Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: A prospective, experimental study in the rat

Abstract

Background: Sepsis is characterized by the loss of the perm-selectivity properties of the glomerular filtration barrier (GFB) with consequent albuminuria. We examined whether the pharmacokinetics-pharmacodynamics (PK/PD) of ceftriaxone (CTX), an extensively protein-bound 3rd generation cephalosporin, is altered during early sepsis and whether an increase in urinary loss of bound-CTX, due to GFB alteration, can occur in this condition. Methods: A prospective, experimental, randomized study was carried out in adult male Sprague-Dawley rats. Sepsis was induced by cecal ligation and puncture (CLP). Rats were divided into two groups: Sham-operated and CLP. CTX (100mg i.p., equivalent to 1g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6h after administration. CTX was measured by High Performance Liquid Chromatography (HPLC). The morphological status of the sialic components of the GFB barrier was assessed by lectin histo-chemistry. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA>90%) for 80 and 100% of Tfree>minimum inhibitory concentration (MIC) for 80 and 100% of dosing interval. Measurements and main results: After CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1×101 CFU in sham rats vs 5×104-1×105CFU in CLP rats). CTX plasma concentrations were higher in CLP than in sham rats at 2 and 4h after administration (difference at 2h was 47.3, p=0.012; difference at 4h was 24.94, p=0.004), while lung penetration tended to be lower. An increased urinary elimination of protein-bound CTX occurred (553±689 vs 149±128mg/L, p<0.05; % of bound/total CTX 22±6 in septic rats vs 11±4 in sham rats, p<0.01) and it was associated with loss of the GFB sialic components. According to Monte Carlo simulation a PTA>90% for 100% of the dosing interval was reached neither for sham nor CLP rats using MIC=1mg/L, the clinical breakpoint for Enterobacteriacee. Conclusions: Sepsis causes changes in the PK of CTX and an alteration in the sialic components of the GFB, with consequent loss of protein-bound CTX. Among factors that can affect drug pharmacokinetics during the early phases of sepsis, urinary loss of both free and albumin-bound antimicrobials should be considered.