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Objectives: The emergence and expansion of carbapenem-resistant Klebsiella pneumoniae infections is a concern due to the lack of 'first-line' antibiotic treatment options. The ceftazidime/avibactam is an important clinical treatment for carbapenem-resistant K. pneumoniae infections but there is an increasing number of cases of treatment failure and drug resistance. Therefore, a potential solution is combination therapies that result in synergistic activity against K. pneumoniae carbapenemase: producing K. pneumoniae (KPC-Kp) isolates and preventing the emergence of KPC mutants resistant to ceftazidime/avibactam are needed in lieu of novel antibiotics.

Methods: To evaluate their synergistic activity, antibiotic combinations were tested against 26 KPC-Kp strains. Antibiotic resistance profiles, molecular characteristics and virulence genes were investigated by susceptibility testing and whole-genome sequencing. Antibiotic synergy was evaluated by in vitro chequerboard experiments, time-killing curves and dose-response assays. The mouse thigh model was used to confirm antibiotic combination activities in vivo. Additionally, antibiotic combinations were evaluated for their ability to prevent the emergence of ceftazidime/avibactam resistant mutations of blaKPC.

Results: The combination of ceftazidime/avibactam plus meropenem showed remarkable synergistic activity against 26 strains and restored susceptibility to both the partnering antibiotics. The significant therapeutic effect of ceftazidime/avibactam combined with meropenem was also confirmed in the mouse model and bacterial loads in the thigh muscle of the combination groups were significantly reduced. Furthermore, ceftazidime/avibactam plus meropenem showed significant activity in preventing the occurrence of resistance mutations.

Conclusions: Our results indicated that the combination of ceftazidime/avibactam plus meropenem offers viable therapeutic alternatives in treating serious infections due to KPC-Kp.

(© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Titel:	Synergistic effects of ceftazidime/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae.
Autor/in / Beteiligte Person:	Zheng, M ; Li, FH ; Liu, J ; Li, WJ ; Yin, RX ; Cai, DT ; Andrey, DO ; Zheng, SL ; Gales, AC ; Zhang, WJ ; Sun, J ; Liao, XP ; Yu, Y
Link:	Zum Volltext
Zeitschrift:	The Journal of antimicrobial chemotherapy, Jg. 79 (2024-05-02), Heft 5, S. 1069-1080
Veröffentlichung:	1997- : London : Oxford University Press ; <i>Original Publication</i>: London, New York, Academic Press., 2024
Medientyp:	academicJournal
ISSN:	1460-2091 (electronic)
DOI:	10.1093/jac/dkae074
Schlagwort:	Animals Mice Female Whole Genome Sequencing Drug Therapy, Combination Carbapenem-Resistant Enterobacteriaceae drug effects Carbapenem-Resistant Enterobacteriaceae genetics Ceftazidime pharmacology Ceftazidime therapeutic use Klebsiella pneumoniae drug effects Klebsiella pneumoniae genetics Drug Combinations Azabicyclo Compounds pharmacology Azabicyclo Compounds therapeutic use Meropenem pharmacology Meropenem administration & dosage Klebsiella Infections drug therapy Klebsiella Infections microbiology Anti-Bacterial Agents pharmacology Anti-Bacterial Agents therapeutic use Drug Synergism Disease Models, Animal beta-Lactamases genetics Microbial Sensitivity Tests Bacterial Proteins genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [J Antimicrob Chemother] 2024 May 02; Vol. 79 (5), pp. 1069-1080. MeSH Terms: Ceftazidime* / pharmacology ; Ceftazidime* / therapeutic use ; Klebsiella pneumoniae* / drug effects ; Klebsiella pneumoniae* / genetics ; Drug Combinations* ; Azabicyclo Compounds* / pharmacology ; Azabicyclo Compounds* / therapeutic use ; Meropenem* / pharmacology ; Meropenem* / administration & dosage ; Klebsiella Infections* / drug therapy ; Klebsiella Infections* / microbiology ; Anti-Bacterial Agents* / pharmacology ; Anti-Bacterial Agents* / therapeutic use ; Drug Synergism* ; Disease Models, Animal* ; beta-Lactamases* / genetics ; Microbial Sensitivity Tests* ; Bacterial Proteins* / genetics ; Animals ; Mice ; Female ; Whole Genome Sequencing ; Drug Therapy, Combination ; Carbapenem-Resistant Enterobacteriaceae / drug effects ; Carbapenem-Resistant Enterobacteriaceae / genetics Grant Information: Switzerland SNSF_ Swiss National Science Foundation Substance Nomenclature: 9M416Z9QNR (Ceftazidime) ; 0 (Drug Combinations) ; 0 (Azabicyclo Compounds) ; 0 (avibactam, ceftazidime drug combination) ; FV9J3JU8B1 (Meropenem) ; 0 (Anti-Bacterial Agents) ; EC 3.5.2.6 (beta-Lactamases) ; EC 3.5.2.6 (carbapenemase) ; 0 (Bacterial Proteins) Entry Date(s): Date Created: 20240325 Date Completed: 20240501 Latest Revision: 20240501 Update Code: 20240502

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Synergistic effects of ceftazidime/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae.