A Rabbit Model to Study Antibiotic Penetration at the Site of Infection for Nontuberculous Mycobacterial Lung Disease: Macrolide Case Study

Firat Kaya, Jacqueline P. Ernest, Katherine LoMauro, Martin Gengenbacher, Abdeldjalil Madani, Wassihun Wedajo Aragaw, Matthew D. Zimmerman, Jansy P. Sarathy, Nadine Alvarez, Isaac Daudelin, Han Wang, Faye Lanni, Danielle M. Weiner, Laura E. Via, Clifton E. Barry, Kenneth N. Olivier, Thomas Dick, Brendan K. Podell, Radojka M. Savic, Veronique Dartois

Research output: Contribution to journalArticlepeer-review

Abstract

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a potentially fatal infectious disease requiring long treatment duration with multiple antibiotics and against which there is no reliable cure. Among the factors that have hampered the development of adequate drug regimens is the lack of an animal model that reproduces the NTM lung pathology required for studying antibiotic penetration and efficacy. Given the documented similarities between tuberculosis and NTM immunopathology in patients, we first determined that the rabbit model of active tuberculosis reproduces key features of human NTM-PD and provides an acceptable surrogate model to study lesion penetration. We focused on clarithromycin, a macrolide and pillar of NTM-PD treatment, and explored the underlying causes of the disconnect between its favorable potency and pharmacokinetics and inconsistent clinical outcome. To quantify pharmacokinetic-pharmacodynamic target attainment at the site of disease, we developed a translational model describing clarithromycin distribution from plasma to lung lesions, including the spatial quantitation of clarithromycin and azithromycin in mycobacterial lesions of two patients on long-term macrolide therapy. Through clinical simulations, we visualized the coverage of clarithromycin in plasma and four disease compartments, revealing heterogeneous bacteriostatic and bactericidal target attainment depending on the compartment and the corresponding potency against nontuberculous mycobacteria in clinically relevant assays. Overall, clarithromycin's favorable tissue penetration and lack of bactericidal activity indicated that its clinical activity is limited by pharmacodynamic, rather than pharmacokinetic, factors. Our results pave the way toward the simulation of lesion pharmacokinetic-pharmacodynamic coverage by multidrug combinations to enable the prioritization of promising regimens for clinical trials.

Original languageEnglish (US)
Article numbere02212-21
JournalAntimicrobial agents and chemotherapy
Volume66
Issue number3
DOIs
StatePublished - Mar 2022
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Keywords

  • Animal model
  • Clarithromycin
  • Lung pathology
  • Macrolides
  • Nontuberculous mycobacteria
  • Tissue penetration

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