Clinical Study of Individualized Vancomycin Dosing Based on Population Pharmacokinetic Model for Severe Infections

1. Research purpose The goal of this clinical trial is to compare the clinical efficacy of individualized dosing based on the population pharmacokinetics (PK) model and empirical dosing of vancomycin in participants with severe infections.

It aims to answer whether individual vancomycin dosing based on population PK model is superior to empirical dosing in terms of clinical efficacy and safety. 2. Research methods 112 subjects who are treated with vancomycin for severe infections caused by suspected or confirmed gram-positive cocci during hospitalization in the Second Xiangya Hospital of Central South University will be prospectively collected (sample size is calculated according to the sample size calculation formula for clinical trials of merits and demerits). Severe gram-positive infection is defined in this study as bacteremia, sepsis, infective endocarditis, pneumonia, and encephalitis/meningitis caused by gram-positive infection with clinical suspicion or evidence of microbiological culture. Eligible participants will be screened according to the inclusion and exclusion criteria established in this study. All excluded cases should be recorded for future reference. At the end of the test, the shedding rate will be calculated and the safety analysis will be carried out.

Before the implementation of the study, the research designer will use computer programmed data processing to generate a random sequence, and the group of participants will be determined according to random numbers. Participants will be randomly assigned to the experimental group and the control group. A single-blind method will be used. Study designers, clinicians, and statistical analysts will be aware of groups of participants, but they do not disclose this information to participants or their authorized representatives.

The experimental group will be guided at the bedside with individualized vancomycin dosing by a drug dosimetry software tool that incorporates a PK model developed by Roberts JA et al. for data from sepsis patients. The model developed by Roberts JA et al. has been validated in multiple centers to have a good ability to predict the concentration-time data of patients. Once the basic information of participants such as gender, age, body weight, and creatinine clearance rate (CCR) is entered, the software tool can calculate the dosing regimen that is estimated to achieve the pharmacodynamic (PD) target. The area under the curve (AUC24) of 400-600mg·h/L is identified as the PD target of vancomycin. The control group will be administered empirically (15-20 mg/kg vancomycin infused intermittently every 8-12 hours depending on the actual body weight of participants).

The trough concentration (Cmin) and peak concentration (Cmax) of vancomycin in the two groups will be measured after the dosing of vancomycin achieve steady state, and the CCR, volume of distribution (Vd) and AUC24 of vancomycin will be calculated based on the first-order PK equation. In addition, demographic data and clinical data of both groups of participants will be collected. Demographic data included sex, age, height, body weight, and body mass index（BMI）. Clinical data included serum creatinine（SCR）, CCR, serum albumin level, vancomycin dosage regimen, body temperature, white blood cell count (WBC), percentage of neutrophils (NEUT%), serum procalcitonin (PCT), serum C-reactive protein (CRP), Acute physiology and Chronic Health Evaluation (APACHE) Ⅱ, Sequential Organ Failure Assessment (SOFA), length of neurological intensive care unit (NICU) stay, 30-day outcomes, and 90-day outcomes. In addition, vancomycin-related adverse reactions and the use of concomitant nephrotoxic drugs will also be collected.