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Comparison of Ofloxacin and Norfloxacin Concentration in Prostatic Tissues in Patients Undergoing Transurethral Resection of the Prostate

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Comparison of Ofloxacin and Norfloxacin Concentration in Prostatic Tissues in Patients Undergoing Transurethral Resection of the Prostate J. Chen, R.R.L. Chen, and H.S. Huang COMPARISON OF OFLOXACIN AND NORFLOXACIN CONCENTRATION IN PROSTATIC TISSUES IN PATIENTS UNDERGOING TRANSURETHRAL RESECTION OF THE PROSTATE Jun Chen, Russel Rhei-Lon Chen,1 and Ho-Shiang Huang Background and purpose: To compare the concentrations of two fluoroquinolones, (J Formos Med Assoc ofloxacin (OFLX) and norfloxacin (NFLX), in the prostate glands of patients who 2001;100:548–52) underwent transurethral resection of the prostate (TUR-P) after oral ingestion of both drugs for surgical prophylaxis. Key words: Methods: Ten patients with clinical symptoms of benign prostatic hyperplasia under- ofloxacin going TUR-P received 200 mg of both drugs per os simultaneously 2 hours before norfloxacin surgery. The concentrations of the drugs in the serum and prostate at the time of prostatitis surgery were measured by high performance liquid chromatography. Patients’ clinical minimum inhibitory characteristics were evaluated, including findings from transrectal ultrasonography of concentration the prostate, prostate specific antigen concentration, renal function tests, and post- prostatectomy operative status. Results: Two hours after administration, the mean serum concentration of OFLX was 4.14 ± 0.64 mg/L (range 0.27–6.37) and of NFLX was 1.10 ± 0.22 mg/L (range 0.02–2.1). The concentration of ORLX in prostatic tissue was 4.10 ± 0.79 µg/g (range 1.70–6.37) and of NFLX was 2.22 ± 0.57 µg/g (range 0.63–4.35). The ratio of the prostatic tissue concentration (P) to the serum concentration (S) was 2.11 for OFLX and 5.71 for NFLX. The concentrations of both drugs exceeded the minimum inhibitory concentration (MIC) for most gram-negative organisms, but NFLX may be unable to exceed the MIC90 of Enterobacter cloacae in some individuals. Leukocytosis and spiking fever developed after TUR-P in two of the 10 patients. Conclusions: Concentrations of OFLX were higher in both serum and prostatic adenoma tissues than those of NFLX (p < 0.001), while NFLX had better penetration into the prostate (P/S ratio) (p < 0.001). The results of this study indicated that the concen- trations of both of these drugs exceeded the MIC for most gram-negative organisms. Antibacterial chemoprophylaxis for urinary tract infec- of a single intravenous dose of pefloxacin (800 mg), tion (UTI) during and after transurethral resection of the prostatic tissue concentrations were found to be well prostate (TUR-P) has long been controversial. Through above the MICs of pefloxacin for the bacteria commonly administration of broad-spectrum antibiotics over a short causing acute and chronic prostatitis [4]. preoperative period or as a single preoperative dose, the Ofloxacin (OFLX) is a pyridonecarboxylic acid postoperative rates of UTI have decreased to less than derivative with a broad spectrum of antibacterial activ- 10% [1, 2]. The newer quinolones almost completely ity in vitro and in vivo [5]. OFLX has been shown to be cover the spectrum of bacteria causing UTI and show a good choice in the treatment of chronic bacterial good results in the treatment of uncomplicated and prostatitis [6]. Norfloxacin (NFLX) is a lipid-soluble complicated UTI [3]. After preoperative administration weak organic acid that binds to plasma proteins to a low Departments of Urology and 1Pharmacy, College of Medicine, National Taiwan University, Taipei. Received: 16 January 2001. Revised: 5 February 2001. Accepted: 10 July 2001. Reprint requests and correspondence to: Dr. Jun Chen, Department of Urology, National Taiwan University, 7 Chung-Shan South Road, Taipei, Taiwan. 