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

## TL;DR

This study compares different antibiotic dosing strategies for dialysis patients, finding that high-dose post-dialysis dosing works well for one drug combination but not others.

## Contribution

The study introduces a Monte Carlo simulation approach to evaluate high-dose post-dialytic antibiotic regimens in hemodialysis patients.

## Key findings

- High-dose post-HD ceftazidime/avibactam maintained high target attainment throughout the week.
- Cefepime and meropenem post-HD dosing failed to sustain targets over 3-day interdialytic periods.
- Higher cefepime doses were linked to increased neurotoxicity risk.

## Abstract

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.

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.

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% fT > MIC for cefepime, ≥ 40% fT > MIC for meropenem and ≥ 50% fT > 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.

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.

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.

The online version contains supplementary material available at 10.1007/s11096-025-02044-5.