Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA.

IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Journal of Antimicrobial Chemotherapy Pub Date : 2024-10-16 DOI:10.1093/jac/dkae363
Sonia Luque Pardos, William Hope, Antigone Kotsaki, Shampa Das, Evangelos J Giamarellos-Bourboulis, Theano Kontopoulouk, Karolina Akinosoglou, Miriam O'Hare, Marie L G Attwood, Karen E Bowker, Alan R Noel, Andrew M Lovering, Mark A J Bayliss, Rebecca N Evans, Alasdair P MacGowan
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Abstract

Background: The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described.

Methods: Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored.

Results: A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target.

Conclusions: Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

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米诺环素联合利福平在 MRSA 引起的复杂皮肤和皮肤结构感染患者中的群体药代动力学/药效学。
背景:描述了米诺环素、利福平和利奈唑胺在MRSA引起的复杂皮肤和软组织感染(cSSTI)患者中的群体药代动力学/药效学(PK/PD):在口服米诺环素加利福平与利奈唑胺的第 4 期研究中收集了样本,结果显示米诺环素加利福平与利奈唑胺的疗效相当。抗生素通过 HPLC 或 LC-MS 进行检测,并使用 Pmetrics 建立了群体 PK 模型。探讨了 PK/PD 指数与患者预后之间的关联:结果:采用一阶输入和消除的三室模型(含一个吸收室)对三种药物的数据进行了最佳描述。最终模型中未包含协变量。米诺环素的清除率和分布容积的人群中位值(95% 可信限)分别为 7.412 L/h (5.121-8.361) 和 14.155 L (6.799-33.901) 。901),利福平为 5.683 L/h(3.703-7.726)和 7.736 L(6.031-8.948),利奈唑胺为 1.970 L/h(1.326-2.499)和 20.169 L(12.857-32.629)。米诺环素的观察值与预测值的最大后验概率-贝叶斯估计图的斜率为 0.999 r20.967,利福平的斜率为 0.998 r20.769,利奈唑胺的斜率为 0.998 r20.895。PK/PD 指数与临床结果无关。在利福平存在的情况下,米诺环素的转化米诺环素fAUC24h/MIC目标值>0.5,96%(49/51)的患者达到了目标值:在MRSA cSSTI患者中建立了米诺环素、利福平和利奈唑胺的人群PK模型,几乎所有患者都达到了预定义的PD指数目标。因此,AUC、MIC或AUC/MIC比值均与临床结果无关。
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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.
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