Intrinsic clarithromycin heteroresistance in Mycobacterium avium

Ai Ito; Yuta Nanjo; Chiaki Kajiwara; Ayako Shiozawa; Naohisa Urabe; Sakae Homma; Kazuma Kishi; Kageto Yamada; Yoshikazu Ishii; Kazuhiro Tateda

doi:10.1016/j.jiac.2024.02.016

Intrinsic clarithromycin heteroresistance in Mycobacterium avium

J Infect Chemother. 2024 Feb 16:S1341-321X(24)00051-5. doi: 10.1016/j.jiac.2024.02.016. Online ahead of print.

Authors

Affiliations

¹ Department of Respiratory Medicine, Toho University Omori Medical Center, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan; Department of Microbiology and Infectious Disease, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
² Department of Microbiology and Infectious Disease, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan; Department of Respiratory Medicine, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address: ynanjyo@juntendo.ac.jp.
³ Department of Microbiology and Infectious Disease, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
⁴ Department of Respiratory Medicine, Toho University Omori Medical Center, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.

PMID: 38369123
DOI: 10.1016/j.jiac.2024.02.016

Abstract

Background: Mycobacterium avium is associated with pulmonary disease in otherwise healthy adults. Several clarithromycin-refractory cases have been reported, including some cases caused by clarithromycin-susceptible strains.

Objectives: To characterize the reason for the discrepancy between clinical response and antibiotic susceptibility results.

Methods: We conducted population analysis of clarithromycin-tolerant and heteroresistant subpopulations of M. avium cultured in vitro and in homogenates of infected lungs of mice. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for 28 M. avium and two M. kansasii strains. Mice were intranasally infected with M. avium and treated with or without clarithromycin (100 mg/kg) thrice weekly. They were sacrificed on day 35 and the bacteria in lung homogenates were tested for clarithromycin resistance. Population analysis assays were performed based on colony growth on plates containing two-fold dilutions of clarithromycin.

Results: The MBC/MIC ratios were ≥8 in all 28 strains of M. avium tested. In the population analysis assay, several colonies were observed on the plates containing clarithromycin concentrations above the MIC (2-64 mg/L). No growth of M. kansasii colonies was observed on the plates containing clarithromycin concentrations ≥2 mg/L. M. avium in the homogenates of infected lungs showed clearer clarithromycin-resistant subpopulations than in vitro, regardless of clarithromycin exposure.

Conclusion: M. avium shows intrinsic heterogeneous resistance (heteroresistance) to clarithromycin. This may explain the observed discrepancies between clarithromycin susceptibility testing results and clinical response to clarithromycin treatment. Further studies are needed to confirm a link between heteroresistance and clinical outcomes.

Keywords: Antibiotic susceptibility; Clarithromycin; Heteroresistance; Mycobacterium avium; Pulmonary disease; Refractory.

Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.