Evaluation of in vitro pharmacodynamic drug interactions of ceftazidime-avibactam with tigecycline in ESBL- and carbapenemase producing Escherichia coli and Klebsiella pneumoniae

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents Pub Date : 2025-01-31 DOI:10.1016/j.ijantimicag.2025.107457

Aneeq Farooq , Bernhard Drotleff , Niklas Kroemer , Mei-Ling Han , Jian Li , Jean Winoc Decousser , David Schrey , Julien Buyck , Nicolas Grégoire , Patrice Nordmann , Sebastian G. Wicha

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引用次数: 0

Abstract

Background

Combination therapy offers a promising option to enhance efficacy and prevent resistance. A comprehensive and quantitative assessment of the last-resort combination of ceftazidime/avibactam and tigecycline is not available.

Objective

This study systematically investigated the pharmacodynamic interaction between ceftazidime/avibactam and tigecycline in clinical and isogenic Escherichia coli and Klebsiella pneumoniae strains harbouring genes that encode various carbapenemases or ESBLs.

Methods

An adaptive in vitro 'dynamic' checkerboard design and pharmacometric modelling were employed for the evaluation of pharmacodynamic interactions in fifteen bacterial isolates. Additionally, time-kill assays and metabolomic analyses were used to provide mechanistic insights.

Results

Antagonistic drug interactions between ceftazidime/avibactam and tigecycline were identified in the majority of tested strains. Time-kill assays confirmed antagonistic interactions, with tigecycline limiting ceftazidime/avibactam total killing. Metabolomic analyses of mono and combined drug exposure to bacteria revealed matching metabolomes in tigecycline alone and the combination with ceftazidime/avibactam, corroborating the identified antagonism between these drugs.

Conclusions

Our study reveals that the antagonistic interaction between ceftazidime/avibactam and tigecycline can undermine ceftazidime/avibactam's efficacy, suggesting limited clinical benefit in combining these antibiotics. Therefore, further research is encouraged to explore this and alternative combinations or approaches that may offer better clinical outcomes.

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头孢他啶-阿维巴坦与替加环素对产ESBL和碳青霉烯酶的大肠杆菌和肺炎克雷伯菌的体外药效学相互作用评价。

背景：联合治疗为提高疗效和预防耐药性提供了一个有希望的选择。目前还没有对头孢他啶/阿维巴坦和替加环素最后联合用药的全面和定量评估。目的：系统研究头孢他啶/阿维巴坦与替加环素在临床及含多种碳青霉烯酶或ESBLs编码基因的大肠杆菌和肺炎克雷伯菌等基因菌株中的相互作用。方法：采用自适应体外“动态”棋盘设计和药效学模型对15株细菌的药效学相互作用进行评价。此外，时间杀伤试验和代谢组学分析用于提供机制见解。结果：大多数被试菌株与头孢他啶/阿维巴坦存在拮抗药物相互作用。时间杀伤试验证实了拮抗相互作用，替加环素限制了头孢他啶/阿维巴坦的总杀伤。单药和联合药物暴露于细菌的代谢组学分析显示，单独使用替加环素和联合使用头孢他啶/阿维巴坦的代谢组相匹配，证实了这些药物之间的拮抗作用。结论：我们的研究表明，头孢他啶/阿维巴坦与替加环素的拮抗相互作用会破坏头孢他啶/阿维巴坦的疗效，提示联合使用这两种抗生素的临床获益有限。因此，鼓励进一步的研究来探索这种方法和其他可能提供更好临床结果的组合或方法。

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来源期刊

International Journal of Antimicrobial Agents 医学-传染病学

CiteScore

21.60

自引率

0.90%

发文量

176

审稿时长

36 days

期刊介绍： The International Journal of Antimicrobial Agents is a peer-reviewed publication offering comprehensive and current reference information on the physical, pharmacological, in vitro, and clinical properties of individual antimicrobial agents, covering antiviral, antiparasitic, antibacterial, and antifungal agents. The journal not only communicates new trends and developments through authoritative review articles but also addresses the critical issue of antimicrobial resistance, both in hospital and community settings. Published content includes solicited reviews by leading experts and high-quality original research papers in the specified fields.