基于PK/PD模型对恩诺沙星可溶性粉在鸡混饮给药方案的药效再评价

Reevaluation of the Efficacy of Enrofloxacin Soluble Powder Mixed Drink Administration Regimen in Chicken by Modelling of Pharmacokinetic and Pharmacodynamic Data

旨在对不同日龄雏鸡开展恩诺沙星可溶性粉混饮给药的药动学研究,并利用获得的药动学参数通过PK/PD模型结合Monte Carlo模拟(Monte Carlo simulation,MCS)评价恩诺沙星可溶性粉推荐给药方案的合理性。分别在1、7和14日龄雏鸡进行恩诺沙星可溶性粉75 mg·L^(-1)(以恩诺沙星计)混饮给药,按预定时间点采集血样,采用经验证的HPLC法测定各时间点每只鸡的血药浓度,拟合药动学参数。将获得的药动学参数与美国临床和实验室标准协会(CLSI)给出的恩诺沙星对禽大肠杆菌的敏感性折点值(0.25μg·mL^(-1))结合计算PK/PD参数,并通过MCS获得当前给药方案在大肠杆菌不同MIC分布下的达标率(target attainment rate,TAR)。结果显示,1、7和14日龄雏鸡3个处理组在第0天达峰浓度(C _(max))分别为0.561、0.564和0.550μg·mL^(-1),24 h曲线下面积(AUC _(0-24))分别为8.85、9.85和9.27μg·h·mL^(-1);3个处理组给药第4天C _(max)分别为0.599、0.550和0.487μg·mL^(-1),平均稳态血药浓度(C_(avg))分别为0.513、0.493和0.432μg·mL^(-1),AUC _(0-24)分别为12.31、11.82和10.37μg·h·mL^(-1),C _(max)/MIC分别为2.40、2.20和1.95,C_(avg)/MIC分别为2.05、1.97和1.73,AUC _(0-24)/MIC分别为49.24、47.28和41.48。恩诺沙星对MIC≤0.25μg·mL^(-1)的大肠杆菌临床分离株,1、7和14日龄雏鸡给药期间TAR为75.01%~76.11%。以上结果表明,恩诺沙星可溶性粉按目前的推荐给药方案对敏感菌PK/PD参数比值和TAR均达不到预期,不仅杀菌效果有限,且易诱导细菌产生耐药性。

The pharmacokinetics of enrofloxacin soluble powder in the drinking water were investigated in chicks of various ages and the PK/PD model combined with Monte Carlo simulation(MCS)was used to evaluate the rationality of enrofloxacin soluble powder administration by the recommended regimen.Chicks were given 75 mg·L^(-1) of enrofloxacin soluble powder(calculated by enrofloxacin)at 1,7 and 14 days of age.At predefined time intervals,blood samples were obtained,the plasma concentration of enrofloxacin was measured by HPLC,and pharmacokinetic parameters were calculated.PK/PD parameters were calculated by combining the pharmacokinetic parameters with the breakpoint(0.25μg·mL^(-1))of enrofloxacin against Escherichia coli in poultry obtained by Clinical and Laboratory Standards Institute(CLSI),and the target attainment rate(TAR)of the current administration regimen under different MIC ranges of Escherichia coli was obtained by MCS.The results showed that C _(max) of chicks at 1,7 and 14 days of age were 0.561,0.564 and 0.550μg·mL^(-1) on day 0 of administration,and AUC _(0-24) were 8.85,9.85 and 9.27μg·h·mL^(-1),respectively.C _(max) of chicks at 1,7,and 14 days of age on day 4 of administration were 0.599,0.550 and 0.487μg·mL^(-1),C a vg were 0.513,0.493 and 0.432μg·mL^(-1);AUC _(0-24) were 12.31,11.82and 10.37μg·h·mL^(-1);C _(max)/MIC were 2.40,2.20 and 1.95;C_(avg)/MIC were 2.05,1.97 and 1.73;AUC _(0-24)/MIC were 49.24,47.28 and 41.48,respectively.When the MIC of enrofloxacin against clinical isolates of Escherichia coli within 0.25μg·mL^(-1),TAR varied from 75.01 percent to 76.11 percent at 1,7,and 14 days of age.The results revealed that enrofloxacin soluble powder failed to achieve the PK/PD parameter ratio and TAR of sensitive bacteria as expected by the currently suggested regimen,which not only limited bactericidal effect,but also easy to induce bacterial drug resistance.