Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 77, Issue 4, Pages 957-968Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkab496
Keywords
-
Funding
- Merck Sharp and Dohme (MSD) Investigator Initiated Studies Program
- Plan Nacional de I+ D+i 2013-2016
- Instituto de Salud Carlos III
- Industria y Competitividad, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016, PI18/00076, PI21/00017]
- European Development Regional Fund ERDF `A way to achieve Europe', Operative program Intelligent Growth
Ask authors/readers for more resources
The study found that resistance development to imipenem/relebactam was slower and reached a lower level compared to ceftolozane/tazobactam in all tested XDR strains. Additionally, imipenem/relebactam resistance remained low even in ST175 isolates that had developed resistance to ceftolozane/tazobactam. Lineages evolved in the presence of ceftolozane/tazobactam exhibited high-level resistance, hypersusceptibility to imipenem/relebactam, and low fitness cost, while lineages evolved in the presence of imipenem/relebactam showed moderate resistance, no cross-resistance to ceftolozane/tazobactam, and high fitness cost.
Objectives To analyse the dynamics and mechanisms of stepwise resistance development to ceftolozane/tazobactam and imipenem/relebactam in XDR Pseudomonas aeruginosa clinical strains. Methods XDR clinical isolates belonging to ST111 (main resistance mechanisms: oprD(-), dacB(-), CARB-2), ST175 (oprD(-), ampR-G154R) and ST235 (oprD(-), OXA-2) high-risk clones were incubated for 24 h in Mueller-Hinton Broth with 0.125-64 mg/L of ceftolozane + tazobactam 4 mg/L or imipenem + relebactam 4 mg/L. Tubes from the highest antibiotic concentration showing growth were reinoculated into fresh medium containing concentrations up to 64 mg/L for 7 consecutive days. Two colonies per strain from each of the triplicate experiments were characterized by determining the susceptibility profiles, whole genome sequencing (WGS), and in vitro fitness through competitive growth assays. Results Resistance development occurred more slowly and reached a lower level for imipenem/relebactam than for ceftolozane/tazobactam in all tested XDR strains. Moreover, resistance development to imipenem/relebactam remained low even for ST175 isolates that had developed ceftolozane/tazobactam resistance during therapy. Lineages evolved in the presence of ceftolozane/tazobactam showed high-level resistance, imipenem/relebactam hypersusceptibility and low fitness cost, whereas lineages evolved in the presence of imipenem/relebactam showed moderate (borderline) resistance, no cross-resistance to ceftolozane/tazobactam and high fitness cost. WGS evidenced that ceftolozane/tazobactam resistance was mainly caused by mutations in the catalytic centres of intrinsic (AmpC) or acquired (OXA) beta-lactamases, whereas lineages evolved in imipenem/relebactam frequently showed structural mutations in MexB or in ParS, along with some strain-specific mutations. Conclusions Imipenem/relebactam could be a useful alternative for the treatment of XDR P. aeruginosa infections, potentially reducing resistance development during therapy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available