Poster, Podium & Video Sessions
Presentation Authors: Kogenta Nakamura*, Nagakute, Japan, Kazuro Ikawa, Hiroshima, Japan, Ikuo Kobayashi, Genya Nishikawa, Keishi Kajikawa, Yoshiharu Kato, Masahito Watanabe, Nagakute, Japan, Motoi Tobiume, Owariasahi, Japan, Kenji Mitsui, Masahiro Narushima, Tokoname, Japan, Kent Kanao, Nagakute, Japan, Norifumi Morikawa, Hiroshima, Japan, Makoto Sumitomo, Nagakute, Japan
Introduction: Piperacillin-tazobactam (8:1) and flomoxef have activities also against Enterobacteriaceae producing extended-spectrum beta-lactamases. These beta-lactam antibiotics are a therapeutic option for bacterial prostatitis and antibacterial prophylaxis in prostatic surgery. However, their clinical pharmacokinetics in prostate tissue and pharmacodynamics at the site of action had been unclear. This study thus examined, for the first time, the clinical pharmacokinetics of piperacillin-tazobactam and flomoxef in prostate tissue, and estimated their pharmacodynamic target attainment at this site.
Methods: Piperacillin-tazobactam (total dose of 2.25 g or 4.5 g) or flomoxef (0.5 g or 1 g) was intravenously administered to 101 patients with benign prostatic hypertrophy prior to TURP. Venous blood and prostate tissue samples were collected 0.5-5 h after starting a 0.5-h infusion. Drug concentrations were measured using high-performance liquid chromatography, analyzed using a three-compartment population pharmacokinetic model, and used to estimate the probability of attaining the bactericidal targets (time above the minimum inhibitory concentration [MIC] for bacteria, 50% for piperacillin and 70% for flomoxef).
Results: Both beta-lactams penetrated similarly into prostate tissue, independently of the dose, with mean prostate tissue/plasma ratios of 0.38-0.49 (maximum drug concentration) and 0.36-0.56 (area under drug concentration-time curve). Tazobactam showed similar pharmacokinetic profile with piperacillin. With this medium degree of penetration, the usual dosages of piperacillin-tazobactam 4.5 g three times daily and flomoxef 1 g twice daily (0.5-h infusions) achieved a favorable target-attainment probability of 91.3-94.0%, in prostate tissue, against clinical isolate populations of Escherichia coli and Klebsiella species (the two major causative bacteria in prostatitis). The prostatic pharmacodynamic-based breakpoint MIC (the highest MIC at which the target-attainment probability in prostate tissue was >90%) was 0.5 mg/L for piperacillin-tazobactam 2.25 g twice daily and 0.25 mg/L for flomoxef 1 g three times daily.
Conclusions: This study revealed the clinical pharmacokinetics of piperacillin-tazobactam and flomoxef in prostate tissue. The results on the site-specific pharmacodynamic target attainment should rationalize and optimize their dosages for prostatitis especially with Enterobacteriaceae producing extended-spectrum beta-lactamases.
Source Of Funding: None