Peritonitis is a limiting complication of peritoneal dialysis, which is treated by intraperitoneal administration of antibiotics. Various dosing strategies are recommended for intraperitoneally administered vancomycin, which leads to large differences in intraperitoneal vancomycin exposure. Based on data from therapeutic drug monitoring, we developed the first-ever population pharmacokinetic model for intraperitoneally administered vancomycin to evaluate intraperitoneal and plasma exposure after dosing schedules recommended by the International Society for Peritoneal Dialysis. According to our model, currently recommended dosing schedules lead to possible underdosing of a large proportion of patients. To prevent this, we suggest avoiding intermittent intraperitoneal vancomycin administration, and for the continuous dosing regimen, we suggest a loading dose of 20 mg/kg followed by maintenance doses of 50 mg/L in each dwell to improve the intraperitoneal exposure. Vancomycin plasma level measurement on the fifth day of treatment with subsequent dose adjustment would prevent it from reaching toxic levels in the few patients who are susceptible to overdose.

Department of Nephrology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Department of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research Leiden University 2311 EZ Leiden The Netherlands

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Internal Department of Strahov General University Hospital Prague 128 00 Prague Czech Republic

Zobrazit více v PubMed

Teitelbaum I. Peritoneal Dialysis. N. Engl. J. Med. 2021;385:1786–1795. doi: 10.1056/NEJMra2100152. PubMed DOI

Salzer W. Antimicrobial-resistant gram-positive bacteria in PD peritonitis and the newer antibiotics used to treat them. Perit. Dial. Int. 2005;25:313–319. doi: 10.1177/089686080502500402. PubMed DOI

Li P.K.-T., Chow K.M., Cho Y., Fan S., E Figueiredo A., Harris T., Kanjanabuch T., Kim Y.-L., Madero M., Malyszko J., et al. ISPD peritonitis guideline recommendations: 2022 update on prevention and treatment. Perit. Dial. Int. 2022;42:110–153. doi: 10.1177/08968608221080586. PubMed DOI

Rubin J. Vancomycin absorption from the peritoneal cavity during dialysis-related peritonitis. Perit. Dial. Int. 1990;10:283–285. doi: 10.1177/089686089001000407. PubMed DOI

Morse G.D., Apicella M.A., Walshe J.J. Absorption of intraperitoneal antibiotics. Drug Intell. Clin. Pharm. 1988;22:58–61. PubMed

Morse G.D., Farolino D.F., Apicella M.A., Walshe J.J. Comparative study of intraperitoneal and intravenous vancomycin pharmacokinetics during continuous ambulatory peritoneal dialysis. Antimicrob. Agents Chemother. 1987;31:173–177. doi: 10.1128/AAC.31.2.173. PubMed DOI PMC

Blowey D.L., Warady B.A., Abdel-Rahman S., Frye R.F., Manley H.J. Vancomycin disposition following intraperitoneal administration in children receiving peritoneal dialysis. Perit. Dial. Int. 2007;27:79–85. doi: 10.1177/089686080702700117. PubMed DOI

Hartinger J.M., Šíma M., Hronová K., Halouzková B.A., Szonowská B., Polakovič V., Bednářová V., Hladinová Z., Tesař V., Slanař O. Vancomycin pharmacokinetics in patients treated with intermittent haemodialysis based on therapeutic drug monitoring. J. Chemother. 2021;34:149–156. doi: 10.1080/1120009X.2021.1979747. PubMed DOI

Šíma M., Hartinger J., Grus T., Slanař O. Initial dosing of intermittent vancomycin in adults: Estimation of dosing interval in relation to dose and renal function. Eur. J. Hosp. Pharm. 2019;28:276–279. doi: 10.1136/ejhpharm-2019-002013. PubMed DOI PMC

Schaefer F., Klaus G., Muller-Wiefel D.E., Mehls O. Intermittent versus continuous intraperitoneal glycopeptide/ceftazidime treatment in children with peritoneal dialysis-associated peritonitis. The Mid-European Pediatric Peritoneal Dialysis Study Group (MEPPS) J. Am. Soc. Nephrol. 1999;10:136–145. doi: 10.1681/ASN.V101136. PubMed DOI

Whitty R., Bargman J.M., Kiss A., Dresser L., Lui P. Residual Kidney Function and Peritoneal Dialysis-Associated Peritonitis Treatment Outcomes. Clin. J. Am. Soc. Nephrol. 2017;12:2016–2022. doi: 10.2215/CJN.00630117. PubMed DOI PMC

