Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
J Clin Microbiol. 2013 Nov;51(11):3547-54. doi: 10.1128/JCM.01498-13. Epub 2013 Aug 21.
Doxycycline is a tetracycline that has been licensed for veterinary use in some countries, but no clinical breakpoints are available for veterinary pathogens. The objectives of this study were (i) to establish breakpoints for doxycycline and (ii) to evaluate the use of tetracycline as a surrogate to predict the doxycycline susceptibility of Staphylococcus pseudintermedius isolates. MICs and inhibition zone diameters were determined for 168 canine S. pseudintermedius isolates according to Clinical and Laboratory Standards Institute (CLSI) standards. Tetracycline resistance genes were detected by PCR, and time-kill curves were determined for representative strains. In vitro pharmacodynamic and target animal pharmacokinetic data were analyzed by Monte Carlo simulation (MCS) for the development of MIC interpretive criteria. Optimal zone diameter breakpoints were defined using the standard error rate-bounded method. The two drugs displayed bacteriostatic activity and bimodal MIC distributions. Doxycycline was more active than tetracycline in non-wild-type strains. MCS and target attainment analysis indicated a certainty of ≥ 90% for attaining an area under the curve (AUC)/MIC ratio of >25 with a standard dosage of doxycycline (5 mg/kg of body weight every 12 h) for strains with MICs of ≤ 0.125 μg/ml. Tetracycline predicted doxycycline susceptibility, but current tetracycline breakpoints were inappropriate for the interpretation of doxycycline susceptibility results. Accordingly, canine-specific doxycycline MIC breakpoints (susceptible, ≤ 0.125 μg/ml; intermediate, 0.25 μg/ml; resistant, ≥ 0.5 μg/ml) and zone diameter breakpoints (susceptible, ≥ 25 mm; intermediate, 21 to 24 mm; resistant, ≤ 20 mm) and surrogate tetracycline MIC breakpoints (susceptible, ≤ 0.25 μg/ml; intermediate, 0.5 μg/ml; resistant, ≥ 1 μg/ml) and zone diameter breakpoints (susceptible, ≥ 23 mm; intermediate, 18 to 22 mm; resistant, ≤ 17 mm) were proposed based on the data generated in this study.
多西环素是一种四环素，已在一些国家获得兽医使用许可，但兽医病原体尚无临床折点。本研究的目的是：(i) 建立多西环素的折点；(ii) 评估四环素作为预测中间葡萄球菌分离株对多西环素敏感性的替代药物。根据临床和实验室标准协会 (CLSI) 标准，测定了 168 株犬中间葡萄球菌分离株的 MIC 和抑菌圈直径。通过 PCR 检测四环素耐药基因，并为代表菌株测定时间杀伤曲线。通过蒙特卡罗模拟 (MCS) 分析体外药效学和目标动物药代动力学数据，为 MIC 解释标准的制定提供依据。采用标准误率限定法定义最佳的抑菌圈直径折点。两药均具有抑菌活性和双峰 MIC 分布。在非野生型菌株中，多西环素比四环素更具活性。MCS 和目标达标分析表明，对于 MIC 值≤0.125μg/ml 的菌株，采用标准剂量多西环素（5mg/kg 体重，每 12 小时 1 次），AUC/MIC 比值>25 的达标率肯定≥90%。四环素可预测多西环素的敏感性，但目前的四环素折点不适合解释多西环素敏感性结果。因此，提出了犬专用多西环素 MIC 折点（敏感，≤0.125μg/ml；中介，0.25μg/ml；耐药，≥0.5μg/ml）和抑菌圈直径折点（敏感，≥25mm；中介，21-24mm；耐药，≤20mm）以及替代四环素 MIC 折点（敏感，≤0.25μg/ml；中介，0.5μg/ml；耐药，≥1μg/ml）和抑菌圈直径折点（敏感，≥23mm；中介，18-22mm；耐药，≤17mm），这些折点是基于本研究的数据提出的。
