Establishing efficacy benchmarks in preclinical tuberculosis (TB) models is essential for optimizing and prioritizing therapeutic regimens. However, standardized classification methods for comparing high-performing regimens are currently lacking. This study defines a quantitative framework utilizing rifampicin-based regimens in a high-burden aerosol BALB/c mouse model, incorporating both male and female mice to…
Tuberculous meningitis (TBM)-related deaths occur early, often within weeks after treatment initiation. Enhanced treatment early in the disease course with agents that effectively penetrate the central nervous system may improve outcomes in TBM.
In the absence of effective patient-stratification approaches, tuberculosis (TB) treatment relies on overtreating most patients to ensure high cure rates. Shortening treatment duration without compromising efficacy is therefore high on the agenda of the global TB community. While new and better drugs are certainly needed, we argue that innovative but…
In Advancing Clinical Therapeutics Globally protocol A5372, a pharmacokinetic study of dolutegravir with 1-month of daily rifapentine/isoniazid, twice-daily dolutegravir offset the induction effects of rifapentine on plasma dolutegravir trough concentrations (C trough ). Here, we characterize the impact on dolutegravir C trough of UGT1A1 , AADAC , and NAT2 polymorphisms…
Tuberculosis (TB) is historically the world’s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a…
Macrophages are the primary host cell type for infection by Mycobacterium tuberculosis in vivo. Macrophages are also key immune effector cells that mediate the control of bacterial growth. However, the specific macrophage phenotypes that are required for optimal immune control of M. tuberculosis infection in vivo remain poorly defined. There are…
By assessing the standard-of-care regimen for tuberculosis (TB) in BALB/c and C3HeB/FeJ mice, we demonstrate that rifampin, with or without pyrazinamide, is essential for an effective bactericidal response and suppression of resistance. Potency measurements in an lipid-rich model and a rabbit caseum assay recapitulate the significance of rifampin as a…
(Mtb) primarily infects macrophages. In vitro without antibiotics, wild-type Mtb hastens death of the macrophages, but the processes leading to rapid cell death are not well understood. Our earlier work indicated that the death of Mtb-infected mouse macrophages in vitro is markedly exacerbated by induction of interferon-β (IFN-β) [L.
