title: Prospectively validated dosing nomograms for maximizing the pharmacodynamics of vancomycin administered by continuous infusion in critically ill patients.
abstract: The efficacy of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA)-related infections has been called into question by recent findings of higher rates of failure of vancomycin treatment of infections caused by strains with high MICs. Continuous infusion may be the best way to maximize the time-dependent activity of vancomycin. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL(Cr)) estimates for use in daily clinical practice to target the steady-state concentrations (C(ss)s) of vancomycin during continuous infusion at 15 to 20 mg/liter (after the administration of an initial loading dose of 15 mg/kg of body weight over 2 h). The correlation between vancomycin clearance (CL(v)) and CL(Cr) was retrospectively assessed in a cohort of critically ill patients (group 1, n = 70) to create a formula for dosage calculation to target C(ss) at 15 mg/liter. The performance of this formula was prospectively validated in a similar cohort (group 2, n = 63) by comparison of the observed and the predicted C(ss)s. A significant relationship between CL(v) and CL(Cr) was observed in group 1 (P < 0.001). The application of the calculated formula to vancomycin dosing in group 2 {infusion rate (g/24 h) = [0.029 x CL(Cr) (ml/min) + 0.94] x target C(ss) x (24/1,000)} led to a significant correlation between the observed and the predicted C(ss)s (r = 0.80, P < 0.001). Two dosing nomograms based on CL(Cr) were created to target the vancomycin C(ss) at 15 and 20 mg/liter in critically ill patients. These nomograms could be helpful in improving the vancomycin treatment of MRSA infections, especially in the presence of borderline-susceptible pathogens and/or of pathophysiological conditions which may enhance the clearance of vancomycin, while potentially avoiding the increased risk of nephrotoxicity observed with the use of high intermittent doses of vancomycin.
authors.affiliation: Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, 33100 Udine, Italy. pea.federico@aoud.sanita.fvg.it
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
authors.forename: Mario
authors.initials: M
authors.lastname: Furlanut
authors.forename: Camilla
authors.initials: C
authors.lastname: Negri
authors.forename: Federica
authors.initials: F
authors.lastname: Pavan
authors.forename: Massimo
authors.initials: M
authors.lastname: Crapis
authors.forename: Francesco
authors.initials: F
authors.lastname: Cristini
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Viale
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D003404:Creatinine / Q000378:metabolism; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008875:Middle Aged; D049451:Nomograms; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013997:Time Factors; D016896:Treatment Outcome; D014640:Vancomycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D003404:Creatinine