Repurposing of carbapenems for the treatment of drug-resistant tuberculosis

The World Health Organization (WHO) estimated that there were 1.6 million deaths worldwide in 2017 from tuberculosis (TB). Today, TB kills more humans than any other infectious agent, even surpassing HIV/AIDS or malaria (WHO TB report 2018). Prolonged treatment with poorly tolerated drugs to treat drugresistant tuberculosis (DR-TB) has further exacerbated this global health crisis. Overall success rate of treating multidrug-resistant (MDR) and extensively drugresistant (XDR) TB is only 54%, which means for a significant number of patients, especially those with XDR-TB, prognosis is death. Factors that make existing treatment options of MDR/XDR-TB inadequate are (1) high incidence of undesirable side effects from the only drugs that are available today to treat these infections, (2) the protracted treatment duration (more than 18 months) and (3) the high cost of the treatment. The WHO has approved several new and repurposing of existing antibiotics for treatment of DR-TB aimed at improving outcomes of MDR/XDR-TB treatment. These recommendations have focused on optimizing all aspects of TB treatment including shortening treatment duration, optimizing dosages and developing new combination regimens. Although new anti-TB drugs, like bedaquiline, delamanid and pretomanid, have been successfully developed, their slow implementation, suboptimal availability and unanticipated cardiac toxicities mean availability of additional antibiotics would provide choices and improve our ability to treat DR-TB. Repurposing of already available antibiotics that are safe and readily accessible can be a practical solution for treating DR-TB, especially in resource-poor settings where majority of TB patients live. One class of antibiotics that matches this profile are the powerful carbapenems of the β-lactam group. There is a long history of their use in treating bacterial infections, they are safe and widely available, and emerging evidence shows that they can be immediately repurposed to treat DR-TB. This book chapter describes recent important developments in the repurposing of carbapenems for MDR and XDR-TB treatment.