Evaluation of high dose post-dialytic versus daily beta-lactam dosing in hemodialysis patients using Monte Carlo simulation

Introduction Daily intravenous dosing of cefepime, meropenem and ceftazidime/avibactam is recommended in patients receiving intermittent hemodialysis (IHD), but requires hospitalization or frequent clinic visits. High dose post-HD administration may offer a more convenient outpatient alternative, but supporting data is limited. Aim To evaluate the feasibility by assessing predicted pharmacokinetic/pharmacodynamic (PK/PD) target attainment and neurotoxicity risk of high-dose post-HD versus daily dosing strategies for cefepime, meropenem, and ceftazidime/avibactam in patients receiving thrice-weekly IHD, using the Monte Carlo simulation (MCS) techniques. Method One-compartment pharmacokinetic models were developed using published data to simulate drug exposure in anuric patients receiving 4-h IHD thrice-weekly. MCS (Crystal Ball, Oracle) assessed the probability of target attainment (PTA) and neurotoxicity risk of various post-HD and daily dosing regimens in 5,000 virtual cohorts for one week. The PK/PD targets were ≥ 60% f T > MIC for cefepime, ≥ 40% f T > MIC for meropenem and ≥ 50% f T > MIC for ceftazidime with ≥ 50% fT > 1 g/mL for avibactam, assuming Pseudomonas aeruginosa or Enterobactarales infections. A PTA ≥ 90% was considered optimal for PK/PD target attainment. Safety was also assessed using the neurotoxicity thresholds. Results All daily regimens achieved PTA ≥ 90% on all simulated days. High-dose post-HD cefepime (1–2 g) and meropenem (2 g) maintained acceptable PTA over 2-day interdialytic periods, but failed to sustain targets through the 3-day period. Ceftazidime/avibactam post-HD dosing (0.94 g–0.94 g–2.5 g) maintained ≥ 90% PTA for ceftazidime throughout the week, though avibactam fell slightly below target on the final day. Predicted neurotoxicity risk was negligible for meropenem and ceftazidime/avibactam, but elevated with higher cefepime doses (1–2 g post-HD and 1 g daily). Cefepime 0.5 g daily, meropenem 0.25–1 g daily, and ceftazidime/avibactam 0.94 g daily or 0.94 g–0.94 g–2.5 g post-HD attained both PK/PD targets and safety targets. Conclusion High-dose post-HD dosing appears feasible for ceftazidime/avibactam but may be inadequate for cefepime and meropenem over a 3-day interdialytic period. Elevated neurotoxicity risk predicted with higher cefepime doses highlights the importance of cautious dosing and consideration of therapeutic drug monitoring.