This study thus examined, for the first time, the clinical PK of doripenem and meropenem in prostate tissue, and esti- mated their PD target attainment at this site.
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MP16-07 CLINICAL PHARMACOKINETICS OF CARBAPENEM ANTIBIOTICS IN PROSTATE TISSUE, AND DOSING CONSIDERATIONS FOR PROSTATITIS BASED ON SITE-SPECIFIC PHARMACODYNAMICS Kogenta Nakamura*, Aichi, Japan; Kazuro Ikawa, Hiroshima, Japan; Genya Nishikawa, Ikuo Kobayashi, Kenji Zennami, Keishi Kajikawa, Takahiko Yoshizawa, Yoshiharu Kato, Masahito Watanabe, Aichi, Japan; Yoshiaki Yamada, Gifu, Japan; Kenji Mitsui, Masahiro Narushima, Kento Kanao, Aichi, Japan; Norifumi Morikawa, Hiroshima, Japan; Makoto Sumitomo, Aichi, Japan INTRODUCTION AND OBJECTIVES: Carbapenems (doripenem and meropenem) are a therapeutic option for bacterial prostatitis and antibacterial prophylaxis in prostatic surgery, especially in patients who are intolerant or resistant to quinolones. However, the clinical pharmacokinetics (PK) of the two carbapenems in prostate tissue and attainment of their pharmacodynamic (PD) targets at site of action had been unclear. This study thus examined, for the first time, the clinical PK of doripenem and meropenem in prostate tissue, and estimated their PD target attainment at this site. METHODS: Doripenem (0.25 g or 0.5 g) or meropenem (0.25 g or 0.5 g) was intravenously administered to 101 patients with benign prostatic hypertrophy prior to TURP. Blood samples and prostate tissue samples were collected 0.5, 1, 1.5, 2, 3, 4 and 5 h after starting a 0.5-h infusion. Drug concentrations in plasma and prostate tissue were measured using high-performance liquid chromatography, analyzed using a three-compartment population pharmacokinetic model, and used to estimate the probability of attaining a bactericidal target (40% of the time above the minimum inhibitory concentration [MIC] for bacteria). RESULTS: These carbapenems penetrated similarly into prostate tissue, independently of the dose, with mean prostate tissue/ plasma ratios of 0.166e0.173 (maximum drug concentration) and 0.177e0.187 (area under drug concentration-time curve). Despite this relatively low penetration by doripenem and meropenem, their usual regimens of 0.25 g three times daily and 0.5 g twice daily (0.5-h infusions) achieved a favorable target-attainment probability value of 90.8e95.9%, in prostate tissue, against clinical isolate populations of Escherichia coli and Klebsiella species (the two major causative bacteria in prostatitis). However, Pseudomonas aeruginosa isolate population needed 0.5 g three times daily for probability values of 55.9% for doripenem and 52.3% for meropenem. The prostatic pharmacodynamic-based breakpoint MIC (the highest MIC at which the targetattainment probability in prostate tissue was more than 90%) was 0.063 mg/L for 0.25 g three times daily and 0.125 mg/L for 0.5 g three times daily, for both drugs. CONCLUSIONS: These results define clinical pharmacokinetics of doripenem and meropenem in prostate tissue, while also rationalizing and optimizing their dosing regimens for prostatitis on the basis of site-specific pharmacodynamic target attainment. Source of Funding: none
MP16-08 SEARCH FOR MICROORGANISMS IN MEN WITH UROLOGIC CHRONIC PELVIC PAIN SYNDROME: A CULTURE-INDEPENDENT ANALYSIS OF CASES AND CONTROLS ENROLLED IN THE TRANS-MAPP EPIDEMIOLOGY/PHENOTYPING (EP) STUDY J. Curtis Nickel*, Kingston, Canada; Alisa Stephens, Philadelphia, PA; Jun Chen, Boston, MA; Richard Landis, Philadelphia, PA; Christopher Mullins, Bethesda, MD; Garth Ehrlich, Philadelphia, PA; The MAPP Research Network, Bethesda, MD INTRODUCTION AND OBJECTIVES: We hypothesized that differences in lower urinary tract microbial populations between male UCPPS patients and normal subjects may be implicated in the etiology of male UCPPS. We used novel state-of-the-art culture-independent methodology to compare the microbiota of the lower urinary tract in men with UCPPS and controls enrolled in the NIH trans-MAPP EP study.
