Importance of beta-lactam pharmacokinetics and pharmacodynamics on the recovery of microbial diversity in the airway of persons with cystic fibrosis.
Importance of beta-lactam pharmacokinetics and pharmacodynamics on the recovery of microbial diversity in the airway of persons with cystic fibrosis.
复制标题
DOI：
10.1136/jim-2021-001824
复制
发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Crandall KA
中科院分区：
文献类型：
--
作者：
Hahn A;Burrell A;Chaney H;Sami I;Koumbourlis AC;Freishtat RJ;Zemanick ET;Louie S;Crandall KA
囊性纤维化(CF)是一种以急性肺加重(PExs)为特征的慢性肺部疾病，经常使用抗生素治疗。抗生素对呼吸道微生物多样性的影响仍然是一个关键的知识缺口。我们试图确定β-内酰胺药代动力学(PK)与药效学丰富度和α多样性之间的关系。27名18岁的儿童参加了这项前瞻性研究。在入院时、抗生素治疗结束(Tr)和1个 月的随访(FU)时采集呼吸道样本。进行元基因组测序，以确定丰富度、α多样性和抗生素耐药基因的存在。测定血浆游离β-内酰胺水平，并进行PK模拟以确定超过最小抑菌浓度(FT>；MIC)的时间。52%的研究对象有足够的FT>；MIC来达到最佳杀菌效果。除F508del纯合性外，在人口学和Pex特征上均无显著差异。在各个时间点，丰富度和阿尔法多样性没有显著差异，两组在Tr的丰富度和阿尔法多样性都比Pex有所下降。然而，在FT>；MIC 充足的患者中，FU的α多样性仍低于PEX，而在FT>；MIC不足的患者中，α多样性增加(香农−0.222 vs+0.452，p=0.031， 和逆向辛普森−1.376 vs+1.388，p=0.032)。氟喹诺酮类药物耐药也多见于FT>；MIC不足的患者(log2倍变化(Log2FC)2.29，p=0.025)。这些发现表明，足够的β-内酰胺类药物的最低抑菌浓度与抗生素暴露后阿尔法多样性的恢复受到抑制有关。
Cystic fibrosis (CF) is a chronic lung disease characterized by acute pulmonary exacerbations (PExs) that are frequently treated with antibiotics. The impact of antibiotics on airway microbial diversity remains a critical knowledge gap. We sought to define the association between beta-lactam pharmacokinetic (PK) and pharmacodynamic target attainment on richness and alpha diversity. Twenty-seven children <18 years of age with CF participated in the prospective study. Airway samples were collected at hospital admission for PEx, end of antibiotic treatment (Tr), and >1 month in follow-up (FU). Metagenomic sequencing was performed to determine richness, alpha diversity, and the presence of antibiotic resistance genes. Free plasma beta-lactam levels were measured, and PK modeling was performed to determine time above the minimum inhibitory concentration (fT>MIC). 52% of study subjects had sufficient fT>MIC for optimal bacterial killing. There were no significant differences in demographics or PEx characteristics, except for F508del homozygosity. No significant differences were noted in richness or alpha diversity at individual time points, and both groups experienced a decrease in richness and alpha diversity at Tr compared with PEx. However, alpha diversity remained decreased at FU compared with PEx in those with sufficient fT>MIC but increased in those with insufficient fT>MIC (Shannon −0.222 vs +0.452, p=0.031, and inverse Simpson −1.376 vs +1.388, p=0.032). Fluoroquinolone resistance was also more frequently detected in those with insufficient fT>MIC (log2 fold change (log2FC) 2.29, p=0.025). These findings suggest sufficient beta-lactam fT>MIC is associated with suppressed recovery of alpha diversity following the antibiotic exposure period.
登录
查看更多内容
影响因子：
9.6
作者：
Smith, AL;Fiel, SB;Burns, JL
通讯作者：
Burns, JL
影响因子：
48
作者：
Segata, Nicola;Waldron, Levi;Ballarini, Annalisa;Narasimhan, Vagheesh;Jousson, Olivier;Huttenhower, Curtis
通讯作者：
Huttenhower, Curtis
在囊性纤维化中，跨年龄和疾病阶段的肺微生物群。
影响因子：
4.6
作者：
Coburn B;Wang PW;Diaz Caballero J;Clark ST;Brahma V;Donaldson S;Zhang Y;Surendra A;Gong Y;Elizabeth Tullis D;Yau YC;Waters VJ;Hwang DM;Guttman DS
通讯作者：
Guttman DS
影响因子：
4.6
作者：
Hahn, Andrea;Fanous, Hani;Crandall, Keith A.
通讯作者：
Crandall, Keith A.
影响因子：
39.2
作者：
MacKenzie T;Gifford AH;Sabadosa KA;Quinton HB;Knapp EA;Goss CH;Marshall BC
通讯作者：
Marshall BC