Ethambutol Partitioning in Tuberculous Pulmonary Lesions Explains Its Clinical Efficacy

• DOI: 10.1128/aac.00924-17
• Publication Date: 2017-07-11T00:25:30Z
• Authors: Matthew Zimmerman; Jodi Lestner; Brendan Prideaux; Paul O'Brien; Isabela Dias-Free...; Chao Chen; Jillian Dietzold; Isaac Daudelin; Firat Kaya; Landry Blanc; Pei-Yu Chen; Steven Park; Padmini Salgame; Jansy Sarathy; Véronique Dartois
• Keywords: Pharmacodynamics

Clinical trials and practice have shown that ethambutol is an important component of the first-line tuberculosis (TB) regime. This contrasts drug's rather modest potency lack activity against nongrowing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile suggests drug may be limited clinical value. Here, we hypothesized this apparent contradiction explained by favorable penetration into TB lesions. First, utilized novel in vitro lesion pharmacokinetic assays predicted good We then employed mass spectrometry imaging laser capture microdissection coupled to liquid chromatography tandem (LCM LC/MS-MS, respectively) show ethambutol, indeed, accumulates diseased tissues penetrates major human-like types represented rabbit model disease with a lesion-to-plasma exposure ratio ranging from 9 12. In addition, exhibits slow but sustained passive diffusion caseum reach concentrations markedly higher than those measured plasma at steady state. results explain why has retained its place regimen, validate our assays, demonstrate critical importance effective for anti-TB drugs. Our findings suggest vivo evaluation should included discovery programs. Finally, first time LCM LC-MS/MS been used quantify small molecule high spatial resolution infected tissues, method can easily extended other infectious diseases.