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METHODS: Each participant (cases and non-UCPPS controls) were asked to provide initial (VB1), midstream (VB2) and post-prostatic massage (VB3) urine specimen. Specimens were analyzed with Ibis T5000 Universal Biosensor technology which employs a polymerase chain reaction e electron spray ionization e time-of-flight e mass spectoscopic- based system to provide comprehensive identification of all bacterial species. Differences between UCPPS patients and controls in the presence of species or the number of different species within a higher level group were tested using PERMANOVA, and Fisher’s Exact test. All tests were conducted at the species, genus,and gramstain level. RESULTS: 417 male subjects (191 cases; 226 controls) were enrolled in the trans-MAPP-EP study. Baseline VB1 and VB2 urine specimens were obtained from 110 UCPPS cases and 115 matched controls (subjects with no UCPPS symptoms). VB3 samples were provided by 67 CP/CPPS and 62 controls. A total of 78, 73 and 54 species (42, 39 and 27 genera) were detected in VB1, VB2 and VB3 respectively. Mean (SD) VB1, VB2 and VB3 species count per person was 1.62 (1.28), 1.38 (1.36) and 1.33(1.24) for cases and 1.75(1.32), 1.23(1.15) and 1.56 (0.97) for controls respectively. Overall species and genus composition significantly differed between UCPPS patients and controls in VB1 only (p¼0.008 species level, p¼0.011 genus level, p¼0.079 Gram-stain level) with overall differences driven by B. cenocepacia (RR¼3.34, p¼0.009), P. acnes (RR 0.38, p¼0.01), and S. capitis/capare (RR¼0.17, p¼0.008). These differences (and similar trends at genus level) remained significant after adjustment for multiple comparisons. No significant differences were observed at the Gram-stain level in VB1 or at any level in VB2 or VB3. CONCLUSIONS: While our results make it difficult to implicate the minor differences in lower urinary tract microbiota (VB1 only) in patients vs controls for a role in the etiology and pathogenesis of UCPPS in males, further work is required to determine if microbial composition or fluctuations influence symptom patterns over time. Source of Funding: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (DK82370, DK82342, DK82315, DK82344, DK82325, DK82345, DK82333, and DK82316)
MP16-09 TRUS CHARACTERISTICS OF CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME: COMPARISON WITH AGE-MATCHED CONTROLS Dorit Zilberman*, Ramat-Gan, Israel; Matvet Tsivian, Durham, NC; Yoram Mor, Gil Raviv, Ramat Gan, Israel INTRODUCTION AND OBJECTIVES: We sought to explore the yield of trans-rectal ultrasound (TRUS) in cases of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: The records of all patients, who were referred for TRUS due to CP/CPPS, were retrospectively reviewed. Digital rectal exam (DRE) was performed before TRUS. The following parameters were recorded: prostate length; width; height; volume; external border; peripheral zone (PZ); transitional zone (TZ); TZ/PZ border; seminal vesicle (SV); presence of median lobe; dilation of vas deferens (VD) or ejaculatory duct (ED); presence of significant post-void residual (PVR). Data were compared to an age-matched control group that had undergone the same imaging for other reasons. RESULTS: Between the years 2004-2012, 216 patients aged 42 years (35-50) underwent DRE and TRUS by a single operator. Per DRE, their prostates appeared smaller (15.5 cc vs. 25 cc, p
