Antimycobacterial Drugs

Abstract

Antimycobacterial drugs are used in the treatment of diseases caused by members of the Mycobacterium genus, including tuberculosis (TB) and leprosy, which have affected man since antiquity, and the nontuberculous mycobacterioses (NTM) that are increasingly recognised. Combination chemotherapy is essential to kill heterogeneous populations of bacterial cells located in different conditions within the host, and to prevent drug resistance. Although combination therapy has been effective in controlling leprosy, the global HIV epidemic and the emergence drug resistance are undermining efforts to control TB. Currently available chemotherapeutic agents are highly effective in managing drug‐sensitive TB, however, the development of new antimycobacterial drugs to manage both drug‐sensitive and drug‐resistant disease is a global health priority. These drugs must be safe, effective and affordable in resource‐limited countries most burdened by TB disease. NTMs are increasingly being identified as human pathogens in both non‐ and immunocompromised patients; more evidence for the most efficacious treatments is required. Key Concepts: Tuberculosis is global health priority with 9 million active cases, and 1.7 million deaths each year, of whom 0.5 million are coinfected with HIV; with 1 in 3 people latently infected globally, there is a huge pool of potential future infection. Mycobacteria are unusual; they are slow growing with a thick waxy cell wall made of lipid rich material which makes penetration by drugs problematic. At any one time, there may be heterogeneous populations of mycobacterial cells in different metabolic states; these may be targeted by different antimycobacterial drugs. Antimycobacterial drugs are used for the treatment of mycobacterial infections, including tuberculosis, leprosy and nontuberculous mycobacateria; the greatest burden of disease is borne by developing countries with limited resources. Combination treatment is required for prolonged periods, usually 6 months or more, to kill heterogeneous mycobacterial cells in different locations within the host, and to prevent resistance developing. Drug resistance develops through spontaneous mutations in the chromosomal DNA. Exposing mycobacteria to monotherapy selects out these resistant strains, as may happen when patients are nonadherent with prescribed therapy. Drug resistance is a major problem in the control of tuberculosis globally; 5% resistant to both rifampicin and isoniazid (MDRTB) the backbones of currently recommended chemotherapy, with around 10% of those also resistant to fluoroquiniolones and second line agents (XDR TB). Leprosy elimination programmes have successfully reduced the prevalence of the disease; patients are rendered noninfectious after the first dose of medication. Nontuberculous mycobacteria are emerging as important human pathogens; there is a pacuity of robust evidence for their optimal management. A large number of new agents with novel mechanisms of action are being trialled to assess their efficacy in treating mycobacterial disease.