Efficacies of omadacycline + amikacin + imipenem and an all-oral regimen omadacycline + clofazimine + linezolid in a mouse model of M. abscessus lung disease

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.IMPORTANCEMycobacteroides 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.

Keywords: M. abscessus; amikacin; clofazimine; imipenem; linezolid; omadacycline.

Fig 1

Burdens of M. abscessus isolates M9501 (a) and M9507 (b) in the lungs of C3HeB/FeJ mice treated with triple-drug regimen omadacycline +amikacin + imipenem with comparator groups are shown. Mean lung CFU ± standard error of the mean at 1 week prior to treatment initiation (week −1), on the day of treatment initiation (week 0), and at the completion of 1, 2, and 4 weeks of treatment is shown. n = 5 per group at timepoints of weeks −1, 0, 1, and 2, and n = 10 per group at week 4. OMC, omadacycline, 15 mg/kg, once daily; AMK, amikacin, 150 mg/kg, once daily; IMI, imipenem, 100 mg/kg/dose, twice daily. Pairwise statistical comparison between each group at each timepoint is included in Table S1.

Fig 2

Burdens of M. abscessus isolates M9501 (a) and M9507 (b) in the lungs of C3HeB/FeJ mice treated with triple-drug regimen omadacycline + clofazimine + linezolid with comparator groups are shown. Mean lung CFU ± standard error of the mean at 1 week prior to treatment initiation (week −1), on the day of treatment initiation (week 0), and at the completion of 1, 2, 4, and 6 weeks of treatment is shown. n = 5 per group at timepoints of weeks −1, 0, 1, 2, and 4, and n = 10 per group at week 6. OMC, omadacycline, 15 mg/kg, once daily; CFZ, clofazimine, 25 mg/kg, once daily; LZD, linezolid, 100 mg/kg, once daily. Pairwise statistical comparison between each group at each timepoint is included in Table S1.