title: Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia.
abstract: OBJECTIVE
  The %fT>MIC of ceftazidime has been shown to correlate with microbiological outcome of Gram-negative bacteria (GNB) in preclinical studies. However, clinical data are still lacking. We explored the relationship of ceftazidime exposure and outcome in patients with nosocomial pneumonia using data from a recent randomized, double-blind Phase 3 clinical trial.
  
  
  METHODS
  Pharmacokinetic (PK) and demographic data from three clinical trials were used to construct a population PK model using non-linear mixed-effects modelling. Individual concentration-time curves and PK/pharmacodynamic indices were determined for individual patients. The MICs used in the analyses were the highest MICs for any GNB cultured at baseline or end of therapy.
  
  
  RESULTS
  A two-compartment model best fit the data, with creatinine clearance as covariate on clearance and age on the central compartment. Classification and regression tree analysis showed a breakpoint value of 44.9% (P<0.0001) for GNB in 154 patients. The Emax model showed a good fit (R(2) =0.93). The benefit of adequate treatment increased from an eradication rate of 0.4848 at %fT>MIC of 0% to 0.9971 at 100%. The EC50 was 46.8% and the EC90 was 95.5% for %fT>MIC. Exposure correlated significantly with both microbiological and clinical outcome at test-of-cure.
  
  
  CONCLUSIONS
  We conclude that exposures to ceftazidime predict microbiological as well as clinical outcome, and the %fT>MIC required to result in a likely favourable outcome is >45% of the dosing interval. This value is similar to that observed in animal models and underscores the principle that adequate dosing can be predicted and is beneficial to patient care.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. muller.research@gmail.com
authors.forename: Anouk E
authors.initials: AE
authors.lastname: Muller
authors.forename: Nieko
authors.initials: N
authors.lastname: Punt
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001419:Bacteria / Q000187:drug effects / Q000302:isolation & purification; D002442:Ceftazidime / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003428:Cross Infection / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002442:Ceftazidime