Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection
Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection
复制标题
头孢喹肟在金黄色葡萄球菌感染中性粒细胞减少小鼠大腿模型中的药效学
DOI：
10.1128/aac.01666-13
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发表时间：
2014-06-01
影响因子：
4.9
通讯作者：
Zeng, Zhenling
中科院分区：
文献类型：
--
作者：
Wang, Jing;Shan, Qi;Zeng, Zhenling
摘要头孢喹酮是一种具有广谱抗菌活性的头孢菌素，包括对金黄色葡萄球菌的抗菌活性。本研究的目的是利用中性粒细胞减少的小鼠大腿感染模型，检测头孢喹酮对金黄色葡萄球菌的体内抗菌活性。用LC-MS/MS法测定感染中性粒细胞减少症小鼠的头孢喹酮动力学和蛋白质结合情况。对感染金黄色葡萄球菌ATCC 29213株的小鼠进行体内抗菌素后效应(PAE)的测定。24 h皮下注射头孢喹酮2.5~320 mg/kg体重，分1、2、3、6或12个剂量，2.9h后呈现时间依赖性杀伤作用，体内产生PAEs，血药浓度超过MIC的时间百分比(%T&gT；MIC)是描述头孢喹酮药效的药代动力学-药效学(PK-PD)指标。随后，我们采用了类似的剂量策略，将头孢喹酮的总剂量增加了4倍，每隔4小时给药一次，以治疗感染另外6株金黄色葡萄球菌的动物。用S型最大效应(Emax)模型估计自由药物血药浓度超过净细菌停滞的MIC(%T&gT；FMIC)、较基线减少0.5-log10 CFU和较基线减少1-log10 CFU的比率的大小，分别为30.28~36.84%、34.38~46.70%、43.50~54.01%。清晰的PAEs和强大的杀菌活性使头孢喹酮成为治疗金黄色葡萄球菌感染的有吸引力的选择。
ABSTRACT Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against Staphylococcus aureus. The objective of our study was to examine the in vivo activity of cefquinome against S. aureus strains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo postantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected with S. aureus strain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and produced in vivo PAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additional S. aureus isolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %T that the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10 CFU reduction from baseline, and a 1-log10 CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused by S. aureus.