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Jun 04, 2024;12 (6): e0010724.

Effect of ceftazidime-avibactam combined with different antimicrobials against carbapenem-resistant .

Yun Wu, Wei Yu, Xiaobing Chu, Jingjia Zhang, Peiyao Jia, XiaoYu Liu, Ying Zhu, YingChun Xu, Qiwen Yang
Author Information
  1. Yun Wu: Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China. ORCID
  2. Wei Yu: Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China.
  3. Xiaobing Chu: Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China.
  4. Jingjia Zhang: Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China.
  5. Peiyao Jia: Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China.
  6. XiaoYu Liu: Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China.
  7. Ying Zhu: Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China. ORCID
  8. YingChun Xu: Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. ORCID
  9. Qiwen Yang: Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. ORCID
PMID: 38712934 DOI: 10.1128/spectrum.00107-24

Abstract

This study aimed to assess the efficacy of ceftazidime-avibactam (CZA) in combination with various antimicrobial agents against carbapenem-resistant (CRKP). We selected 59 clinical CRKP isolates containing distinct drug resistance mechanisms. The minimum inhibitory concentrations (MICs) of meropenem (MEM), colistin (COL), eravacycline (ERA), amikacin (AK), fosfomycin (FOS), and aztreonam (ATM), both individually and in combination with CZA, were tested using the checkerboard method. The interactions of antimicrobial agent combinations were assessed by fractional inhibitory concentration index (FICI) and susceptible breakpoint index (SBPI). The time-kill curve assay was employed to dynamically evaluate the effects of these drugs alone and in combination format. In the checkerboard assay, the combination of CZA+MEM showed the highest level of synergistic effect against both KPC-producing and carbapenemase-non-producing isolates, with synergy rates of 91.3% and 100%, respectively. Following closely was the combination of FOS+CZA . For metallo-beta-lactamases (MBLs) producing strains, ATM+CZA displayed complete synergy, while the combination of MEM+CZA showed a synergy rate of only 57.14% for NDM-producing strains and 91.67% for IMP-producing strains. In the time-kill assay, MEM+CZA also demonstrated significant synergistic effects against the two KPC-2-producing isolates (Y070 and L70), the two carbapenemase-non-producing isolates (Y083 and L093), and the NDM-1-producing strain L13, with reductions in log CFU/mL exceeding 10 compared to the control. Against the IMP-producing strain Y047, ATM+CZA exhibited the highest synergistic effect, resulting in a log CFU/mL reduction of 10.43 compared to the control. The combination of CZA and MEM exhibited good synergistic effects against KPC-producing and non-enzyme-producing strains, followed by the FOS+CZA combination. Among MBL-producing strains, ATM+CZA demonstrated the most pronounced synergistic effect. However, the combinations of CZA with ERA, AK, and COL show irrelevant effects against the tested clinical isolates.
IMPORTANCE: Our study confirmed the efficacy of the combination CZA+MEM against KPC-producing and non-carbapenemase-producing strains. For metalloenzyme-producing strains, CZA+ATM demonstrated the most significant synergy. Additionally, CZA exhibited a notable synergy effect when combined with FOS. These combination therapies present promising new options for the treatment of CRKP infection.

Keywords

antimicrobial agent combinations carbapenem-resistant Klebsiella pneumoniae ceftazidime-avibactam checkerboard test time-kill curve assay

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MeSH Term

Azabicyclo Compounds
Klebsiella pneumoniae
Ceftazidime
Drug Combinations
Microbial Sensitivity Tests
Humans
Anti-Bacterial Agents
Klebsiella Infections
Carbapenem-Resistant Enterobacteriaceae
Drug Synergism
beta-Lactamases
Carbapenems
Drug Resistance, Multiple, Bacterial
Bacterial Proteins
Fosfomycin
Aztreonam

Chemicals

Azabicyclo Compounds
avibactam, ceftazidime drug combination
Ceftazidime
Drug Combinations
Anti-Bacterial Agents
beta-Lactamases
Carbapenems
Bacterial Proteins
carbapenemase
Fosfomycin
Aztreonam
Journal Article

Word Cloud

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