Efficacies of omadacycline + amikacin + imipenem and an all-oral regimen omadacycline + clofazimine + linezolid in a mouse model of
M. abscessus
lung disease
Authors: Ignatius Elisa H. , Rimal Binayak , Panthi Chandra M. , Belz Daniel C. , Lippincott Christopher K. , Deck Daniel H. , Serio Alisa W. , Lamichhane Gyanu 
Published: July 2024

ABSTRACT

Treatment outcomes for
Mycobacteroides abscessus
(
Mab
, also known as
Mycobacterium abscessus
) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating
Mab
disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against
Mab
. Since any new antibiotic effective against
Mab
is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary
Mab
clinical isolates in a mouse model of
Mab
lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with
Mab
burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced
Mab
levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen’s effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in
Mab
disease patients is needed to determine the most effective omadacycline-containing regimen.

IMPORTANCE

Mycobacteroides abscessus
is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating
M. abscessus
disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against
M. abscessus
. Using a mouse model that mimics
M. abscessus
disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with
M. abscessus
patients is necessary to optimize omadacycline-based treatment strategies for this disease.