We investigate the antimicrobial activity of combined colistin and gamithromycin against nine Pasteurella multocida strains by testing in vitro susceptibility. Two high-colistin minimal inhibitory concentration (MIC) isolates (D18 and T5) and one low-colistin MIC isolate (WJ11) were used in time-kill tests and therapeutic effect experiments using a neutropenic murine pneumonia model over 24 h. Pharmacokinetics (PK) in plasma was calculated along with pharmacodynamics (PD) to determine the PK/PD index. Synergy between colistin and gamithromycin was observed using high-colistin MIC isolates, equating to a 128- or 256-fold and 4- or 8-fold reduction in colistin and gamithromycin concentration, respectively. Interestingly, no synergistic effect of the combination on low-colistin MIC isolates was observed. However, regardless of the MIC difference among isolates, each drug tended to reach the same concentration in all isolates subjected to combined treatments, which was verified by the time-kill tests presenting similar rates and extent of killing for isolates D18, T5, and WJ11. The AUC_{(0–24 h)}/MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.89. The relevant gamithromycin doses for combined therapy were determined, and the value decreased from 6- to 35-fold compared with monotherapy. Combined colistin and gamithromycin therapy provides a more potent therapeutic regimen than monotherapy against P. multocida strains.

我们通过体外药敏试验研究了粘菌素和加米霉素联合用药对九种多杀性巴氏杆菌菌株的抗菌活性。使用中性粒细胞减少性小鼠肺炎模型，将两种高粘菌素最低抑菌浓度 (MIC) 分离株（D18 和 T5）和一种低粘菌素 MIC 分离株（WJ11）用于 24 小时以上的时间杀灭试验和治疗效果实验。计算血浆中的药代动力学（PK）和药效学（PD）以确定 PK/PD 指数。使用高粘菌素 MIC 分离株观察到粘菌素和加米霉素之间的协同作用，相当于粘菌素和加米霉素浓度分别降低 128 或 256 倍和 4 或 8 倍。有趣的是，没有观察到该组合对低粘菌素 MIC 分离株有协同作用。然而，无论分离株之间的 MIC 差异如何，每种药物在接受联合治疗的所有分离株中趋于达到相同的浓度，这通过时间杀灭测试得到验证，显示分离株 D18、T5 和 WJ11 的杀灭率和程度相似。采用AUC _{（ 0-24 h）} /MIC指数评价PK与PD的关系，相关性为% _3E0.89 。确定了联合治疗的相关加米霉素剂量，与单药治疗相比，该值降低了6至35倍。多杀性巴氏杆菌菌株的联合粘菌素和加米霉素治疗提供了比单一疗法更有效的治疗方案。