Supplementary Material for: Variability in Antibiotic Dosing and Resistance Development During Continuous Renal Replacement Therapy in Critically Ill Patients

Background: Antibiotic dosing in critically ill patients receiving continuous renal replacement therapy (CRRT) is challenging due to altered pharmacokinetics, variability in CRRT delivery, and limited dosing guidance. Optimizing therapy is essential, as underdosing may drive resistance and overdosing may increase toxicity, including cefepime-associated neurotoxicity. Methods: We conducted a retrospective single-center study of ICU patients who received CRRT and at least one dose of cefepime, meropenem, or piperacillin-tazobactam between 2016 and 2020. Delivered CRRT dose was calculated from effluent rates. Daily antibiotic doses across CRRT phases were summarized, and resistance development was evaluated for Pseudomonas aeruginosa and Enterobacter cloacae using logistic regression. Results: Of 954 eligible ICU patients, 661 met inclusion criteria. Median delivered CRRT dose was 29.5 mL/kg/h (IQR 25.0–33.5); 57.7% received ≥30 mL/kg/h, while only 9.6% were within the KDIGO-recommended 20–24.9 mL/kg/h. Median CRRT duration was 144 h (IQR 84–312), initiated a median of 2.3 days after ICU admission. Median daily doses during CRRT were 2.5 g for cefepime, 1.5 g for meropenem, and 10.8 g for piperacillin-tazobactam. Treatment-emergent resistance occurred in 17.6% of P. aeruginosa and 14.3% of E. cloacae isolates, while baseline resistance was common in E. coli (20.5%) and K. pneumoniae (27.3%). In multivariable models, longer treatment duration (OR 1.07/day, 95% CI 1.06–1.08), higher CRRT dose (OR 1.13 per 5 mL/kg/h, 95% CI 1.10–1.16), and lower daily antibiotic dose (OR 0.65 per g/day, 95% CI 0.61–0.70) were independently associated with cefepime resistance (AUC 0.73), with similar findings for meropenem (AUC 0.80). Conclusion: Antibiotic dosing during CRRT was at the lower end of the therapeutic range and was associated with treatment-emergent resistance in exploratory analyses. These findings highlight the potential importance of CRRT-informed dosing strategies and underscore the need for careful balance between efficacy and toxicity.