Data for study "A Multicenter Study to Standardize a Mouse Pneumonia Model with Pseudomonas aeruginosa and Klebsiella pneumoniae for Antibiotic Development"
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The rise of antimicrobial resistance (AMR) underscores the urgent need for new therapeutic strategies. Reliable animal data is crucial for accelerating antibiotic development, and standardized murine infection models, such as the neutropenic mouse pneumonia model, could be key to enabling the generation of efficacy data with improved reproducibility and comparability among different laboratories. Improving reproducibility is essential for enhancing clinical translation. This study aims to establish a standardized murine pneumonia model to enhance the translation of preclinical findings into clinical applications. Using a consensus lung infection protocol, we tested 32 Klebsiella pneumoniae and Pseudomonas aeruginosa strains. Fifteen strains met our predefined virulence criteria—demonstrating at least a one log10 increase in bacterial load from baseline to endpoint while sustaining mouse survival for at least 12 hours post-inoculation. These strains are deposited at the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ) and available to researchers. Further studies at two or three independent sites (depending on strain) confirmed the virulence of eight strains, showing minimal variability in bacterial growth. These strains were incorporated into the COMBINE Preclinical Bacterial Strain Repository (PBSR) held at DSMZ. Based on these findings, we propose standardized experimental conditions, together with this defined strain panel, as a robust murine pneumonia model for preclinical testing of novel antibacterial therapies. This model provides a reproducible and well-characterized foundation for evaluating new anti-infective candidates. Ultimately, we believe the COMBINE protocol can improve the reliability and comparability of preclinical efficacy testing, and potentially reduce the number of animals needed, thus also contributing to the 3R (reduce, refine, replace) principles in animal welfare. COMBINE Pneumonia Model resources COMBINE preclinical repository with bacterial strains found to be reproducibly virulent and fulfilling performance criteria in the COMBINE standardised pneumonia mouse model. Data from the COMBINE Multicenter Study to Standardize a Mouse Pneumonia Model with Pseudomonas aeruginosa and Klebsiella pneumoniae for Antibiotic Development Arrazuria R, Kerscher B, Huber KE, Hoover JL, Lundberg CV, Hansen JU, Sordello S, Renard S, Aranzana-Climent V, Hughes D, Gribbon P, Friberg LE, Bekeredjian-Ding I (2022): Expert workshop summary: Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections.Front Microbiol 13: 988725. Arrazuria R, Kerscher B, Huber KE, et al. Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents. Frontiers in Microbiology. 2022;13:988728.
抗菌药物耐药性（antimicrobial resistance, AMR）的持续蔓延，凸显了开发新型治疗策略的迫切需求。可靠的动物实验数据对于加速抗生素研发至关重要，而标准化的小鼠感染模型——如中性粒细胞减少性小鼠肺炎模型——或是实现可提升不同实验室间重复性与可比性的药效数据生成的关键。提升实验重复性对于推动临床转化至关重要。本研究旨在建立标准化的小鼠肺炎模型，以强化临床前研究发现向临床应用的转化。 采用共识性肺部感染操作方案，本研究对32株肺炎克雷伯菌（Klebsiella pneumoniae）和铜绿假单胞菌（Pseudomonas aeruginosa）菌株进行了测试。其中15株符合我们预先设定的毒力判定标准：从接种基线至实验终点，细菌载量至少升高1个对数10量级，且小鼠在接种后至少存活12小时。这些菌株已保藏于德国微生物和细胞培养物保藏中心（German Collection of Microorganisms and Cell Cultures GmbH, DSMZ），可供全球研究人员获取。 在2至3个独立实验站点（依菌株类型而定）开展的进一步验证研究证实了其中8株菌株的毒力，其细菌生长的变异度极低。上述菌株已被纳入保藏于DSMZ的COMBINE临床前细菌菌株库（COMBINE Preclinical Bacterial Strain Repository, PBSR）。基于上述研究结果，我们提出将标准化实验条件与这套经过筛选的菌株组合相结合，作为一款稳健的小鼠肺炎模型，用于新型抗菌疗法的临床前药效测试。该模型可为评估新型抗感染候选药物提供可重复且特征明确的实验基础。最终，我们认为COMBINE方案能够显著提升临床前药效测试的可靠性与可比性，还有望减少实验所需动物数量，因此也符合动物福利领域的3R（减少、优化、替代）原则。 COMBINE肺炎模型相关资源 ——包含在COMBINE标准化小鼠肺炎模型中被证实具有可重复毒力且满足性能标准的细菌菌株的COMBINE临床前菌株库。 ——来自COMBINE多中心研究的相关数据，该研究旨在建立针对铜绿假单胞菌与肺炎克雷伯菌的标准化小鼠肺炎模型，以推动抗生素研发。 Arrazuria R, Kerscher B, Huber KE, Hoover JL, Lundberg CV, Hansen JU, Sordello S, Renard S, Aranzana-Climent V, Hughes D, Gribbon P, Friberg LE, Bekeredjian-Ding I (2022): 专家研讨会总结：推进标准化小鼠模型研发以评估抗菌药物耐药性肺部感染的治疗方案. 微生物学前沿 13: 988725. Arrazuria R, Kerscher B, Huber KE, 等. 用于评估抗菌药物的小鼠细菌性肺炎模型的变异度. 微生物学前沿. 2022;13:988728.
