Efficacy of Omadacycline-Containing Regimen in a Mouse Model of Pulmonary Mycobacteroides abscessus Disease

Abstract

Mycobacteroides abscessus is an opportunistic pathogen in people with structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. Pulmonary M. abscessus infection causes progressive symptomatic and functional decline as well as diminished lung function and is often incurable with existing antibiotics. We investigated the efficacy of a new tetracycline, omadacycline, in combination with existing antibiotics recommended to treat this indication, in a mouse model of M. abscessus lung disease. Amikacin, azithromycin, bedaquiline, biapenem, cefoxitin, clofazimine, imipenem, linezolid, and rifabutin were selected as companions to omadacycline. M. abscessus burden in the lungs of mice over a 4-week treatment duration was considered the endpoint. Omadacycline in combination with linezolid, imipenem, cefoxitin, biapenem, or rifabutin exhibited early bactericidal activity compared to any single drug. Using three M. abscessus isolates, we also determined the in vitro frequency of spontaneous resistance against omadacycline to be between 1.9 × 10^-10 and 6.2 × 10^-10 and the frequency of persistence against omadacycline to be between 5.3 × 10^-6 and 1.3 × 10^-5. Based on these findings, the combination of omadacycline and select drugs that are included in the recent treatment guidelines may exhibit improved potency to treat M. abscessus lung disease. IMPORTANCE M. abscessus disease incidence is increasing in the United States. This disease is difficult to cure with existing antibiotics. In this study, we describe the efficacy of a new tetracycline antibiotic, omadacycline, in combination with an existing antibiotic to treat this disease. A mouse model of M. abscessus lung disease was used to assess the efficacies of these experimental treatment regimens. Omadacycline in combination with select existing antibiotics exhibited bactericidal activity during the early phase of treatment.

Keywords: Mycobacterium abscessus; Mycobacteroides abscessus; amikacin; azithromycin; bedaquiline; biapenem; cefoxitin; clofazimine; imipenem; linezolid; omadacycline; rifabutin.

FIG 1

M. abscessus burdens in the lungs of mice treated with omadacycline and a companion antibiotic. Burdens of M. abscessus in the lungs of C3HeB/FeJ mice at weeks −1, 0, +1, +2, and +4 (n = 5 per group per time point) represented as mean CFU ± standard deviation are shown. Time point week −1 corresponds to the day after mice were infected with M. abscessus ATCC 19977, week 0 corresponds to the day antibiotic treatment was initiated, and weeks +1, +2, and +4 correspond to 1, 2, and 4 weeks, respectively, following daily treatment with stated antibiotics. PBS, phosphate-buffered saline control; OMC, omadacycline (15 mg/kg, once daily, administered via subcutaneous injection); AMK, amikacin (150 mg/kg, once daily, subcutaneous injection); AZM, azithromycin (100 mg/kg, once daily, oral); BDQ, bedaquiline (25 mg/kg, once daily, oral); BIA, biapenem (200 mg/kg per dose, twice daily, subcutaneous injection); CFZ, clofazimine (25 mg/kg, once daily, oral); FOX, cefoxitin (600 mg/kg per dose, twice daily, subcutaneous injection); IMI, imipenem (100 mg/kg per dose, twice daily, subcutaneous injection); LZD, linezolid (100 mg/kg, once daily, oral); RFB, rifabutin (20 mg/kg, once daily, oral). For efficacy assessment of dual drugs, corresponding single drugs were included at the same dose and dosing frequency. Pairwise statistical analysis between each treatment group at each time point is included in Table S1 in the supplemental material.