title: Pharmacodynamic target attainment analysis against Streptococcus pneumoniae using levofloxacin 500 mg, 750 mg and 1000 mg once daily in plasma (P) and epithelial lining fluid (ELF) of hospitalized patients with community acquired pneumonia (CAP).
abstract: The pharmacokinetics and pharmacodynamics of levofloxacin in patients with respiratory infections such as community-acquired pneumonia (CAP) are poorly documented. This work aimed at assessing the pharmacodynamic target attainment against Streptococcus pneumoniae using levofloxacin 500 mg, 750 mg and 1000 mg administered once daily in plasma (P) and epithelial lining fluid (ELF) of hospitalized patients with community acquired pneumonia. The pharmacokinetics of levofloxacin in elderly (>/=65 years) compared with younger patients (<65 years) hospitalized with CAP were simulated. Susceptibility data with S. pneumoniae from our ongoing national surveillance study (Canadian Respiratory Organism Susceptibility Study-CROSS) were then used to produce pharmacodynamic indices of AUC(0-24)/MIC(all.) Monte Carlo simulations were then used to analyse target attainment of levofloxacin using doses of 500 mg, 750 mg and 1000 mg once daily to achieve free drug AUC(0-24)/MIC(all) >/= 30-100 versus S. pneumoniae in patients with CAP. Pharmacokinetics of levofloxacin simulated after 500 mg, 750 mg and 1000 mg once daily dosing resulted in levofloxacin volume of distribution: elderly patients = younger patients, while levofloxacin clearance was: elderly patients < younger patients. Levofloxacin t(1/2) values were longer in elderly patients (9.8 +/- 2.5h) than younger patients with CAP (7.4 +/- 2.5h). Free levofloxacin AUC(0-24) as well as AUC(0-24)/MIC(all) for S. pneumoniae were higher in elderly patients than younger patients. Monte Carlo simulation using levofloxacin 500 mg yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 in P and ELF (95.7% and 98.1%) in elderly and younger patients (72.7% and 80.6%) respectively. Levofloxacin 750 mg and 1000 mg once daily had probability of achieving free-drug AUC(0-24)/MIC(all) of 30 in P/ELF of 98.1%/98.6% and 99.2%/99.0%, respectively, in elderly patients compared with 89.9%/94.1% and 95.2%/96.5%, respectively, for younger patients. Probability of achieving of AUC(0-24)/MIC(all) of 100 in P or ELF was very low in both patient populations at different doses except in the case of elderly patients receiving levofloxacin in a dose of 1000 mg once daily P/ELF of 78.5%/87.0%. We conclude that levofloxacin pharmacokinetics in elderly patients with CAP are markedly different from those of younger patients. Levofloxacin 750 mg OD provides high probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 in both plasma and epithelial lining fluid in patients with CAP including younger patients. Levofloxacin 500 mg OD provides high probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 in elderly patients with CAP, although we favour the 750 mg dosing in these patients as well. Levofloxacin 750 mg OD results in high probability of pharmacodynamic target attainment and improved bacteriological outcome against S. pneumoniae in patients with CAP.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Man., Canada. anoreddin@umn.edu
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Noreddin
authors.forename: Theodore K
authors.initials: TK
authors.lastname: Marras
authors.forename: Kevin
authors.initials: K
authors.lastname: Sanders
authors.forename: Charles K N
authors.initials: CK
authors.lastname: Chan
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Hoban
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D017714:Community-Acquired Infections / Q000382:microbiology*; D004333:Drug Administration Routes; D005260:Female; D006760:Hospitalization; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D064704:Levofloxacin; D015242:Ofloxacin