Data_Sheet_1_Evaluation of polymyxin B AUC/MIC ratio for dose optimization in patients with carbapenem-resistant Klebsiella pneumoniae infection.docx

Polymyxin B has been used as a last-line therapy for the treatment of carbapenem-resistant gram-negative bacterial infection. The pharmacokinetic/pharmacodynamic index (AUC/MIC) of polymyxin B has not been clinically evaluated, given that the broth microdilution method for polymyxin susceptibility testing is rarely used in hospitals. This study analyzed data from 77 patients with carbapenem-resistant Klebsiella pneumoniae infections. Among the samples, 63 K. pneumoniae isolates had MIC values of 1.0 mg/L as measured by broth microdilution but 0.5 mg/L as measured using the Vitek 2 system. Polymyxin B AUC/MIC was significantly associated with clinical response (p = 0.002) but not with 30-day all-cause mortality (p = 0.054). With a target AUC/MIC value of 50, Monte Carlo simulations showed that a fixed dose of 100 mg/12 h and three weight-based regimens (1.25 mg/kg/12 h for 80 kg and 1.5 mg/kg/12 h for 70 kg/80 kg) achieved a cumulative fraction of response >90% regardless of renal function, but the risk of nephrotoxicity was high. For patients with carbapenem-resistant K. pneumoniae infections, the underestimation of polymyxin resistance in automated systems need to be taken into account when optimizing polymyxin B dosing based on pharmacokinetic/pharmacodynamic principles.

多粘菌素B已被用作治疗碳青霉烯类耐药革兰氏阴性菌感染的最后一线治疗方案。鉴于在医院中，多粘菌素敏感性测试的肉汤微量稀释法鲜有应用，因此尚未对多粘菌素B的药代动力学/药效学指数（AUC/MIC）进行临床评估。本研究分析了77例碳青霉烯类耐药肺炎克雷伯菌感染患者的数据。在样本中，63株肺炎克雷伯菌的MIC值为1.0 mg/L，通过肉汤微量稀释法测定，而使用Vitek 2系统测定为0.5 mg/L。多粘菌素B的AUC/MIC与临床反应显著相关（p=0.002），但与30天全因死亡率无显著关联（p=0.054）。在目标AUC/MIC值为50的情况下，蒙特卡洛模拟表明，固定剂量为100 mg/12 h和三种基于体重的治疗方案（80 kg患者为1.25 mg/kg/12 h，70 kg/80 kg患者为1.5 mg/kg/12 h）均能在不考虑肾功能的情况下实现累积反应分数超过90%，但肾毒性风险较高。对于碳青霉烯类耐药肺炎克雷伯菌感染的患者，在根据药代动力学/药效学原理优化多粘菌素B的剂量时，需要考虑自动化系统中对多粘菌素耐药性低估的问题。