Pharmacokinetics and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle
Pharmacokinetics and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle
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DOI：
10.1111/jvp.12267
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发表时间：
2016-04-01
影响因子：
1.3
通讯作者：
Tessman, R. K.
中科院分区：
文献类型：
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作者：
DeDonder, K. D.;Apley, M. D.;Tessman, R. K.
本研究的目的是确定（i）当饲养牛被诊断患有牛呼吸道疾病（BRD）并接受加米霉素治疗时，个体药代动力学参数与治疗结果之间是否存在相关性（Zactran（（R）））和（ii）治疗结果与血浆或肺上皮衬里液中加米霉素浓度之间是否存在更强的相关性（PELF）效应隔室。研究设计是一项前瞻性、设盲、随机化临床试验，采用三组60头（362- 592磅）阉牛/公牛，在原产地内随机分配至假注射或加米霉素大量给药组。由对治疗设盲的兽医每天评价牛的BRD体征。入组符合BRD病例定义的动物，并将其分配至样本采集方案，该方案包括用于细菌分离（支气管肺泡灌洗液和鼻咽拭子）和加米霉素浓度测定（PELF和血浆）的样本。采用肉汤微量稀释法，使用含有浓度为0.03 - 16 g/mL加米霉素的冷冻板，测定溶血性支原体（n=287）和多杀性巴氏杆菌（n=257）的加米霉素敏感性。使用来自已发表和未发表研究的丰富数据集，开发了PELF中加米霉素的双室血浆药代动力学模型（含额外隔室）。然后使用非线性混合效应模型将我们研究中的稀疏数据拟合到该模型中，以估计各个参数值。所得参数估计值用于模拟本研究中每只动物的完整时间-浓度曲线。使用非房室方法分析这些曲线，以便计算每个个体的血浆和PELF（也是T>MIC）的PK/PD指数（AUC（24）/MIC、AUC/MIC、C-MAX/MIC）。计算的PK/PD指数表明，对于溶血性支原体和多杀性巴氏杆菌，相对于靶病原体的MIC，较高的药物暴露浓度和暴露持续时间有利于成功的病例结局。治疗成功率和PELF AUC（0-24）/MIC之间存在显著相关性。与之前发表的两份报告中的健康小牛相比，本研究中的小牛证明血浆中的清除率和分布容积增加。最终，本研究的结果表明，较高的PK/PD指数可预测阳性治疗结局。
The objectives of this study were to determine (i) whether an association exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran((R))) at the label dose and (ii) whether there was a stronger association between treatment outcome and gamithromycin concentration in plasma or in the pulmonary epithelial lining fluid (PELF) effect compartment. The study design was a prospective, blinded, randomized clinical trial utilizing three groups of 60 (362-592lb) steers/bulls randomly allocated within origin to sham injection or gamithromycin mass medication. Cattle were evaluated daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of samples for bacterial isolation (bronchoalveolar lavage fluid and nasopharyngeal swabs) and gamithromycin concentration determination (PELF and plasma). Gamithromycin susceptibility of M.haemolytica (n=287) and P.multocida (n=257) were determined using broth microdilution with frozen panels containing gamithromycin at concentrations from 0.03 to 16g/mL. A two-compartment plasma pharmacokinetic model with an additional compartment for gamithromycin in PELF was developed using rich data sets from published and unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values. The resulting parameter estimates were used to simulate full time-concentration profiles for each animal in this study. These profiles were analyzed using noncompartmental methods so that PK/PD indices (AUC(24)/MIC, AUC/MIC, C-MAX/MIC) could be calculated for plasma and PELF (also T>MIC) for each individual. The calculated PK/PD indices were indicative that for both M.haemolytica and P.multocida a higher drug exposure in terms of concentration, and duration of exposure relative to the MIC of the target pathogen, was favorable to a successful case outcome. Asignificant association was found between treatment success and PELF AUC(0-24)/MIC for P.multocida. The calves in this study demonstrated an increased clearance and volume of distribution in plasma as compared to the healthy calves in two previously published reports. Ultimately, the findings from this study indicate that higher PK/PD indices were predictive of positive treatment outcomes.