Ex Vivo Characterization of Effects of Renal Replacement Therapy Modalities and Settings on Pharmacokinetics of Meropenem and Vaborbactam

The combination product meropenem-vaborbactam, with activity against KPC-producing carbapenem-resistant Enterobacteriaceae, is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem-vaborbactam during continuous venovenous hemofiltration (CVVH). An ex vivo model was used to examine the effects of a matrix of operational settings. Vaborbactam did not adsorb to AN69 (acrylonitrile and sodium methallylsulfonate copolymer) ST100 (surface area, 1 m(2)) hemofilter; the mean (±standard deviation [SD]) meropenem adsorption was 9% (±1%). The sieving coefficients (mean ± SD) with AN69 ST100 and ST150 (surface area, 1.5 m(2)) filters ranged from 0.97 ± 0.16 to 1.14 ± 0.12 and from 1.13 ± 0.01 to 1.53 ± 0.28, respectively, for meropenem and from 0.64 ± 0.39 to 0.90 ± 0.14 and 0.78 ± 0.18 to 1.04 ± 0.28, respectively, for vaborbactam. At identical settings, vaborbactam sieving coefficients were 25% to 30% lower than for meropenem. Points of dilution, blood flow rates, or effluent flow rates did not affect sieving coefficients for either drug. However, doubling the effluent flow rate resulted in >50 to 100% increases in filter clearance for both drugs. Postfilter dilution resulted in 40 to 80% increases in filter clearance at a high effluent flow rate (4,000 ml/h), compared with ∼15% increases at a low effluent flow rate (1,000 ml/h) for both drugs. For all combinations of setting and filters tested, vaborbactam clearance was lower than that of meropenem by ∼20 to 40%. Overall, meropenem-vaborbactam is efficiently cleared in CVVH mode.