Therapeutic drug monitoring (TDM) of β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations: insights from a pharmacometric simulation study.

IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Journal of Antimicrobial Chemotherapy Pub Date : 2024-10-22 DOI:10.1093/jac/dkae375
Amaury O'Jeanson, Elisabet I Nielsen, Lena E Friberg
{"title":"Therapeutic drug monitoring (TDM) of β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations: insights from a pharmacometric simulation study.","authors":"Amaury O'Jeanson, Elisabet I Nielsen, Lena E Friberg","doi":"10.1093/jac/dkae375","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear.</p><p><strong>Objectives: </strong>Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest.</p><p><strong>Methods: </strong>Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis.</p><p><strong>Results: </strong>Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination.</p><p><strong>Conclusions: </strong>This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Antimicrobial Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/jac/dkae375","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
引用次数: 0

Abstract

Background: The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear.

Objectives: Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest.

Methods: Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis.

Results: Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination.

Conclusions: This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
β-内酰胺/β-内酰胺酶抑制剂(BL/BLI)药物组合的治疗药物监测(TDM):药效学模拟研究的启示。
背景:产β-内酰胺酶细菌的出现导致了β-内酰胺(BL)抗生素和β-内酰胺酶抑制剂(BLI)药物组合的使用。尽管治疗药物监测(TDM)已被认可用于β-内酰胺类抗生素,但治疗药物监测对β-内酰胺类药物的影响仍不明确:评估在感染部位是否能获得有效暴露的 BLIs,并评估 BLIs 的 TDM 是否有意义:方法:使用9种BL和BLI化合物的群体药代动力学模型模拟在EMA批准的剂量方案下感染部位的药物浓度,同时考虑血浆蛋白结合和组织渗透。预测的靶点浓度用于达标概率(PTA)分析:结果:使用 EUCAST 目标,在不同感染部位,对于具有典型肾清除率(CrCL 为 80 mL/min)的患者,BLs 的 PTA 令人满意(≥90%)。然而,BLIs 的结果却各不相同。阿维菌素仅在血浆中达到了令人满意的 PTA 值,而在腹部(78%)、肺部(73%)和前列腺(23%)中的 PTA 值则有所降低。同样,他唑巴坦在腹腔内感染(79%)、尿路感染(64%)和前列腺炎(34%)中的 PTA 值也不尽人意。亚胺培南-雷巴坦和美罗培南-瓦博拉巴坦的 PTA 值总体令人满意,但后一种组合在前列腺炎和高 MIC 感染中除外:本研究强调了仅仅依赖于BL的TDM的风险,因为这可能表明BL的暴露量是可接受的,而BLI的浓度,以及由此产生的组合,可能导致细菌杀灭效果不理想。因此,在临床实践中,根据BLIs(尤其是阿维巴坦和他唑巴坦)的血浆浓度测量结果进行剂量调整,以获得目标部位的有效暴露量,可能会很有价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
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
Emergence of the mobile RND-type efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae clinical isolates in Japan. Rapid viral suppression using integrase inhibitors during acute HIV-1 infection. Resistance profiles of carbapenemase-producing Enterobacterales in a large centre in England: are we already losing cefiderocol? Comment on: Antiviral effect of Evusheld in COVID-19 hospitalized patients infected with pre-Omicron or Omicron variants: a modelling analysis of the randomized DisCoVeRy trial. Oral antimicrobial agents in patients with short bowel syndrome: worth a try!-authors' response.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1