Polymyxin B therapy based on therapeutic drug monitoring in carbapenem-resistant organisms sepsis: the PMB-CROS randomized clinical trial

• Published in: Critical care (London, England) Vol. 27; no. 1; pp. 232 - 15
• Main Authors: Liu, Shaohua, Wu, Ying, Qi, Shaoyan, Shao, Huanzhang, Feng, Min, Xing, Lihua, Liu, Hongmei, Gao, Yanqiu, Zhu, Zhiqiang, Zhang, Shuguang, Du, Yuming, Lu, Yibin, Yang, Jing, Chen, Pingyan, Sun, Tongwen
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.06.2023; BioMed Central; BMC
• Subjects: Antibiotics; Bacteria; Carbapenem-resistant gram-negative bacteria; Care and treatment; Critical care; Diagnosis; Dosage and administration; Drug dosages; Drug resistance; Drug resistance in microorganisms; Drug utilization; Infections; Informed consent; Methods; Mortality; Optimization dose; Physicians; Plasma; Pneumonia; Polymyxin B; Prevention; Sepsis; Severe infection; Statistical analysis; Therapeutic drug monitoring; China; Optimization dose; Therapeutic drug monitoring; Severe infection; Carbapenem-resistant gram-negative bacteria; Polymyxin B
• ISSN: 1364-8535; 1466-609X; 1364-8535; 1466-609X; 1366-609X
• DOI: 10.1186/s13054-023-04522-6

The appropriate administration regimen of polymyxin B is yet controversial. The present study aimed to explore the optimal dose of polymyxin B under therapeutic drug monitoring (TDM) guidance. In China's Henan province, 26 hospitals participated in a randomized controlled trial. We included patients with sepsis caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) susceptible to polymyxin B. The patients were randomly divided into a high-dose (HD) group or a low-dose (LD) group and received 150 mg loading dose, 75 mg every 12 h and 100 mg loading dose, 50 mg every 12 h, respectively. TDM was employed to determine if the dose of polymyxin B needs adjustment based on the area under the concentration-time curve across 24 h at a steady state (ssAUC ) of 50-100 mg h/L. The primary outcome was the 14-day clinical response, and the secondary outcomes included 28- and 14-day mortality. This trial included 311 patients, with 152 assigned to the HD group and 159 assigned to the LD group. Intention-to-treat analysis showed that the 14-day clinical response was non-significant (p = 0.527): 95/152 (62.5%) in the HD group and 95/159 (59.7%) in the LD group. Kaplan-Meier's 180-day survival curve showed survival advantage in the HD group than in the LD group (p = 0.037). More patients achieved the target ssAUC in the HD than in the LD group (63.8% vs. 38.9%; p = 0.005) and in the septic shock subgroup compared to all subjects (HD group: 71.4% vs. 63.8%, p = 0.037; LD group: 58.3% vs. 38.9%, p = 0.0005). Also, the target AUC compliance was not correlated with clinical outcomes but with acute kidney injury (AKI) (p = 0.019). Adverse events did not differ between the HD and LD groups. A fixed polymyxin B loading dose of 150 mg and a maintenance dose of 75 mg every 12 h was safe for patients with sepsis caused by CR-GNB and improves long-term survival. The increased AUC was associated with increased incidence of AKI, and TDM results were valued to prevent AKI. Trial registration Trial registration ClinicalTrials.gov: ChiCTR2100043208, Registration date: January 26, 2021.