title: Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat.
abstract: 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.
  
  
  
  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 (100 mg i.p., equivalent to 1 g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6 h 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.
  
  
  
  After CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1 × 101CFU 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 4 h after administration (difference at 2 h was 47.3, p = 0.012; difference at 4 h 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 ± 128 mg/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 = 1 mg/L, the clinical breakpoint for Enterobacteriacee.
  
  
  
  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.
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Selmi
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy. beatriceloriga@libero.it.
authors.forename: Beatrice
authors.identifier: 0000-0002-4890-0898
authors.initials: B
authors.lastname: Loriga
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Vitali
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Carlucci
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Di Filippo
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Carta
authors.affiliation: Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090, Pesche, IS, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sgambati
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Tofani
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
authors.forename: Angelo Raffaele
authors.initials: AR
authors.lastname: De Gaudio
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Novelli
authors.affiliation: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Adembri
mesh_terms: D000818:Animals; D002432:Cecum / Q000187:drug effects / Q000473:pathology; D002443:Ceftriaxone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D003198:Computer Simulation; D008026:Ligation; D008297:Male; D009010:Monte Carlo Method; D010835:Phytohemagglutinins / Q000378:metabolism; D011446:Prospective Studies; D011677:Punctures; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D010835:Phytohemagglutinins; C100156:leukoagglutinins, plants; D002443:Ceftriaxone
keywords: Ceftriaxone; Glomerular filtration barrier; Glycocalyx; Monte Carlo simulation; Pharmacokinetics/pharmacodynamics; Sepsis; Sialic acids