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Randomized Controlled Trial
. 2023 Jun 13;27(1):232.
doi: 10.1186/s13054-023-04522-6.

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

Shaohua Liu #  1 , Ying Wu #  2 , Shaoyan Qi  3 , Huanzhang Shao  4 , Min Feng  5 , Lihua Xing  6 , Hongmei Liu  7 , Yanqiu Gao  8 , Zhiqiang Zhu  9 , Shuguang Zhang  1 , Yuming Du  5 , Yibin Lu  10 , Jing Yang  11 , Pingyan Chen  2 , Tongwen Sun  12
Affiliations
Randomized Controlled Trial

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

Shaohua Liu et al. Crit Care. .

Abstract

Background: 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.

Methods: 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 (ssAUC0-24) 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.

Results: 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 ssAUC0-24 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.

Conclusion: 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.

Keywords: Carbapenem-resistant gram-negative bacteria; Optimization dose; Polymyxin B; Severe infection; Therapeutic drug monitoring.

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Conflict of interest statement

None of the authors has any conflict of interest to declare.

Figures

Fig. 1
Fig. 1
Trial profile
Fig. 2
Fig. 2
Kaplan–Meier’s survival curve of 180 days
Fig. 3
Fig. 3
The target AUC compliance of polymyxin B
Fig. 4
Fig. 4
Forest plots for subgroup analysis of infection sites and bacteria. CRE = carbapenem-resistant Enterobacteriaceae. CRAB = carbapenem-resistant Acinetobacter baumannii. CRPA = carbapenem-resistant Pseudomonas aeruginosa. Results for subgroup infected at other sites and subgroup infected with multiple bacteria are not applicable since a denominator value of zero is illegal
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