P-1404. Optimizing Preclinical Models and Therapeutic Combinations for Nontuberculous Mycobacterial Lung Disease

TL;DR

This study improves preclinical models for lung disease caused by nontuberculous mycobacteria and identifies effective oral drug combinations.

Contribution

The study introduces improved murine models for Mycobacteroides abscessus and identifies synergistic oral therapies.

Findings

Four clinical isolates of Mab showed higher lung disease burden and delayed systemic spread compared to the reference strain.

Dual-agent oral therapies reduced pulmonary disease burden as effectively as standard treatments in mice.

Improved models allow for more accurate preclinical testing with reduced overhead.

Abstract

Pulmonary disease caused by the nontuberculous mycobacteria (NTMs) Mycobacteroides abscessus (Mab) and M. avium (MAC) is a rising clinical concern, with increased incidence above expectation from advances in detection. Prolonged, multimodal antibiotic treatment that often relies on a parenteral agent remains burdensome for patients with low cure rates and high morbidity. More tolerable and effective therapeutic combinations are needed, with a focus on orally bioavailable agents. This in turn requires more accurate preclinical modeling than currently possible with the single available Mab reference strain.

For Mab preclinical model testing, mice were exposed to one of 16 clinical pulmonary Mab isolates or the reference strain ATCC 19977 via aerosol and followed with lungs, spleen, and liver collected every 2 weeks. Disease burden was assessed by colony forming unit assay and by histopathologic analysis. For drug synergy testing, combinations were first validated in vitro by full checkerboard assay. For in vivo studies, NTM-infected mice were administered either placebo, single-agent, dual agent, or triple agent regimens. Pulmonary disease burden was assessed at 2-week intervals alongside serial drug MIC testing on recovered organisms.

ATCC 19977 resulted in early, aggressive disease dissemination and less pulmonary disease burden than the majority of clinical pulmonary Mab isolates. Four clinical isolates, one each for smooth and rough phenotypes of the subspecies massiliense and abscessus, were identified with high lung disease penetration and delayed disease dissemination. Multiple dual-agent combinatorial treatments reduced pulmonary NTM burden comparably to standard of care in in vivo murine pulmonary NTM infection.

Here we present four improved murine models for Mab pulmonary disease for both clinically relevant subspecies with higher lung disease burden and reduced systemic dissemination compared to the current reference strain. This will permit more accurate modeling and drug testing for multiple Mab pulmonary disease scenarios with reduced preclinical overhead. We further find synergy between multiple orally bioavailable agents that may permit simplified, more tolerable regimens early in NTM pulmonary disease treatment.

All Authors: No reported disclosures