Rybak M.J., Le J., Lodise T.P., Levine D.P., Bradley J.S., Liu C., Mueller B.A., Pai M.P., Wong-Beringer A., Rotschafer J.C., et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am. J. Health Syst. Pharm. 2020;77:835–864. doi: 10.1093/ajhp/zxaa036. PubMed DOI

Tobudic S., Poeppl W., Kratzer C., Vychytil A., Burgmann H. Comparative in vitro antimicrobial activity of vancomycin, teicoplanin, daptomycin and ceftobiprole in four different peritoneal dialysis fluids. Eur. J. Clin. Microbiol. Infect. Dis. 2012;31:1327–1334. doi: 10.1007/s10096-011-1446-0. PubMed DOI

Sima M., Hartinger J., Netikova I.S., Slanar O. Creatinine Clearance Estimations for Vancomycin Maintenance Dose Adjustments. Am. J. Ther. 2017;25:e602–e604. doi: 10.1097/MJT.0000000000000616. PubMed DOI

Lindbom L., Pihlgren P., Jonsson N. PsN-Toolkit—A collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput. Methods Programs Biomed. 2005;79:241–257. doi: 10.1016/j.cmpb.2005.04.005. PubMed DOI

Lindbom L., Ribbing J., Jonsson E.N. Perl-speaks-NONMEM (PsN)--a Perl module for NONMEM related programming. Comput. Methods Programs Biomed. 2004;75:85–94. doi: 10.1016/j.cmpb.2003.11.003. PubMed DOI

Keizer R.J., van Benten M., Beijnen J.H., Schellens J.H., Huitema A.D. Piraña and PCluster: A modeling environment and cluster infrastructure for NONMEM. Comput. Methods Programs Biomed. 2011;101:72–79. doi: 10.1016/j.cmpb.2010.04.018. PubMed DOI

Comets E., Brendel K., Mentré F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: The npde add-on package for R. Comput. Methods Programs Biomed. 2008;90:154–166. doi: 10.1016/j.cmpb.2007.12.002. PubMed DOI

Wise R., Andrews J.M. The bactericidal activity of gatifloxacin in plasma and urine. Clin. Microbiol. Infect. 1998;4:392–396. doi: 10.1111/j.1469-0691.1998.tb00083.x. PubMed DOI

Stevenson S., Tang W., Cho Y., Mudge D., Hawley C., Badve S., Johnson D.W. The role of monitoring vancomycin levels in patients with peritoneal dialysis-associated peritonitis. Perit. Dial. Int. 2015;35:222–228. doi: 10.3747/pdi.2013.00156. PubMed DOI PMC

Blunden M., Zeitlin D., Ashman N., Fan S.L. Nephrology Dialysis Transplantation. Volume 22. Oxford University Press; Oxford, UK: 2007. Single UK centre experience on the treatment of PD peritonitis--antibiotic levels and outcomes; pp. 1714–1719. PubMed

Aljutayli A., Marsot A., Nekka F. An Update on Population Pharmacokinetic Analyses of Vancomycin, Part I: In Adults. Clin. Pharmacokinet. 2020;59:671–698. doi: 10.1007/s40262-020-00866-2. PubMed DOI

Zaric R.Z., Milovanovic J., Rosic N., Milovanovic D., Zecevic D.R., Folic M., Jankovic S. Pharmacokinetics of vancomycin in patients with different renal function levels. Open Med. 2018;13:512–519. doi: 10.1515/med-2018-0068. PubMed DOI PMC

Zhou Y., Gao F., Chen C., Ma L., Yang T., Liu X., Liu Y., Wang X., Zhao X., Que C., et al. Development of a Population Pharmacokinetic Model of Vancomycin and its Application in Chinese Geriatric Patients with Pulmonary Infections. Eur. J. Drug Metab. Pharmacokinet. 2019;44:361–370. doi: 10.1007/s13318-018-0534-2. PubMed DOI PMC

Hui K., Patel K., Nalder M., Nelson C., Buising K., Pedagogos E., Kong D.C.M., Kirkpatrick C.M.J. Optimizing vancomycin dosage regimens in relation to high-flux haemodialysis. J. Antimicrob. Chemother. 2019;74:130–134. doi: 10.1093/jac/dky371. PubMed DOI

Dose Optimization and Targeting Strategies of Anti-Infective Agents