Potency of Omadacycline against Mycobacteroides abscessus Clinical Isolates In Vitro and in a Mouse Model of Pulmonary Infection

Abstract

The incidence of nontuberculous mycobacterial diseases in the US is rising and has surpassed tuberculosis. Most notable among the nontuberculous mycobacteria is Mycobacteroides abscessus , an emerging environmental opportunistic pathogen capable of causing chronic infections. M. abscessus disease is difficult to treat and the current treatment recommendations include repurposed antibiotics, several of which are associated with undesirable side effects. In this study, we have evaluated the activity of omadacycline, a new tetracycline derivative, against M. abscessus using in vitro and in vivo approaches. Omadacycline exhibited an MIC 90 of 0.5 μg/ml against a panel of 32 contemporary M. abscessus clinical isolates several of which were resistant to antibiotics that are commonly used for treatment of M. abscessus disease. Omadacycline when combined with clarithromycin, azithromycin, cefdinir, rifabutin or linezolid also exhibited synergism against several M. abscessus strains and did not exhibit antagonism when combined with an additional nine antibiotics also commonly considered to treat M. abscessus disease. Concentration-dependent activity of omadacycline was observed in time-kill assessments. Efficacy of omadacycline was evaluated in a mouse model of lung infection against four M. abscessus strains. A dose equivalent to the 300 mg standard oral human dose was used. Compared to the untreated control group, within four weeks of treatment, 1 to 3 log 10 fewer M. abscessus colony forming units were observed in the lungs of mice treated with omadacycline. Treatment outcome was biphasic, with bactericidal activity observed after the first two weeks of treatment against all four M. abscessus strains.

T405, a New Penem, Exhibits In Vivo Efficacy against M. abscessus and Synergy with β-Lactams Imipenem and Cefditoren

“…Overall, Mab burden was maintained in the lungs of mice during the course of study and did not alter significantly as would be expected during a chronic Mab infection. In mice treated with imipenem+probenecid, the positive-control comparator group, Mab lung burden gradually declined over the course of the experiment and reproduced prior observations of imipenem against Mab ATCC 19977 ( 28 , 37 ). Similar to the effect of imipenem, T405 also exhibited bactericidal activity throughout the treatment duration as Mab lung burden in mice receiving T405+probenecid gradually declined following the onset of treatment.…”

Omadacycline Potentiates Clarithromycin Activity Against Mycobacterium abscessus

“…Recently published two articles also discovered an in vitro synergistic effect of CLA-OMD against Mab similar to this study (Gumbo et al, 2020;Nicklas et al, 2021). In the Nicklas et al study, OMA in combination with CLA exhibited synergy against a Mab clinical isolate with a FIC index of ≤0.5 (Nicklas et al, 2021). This result strongly supports our new findings for this study.…”

“…On October 2, 2018, OMD was approved by the US Food and Drug Administration (FDA) for the treatment of adults with community-acquired bacterial pneumonia and acute skin, and skin structure, infections ( Markham and Keam, 2018 ). OMD has shown positive in vitro activity against Mab with promising results (MIC 90 ; 2 mg/L) ( Kaushik et al, 2019 ; Nicklas et al, 2021 ). Recently, in vivo efficacy of OMD evaluated at a dose equivalent to the 300 mg standard oral human dose showed a 1 to 3 log10 reduction in bactericidal activity against all tested Mab strains, compared to an untreated control group ( Nicklas et al, 2021 ).…”

“…OMD has shown positive in vitro activity against Mab with promising results (MIC 90 ; 2 mg/L) ( Kaushik et al, 2019 ; Nicklas et al, 2021 ). Recently, in vivo efficacy of OMD evaluated at a dose equivalent to the 300 mg standard oral human dose showed a 1 to 3 log10 reduction in bactericidal activity against all tested Mab strains, compared to an untreated control group ( Nicklas et al, 2021 ). Considering the steady-state area under the curve (AUC), and MICs obtained against Mab , the free drug AUC/MIC ratios for OMD, given intravenously, is expected to be approximately eight to ten times higher than TGC ( Kaushik et al, 2019 ).…”

Glby, Encoded by MAB_3167c , Is Required for In Vivo Growth of Mycobacteroides abscessus and Exhibits Mild β-Lactamase Activity

“…Mab infection can be acquired from the environment, from infected individuals or via fomite intermediates ( 11 – 16 ). A recent report declared Mab “an environmental bacterium turned clinical nightmare” ( 17 ) citing the following reasons: (i) Mab disease is associated with rapid lung function decline and is often incurable ( 5 , 18 , 19 ); (ii) there are no FDA approved drugs to treat Mab disease, and the cure rate with the current treatment regimens, which are based on repurposed antibiotics that need to be taken daily for at least 1 year, is only 30% to 50% ( 20 ); and (iii) Mab is intrinsically resistant to most antibiotics used today to treat Mab disease ( 21 , 22 ). To make matters worse, a number of antibiotics from this limited selection are associated with frequent toxicities ( 23 ).…”