NOVEL INSIGHTS INTO PHARMACOKINETICS OF INTRAPERITONEAL CEFEPIME DURING AUTOMATED PERITONEAL DIALYSIS

Background and Aims:
Peritoneal dialysis-associated Peritonitis (PDAP) is a serious complication of automated peritoneal dialysis (APD), associated with high mortality, morbidity, and the potential need for transitioning to alternative dialysis modalities. Current ISPD guidelines recommend intraperitoneal (IP) cefepime, a fourth-generation cephalosporin, as a potential first-line monotherapy for treating infectious peritonitis in APD patients. However, data on the pharmacokinetics (PK) and optimal cefepime dosing in this population remain scarce. This study aimed to assess and optimize the PK characteristics of cefepime in APD patients by administering it during short rather than long dwells, using an open-labeled, prospective, and descriptive design.

Method:
Eight adult APD patients with no recent history of infections were enrolled. A single 2g dose of cefepime was injected into a preheated (37°C) 5-liter peritoneal dialysis fluid (PDF) bag and administered intraperitoneally using a HomechoicePro Cycler® (Baxter). Thereby, cefepime was delivered during the short dwell cycles, followed by an antibiotic-free long dwell phase, facilitating its back-diffusion from the serum into the peritoneal cavity. Blood, peritoneal fluid, and urine samples were collected at predefined intervals to evaluate the PK profile.
Laboratory analysis was conducted using high-performance liquid chromatography (HPLC), with each sample analyzed in triplicate. Results were compared to minimum inhibitory concentration (MIC) breakpoints for PDAP-causing bacteria, as outlined in EUCAST Version 15.0 (2025). Cefepime threshold concentrations of interest were 0.125, 0.5, 1, 4, and 8 mg/L.

Results:
The mean peak serum concentration (cmax-serum) of cefepime was 15.14 mg/L (SD ± 3.87 mg/L; 9.64 – 21.00 mg/L), reached on average 6 hours (SD ± 1.43 h; 4.5 – 9 h) after the start of the short cycle dwells. The mean peak concentration in the dialysate (cmax-dialysate) was 310.06 mg/L (SD ± 57.60 mg/L; 224.13 - 412.23 mg/L).
The mean duration during which cefepime concentrations exceeded the MIC (tserum>MIC) of 8 mg/L and 4 mg/L in serum was 70.76 % (SD ± 18.60 %; 40.1 - 96.52 %) and 96.27 % (SD ± 1.32 %; 95.40 - 97.59 %) of the 24-hour study duration, respectively. At 24 hours, 2 out of 8 patients maintained serum concentrations exceeding the MIC of 8 mg/L, while all participants exhibited serum concentrations above the threshold of 4 mg/L throughout the 24-hour study period.
In the dialysate, the mean duration during which cefepime concentrations exceeded the MIC (tdialysate>MIC) of 8 mg/L and 4 mg/L was 77.09 % (SD ± 17.95 %; 41.71 - 99.76 %) and 99.82 % (SD ± 0.28 %; 99.35 - 100.00 %) of the study duration, respectively. At 24 hours, 1 out of 8 patients maintained dialysate concentrations exceeding the MIC of 8 mg/L, while 7 of 8 patients had dialysate concentrations above the MIC of 4 mg/L.

Conclusion:
This study proposes an alternative treatment strategy for PDAP in APD patients, highlighting its potential to achieve highly effective serum and IP cefepime concentrations. The findings will be further evaluated and validated using Monte Carlo simulations.

Figures:
Figure 1: Cefepime concentration in the serum over time following IP administration. The four dashed lines represent the EUCAST-recommended MIC breakpoints for relevant bacteria.

Figure 2: Cefepime concentration in the dialysate over time following IP administration. For the horizontal lines, see Figure 1.

Acknowledgment: The authors sincerely appreciate the ISPD’s endorsement and the support of the NÖ Landesgesundheitsagentur, the legal entity of University Hospitals in Lower Austria, the Karl Landsteiner Institut für Nephrologie und Hämatoonkologie, and the Karl Landsteiner University of Health Sciences for providing the organizational framework for this research. Furthermore, we extend our gratitude to all our participants, laboratory staff, and research personnel whose contributions were crucial to the success of this study. AI tools were utilized for grammar correction and language refinement.