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Abstract

Background

Mycobacterium abscessus (MAB) is a highly drug-resistant nontuberculous mycobacterium (NTM) that is an important cause of pulmonary disease (PD). Treatment is limited by the lack of active oral drugs and frequent adverse reactions. EBO is a novel oral, boron-containing antimicrobial that inhibits bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis. It has demonstrated encouraging in vitro and in vivo efficacy against MAB in small, limited preclinical studies and is currently in clinical development for the treatment of other NTM-PD. This study evaluated EBO minimal inhibitory concentrations (MIC) against a larger number of recent MAB isolates.

Methods

MAB isolates collected in 2021 from the United States (n=122) from respiratory sources and in 2019-2022 from Europe (n=25) from respiratory and other sources were tested by broth microdilution according to Clinical and Laboratory Standards Institute guidelines using frozen microtiter panels manufactured by ThermoFisher against EBO and a panel of 13 antimicrobials with anti-MAB activity. MIC values were determined after 4-5 days of incubation; if an isolate was susceptible to clarithromycin (CLR) at day 5, it was reread at day 14 to assess for inducible macrolide resistance. Descriptive analyses were done on the MIC values.

Results
Of the 147 MAB isolates, 101 were subspecies abscessus, 6 were bolletii, and 40 were massiliense. EBO MIC50/MIC90 for all isolates were 0.06/0.12 mg/L. MICs ranged from 0.03 - 0.25 mg/L and were consistent across subspecies (Table 1). MIC ranges, MIC50, and MIC90 values for all agents are summarized in Table 2. 95 isolates (64.6%) were CLR-resistant, consisting of 73 isolates with inducible and 22 with constitutive resistance. The EBO MIC50/MIC90 values for either CLR-resistant or amikacin (AMK)-resistant isolates remained 0.06/0.12 mg/L.
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Conclusion

EBO demonstrated potent in vitro activity against MAB with MICs from 0.03-0.25 mg/L with similar activity against all subspecies. EBO MICs remained low against MAB isolates that were resistant to other agents, including CLR and AMK. These data demonstrate EBO’s promising in vitro activity versus MAB regardless of subspecies or resistance to current agents and support clinical evaluation of EBO as a therapeutic option for MAB disease.

Disclosures

Tiffany Keepers White, PhD, AN2 Therapeutics: Employee|AN2 Therapeutics: Stocks/Bonds Charles L. Daley, MD, AN2: Advisor/Consultant|AN2: Grant/Research Support|Aztrazeneca: Advisor/Consultant|Beyond Air: Grant/Research Support|Bill and Melinda Gates Foundation: Data Monitoring Committee|Bugworks: Grant/Research Support|Genentech: Advisor/Consultant|Hyfe: Advisor/Consultant|Insmedd: Advisor/Consultant|Insmedd: Grant/Research Support|Juvabis: Grant/Research Support|Lilly: Data Monitoring Committee|MannKind: Advisor/Consultant|Matinas: Advisor/Consultant|Otsuka: Data Monitoring Committee|Paratek: Advisor/Consultant|Paratek: Grant/Research Support|Pfizer: Advisor/Consultant|Spero: Advisor/Consultant|Zambon: Advisor/Consultant

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Author notes

Session: 218. Experimental Therapeutics

Saturday, October 14, 2023: 10:54 AM

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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