Determinants of ceftriaxone clearance by continuous venovenous hemofiltration and hemodialysis

Study Objective. To guide individual ceftriaxone dosages in patients receiv ing continuous renal replacement therapy Design. Prospective, outpatient study. Setting. University-affiliated general clinical research center. Patients. Eight patients receiving hemodialysis. Intervention. We performed controlled clearance studies with three hemofilt ers: an acrylonitrile copolymer 0.6 m(2) (AN69), polymethylmethacrylate 2.1 m(2) (PMMA), and polysulfone 0.65 m(2) (PS). Measurements and Main Results. Subjects received ceftriaxone 1000 mg intrav enously before the start of a clearance study. The concentration of ceftria xone in multiple plasma and dialysate-ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (Cl-d iffusion) and sieving coefficients (SC) of ceftriaxone, urea, and creatinin e were compared by a mixed-model repeated-measures analysis of variance wit h filter and blood, dialysate inflow or ultrafiltration rate as the main ef fect and patient as a random effect. The fraction of ceftriaxone bound to p lasma proteins was 43 +/- 15% (range 13-92%). Concentration dependence was evident in all three groups. The fraction unbound to plasma proteins (f(up) ) at the time that SCs were determined was significantly lower in the PS gr oup (0.16 +/- 0.07) than the AN69 group (0.30 +/- 0.17, p<0.01), but simila r to that in the PMMA group (0.27 +/- 0.12). Despite the higher f(up), the SC of unbound ceftriaxone with the AN69 filter (0.48 +/- 0.13) was signific antly lower than values for the PMMA (0.86 +/- 0.33) and PS (0.82 +/- 0.22) groups (p<0.05). Continuous venovenous hemofiltration clearance of urea an d unbound ceftriaxone increased significantly only for the PMMA (p=0.006) a nd PS (p=0.015) filters when the ultrafiltration rate was increased. Signif icant linear relationships (p<0.0001) were observed between Cl-diffusion of unbound ceftriaxone and clearance of urea for all three filters: AN69 slop e = 0.57, PMMA slope = 0.90, and PS slope = 1.02. The slope of this relatio nship for the AN69 filter was significantly lower than for the other two fi lters. Conclusion. Ceftriaxone clearance was significantly increased and membrane dependent during continuous venovenous hemofiltration and continuous venove nous hemodialysis. Thus individual ceftriaxone dosages for patients receivi ng continuous renal replacement therapies should incorporate extracorporeal clearance.