Ethambutol Partitioning in Tuberculous Pulmonary Lesions Explains Its Clinical Efficacy.

Journal:
Antimicrobial agents and chemotherapy, Volume: 61, Issue: 9
Published:
September 24, 2017
PMID:
28696241
Authors:
Matthew Zimmerman M, Jodi Lestner J, Brendan Prideaux B, Paul O'Brien P, Isabela Dias-Freedman I, Chao Chen C, Jillian Dietzold J, Isaac Daudelin I, Firat Kaya F, Landry Blanc L, Pei-Yu Chen PY, Steven Park S, Padmini Salgame P, Jansy Sarathy J, VĂ©ronique Dartois V
Abstract:

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