title: Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.
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.
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan. Electronic address: ikuok@aichi-med-u.ac.jp.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kobayashi
authors.affiliation: Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Kazuro
authors.initials: K
authors.lastname: Ikawa
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Kogenta
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Genya
authors.initials: G
authors.lastname: Nishikawa
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Kajikawa
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yoshizawa
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Zennami
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Kent
authors.initials: K
authors.lastname: Kanao
authors.affiliation: Department of Urology, Asahi Laborers' Hospital, Aichi 488-8585, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Tobiume
authors.affiliation: Department of Urology, Kani Tono Hospital, Kani, Gifu 509-0206, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Urology, Tokoname Municipal Hospital, 4-5 Koiehonmachi, Tokoname 479-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mitsui
authors.affiliation: Department of Urology, Meitetsu Hospital, 2-26-11 Sako, Nishi-ku, Nagoya 451-8511, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Narushima
authors.affiliation: Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Morikawa
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sumitomo
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019072:Antibiotic Prophylaxis; D019540:Area Under Curve; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007709:Klebsiella / Q000187:drug effects; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D010878:Piperacillin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D011467:Prostate / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000601:surgery; D011472:Prostatitis / Q000188:drug therapy* / Q000378:metabolism; D011511:Proteus / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D020728:Transurethral Resection of Prostate
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: Monte Carlo simulation; Pharmacokinetics/pharmacodynamics; Piperacillin–tazobactam; Prostatitis; Three-compartment model; Transuretheral resection of the prostate