Acquired blaCfxA-3 carried by a conjugative transposon or duplicated intrinsic blaCME-3 mediates cefiderocol resistance in Elizabethkingia anophelis clinical isolates

Ya-Sung Yang; Yu-Lin Lee; Yuag-Meng Liu; Chen-Feng Kuo; Mei-Chen Tan; Wei-Cheng Huang; Shu-Yuan Hsu; Yea-Yuan Chang; Hung-Sheng Shang; Shu-Chen Kuo

doi:10.1016/j.ijantimicag.2024.107378

Acquired bla_CfxA-3 carried by a conjugative transposon or duplicated intrinsic bla_CME-3 mediates cefiderocol resistance in Elizabethkingia anophelis clinical isolates

Int J Antimicrob Agents. 2024 Nov 5:107378. doi: 10.1016/j.ijantimicag.2024.107378. Online ahead of print.

Authors

Ya-Sung Yang¹, Yu-Lin Lee², Yuag-Meng Liu³, Chen-Feng Kuo⁴, Mei-Chen Tan⁵, Wei-Cheng Huang⁵, Shu-Yuan Hsu⁶, Yea-Yuan Chang⁷, Hung-Sheng Shang⁸, Shu-Chen Kuo⁹

Affiliations

¹ Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
² Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
³ Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
⁴ Department of Infectious Diseases, Taipei MacKay Memorial Hospital, Taipei, Taiwan.
⁵ National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
⁶ Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.
⁷ Division of Infectious Diseases, Department of Internal Medicine, Taipei City Hospital Renai Branch, Taipei, Taiwan.
⁸ Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁹ National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan; National Yang Ming Chiao Tung University, Department of Biological Science & Technology, Taiwan. Electronic address: sckuo@nhri.edu.tw.

PMID: 39510324
DOI: 10.1016/j.ijantimicag.2024.107378

Abstract

Objectives: Elizabethkingia spp. are resistant to multiple antibiotics. This study aimed to determine in vitro and in vivo activities of cefiderocol against Elizabethkingia spp. and to investigate resistance mechanisms.

Methods: Bloodstream isolates were collected from four hospitals. In vitro and in vivo activities were determined using broth microdilution and the wax moth model, respectively. Genome comparison and gene editing were used to confirm the contribution of target genes. Conjugation experiments and serial passage were used to determine transferability and stability, respectively. A MIC of ≤ 4 mg/L was designated as the susceptibility breakpoint.

Results: Among 228 non-duplicated isolates, 226 exhibited a MIC of ≤ 4 mg/L with MIC_50/90 of 1/2 mg/L. Two isolates had a MIC of 128 mg/L; both source patients had multiple comorbidities, were ventilator-dependent, and had not received cefiderocol previously. Resistance was attributable to acquisition of bla_CfxA-3, carried by a conjugative transposon from Prevotella jejuni, and duplication of intrinsic bla_CME-3, which led to its overexpression. tetQ coexisted with bla_CfxA-3 in this conjugative transposon and minocycline facilitated its transfer among E. anophelis. Antibiotics prescribed for source patients did not induce bla_CME-3 duplication. The stabilities of bla_CfxA-3 and double bla_CME-3 were 100% and > 90%, respectively, after 10-day serial passage. Cefiderocol failed to rescue moth larvae infected with resistant strains, but removal of resistance mechanisms restored in vivo efficacy.

Conclusions: Cefiderocol was in vitro and in vivo active against Elizabethkingia spp. but resistance may emerge due to the availability, transferability, and/or stability of resistance mechanisms.

Keywords: Antibiotic resistance; Cefiderocol; Elizabethkingia; Multidrug resistance; Resistance genes.