Mechanisms of Resistance to the Novel Antibiotic Combination Ceftazidme/Avibactam and to Avibavtam Alone in Salmonella Enterica Serovar Senftenberg
The use of β-lactam/β-lactamase inhibitors combinations has been the most significant revolution to overcome β-lactamases resistance. In 2015, the Food and Drug Administration approved the use of ceftazidime/avibactam for infections caused by Enterobacteriaceae and Pseudomonas aeruginosa. Only limited data are currently available for resistance to this combination. The study, for the first time, aims to examine mechanisms of resistance to avibactam and to ceftazidime/avibactam in Salmonella senftenberg. Bacteria were challenged with gradually increasing concentrations of either avibactam or ceftazidime/avibactam, and developed resistance to the drugs at 10-fold of the initial MIC after 43 serial transfers. Whole genome and RNA sequencing was applied to determine whether new genetic variations are associated with the resistance. No mutations or hyperproduction of β-lactamases were found. Acquisition of ceftazidime/avibactam resistance was associated with mutations in PBP 2 and 3, porin, and major facilitator superfamily (MFS) transporter, whereas acquisition of avibactam resistance was associated with mutations in PBP2, S6 unit of 30S rRNA, MFS and ATP binding cassette (ABC) transporters. Altogether, this study raises the concern regarding the ability of ceftazidime-susceptible bacteria to develop resistance to this novel combination, a resistance that is also correlated with cross-resistance to other antibiotics.
Yosra Ahmad Modafer,
"Mechanisms of Resistance to the Novel Antibiotic Combination Ceftazidme/Avibactam and to Avibavtam Alone in Salmonella Enterica Serovar Senftenberg"
ETD Collection for Tennessee State University.