Ceftolozane/Tazobactam Resistance and Mechanisms in Carbapenem-Nonsusceptible Pseudomonas aeruginosa

This study established the activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible (CNSPA) clinical isolates recovered from Singapore between 2009 and 2020. C/T susceptibility rates were low, at 37.9%. Cross-r...

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Published inmSphere Vol. 6; no. 1
Main Authors Teo, Jocelyn Qi-Min, Lim, Jie Chong, Tang, Cheng Yee, Lee, Shannon Jing-Yi, Tan, Si Hui, Sim, James Heng-Chiak, Ong, Rick Twee-Hee, Kwa, Andrea Lay-Hoon
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 27.01.2021
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Summary:This study established the activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible (CNSPA) clinical isolates recovered from Singapore between 2009 and 2020. C/T susceptibility rates were low, at 37.9%. Cross-resistance to ceftazidime/avibactam was observed, although susceptibility to the agent was slightly higher, at 41.0%. Whole-genome sequencing revealed that C/T resistance was largely mediated by the presence of horizontally acquired -lactamases, especially metallo- -lactamases. These were primarily disseminated in well-recognized high-risk clones belonging to sequence types (ST) 235, 308, and 179. C/T resistance was also observed in several non-carbapenemase-producing isolates, in which resistance was likely mediated by -lactamases and, to a smaller extent, mutations in AmpC-related genes. There was no obvious mechanism of resistance observed in five isolates. The high C/T resistance highlights the limited utility of the agent as an empirical agent in our setting. Knowledge of local molecular epidemiology is crucial in determining the potential of therapy with novel agents. infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel -lactam/ -lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant infections. Our findings demonstrate geographical variation in C/T susceptibility owing to the distinct local molecular epidemiology. This study adds on to the growing knowledge of C/T resistance, particularly mutational resistance, and will aid in the design of future β-lactams and -lactamase inhibitors. WGS proved to be a useful tool to understand the resistome and its contribution to emerging resistance in novel antimicrobial agents.
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Present address: Shannon Jing-Yi Lee, NovogeneAIT Genomics Singapore Pte Ltd., Singapore, Singapore.
Jocelyn Qi-Min Teo and Jie Chong Lim contributed equally to this work. Author order was determined by random coin toss. Rick Twee-Hee Ong and Andrea Lay-Hoon Kwa also contributed equally to this work.
Citation Teo JQ, Lim JC, Tang CY, Lee SJ, Tan SH, Sim JH, Ong RT, Kwa AL. 2021. Ceftolozane/tazobactam resistance and mechanisms in carbapenem-nonsusceptible Pseudomonas aeruginosa. mSphere 6:e01026-20. https://doi.org/10.1128/mSphere.01026-20.
ISSN:2379-5042
2379-5042
DOI:10.1128/MSPHERE.01026-20