Pharmacokinetics of intraperitoneal cefalothin and cefazolin in patients being treated for peritoneal dialysis-associated peritonitis

Background: The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. Methods: As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent samples were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non-compartmental approach. Results: Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p < 0.0001) despite a similar concentration in PD effluent (37 vs 38 mg/L, p = 0.58). Lower antibiotic concentrations were noted during PD dwells not containing antibiotic, particularly cefalothin, which was frequently undetectable in plasma and PD effluent. The median duration that the unbound antibiotic concentration was above the minimum inhibitory concentration (MIC) was approximately 13% (plasma) and 25% (IP) for cefalothin, and 100% (plasma and IP) for cefazolin, of the dosing interval. Conclusions: When IP cefalothin or cefazolin is allowed to dwell for 6 hours, sufficient PD effluent concentrations are present for common pathogens during this time. However, with once-daily IP dosing, in contrast to cefazolin, there is a risk of subtherapeutic plasma and PD effluent cefalothin concentrations, so more frequent dosing may be required.