Population Pharmacokinetic Study of Cefazolin Dosage Adaptation in Bacteremia and Infective Endocarditis Based on a Nomogram

Abstract

Optimal dosing of continuous-infusion cefazolin can be challenging in patients being treated for bacteremia or infective endocarditis. The aim of this work is to describe and analyze the pharmacokinetics of cefazolin in those patients using a population pharmacokinetics modeling approach and to establish a nomogram to determine the optimal daily dose. Population pharmacokinetics were modeled using the Pmetrics package for R. Plasma concentrations were collected retrospectively from patients treated with continuous-infusion cefazolin for bacteremia or infective endocarditis. The influence of multiple parameters, including renal function, total body weight, body mass index, body surface area (BSA), ideal weight, lean body weight, height, and age, was tested. The probabilities of target attainment for selected target concentrations (40, 60, and 80 mg/liter) were calculated. A dosing nomogram was then developed, using the absolute value of the glomerular filtration rate (aGFR), to determine the optimal daily dose required to achieve the target concentrations in at least 90% of patients. In total, 346 cefazolin plasma concentrations from 162 patients were collected. A one-compartment model best described the data set. The only covariate was aGFR, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and the patient's body surface area, for the rate of elimination. Using the nomogram, achieving a cefazolin concentration target of 40 mg/liter with a success rate of at least 90% and with an aGFR of 30, 60, 90, and 120 ml/min requires a daily dose of 2.6, 4.3, 6.1, and 8.0 g/day, respectively. These results confirm the interest of posology adaptation of cefazolin according to aGFR.

Keywords: bacteremia; cefazolin; continuous infusion; infective endocarditis; nonparametric modeling; population pharmacokinetics.

FIG 1

Observed versus population predicted cefazolin concentrations (A) and individual predicted cefazolin concentrations (B). The dashed lines represent identity. The full line is the linear regression line (R² = 0.64 for panel A and R² = 0.86 for panel B).

FIG 2

Visual predictive checks (left) and prediction-corrected visual predictive checks (right) of cefazolin concentrations against absolute values of the glomerular filtration rate (aGFR). Open circles are observed cefazolin concentrations. Solid lines represent the 5th, 50th, and 95th percentiles for observed concentrations. Dashed lines represent the 5th, 50th, and 95th percentiles for simulated concentrations. The vertical lines at the top of the plots are bin separators.

FIG 3

Nomogram of the daily dose of continuous-infusion cefazolin to be administered after a loading dose to attain steady-state plasma concentration targets of 40 mg/liter (full line), 60 mg/liter (dashed line), and 80 mg/liter (dotted line) in 90% of the studied population, accounting for renal function estimated by the CKD-EPI formula and expressed as an absolute value (aGFR). Equations were defined as y = 0.0001x² + 0.448x + 1.2112 for the 40-mg/liter target, y = 0.0002x² + 0.0699x + 1.705 for the 60-mg/liter target, and y = 0.0003x² + 0.0837x + 2.3808 for the 80-mg/liter target, with x being the aGFR and y being the cefazolin daily dose.