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Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo.
J Antimicrob Chemother. 2019 11 01; 74(11):3211-3216.JA

Abstract

OBJECTIVES

The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro.

METHODS

Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time-kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination.

RESULTS

The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time-kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival.

CONCLUSIONS

Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time-kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

Authors+Show Affiliations

Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.

Pub Type(s)

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

Language

eng

PubMed ID

31365094

Citation

Göttig, Stephan, et al. "Emergence of Ceftazidime/avibactam Resistance in KPC-3-producing Klebsiella Pneumoniae in Vivo." The Journal of Antimicrobial Chemotherapy, vol. 74, no. 11, 2019, pp. 3211-3216.
Göttig S, Frank D, Mungo E, et al. Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo. J Antimicrob Chemother. 2019;74(11):3211-3216.
Göttig, S., Frank, D., Mungo, E., Nolte, A., Hogardt, M., Besier, S., & Wichelhaus, T. A. (2019). Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo. The Journal of Antimicrobial Chemotherapy, 74(11), 3211-3216. https://doi.org/10.1093/jac/dkz330
Göttig S, et al. Emergence of Ceftazidime/avibactam Resistance in KPC-3-producing Klebsiella Pneumoniae in Vivo. J Antimicrob Chemother. 2019 11 1;74(11):3211-3216. PubMed PMID: 31365094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo. AU - Göttig,Stephan, AU - Frank,Denia, AU - Mungo,Eleonora, AU - Nolte,Anika, AU - Hogardt,Michael, AU - Besier,Silke, AU - Wichelhaus,Thomas A, PY - 2019/04/12/received PY - 2019/06/14/revised PY - 2019/07/03/accepted PY - 2019/8/1/pubmed PY - 2020/9/17/medline PY - 2019/8/1/entrez SP - 3211 EP - 3216 JF - The Journal of antimicrobial chemotherapy JO - J Antimicrob Chemother VL - 74 IS - 11 N2 - OBJECTIVES: The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. METHODS: Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time-kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. RESULTS: The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time-kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. CONCLUSIONS: Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time-kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/31365094/Emergence_of_ceftazidime/avibactam_resistance_in_KPC_3_producing_Klebsiella_pneumoniae_in_vivo_ L2 - https://academic.oup.com/jac/article-lookup/doi/10.1093/jac/dkz330 DB - PRIME DP - Unbound Medicine ER -