Detection and characterization of eravacycline heteroresistance in clinical bacterial isolates

Yingfeng Zhang; Dongdong Liu; Yongzhu Liu; Qiwei Li; Hongwei Liu; Peng Zhou; Yaqin Liu; Lili Chen; Weiguo Yin; Yang Lu

doi:10.3389/fmicb.2024.1332458

Detection and characterization of eravacycline heteroresistance in clinical bacterial isolates

Front Microbiol. 2024 Mar 27:15:1332458. doi: 10.3389/fmicb.2024.1332458. eCollection 2024.

Authors

Yingfeng Zhang^#^{1

2}, Dongdong Liu^#³, Yongzhu Liu^#⁴, Qiwei Li³, Hongwei Liu², Peng Zhou², Yaqin Liu², Lili Chen¹, Weiguo Yin², Yang Lu²

Affiliations

¹ Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
² Department of Laboratory Medicine, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.
³ Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
⁴ Department of Gynecology, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.

^# Contributed equally.

Abstract

Eravacycline (ERV) has emerged as a therapeutic option for the treatment of carbapenem-resistant pathogens. However, the advent of heteroresistance (HR) to ERV poses a challenge to these therapeutic strategies. This study aimed to investigate ERV HR prevalence among common clinical isolates and further characterize ERV HR in carbapenem-resistant Klebsiella pneumoniae (CRKP). A total of 280 clinical pathogens from two centers were selected for HR and analyzed using population analysis profiling (PAP) and modified E-tests. The PAP assay revealed an overall ERV HR prevalence of 0.7% (2/280), with intermediate heterogeneity observed in 24.3% (68/280) of strains. The proportion of heteroresistant strains was 18.3% according to modified E-test results. A time-killing assay demonstrated that CRKP CFU increased significantly after 10 h of ERV treatment, contributing to the reduced bactericidal effect of ERV in vitro. Interestingly, dual treatment with ERV and polymyxin B effectively inhibited the total CFU, simultaneously reducing the required polymyxin B concentration. Furthermore, fitness cost measurements revealed a growth trade-off in CRKP upon acquiring drug resistance, highlighting fitness costs as crucial factors in the emergence of ERV HR in CRKP. Overall, the findings of the current study suggest that ERV HR in clinical strains presents a potential obstacle in its clinical application.

Keywords: carbapenem-resistant Klebsiella pneumoniae; eravacycline; fitness cost; heteroresistance; time-killing assay; whole-genome sequencing.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Natural Science Foundation of Hunan Province (2023JJ30502), the Traditional Chinese Medicine Bureau of Guangdong Province (No. 20232036), the Research Capacity Improvement Project of Guangzhou Medical University, the Guangdong Provincial Medical Science and Technology Research Fund Project (B2023348), and the Research Projects of Guangdong Provincial Administration of Traditional Chinese Medicine (20231147).