Ceftolozane/Tazobactam Resistance and Mechanisms in Carbapenem-Nonsusceptible Pseudomonas aeruginosa
| Autor: | Cheng Yee Tang, Andrea L. Kwa, Rick Twee-Hee Ong, Jie Chong Lim, Si Hui Tan, Jocelyn Qi-Min Teo, Shannon Jing-Yi Lee, James Heng Chiak Sim |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Tazobactam
Carbapenem ceftolozane/tazobactam Avibactam Ceftazidime Microbial Sensitivity Tests Biology medicine.disease_cause Microbiology Clinical Science and Epidemiology molecular characterization 03 medical and health sciences chemistry.chemical_compound Drug Resistance Multiple Bacterial medicine Molecular Biology 030304 developmental biology 0303 health sciences Whole Genome Sequencing Molecular epidemiology 030306 microbiology Pseudomonas aeruginosa QR1-502 Anti-Bacterial Agents Cephalosporins Resistome Carbapenems chemistry Ceftolozane Genome Bacterial Research Article medicine.drug |
| Zdroj: | mSphere, Vol 6, Iss 1 (2021) mSphere |
| ISSN: | 2379-5042 |
| DOI: | 10.1128/msphere.01026-20 |
| Popis: | Pseudomonas aeruginosa 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 β-lactam/β-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections. This study established the in vitro activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible Pseudomonas aeruginosa (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 β-lactamases, especially metallo-β-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 β-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. IMPORTANCE Pseudomonas aeruginosa 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 β-lactam/β-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa 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 β-lactamase inhibitors. WGS proved to be a useful tool to understand the P. aeruginosa resistome and its contribution to emerging resistance in novel antimicrobial agents. |
| Databáze: | OpenAIRE |
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