title: Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal.
abstract: OBJECTIVE
  To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock.
  
  
  METHODS
  Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling.
  
  
  RESULTS
  The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h(-1) (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low.
  
  
  CONCLUSIONS
  Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l(-1)).
authors.affiliation: CHRU de Tours, Université François Rabelais, Service de réanimation médicale, Tours, France. garot@med.univ-tours.fr
authors.forename: Denis
authors.initials: D
authors.lastname: Garot
authors.forename: Renaud
authors.initials: R
authors.lastname: Respaud
authors.forename: Philippe
authors.initials: P
authors.lastname: Lanotte
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simon
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Mercier
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehrmann
authors.forename: Dominique
authors.initials: D
authors.lastname: Perrotin
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Dequin
authors.forename: Chantal
authors.initials: C
authors.lastname: Le Guellec
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002443:Ceftriaxone / Q000493:pharmacokinetics*; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D018805:Sepsis / Q000378:metabolism* / Q000401:mortality
chemical_list: D000900:Anti-Bacterial Agents; D002443:Ceftriaxone