Discussion
CR-GNB infection, toxicity, PK/PD, CR-GNB, infection, sepsis, CR-GNB infections
INFECTION, SEPSIS, DISEASES
The clinical and microbiological outcomes of different doses of polymyxin B in the treatment of sepsis caused by CR-GNB were similar, although more patients in the HD group (63.8%) achieved a ssAUCThis is the first randomized controlled trial comparing different polymyxin B doses in the treatment of severe CR-GNB infections under TDM. Based on the results of a published murine thigh infection model study, when the MIC of polymyxin B to CR-GNB is ≤ 2 mg/L, the lower bound of the target window is estimated to be a ssAUCIn the current study, only a minority of patients (32%) who failed to achieve the target AUC received dosage adjustments and rechecked plasma concentration of polymyxin B. Such a finding indicated that TDM could not be carried out smoothly in clinical practice because it is time-consuming and requires multiple blood samples at different time points to determine whether ssAUCInterestingly, a higher proportion of patients reached the ssAUCData from our prospective study indicated there was no correlation between whether ssAUCThe most accurate PK/PD index for colistin is the ratio of the area under the unbound concentration–time curve to the MIC (fAUC/MIC), which is also applicable to polymyxin B. In murine thigh infection models, the fAUC/MIC value for 2-log bacterial killing was approximately 20 [Some studies speculated that the total dose of polymyxin B is highly related to both efficacy and toxicity, irrespective of patient weight [Our previous real-world study of 100 patients with CR-GNB infections treated with polymyxin B found that the 28-day mortality was 40%, and about 50% of patients in the study were administered a fixed daily dose of 100 mg of polymyxin B [Nevertheless, the present trial has several limitations, which might explain the lack of clinical difference between the two groups treated with different doses of polymyxin B for severe CR-GNB infection. First, there was sample shortage and selection bias. We may be able to make some inferences if the sample size is increased because a 7% difference was detected in the 28-day mortality between the two groups. Moreover, patients who received high doses of polymyxin B had elevated body weight which could have affected the results. Next, the dosage of polymyxin B in both groups was lower than the standard recommended dosage; the higher initial dose group received a mean maintenance dose of 2.14 (IQR 2, 2.5) mg/kg/day, and the lower initial dose group received a mean maintenance dose of 1.54 (IQR 1.41, 1.75) mg/kg/day, and only 64.6% and 47.3% achieved ssAUCPatients with CR-GNB infections have various diseases and poor physical condition, which are likely to affect clinical outcomes. Accumulating evidence showed that polymyxin B has differential efficacy according to types [