title: Pharmacodynamic analysis of the microbiological efficacy of telithromycin in patients with community-acquired pneumonia.
abstract: OBJECTIVE
  Telithromycin, a ketolide antibacterial, demonstrates concentration-dependent bactericidal activity against the major pathogens causing community-acquired respiratory tract infections. The objective of this study was to explore the relationships between pharmacokinetic/pharmacodynamic predictor variables, such as area under the plasma concentration-time curve (AUC) over minimum inhibitory concentration (MIC) [AUC/MIC], maximum plasma concentration (C(max)) over MIC (C(max)/MIC) and microbiological outcome from telithromycin therapy for community-acquired pneumonia (CAP).
  
  
  METHODS
  Data were pooled from five phase III studies of oral telithromycin (800 mg once daily for 7-10 days) for the outpatient treatment of adults with CAP. Only subjects with a single pathogen isolated at baseline, a telithromycin MIC determination and at least one plasma pharmacokinetic sample were included. Bacteriologically modified intent-to-treat (bmITT) and bacteriologically evaluable per protocol (PPb) populations were analysed. Individual AUC and C(max) Bayesian estimates were obtained with a population pharmacokinetic model. Logistic regression, nonparametric smoothing, and classification analysis and regression tree (CART) were used to assess the relationship between AUC/MIC and C(max)/MIC and microbiological outcome by pathogen.
  
  
  RESULTS
  The bmITT population included 224 patients (Streptococcus pneumoniae in 113, Haemophilus influenzae in 89 and Staphylococcus aureus in 22). Median telithromycin MIC was 0.015 microg/mL for S. pneumoniae, 2.0 microg/mL for H. influenzae and 0.12 microg/mL for S. aureus, with median AUC/MIC of 907.1, 6.9 and 98.4, and median C(max)/MIC of 172.0, 1.3 and 20.4 for the three pathogens, respectively. Both logistic regression and nonparametric smoothing showed the probability of microbiological cure to be consistently greater than 90% over the observed range of predictor variables. No reliable AUC/MIC or C(max)/MIC breakpoints were identified by CART.
  
  
  CONCLUSIONS
  Telithromycin exhibits near-maximal efficacy against three major pathogens causing CAP at a dose of 800 mg once daily.
authors.affiliation: Aventis Pharmaceuticals, Bridgewater, New Jersey, USA. jun.shi@frx.com
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.forename: Marc
authors.initials: M
authors.lastname: Pfister
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Jenkins
authors.forename: Sunny
authors.initials: S
authors.lastname: Chapel
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.forename: Ruedi E
authors.initials: RE
authors.lastname: Port
authors.forename: Dan
authors.initials: D
authors.lastname: Howard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001499:Bayes Theorem; D017714:Community-Acquired Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006193:Haemophilus influenzae / Q000187:drug effects; D006801:Humans; D048628:Ketolides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D018709:Statistics, Nonparametric; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; C106791:telithromycin