In vivo divergent evolution of cross-resistance to new β-lactam/β-lactamase inhibitor combinations in Pseudomonas aeruginosa following ceftazidime/avibactam treatment

Heng Cai; Minhua Chen; Yue Li; Nanfei Wang; Hanming Ni; Piaopiao Zhang; Xiaoting Hua; Yunsong Yu

doi:10.1007/s15010-024-02432-5

In vivo divergent evolution of cross-resistance to new β-lactam/β-lactamase inhibitor combinations in Pseudomonas aeruginosa following ceftazidime/avibactam treatment

Infection. 2024 Nov 8. doi: 10.1007/s15010-024-02432-5. Online ahead of print.

Authors

Heng Cai^#^{1

2

3}, Minhua Chen^#^{1

2

3}, Yue Li^{1

2

3}, Nanfei Wang^{1

2

3}, Hanming Ni^{1

2

3}, Piaopiao Zhang^{1

2

3}, Xiaoting Hua^{4

5

6}, Yunsong Yu^{7

8

9}

Affiliations

¹ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China.
⁴ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
⁵ Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
⁶ Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China. [email protected].
⁷ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
⁸ Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
⁹ Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China. [email protected].

^# Contributed equally.

PMID: 39514175
DOI: 10.1007/s15010-024-02432-5

Abstract

Purpose: To describe and characterize the evolutionary process of cross-resistance to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam of a carbapenem-resistant Pseudomonas aeruginosa (CRPA) lineage isolated from a patient receiving two courses of ceftazidime/avibactam treatment.

Methods: The minimum inhibitory concentrations (MICs) of strains were determined by broth microdilution methods. The mutant genes were identified by the whole genome sequencing results. Cloning, knockout and complementation experiments were used to evaluate the impact of the resistance relative genes on the MICs. Reverse transcription-quantitative PCR was used to evaluate the relative expression of ampC and mexA. The fitness cost was measured by growth curve tests.

Results: A total of 24 CRPA strains were isolated encompassing the whole ceftazidime/avibactam treatment. The CRPA strains developed high-level resistance to ceftazidime/avibactam and cross-resistance to ceftolozane/tazobactam or imipenem/relebactam, clustering into clade A and clade B, respectively. In both clades, the overexpression of AmpC was crucial to ceftazidime/avibactam resistance, which was driven by AmpD deficiency in clade A and dacB mutation in clade B, respectively. In clade A, mraY mutation and a new allele of AmpC (bla_PDC-575) elevated resistance to ceftazidime/avibactam, with bla_PDC-575 also conferring resistance to ceftolozane/tazobactam. In clade B, mexB mutation was associated with the resistance to both ceftazidime/avibactam and imipenem/relebactam. Moreover, the fitness costs of P. aeruginosa strains typically increased with the higher MICs of ceftazidime/avibactam.

Conclusion: Divergent resistance evolution resulted in a complex phenotype in the CRPA lineage, posing significant challenge to clinical treatment. The resistance surveillance needs to be prioritized, and new therapeutic strategies are urgently required.

Keywords: Pseudomonas aeruginosa; Ceftazidime/avibactam; Ceftolozane/tazobactam; Cross-resistance; Imipenem/relebactam; Resistance evolution.