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NIH grant 1R21AI201981-01: Cethromycin-based treatment of M. avium disease
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: DAVID Joseph SULLIVAN. Award: $233250.
Start: 2026-07-23T00:00:00.
PROJECT SUMMARY
Mycobacterium avium (M. avium) is the most common non-tuberculous mycobacterium (NTM) causing
chronic lung disease, particularly in individuals with underlying structural lung disorders or immune
suppression. Incidence in the United States now surpasses that of tuberculosis, and long-term mortality
remains high, with 5–10 year survival rates ranging from 54% to 76%. Current therapies rely on prolonged
multidrug regimens, where macrolides are the cornerstone. However, treatment is undermined by intrinsic
resistance, limited drug efficacy, and toxicities such as those associated with liposomal amikacin, the only
FDA-approved therapy. Thus, new regimens that improve efficacy and reduce resistance emergence are
urgently needed.
Cethromycin, a next-generation macrolide (ketolide), demonstrates superior in vitro activity against M. avium
clinical isolates, including strains resistant to conventional macrolides. Preliminary data indicate more
synergism with companion drugs compared to azithromycin or clarithromycin, suggesting cethromycin may
represent a more effective backbone drug for M. avium therapy. This study aims to determine whether
cethromycin-based regimens offer superior efficacy over current standard-of-care regimens. Specific Aim 1
will identify companion drugs that minimize resistance emergence by systematically evaluating resistance
dynamics of cethromycin alone and in combinations under prolonged drug exposure. Emphasis will be placed
on regimens that exhibit reciprocal suppression of resistance, offering the greatest potential for durable cure.
Specific Aim 2 will assess treatment efficacy in a validated mouse model of chronic M. avium lung disease.
Pharmacokinetic (PK) and pharmacodynamic (PD) studies of cethromycin combinations with candidate
partners (bedaquiline, ethambutol, rifampin) will be performed, measuring bacterial clearance and resistance
prevention. Outcomes will be benchmarked against standard therapy to directly test whether cethromycin
improves treatment efficacy. By integrating resistance suppression (Aim 1) with in vivo synergism (Aim 2),
this project will establish a translational framework for advancing cethromycin-based regimens toward clinical
evaluation.document fetched 2026-08-02 08:24