The Treatment of Tuberculosis

Abstract

Tuberculosis (TB) remains a leading cause of infectious death worldwide, and poverty is a major driver. Clinically, TB presents as “latent” TB and active TB disease, and the treatment for each is different. TB drugs can display “early bactericidal activity (EBA)” and / or “sterilizing activity” (clearing persisters). Isoniazid is excellent at the former, and rifampin is excellent at the latter. Pyrazinamide and ethambutol complete the first‐line regimen for drug‐susceptible TB, each playing a specific role. Drug‐resistant TB is an increasing concern, being met, in part, with repurposed drugs (including moxifloxacin, levofloxacin, linezolid, clofazimine, and beta‐lactams) and new drugs (including bedaquiline, pretomanid, and delamanid). One challenge is to select drugs without overlapping adverse drug reaction profiles. QTc interval prolongation is one such concern, but to date, it has been manageable. Drug penetration into organism sanctuaries, such as the central nervous system, bone, and pulmonary TB cavities remain important challenges. The pharmacodynamics of most TB drugs can be described by the area under the curve (AUC) divided by the minimal inhibitory concentration (MIC). The hollow fiber infection model (HFIM) and various animal models (especially mouse and macaque) allow for sophisticated pharmacokinetic/pharmacodynamic experiments. These experiments may hasten the selection of the most potent, shortest possible regimens to treat even extremely drug resistant TB. These findings can be translated to humans by optimizing drug exposure in each patient, using therapeutic drug monitoring and dose individualization.

Adverse Drug Reactions Related to Treatment of Drug-Susceptible Tuberculosis in Brazil: A Prospective Cohort Study

“…Isoniazid can cause toxicity in several ways: can lead to decreased synthesis of g-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter of the Central Nervous System. Other neuro-psychiatric disorders were described in our study, like headache, hallucination, agitation, insomnia and, despite being rare (11 cases), the events observed motivated drug replacement (21,26,27).…”

Drug Repurposing for Tuberculosis

“…Linezolid, also known as Zyvox, is a first-generation oxazolidinones which are a class of antibiotics that inhibits bacterial protein synthesis. Linezolid works by binding to a site on the bacterial ribosome thereby preventing the formation of a functional 70S ribosomal unit which is an essential component of the bacterial translation process [14][15][16][17]. Linezolid was initially approved for the treatment of infections originating from Gram-positive bacteria and used primarily in the treatment of complicated skin infections such as methicillin-resistant Staphylococcus aureus (MRSA).…”

Predicting in vivo activity of combination therapies from in vitro drug pairs in diverse environments

“…The development of 30+ new antibiotics for tuberculosis is a mixed blessing: the space of possible multi-drug regimens is too vast to test in human studies, or even in mice. 3 Therefore, strategies are needed to prioritize drug combinations for in vivo and clinical development.…”