Penetration of piperacillin–tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics

• Published in: Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 21; no. 8; pp. 575 - 580
• Main Authors: Kobayashi, Ikuo, Ikawa, Kazuro, Nakamura, Kogenta, Nishikawa, Genya, Kajikawa, Keishi, Yoshizawa, Takahiko, Watanabe, Masahito, Kato, Yoshiharu, Zennami, Kenji, Kanao, Kent, Tobiume, Motoi, Yamada, Yoshiaki, Mitsui, Kenji, Narushima, Masahiro, Morikawa, Norifumi, Sumitomo, Makoto
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.08.2015
• Subjects: Aged; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Antibiotic Prophylaxis; Area Under Curve; Escherichia coli - drug effects; Hematology, Oncology and Palliative Medicine; Humans; Infusions, Intravenous; Klebsiella - drug effects; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Monte Carlo simulation; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - blood; Penicillanic Acid - pharmacokinetics; Penicillanic Acid - therapeutic use; Pharmacokinetics/pharmacodynamics; Piperacillin - blood; Piperacillin - pharmacokinetics; Piperacillin - therapeutic use; Piperacillin–tazobactam; Prostate - metabolism; Prostatic Hyperplasia - surgery; Prostatitis; Prostatitis - drug therapy; Prostatitis - metabolism; Proteus - drug effects; Pseudomonas aeruginosa - drug effects; Three-compartment model; Transuretheral resection of the prostate; Transurethral Resection of Prostate; Piperacillin–tazobactam; Three-compartment model; Prostatitis; Transuretheral resection of the prostate; Pharmacokinetics/pharmacodynamics; Monte Carlo simulation
• ISSN: 1341-321X; 1437-7780
• DOI: 10.1016/j.jiac.2015.04.015

Abstract This study aimed to investigate the penetration of PIPC–TAZ into human prostate, and to assess effectiveness of PIPC–TAZ against prostatitis by evaluating site-specific PK–PD. Patients with prostatic hypertrophy ( n  = 47) prophylactically received a 0.5 h infusion of PIPC–TAZ (8:1.2–0.25 g or 4–0.5 g) before transurethral resection of the prostate. PIPC–TAZ concentrations in plasma (0.5–5 h) and prostate tissue (0.5–1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria ( T  > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC–TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration ( Cmax ) and the area under the drug concentration–time curve (AUC). Against MIC distributions for isolates of Escherichia coli , Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T  > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T  > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC–TAZ is appropriate for the treatment of prostatitis from the site-specific PK–PD perspective.