Optimization of meropenem and piperacillin dosing during CRRT interruption and liberation in critically ill patients: an in silico sub-study from the SMARRT Study.

BACKGROUND: Evidence guiding antimicrobial dosing during interruptions and liberation from continuous renal replacement therapy (CRRT) is lacking. We aimed to optimize meropenem and piperacillin dosing during 6-h and 24-h interruptions. METHODS: This Monte Carlo simulation used validated population pharmacokinetic models from the SMARRT study, which enrolled 300 patients receiving renal replacement therapy. We assessed the probability of target attainment (PTA) for various regimens during 6 h and 24 h interruptions, considering CRRT intensities and urine outputs. Efficacy targets were unbound concentrations above MIC (2-8 mg/L for meropenem; 16-64 mg/L for piperacillin), with toxicity thresholds of >45 mg/L and >160 mg/L. Regimens with PTA >90% and toxicity risk <15% were selected. RESULTS: During 6-h interruptions, maintain the dose if the total daily dose does not exceed 3 g (meropenem) or 8 g (piperacillin), at CRRT intensities of 1.5-2.5 L/h, and up to 4 g and 12 g, respectively, at >2.5 L/h for anuric patients. In patients with urine output (≥500 mL/24h for meropenem, ≥100 mL/24h for piperacillin), higher limits apply, namely 4 g/24h at 1.5 - 2.5 L/h and 6 g/24h at >2.5 L/h for meropenem; 12 g/24h at 1.5-3.5 L/h for piperacillin. Higher daily doses should be withheld. For CRRT liberation, antimicrobials should be adjusted according to the therapeutic target and infusion regimen. Continuous infusion provided the best exposure, achieving ≥90% PTA with meropenem 1.5-3 g/24 h and piperacillin 6-8 g/24 h while reducing toxicity risk. CONCLUSION: Our study provides recommendations for meropenem and piperacillin during CRRT interruptions and liberation.