Overview

Pharmacokinetics of Meropenem and Aztreonam After Intraperitoneal Administration Via Cycler-therapy in APD Patients Without Peritonitis

Status:
COMPLETED

Trial end date:
2022-07-24

Target enrollment:

Participant gender:

Summary

Peritoneal dialysis-associated peritonitis (PDAP) remains one of the most serious complications in patients undergoing peritoneal dialysis (PD), contributing significantly to hospitalization, technique failure, and mortality. Intraperitoneal (IP) antibiotic administration is the standard of care in PDAP, as it provides high local drug concentrations at the site of infection. However, dosing recommendations are largely based on pharmacokinetic (PK) studies in continuous ambulatory peritoneal dialysis (CAPD) patients. Automated peritoneal dialysis (APD), now widely used, differs significantly from CAPD in terms of dialysate volumes, frequency of exchanges, and peritoneal clearance. As a result, extrapolation of CAPD-based dosing regimens may lead to antibiotic underdosing in APD patients. This prospective, open-label, single-center descriptive PK study investigates the plasma and dialysate concentration-time profiles of meropenem and aztreonam after IP administration into the short-dwell cycler exchanges during nighttime APD. The rationale is that administration into the early short dwells may ensure adequate antibiotic levels both during active cycling (when frequent exchanges may clear the drug rapidly) and during the subsequent long daytime dwell through back-diffusion from systemic circulation. Twelve stable APD patients without peritonitis will be enrolled (6 per drug group). Inclusion requires patients to be on a stable APD regimen for at least one month using glucose-based dialysate for short nighttime dwells and Icodextrin for the daytime dwell. Patients with current infections, recent peritonitis, or significant comorbid conditions are excluded. On the study day, each participant will receive either: Meropenem: 0.75 g added to a 5L glucose-based peritoneal dialysis fluid (PDF) bag, or Aztreonam: 2 g prepared similarly. The antibiotic-containing 5L PDF bag is used as the first bag in the APD cycler session, followed by a second 5L antibiotic-free PDF bag, yielding a total of five 2L nighttime exchanges. After cycler therapy, a 1.5L Icodextrin fill is instilled for the long daytime dwell. Sampling includes: Venous blood: at 0 (pre-dose), 1, 2, 4.5, 6.5, 9, 10, 12, 16, and 24 hours. Dialysate: inflow/outflow from each cycle and at defined intervals during the Icodextrin dwell (up to 24 hours). Urine: 5 mL from a 24-hour collection in patients with residual renal function. Drug concentrations in plasma, dialysate, and urine will be quantified using validated high-performance liquid chromatography (HPLC) techniques. Primary PK endpoints include area under the curve (AUC), maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and half-life (t) in each compartment. Secondary endpoints include ratios of AUC and Cmax across compartments, time above the minimal inhibitory concentration (T\>MIC), and AUC0-24/MIC. This study does not include formal hypothesis testing but aims to generate descriptive PK data to inform optimized dosing of meropenem and aztreonam for APD patients. Currently, there is a lack of pharmacokinetic data guiding IP antibiotic dosing specifically in APD. The study's findings may support more accurate and effective antibiotic administration protocols for PDAP and potentially for the treatment of other systemic infections (e.g., pneumonia) in this population. The anticipated benefit is improved antimicrobial efficacy through better PK/PD target attainment while avoiding the need for intravenous therapy. The risk to participants is minimal, consisting primarily of standard procedures (blood draws, single-dose IP drug administration). Ethical approval has been obtained, and all participants will provide written informed consent. The study complies with Good Clinical Practice (GCP) and relevant regulatory and ethical standards, including the Declaration of Helsinki.

Phase:

PHASE2

Details

Lead Sponsor:

Karl Landsteiner Insitute for Nephrology and Haemato-Oncology

Collaborators:

Karl Landsteiner University of Health Sciences
Medical University of Cologne
University Hospital St. Polten
University of Vienna

Treatments:

Aztreonam
Meropenem