建立适用于鼠肺炎模型的肺炎克雷伯氏菌和铜绿假单胞菌的多种表型挑战集。

IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Journal of Antimicrobial Chemotherapy Pub Date : 2024-10-30 DOI:10.1093/jac/dkae388
Andrew J Fratoni, Alissa M Padgett, Erin M Duffy, David P Nicolau
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引用次数: 0

摘要

背景:临床前小鼠感染模型缺乏实验室间的统一性,导致结果比较和数据可重复性变得复杂。欧洲创新药物倡议资助的联盟(COMBINE)制定了标准化的小鼠中性肺炎方案,以解决这些问题。虽然模型方法已经标准化,但结果一致性的一个主要障碍是缺乏具有明确活力和变异性的可用细菌。在此,我们建立了一套适用于 COMBINE 方案的肺炎克雷伯氏菌和铜绿假单胞菌的多样化挑战集,以进一步减少实验的不一致性,并提高不同实验室生成的数据的可解释性:对 66 株肺炎克雷伯菌和 65 株铜绿假单胞菌进行了表型分析,分析了它们对替加环素(仅肺炎克雷伯菌)、左氧氟沙星、美罗培南、头孢克肟和妥布霉素的耐药性。将 59 个分离株引入 COMBINE 模型,以评估起始细菌接种的充分性、由此产生的基线细菌负荷、24 小时内达到≥1 log10cfu/lung 的生长量、死亡时间和死亡率百分比。对 45 个显示出理想最低抑菌浓度曲线的分离物进行了重复体内试验,以评估目标参数:结果:在起始细菌负荷≥7 log10cfu/肺时,83%的肺炎克氏菌在 24 小时内达到了生长要求。铜绿假单胞菌在模型中生长良好:在起始细菌量为 6 log10cfu/肺时,90% 的分离物达到了生长目标。肺炎克氏菌的死亡率可以忽略不计,但铜绿假单胞菌的死亡率很高。有 11/59 个分离株的 24 小时生长目标达标率较低或不一致:结论:通过在 COMBINE 肺炎模型中建立的可存活分离株的多样性,未来的转化研究可以在实验室之间建立疗效基准。
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Establishment of a diverse pheno-genotypic challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa suitable for use in the murine pneumonia model.

Background: Preclinical murine infection models lack inter-laboratory uniformity, complicating result comparisons and data reproducibility. The European Innovative Medicines initiative-funded consortium (COMBINE) has developed a standardized murine neutropenic pneumonia protocol to address these concerns. While model methods have been standardized, a major obstacle to consistent results is the lack of available bacteria with defined viability and variability. Herein, we establish a diverse challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa suitable for use in the COMBINE protocol to further minimize experimental inconsistency and improve the interpretability of data generated among differing laboratories.

Materials and methods: Sixty-six K. pneumoniae and 65 P. aeruginosa were phenotypically profiled against tigecycline (K. pneumoniae only), levofloxacin, meropenem, cefiderocol and tobramycin. Fifty-nine isolates were introduced into the COMBINE model to assess the sufficiency of the starting bacterial inoculation, resultant baseline bacterial burden, achievement of ≥1 log10cfu/lung growth at 24 h, time to and percentage mortality. Forty-five isolates displaying desirable minimum inhibitory concentration profiles were subjected to replicate in vivo testing to assess target parameters.

Results: 83% of K. pneumoniae reached the prerequisite growth at 24 h using a starting bacterial burden ≥7 log10cfu/lung. P. aeruginosa isolates grew well in the model: 90% achieved the growth target with a starting bacterial burden of 6 log10cfu/lung. Mortality was negligible for K. pneumoniae but high for P. aeruginosa. Poor or inconsistent achievement of the 24 h growth target was seen in 11/59 isolates.

Conclusions: With this diverse cache of viable isolates established in the COMBINE pneumonia model, future translational studies can be undertaken to set efficacy benchmarks among laboratories.

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来源期刊
CiteScore
9.20
自引率
5.80%
发文量
423
审稿时长
2-4 weeks
期刊介绍: The Journal publishes articles that further knowledge and advance the science and application of antimicrobial chemotherapy with antibiotics and antifungal, antiviral and antiprotozoal agents. The Journal publishes primarily in human medicine, and articles in veterinary medicine likely to have an impact on global health.
期刊最新文献
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