一种新型药效学优化的碳青霉烯保留抗生素WCK 4282(头孢吡肟/他唑巴坦)在健康、肺部和大腿感染的中性粒细胞减少小鼠上皮内膜液中的药代动力学和渗透

IF 1.9 4区 医学 Q3 INFECTIOUS DISEASES
Rajesh Chavan, Vineet Zope, Kiran Patil, Swapna Takalkar, Pavan Tayde, Kushal Umarkar, Ravindra Yeole, Sachin Bhagwat
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引用次数: 0

摘要

目的:头孢吡肟(FEP)是第四代头孢菌素与β-内酰胺酶抑制剂他唑巴坦(TAZ)联合开发的一种药效学优化的固定剂量组合(FEP- 2g + TAZ- 2g),用于治疗多重耐药革兰氏阴性感染。为了进行暴露-反应分析以建立药代动力学(PK)/药效学(PD)靶点,在用于评估体内疗效的临床相关动物感染模型中,表征替代区室(如血浆和肺)中化合物的PK谱至关重要。在目前的研究中,对中性粒细胞减少、未感染、肺部感染和大腿感染小鼠的血浆和上皮衬里液(ELF)中FEP和TAZ的PKs进行了评估。方法:中性粒细胞减少小鼠经鼻或肌内注射每毫升106 ~ 107个菌落形成单位的大肠杆菌引起肺部或大腿感染。感染2小时后,皮下注射25 + 25、50 + 50和100 + 100 mg/kg单剂量WCK 4282。在给药后8小时收集血浆和支气管肺泡灌洗液。结果:健康小鼠和感染小鼠血浆/ELF中FEP和TAZ的PK无显著差异。FEP和TAZ在中性粒细胞减少感染小鼠的血浆PK谱与适度的ELF渗透呈线性和剂量正比关系。与健康小鼠相比,FEP和TAZ在大腿感染小鼠中的ELF暴露量略低,而在肺部感染小鼠中的暴露量较高。无论健康状况如何,FEP和TAZ的曲线下平均ELF/血浆面积穿透比相似且具有可比性(0.42-0.43)。结论:本研究估计的FEP和TAZ PK参数将有助于PK- pd研究的剂量选择,以进行即将进行的体内疗效研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetics and Penetration of a Novel Pharmacodynamically Optimized, Carbapenem-Sparing Antibiotic, WCK 4282 (Cefepime/Tazobactam), into Epithelial Lining Fluid of Healthy, Lung-, and Thigh-Infected Neutropenic Mice.

Objectives: Cefepime (FEP), a fourth-generation cephalosporin combined with tazobactam (TAZ), a β-lactamase inhibitor, is being developed by Wockhardt as a pharmacodynamically optimized fixed dose combination (FEP-2 g + TAZ-2 g) for the treatment of multidrug-resistant Gram-negative infections. To undertake an exposure-response analysis for establishing pharmacokinetic (PK)/pharmacodynamic (PD) targets, it is crucial to characterize the PK profile of compounds in surrogate compartments, such as plasma and lung, in clinically relevant animal infection models used to evaluate in vivo efficacy. In the current study, PKs of FEP and TAZ were assessed in plasma and in epithelial lining fluid (ELF) of neutropenic noninfected, lung-infected, and thigh-infected mice. Methods: Neutropenic mice were infected by intranasal or intramuscular administration of 106-107 colony-forming units per milliliter of Escherichia coli to develop infection in lung or thigh. Post 2 hours of infection, single doses of WCK 4282 at 25 + 25, 50 + 50, and 100 + 100 mg/kg were subcutaneously administered. Plasma and bronchoalveolar lavage fluid were collected up to 8 hours post-administration of doses. Results: The PK of FEP and TAZ in plasma/ELF in healthy and infected mice did not differ significantly. The plasma PK profiles of FEP and TAZ were linear and dose proportional with modest ELF penetrations in the neutropenic infected mice. The ELF exposures of FEP and TAZ were slightly lower in thigh-infected mice and higher in lung-infected mice when compared with healthy mice. Irrespective of health condition, the mean ELF/plasma area under the curve penetration ratio for FEP and TAZ was similar and comparable (0.42-0.43). Conclusion: The estimates of FEP and TAZ PK parameters estimated in the current study would help in PK-PD studies for the selection of doses for upcoming in vivo efficacy studies.

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来源期刊
Microbial drug resistance
Microbial drug resistance 医学-传染病学
CiteScore
6.00
自引率
3.80%
发文量
118
审稿时长
6-12 weeks
期刊介绍: Microbial Drug Resistance (MDR) is an international, peer-reviewed journal that covers the global spread and threat of multi-drug resistant clones of major pathogens that are widely documented in hospitals and the scientific community. The Journal addresses the serious challenges of trying to decipher the molecular mechanisms of drug resistance. MDR provides a multidisciplinary forum for peer-reviewed original publications as well as topical reviews and special reports. MDR coverage includes: Molecular biology of resistance mechanisms Virulence genes and disease Molecular epidemiology Drug design Infection control.
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