Li Yanqin, Xie Mengjuan, Zhou Junwen, Lin Hao, Xiao Tianan, Wu Liqin, Ding Huanzhong, Fang Binghu
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Front Microbiol. 2020 Sep 22;11:511356. doi: 10.3389/fmicb.2020.511356. eCollection 2020.
We investigate the antimicrobial activity of combined colistin and gamithromycin against nine strains by testing 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 /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 strains.
我们通过药敏试验研究了黏菌素和加替米星联合使用对9株菌株的抗菌活性。使用两株高黏菌素最小抑菌浓度（MIC）分离株（D18和T5）和一株低黏菌素MIC分离株（WJ11）进行了时间杀菌试验，并在24小时内使用中性粒细胞减少小鼠肺炎模型进行了治疗效果实验。计算了血浆中的药代动力学（PK）以及药效学（PD）以确定PK/PD指数。使用高黏菌素MIC分离株观察到黏菌素和加替米星之间的协同作用，这相当于黏菌素和加替米星浓度分别降低了128倍或256倍以及4倍或8倍。有趣的是，未观察到该组合对低黏菌素MIC分离株的协同作用。然而，无论分离株之间的MIC差异如何，在接受联合治疗的所有分离株中，每种药物的浓度往往相同，这通过对分离株D18、T5和WJ11的时间杀菌试验呈现出相似的杀菌速率和程度得到了验证。使用AUC/MIC指数评估PK与PD之间的关系，相关性>0.89。确定了联合治疗的相关加替米星剂量，与单药治疗相比，该值降低了6至35倍。与单药治疗相比，黏菌素和加替米星联合治疗对菌株提供了更有效的治疗方案。
