Huguet Anne-Sophie, Gourbeyre Ophélie, Bernand Agathe, Philibert Charline, Bousquet-Melou Alain, Lallemand Elodie A, Ferran Aude A
INTHERES, INRAE, ENVT, University of Toulouse, Toulouse, France.
Front Pharmacol. 2024 Nov 18;15:1458496. doi: 10.3389/fphar.2024.1458496. eCollection 2024.
causes life-threatening respiratory disease in foals. The standard treatment typically involves a combination of rifampicin and a macrolide antibiotic. Although previous studies have demonstrated the activity of these antibiotics against , the tested concentrations often do not reflect those achievable in foals.
Therefore, this study was performed to evaluate the bactericidal activity of rifampicin, doxycycline, and four macrolides (clarithromycin, azithromycin, gamithromycin and tulathromycin) individually and in combination, at concentrations observed at the target site of infection in foals. Additionally, we investigated the efficacy of these antibiotics at different pH levels to replicate the conditions in the pulmonary epithelial lining fluid and within macrophages, where can reside. We assessed the activity of antibiotics against a virulent strain of by determining the minimum inhibitory concentration (MIC) and performing checkerboard and time-kill curve assays with drugs both alone and in combination.
Time-kill curves with rifampicin or doxycycline demonstrated a reduction in counts by more than 3 log CFU/mL. Among the macrolides, tulathromycin was ineffective, while clarithromycin achieved bacterial elimination within 24 h under both extracellular and intracellular conditions. Gamithromycin and azithromycin exhibited bactericidal activity only in extracellular conditions, with no effect on the bacteria at pH 5.8. The checkerboard assay did not reveal any strong synergistic or antagonistic effects for rifampicin or doxycycline when combined with macrolides. In time-kill curves performed with maximal local concentrations achievable in foals, the combinations of rifampicin or doxycycline with macrolides did not increase the bacterial killing rate compared with the drugs alone, except for the combination of rifampicin with azithromycin, which showed slightly faster activity. However, the lower concentrations of doxycycline and clarithromycin that might be present 24 h after treatment in foals were effective in killing bacteria under intracellular conditions only when used in combination, and not when used alone.
Our study suggests that clarithromycin can be used either alone or with doxycycline and that its use in combination with rifampicin should be reconsidered. Nevertheless, further studies are required to assess the clinical efficacy and potential side effects of doxycycline in foals.
在幼驹中引发危及生命的呼吸道疾病。标准治疗通常包括利福平与大环内酯类抗生素联合使用。尽管先前的研究已证明这些抗生素对……具有活性，但所测试的浓度往往不能反映幼驹体内可达到的浓度。
因此，本研究旨在评估利福平、多西环素以及四种大环内酯类药物（克拉霉素、阿奇霉素、加米霉素和泰拉霉素）在幼驹感染靶部位观察到的浓度下单独及联合使用时的杀菌活性。此外，我们研究了这些抗生素在不同pH水平下的疗效，以模拟肺上皮衬液和巨噬细胞内的条件，……可在其中生存。我们通过测定最低抑菌浓度（MIC）并单独及联合使用药物进行棋盘法和时间杀菌曲线试验，评估了抗生素对一种强毒株……的活性。
利福平或多西环素的时间杀菌曲线显示细菌计数减少超过3 log CFU/mL。在大环内酯类药物中，泰拉霉素无效，而克拉霉素在细胞外和细胞内条件下均在24小时内实现了细菌清除。加米霉素和阿奇霉素仅在细胞外条件下表现出杀菌活性，在pH 5.8时对细菌无作用。棋盘法试验未显示利福平或多西环素与大环内酯类药物联合使用时有任何强烈的协同或拮抗作用。在以幼驹体内可达到的最大局部浓度进行的时间杀菌曲线试验中，利福平或多西环素与大环内酯类药物联合使用时，与单独使用药物相比，除利福平与阿奇霉素联合使用显示出稍快的活性外，细菌杀灭率并未提高。然而，幼驹治疗24小时后可能存在的较低浓度的多西环素和克拉霉素，仅在联合使用时在细胞内条件下对细菌有效，单独使用时无效。
我们的研究表明克拉霉素可单独使用或与多西环素联合使用，其与利福平联合使用的情况应重新考虑。然而，需要进一步研究评估多西环素在幼驹中的临床疗效和潜在副作用。
