolution of drug-resistant pathogens, to enhance the current treatment efficacy by combining more than two antibiotic drugs, and for the efficient treatment of numerous infectious diseases including TB, HIV/AIDS, malaria. However, the disease-causing pathogens became resistant to multiple antibiotic drugs and can no longer be destroyed. One of the influencing factors of antibiotic drug combination treatment success failure is pathogen-host-antibiotic interaction which affect the combined drug outcomes and may influence evolution of multidrug-resistant strains. In such context, the main objective of this review paper was to assess the impacts of pathogen-host-antibiotic interaction in the evolution and spread of multi-drug resistant pathogens against drug-combination therapy. Understanding the potential mechanisms of drug-drug, host-antibiotic and host-pathogen interactions help to inform decisions as to set-up in clinical settings in order to limit the evolution and spread of multi- drug resistant bacterial strains. Most significantly, in the near future sustainable bacterial infection therapies for potential adaptive pathogens include synergy-based drug combination and host-directed therapies in drug combination could be exercised to tackle the multi-drug resistance crisis by enhancing the combined drug treatment efficacy and prevent bacteria adapting to combination treatments.