1. In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment
- Author
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Stefano Pongolini, Sara K. Tedeschi, Silvia Lidia Volpe, Russell E. Lewis, Simone Ambretti, Paolo Gaibani, Francesco Cristini, Andrea Berlingeri, Maddalena Giannella, Michele Bartoletti, Erika Scaltriti, Caterina Campoli, Gaibani, Paolo, Campoli, Caterina, Lewis, Russell E., Volpe, Silvia Lidia, Scaltriti, Erika, Giannella, Maddalena, Pongolini, Stefano, Berlingeri, Andrea, Cristini, Francesco, Bartoletti, Michele, Tedeschi, Sara, and Ambretti, Simone
- Subjects
0301 basic medicine ,Microbiology (medical) ,Carbapenem ,Klebsiella pneumoniae ,Avibactam ,030106 microbiology ,Population ,Porins ,Ceftazidime ,Microbial Sensitivity Tests ,Drug resistance ,Biology ,Meropenem ,beta-Lactamases ,Microbiology ,Evolution, Molecular ,03 medical and health sciences ,chemistry.chemical_compound ,Bacterial Proteins ,Drug Resistance, Multiple, Bacterial ,polycyclic compounds ,medicine ,Humans ,Pharmacology (medical) ,education ,Phylogeny ,Pharmacology ,education.field_of_study ,Whole Genome Sequencing ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,Ceftazidime/avibactam ,biology.organism_classification ,Anti-Bacterial Agents ,Klebsiella Infections ,Drug Combinations ,Carbapenem-Resistant Enterobacteriaceae ,Infectious Diseases ,chemistry ,Mutation ,Azabicyclo Compounds ,medicine.drug - Abstract
Objectives KPC-producing Klebsiella pneumoniae (KPC-Kp) represent a serious problem worldwide. Herein, we describe the evolution of ceftazidime/avibactam resistance by sequencing longitudinal clinical isolates from a patient with KPC-Kp bloodstream infection undergoing ceftazidime/avibactam treatment. Methods WGS was performed on one ceftazidime/avibactam-susceptible KPC-Kp (BOT-CA-S) and two phenotypically different ceftazidime/avibactam-resistant KPC-Kp with low (BOT-CA-R) and high (BOT-EMO) carbapenem MICs. The population diversity was assessed by the frequency of allele mutations and population analysis profiles (PAPs). Results Phylogenetic analysis demonstrated clonal relatedness of the KPC-Kp isolates, all belonging to the clone ST1519. The D179Y mutation in blaKPC-3 was detected in both of the ceftazidime/avibactam-resistant KPC-Kp, whereas it was absent in the ceftazidime/avibactam-susceptible isolate. The mutation emerged independently in the two ceftazidime/avibactam-resistant isolates and was associated with a significant reduction in carbapenem MICs in BOT-CA-R, but not in BOT-EMO. WGS analysis revealed that the frequency of the D179Y mutation was 96.32% and 51.05% in BOT-CA-R and BOT-EMO, respectively. PAP results demonstrated that carbapenem resistance in BOT-EMO was due to the coexistence of mixed subpopulations harbouring WT and mutated blaKPC-3. A bacterial subpopulation with high ceftazidime/avibactam resistance for BOT-EMO KPC-Kp showed low carbapenem MICs, whereas a subpopulation with high meropenem resistance had a low MIC of ceftazidime/avibactam. Conclusions Our analysis indicates that mixed subpopulations of ceftazidime/avibactam-resistant KPC-Kp emerge after ceftazidime/avibactam treatment. The evolution of different subpopulations that are highly resistant to ceftazidime/avibactam likely contributes to treatment failure, thereby highlighting the need for combination treatment strategies to limit selection of ceftazidime/avibactam-resistant KPC-Kp subpopulations.
- Published
- 2018