title: Pharmacokinetic/pharmacodynamic target attainment of intravenous β-lactam regimens against Gram-negative bacteria isolated in a Brazilian teaching hospital.
abstract: BACKGROUND
  Monte Carlo simulations have been used for selecting optimal antibiotic regimens for treatment of bacterial infections. The aim of this study was to assess the pharmacokinetic and pharmacodynamic target attainment of intravenous β-lactam regimens commonly used to treat bloodstream infections (BSIs) caused by Gram-negative rod-shaped organisms in a Brazilian teaching hospital.
  
  
  METHODS
  In total, 5,000 patients were included in the Monte Carlo simulations of distinct antimicrobial regimens to estimate the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) for the requisite periods to clear distinct target organisms. Microbiological data were obtained from blood culture isolates harvested in our hospital from 2008 to 2010.
  
  
  RESULTS
  In total, 614 bacterial isolates, including Escherichia coli, Enterobacterspp., Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, were analyzed Piperacillin/tazobactam failed to achieve a cumulative fraction of response (CFR) > 90% for any of the isolates. While standard dosing (short infusion) of β-lactams achieved target attainment for BSIs caused by E. coliand Enterobacterspp., pharmacodynamic target attainment against K. pneumoniaeisolates was only achieved with ceftazidime and meropenem (prolonged infusion). Lastly, only prolonged infusion of high-dose meropenem approached an ideal CFR against P. aeruginosa; however, no antimicrobial regimen achieved an ideal CFR against A. baumannii.
  
  
  CONCLUSIONS
  These data reinforce the use of prolonged infusions of high-dose β-lactam antimicrobials as a reasonable strategy for the treatment of BSIs caused by multidrug resistant Gram-negative bacteria in Brazil.
authors.affiliation: Grupo de Racionalização de Antimicrobianos em Doentes Críticos, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Guilherme Henrique
authors.initials: GH
authors.lastname: Furtado
authors.affiliation: Grupo de Racionalização de Antimicrobianos em Doentes Críticos, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cardinal
authors.affiliation: Grupo de Racionalização de Antimicrobianos em Doentes Críticos, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Rodrigo Spineli
authors.initials: RS
authors.lastname: Macedo
authors.affiliation: Grupo de Racionalização de Antimicrobianos em Doentes Críticos, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Juliana Oliveira
authors.initials: JO
authors.lastname: Silva
authors.affiliation: Grupo de Racionalização de Antimicrobianos em Doentes Críticos, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Eduardo Alexandrino
authors.initials: EA
authors.lastname: Medeiros
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Joseph Levente
authors.initials: JL
authors.lastname: Kuti
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: David Paul
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001938:Brazil; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000145:classification / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D006784:Hospitals, Teaching; D006801:Humans; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D013997:Time Factors; D047090:beta-Lactams / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams