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

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 (t½) 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.

Timeline

Start

2021-08-31

Primary completion

2022-07-24

Completion

2022-07-24

Publications

• Background de Vin F, Rutherford P, Faict D. Intraperitoneal administration of drugs in peritoneal dialysis patients: a review of compatibility and guidance for clinical use. Perit Dial Int. 2009 Jan-Feb;29(1):5-15.
• Background Kussmann M, Schuster L, Wrenger S, Pichler P, Reznicek G, Burgmann H, Poeppl W, Zeitlinger M, Wiesholzer M. Influence of Different Peritoneal Dialysis Fluids on the In Vitro Activity of Cefepime, Ciprofloxacin, Ertapenem, Meropenem and Tobramycin Against Escherichia Coli. Perit Dial Int. 2016 11-12;36(6):662-668. doi: 10.3747/pdi.2015.00161. Epub 2016 Sep 28.
• Background Wiesholzer M, Pichler P, Reznicek G, Wimmer M, Kussmann M, Balcke P, Burgmann H, Zeitlinger M, Poeppl W. An Open, Randomized, Single-Center, Crossover Pharmacokinetic Study of Meropenem after Intraperitoneal and Intravenous Administration in Patients Receiving Automated Peritoneal Dialysis. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2790-7. doi: 10.1128/AAC.02664-15. Print 2016 May.
• Background Warady BA, Bakkaloglu S, Newland J, Cantwell M, Verrina E, Neu A, Chadha V, Yap HK, Schaefer F. Consensus guidelines for the prevention and treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update. Perit Dial Int. 2012 Jun;32 Suppl 2(Suppl 2):S32-86. doi: 10.3747/pdi.2011.00091. No abstract available.
• Background Peerapornratana S, Chariyavilaskul P, Kanjanabuch T, Praditpornsilpa K, Eiam-Ong S, Katavetin P. Short-Dwell Cycling Intraperitoneal Cefazolin Plus Ceftazidime in Peritoneal Dialysis Patients. Perit Dial Int. 2017 Mar-Apr;37(2):218-224. doi: 10.3747/pdi.2015.00300. Epub 2016 Oct 13.
• Background Manley HJ, Bailie GR. Treatment of peritonitis in APD: pharmacokinetic principles. Semin Dial. 2002 Nov-Dec;15(6):418-21. doi: 10.1046/j.1525-139x.2002.00103.x.
• Background Salzer W. Antimicrobial-resistant gram-positive bacteria in PD peritonitis and the newer antibiotics used to treat them. Perit Dial Int. 2005 Jul-Aug;25(4):313-9.
• Background Van Ende C, Tintillier M, Cuvelier C, Migali G, Pochet JM. Intraperitoneal meropenem administration: a possible alternative to the intravenous route. Perit Dial Int. 2010 Mar-Apr;30(2):250-1. doi: 10.3747/pdi.2009.00052. No abstract available.
• Background Li PK, Szeto CC, Piraino B, de Arteaga J, Fan S, Figueiredo AE, Fish DN, Goffin E, Kim YL, Salzer W, Struijk DG, Teitelbaum I, Johnson DW. ISPD Peritonitis Recommendations: 2016 Update on Prevention and Treatment. Perit Dial Int. 2016 Sep 10;36(5):481-508. doi: 10.3747/pdi.2016.00078. Epub 2016 Jun 9. No abstract available.
• Background Hsieh YP, Chang CC, Wang SC, Wen YK, Chiu PF, Yang Y. Predictors for and impact of high peritonitis rate in Taiwanese continuous ambulatory peritoneal dialysis patients. Int Urol Nephrol. 2015 Jan;47(1):183-9. doi: 10.1007/s11255-014-0763-5. Epub 2014 Jul 18.
• Background Szeto CC, Wong TY, Chow KM, Leung CB, Li PK. Are peritoneal dialysis patients with and without residual renal function equivalent for survival study? Insight from a retrospective review of the cause of death. Nephrol Dial Transplant. 2003 May;18(5):977-82. doi: 10.1093/ndt/gfg027.
• Background Perez Fontan M, Rodriguez-Carmona A, Garcia-Naveiro R, Rosales M, Villaverde P, Valdes F. Peritonitis-related mortality in patients undergoing chronic peritoneal dialysis. Perit Dial Int. 2005 May-Jun;25(3):274-84.
• Background Ghali JR, Bannister KM, Brown FG, Rosman JB, Wiggins KJ, Johnson DW, McDonald SP. Microbiology and outcomes of peritonitis in Australian peritoneal dialysis patients. Perit Dial Int. 2011 Nov-Dec;31(6):651-62. doi: 10.3747/pdi.2010.00131. Epub 2011 Jun 30.
• Background Davenport A. Peritonitis remains the major clinical complication of peritoneal dialysis: the London, UK, peritonitis audit 2002-2003. Perit Dial Int. 2009 May-Jun;29(3):297-302.
• Background Brown MC, Simpson K, Kerssens JJ, Mactier RA; Scottish Renal Registry. Peritoneal dialysis-associated peritonitis rates and outcomes in a national cohort are not improving in the post-millennium (2000-2007). Perit Dial Int. 2011 Nov-Dec;31(6):639-50. doi: 10.3747/pdi.2010.00185. Epub 2011 Jul 31.
• Background Boudville N, Kemp A, Clayton P, Lim W, Badve SV, Hawley CM, McDonald SP, Wiggins KJ, Bannister KM, Brown FG, Johnson DW. Recent peritonitis associates with mortality among patients treated with peritoneal dialysis. J Am Soc Nephrol. 2012 Aug;23(8):1398-405. doi: 10.1681/ASN.2011121135. Epub 2012 May 24.

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