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In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment.
J Antimicrob Chemother 2018; 73(6):1525-1529JA

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.

Authors+Show Affiliations

Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.Operative Unit of Infectious Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy.Operative Unit of Infectious Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy. Department of Medical and Surgical Sciences DIMEC, University of Bologna, Bologna, Italy.Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.Risk Analysis Unit, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna (IZSLER), Parma, Italy.Operative Unit of Infectious Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy. Department of Medical and Surgical Sciences DIMEC, University of Bologna, Bologna, Italy.Risk Analysis Unit, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna (IZSLER), Parma, Italy.Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.Operative Unit of Infectious Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy.Operative Unit of Infectious Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy.Operative Unit of Infectious Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy.Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29566151

Citation

Gaibani, Paolo, et al. "In Vivo Evolution of Resistant Subpopulations of KPC-producing Klebsiella Pneumoniae During Ceftazidime/avibactam Treatment." The Journal of Antimicrobial Chemotherapy, vol. 73, no. 6, 2018, pp. 1525-1529.
Gaibani P, Campoli C, Lewis RE, et al. In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment. J Antimicrob Chemother. 2018;73(6):1525-1529.
Gaibani, P., Campoli, C., Lewis, R. E., Volpe, S. L., Scaltriti, E., Giannella, M., ... Ambretti, S. (2018). In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment. The Journal of Antimicrobial Chemotherapy, 73(6), pp. 1525-1529. doi:10.1093/jac/dky082.
Gaibani P, et al. In Vivo Evolution of Resistant Subpopulations of KPC-producing Klebsiella Pneumoniae During Ceftazidime/avibactam Treatment. J Antimicrob Chemother. 2018 06 1;73(6):1525-1529. PubMed PMID: 29566151.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment. AU - Gaibani,Paolo, AU - Campoli,Caterina, AU - Lewis,Russell E, AU - Volpe,Silvia Lidia, AU - Scaltriti,Erika, AU - Giannella,Maddalena, AU - Pongolini,Stefano, AU - Berlingeri,Andrea, AU - Cristini,Francesco, AU - Bartoletti,Michele, AU - Tedeschi,Sara, AU - Ambretti,Simone, PY - 2017/09/22/received PY - 2018/02/15/accepted PY - 2018/3/23/pubmed PY - 2019/9/14/medline PY - 2018/3/23/entrez SP - 1525 EP - 1529 JF - The Journal of antimicrobial chemotherapy JO - J. Antimicrob. Chemother. VL - 73 IS - 6 N2 - 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. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/29566151/In_vivo_evolution_of_resistant_subpopulations_of_KPC_producing_Klebsiella_pneumoniae_during_ceftazidime/avibactam_treatment_ L2 - https://academic.oup.com/jac/article-lookup/doi/10.1093/jac/dky082 DB - PRIME DP - Unbound Medicine ER -