Optimizing Antimicrobial Dosing for Critically Ill Patients with MRSA Infections: A New Paradigm for Improving Efficacy during Continuous Renal Replacement Therapy

Abstract

The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30–35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6–8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8–10 mg/kg every 24 h was optimal under 30–35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin.

Determination of vancomycin exposure target and individualized dosing recommendations for critically ill patients undergoing continuous renal replacement therapy

“…Based on the covariates included in the model, the simulated population was classified according to CRRT intensity, which was subdivided into five categories: 20–25 mL/kg/h, 25.1–30 mL/kg/h, 30.1–35 mL/kg/h, 35.1–40 mL/kg/h, and 40.1–45 mL/kg/h, and this was determined according to the current published literatures 4,9 and clinical practice. The optimal dosage regimens for each subgroup were affected by CRRT intensities.…”

“…Individualized dosing recommendations for these patients are derived from the optimized exposure target using PPK/PD analysis. Target balancing efficacy and toxicity (AUC = 427–600) were applied, which increased the accuracy compared with other studies that only considered the lower limit (AUC ≥ 400) 9,17 . It is recommended to choose initial dosage regimens according to the different CRRT intensities due to the correlation between drug clearance and CRRT intensity.…”

“…CRRT complicates the factors influencing drug exposure and contributes to overall pharmacokinetic (PK) and PK/pharmacodynamic (PD) variability, 8 which suggests the inappropriateness of applying the same exposure target of vancomycin in adults to critically ill patients undergoing CRRT 4 . Meanwhile, a previous study 9 found that different CRRT modalities do not significantly affect the clearance of vancomycin, which supports the analysis of vancomycin without distinguishing the specific CRRT modality. The exposure–efficacy relationship for vancomycin has not been clearly defined in ICU patients undergoing CRRT.…”

Vancomycin therapeutic drug monitoring in patients on continuous renal replacement therapy: a retrospective study

“…Vancomycin shows approximately 55% protein binding, and only free drug can be cleared by CRRT. 20 , 22 When patients with hypoproteinemia receive vancomycin, the increasing amount of free drug can be cleared more easily by CRRT, leading to concentrations that do not meeting the target.…”

“…When the concentration was not within the target concentration range, only 46.2% of patients received an adjustment. 21 Clinicians in our study were watching more carefully for supertherapeutic concentrations because more patients 20,22 When patients with hypoproteinemia receive vancomycin, the increasing amount of free drug can be cleared more easily by CRRT, leading to concentrations that do not meeting the target.…”