title: Vancomycin dosage optimization in patients with malignant haematological disease by pharmacokinetic/pharmacodynamic analysis.
abstract: BACKGROUND
  The use of vancomycin against Staphylococcus aureus is currently debated because of the increasing resistance developed by this pathogen. Nevertheless, antibacterial effectiveness is a limited resource that must be protected and restored. Novel dosage strategies based on pharmacokinetic/pharmacodynamic analyses are needed to retain effectiveness that could improve drug exposure in patients infected with such pathogens.
  
  
  OBJECTIVE
  The aim of this study was to assess whether standard or higher vancomycin dosages are required to increase the probability of attaining a target pharmacokinetic/pharmacodynamic index for several staphylococcal strains and thus to estimate the minimum vancomycin daily dose related to a high probability of effective treatment in patients with malignant haematological disease.
  
  
  METHODS
  Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR) for different vancomycin daily dosages, using a population pharmacokinetic model previously defined in patients with malignant haematological disease and the minimum inhibitory concentration (MIC) distribution for vancomycin against several staphylococcal species (vancomycin-susceptible S. aureus and vancomycin-intermediate S. aureus [VISA], S. epidermidis, S. haemolyticus and coagulase-negative Staphylococcus [CNS] species) obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in order to predict the dose that would achieve the pharmacokinetic/pharmacodynamic index value associated with efficacy (the area under the concentration-time curve from 0 to 24 hours divided by the MIC [AUC(24)/MIC >/=400]).
  
  
  RESULTS
  CFR values showed dependence on the renal function of the patient and the causative pathogen. Only in patients with a creatinine clearance (CL(CR)) <60 mL/min did the standard vancomycin dosage (2000 mg/day) induce CFRs >60% for all staphylococci, except the VISA strains. CFRs for S. aureus of 90.6%, 47.3% and 31.2% for CL(CR) values of <60, 60-120 and >120 mL/min, respectively, were obtained, whereas for the VISA strains, the corresponding values were only 14.0%, 0.3% and 0%. The impact of potential pathogens on CFRs is also significant. According to our pharmacokinetic/pharmacodynamic analysis, in patients with normal renal function (CL(CR) between 60 and 120 mL/min) vancomycin 2000 mg/day leads to a risk of not achieving the recommended AUC(24)/MIC breakpoint of 52.7%, 70.4%, 74.9% and 80.3% for S. aureus, S. haemolyticus, CNS and S. epidermidis, respectively. Application of our results to clinical practice graphically allows us to obtain the recommended dose for any a priori-selected probability of attaining the AUC(24)/MIC ratio of >/=400 and to evaluate the CFRs for any dosing regimen used in this population group, depending on the patients' renal function.
  
  
  CONCLUSIONS
  Application of pharmacokinetic/pharmacodynamic analysis based on Monte Carlo simulation offers an excellent tool for selecting the therapeutic option with the highest probability of clinical success in patients with malignant haematological disease. Thus, for vancomycin-susceptible S. aureus, if a CFR >/=80 is assumed as clinically acceptable, vancomycin doses of 1500, 3000 and 4000 mg/day for a CL(CR) of <60, 60-120 and >120 mL/min, respectively, will be required.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Salamanca, Salamanca, Spain. gatta@usal.es
authors.forename: Maria del Mar
authors.initials: Mdel M
authors.lastname: Fernández de Gatta
authors.forename: Dolores
authors.initials: D
authors.lastname: Santos Buelga
authors.forename: Amparo
authors.initials: A
authors.lastname: Sánchez Navarro
authors.forename: Alfonso
authors.initials: A
authors.lastname: Dominguez-Gil
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: García
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016908:Gram-Positive Bacterial Infections / Q000150:complications / Q000188:drug therapy*; D019337:Hematologic Neoplasms / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D015233:Models, Statistical; D009010:Monte Carlo Method; D013210:Staphylococcus / Q000187:drug effects*; D014640:Vancomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin