Document Type
Article
Publication Date
5-2-2024
Original Citation
Castanheira M,
Kimbrough J,
Lindley J,
Doyle T,
Ewald J,
Sader H.
In vitro development of resistance against antipseudomonal agents: comparison of novel beta-lactam/beta-lactamase inhibitor combinations and other beta-lactam agents Antimicrob Agents Chemother. 2024;68(5):e0136323.
Keywords
JGM, Microbial Sensitivity Tests, Anti-Bacterial Agents, Pseudomonas aeruginosa, beta-Lactamase Inhibitors, Azabicyclo Compounds, Meropenem, Tazobactam, Ceftazidime, beta-Lactams, Piperacillin, Tazobactam Drug Combination, Drug Combinations, Cephalosporins, Cefepime, Humans, Piperacillin, Whole Genome Sequencing, Drug Resistance, Multiple, Bacterial
JAX Source
Antimicrob Agents Chemother. 2024;68(5):e0136323.
ISSN
1098-6596
PMID
38526050
DOI
https://doi.org/10.1128/aac.01363-23
Abstract
We subjected seven P. aeruginosa isolates to a 10-day serial passaging against five antipseudomonal agents to evaluate resistance levels post-exposure and putative resistance mechanisms in terminal mutants were analyzed by whole-genome sequencing analysis. Meropenem (mean, 38-fold increase), cefepime (14.4-fold), and piperacillin-tazobactam (52.9-fold) terminal mutants displayed high minimum inhibitory concentration (MIC) values compared to those obtained after exposure to ceftolozane- tazobactam (11.4-fold) and ceftazidime-avibactam (5.7-fold). Fewer isolates developed elevated MIC values for other β-lactams and agents belonging to other classes when exposed to meropenem in comparison to other agents. Alterations in nalC and nalD, involved in the upregulation of the efflux pump system MexAB-OprM, were common and observed more frequently in isolates exposed to ceftazidime-avibactam and merope nem. These alterations, along with ones in mexR and amrR, provided resistance to most β-lactams and levofloxacin but not imipenem. The second most common gene altered was mpl, which is involved in the recycling of the cell wall peptidoglycan. These alterations were mainly noted in isolates exposed to ceftolozane-tazobactam and piperacillin-tazobactam but also in one cefepime-exposed isolate. Alterations in other genes known to be involved in β-lactam resistance (ftsI, oprD, phoP, pepA, and cplA) and multiple genes involved in lipopolysaccharide biosynthesis were also present. The data generated here suggest that there is a difference in the mechanisms selected for high-level resistance between newer β-lactam/β-lactamase inhibitor combinations and older agents. Nevertheless, the isolates exposed to all agents displayed elevated MIC values for other β-lactams (except imipenem) and quinolones tested mainly due to alterations in the MexAB-OprM regulators that extrude these agents.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.