548 J Formos Med Assoc 2001 • Vol 100 • No 8 Ofloxacin and Norfloxacin Concentrations in Serum and Prostate Adenoma extent [7]. Because recurrent UTI in men was thought in a homogenizer, to which was added 3 mL of 0.1 M to be frequently associated with prostatic infection, phosphate buffered saline (PBS). The sample was then Sabbaj et al compared the efficacy of NFLX to co- homogenized for 3 minutes. After centrifuging at trimoxazole in male patients with recurrent UTI. They 3000 rps for 10 minutes, the supernatant was used for concluded that NFLX was more efficacious than co- analysis. A mixture of 200 µL of serum or tissue trimoxazole in eradicating bacteria in the prostate supernatant, 200 µL of internal standard solution (1.5 (93% vs 67%) [7]. This study evaluated the extent of µg pipemidic acid dissolved in PBS), and 5 mL of penetration of OFLX and NFLX, the two most widely dichloromethane were vortexed for 1 minute. The used fluoroquinolones in Taiwan, in serum and pros- mixture was then centrifuged at 3,000g for 10 minutes, tatic adenoma tissue 2 hours after oral administration. and 4 mL of the dichloromethane layer was transferred The effectiveness of these agents in the prevention of to a clean evaporative tube and evaporated under an postoperative UTI was also evaluated. air gas stream. The residue was dissolved in 200 µL mobile phase (15 mM phosphate buffer pH = 7.0 containing 20 mM tetrabutylam-monium hydrogen sulfate with acetonitril (10:1, v/v)) and treated in a atients and Methods thermomixer and with ultrasound. Of the final sample, P 20 µl was injected onto the HPLC column. A Hitachi F-1000 fluorescence-detector (Ibaragi, Japan) and a Sample collection LoiChrosper 100 RP-18 (150 X 4.6 mm, 5 µm) column Ten patients with benign prostatic hyperplasia were were employed for the analysis at a flow rate of admitted to National Taiwan University Hospital 1 mL/minute at 30°C. The retention time for pipemidic (NTUH) to undergo transurethral resection of the acid (internal standard) was 3.4 minutes, for OFLX was prostate. None of the patients had received OFLX or 5.14 minutes, and for NFLX was 9.5 minutes. Concen- NFLX within the preceding 72 hours. Every patient trations of OFLX and NFLX obtained from the received a single oral dose of OFLX (200 mg) and serum were expressed as mg per L and from prostatic NFLX (200 mg) simultaneously 2 hours before stan- specimens were expressed as µg per g of prostate dard TUR-P was performed. Before administering these tissue. Values were recorded as the mean of duplicate two drugs, 10 mL of venous blood was collected, and measurements for each specimen. Differences were another 5 mL of blood was collected 2 hours after assessed using a paired t-test, with a p value of less than administration. Blood cell count (CBC), urinary 0.05 indicating statistical significance. analysis, blood urea nitrogen (BUN), and creatinine concentration (Cr) were measured before and 3 days after TUR-P. Prostate-specific antigen (PSA) concen- tration was measured once before surgery (TANDEM- ε–PSA, Hybritech Inc, San Diego, CA, USA). Transrectal Results ultrasonography of the prostate (TRUS-P) was per- formed on every patient to measure the volume and The clinical characteristics of patients before and after estimate the weight of the whole prostate and adenoma TUR-P are listed in Table 1. The pathology of the (Bruel & Kjaer Model 8551 multiplane transducer). prostatic adenoma showed nodular hyperplasia in all During TUR-P, we selected a portion of the resected patients except patient 10, who had adenocarcinoma, prostatic adenoma strips (approximately 1 g) and though his PSA concentration was 1.0 and PSA density washed them thoroughly with physiologic saline in the was 0.05. Furthermore, pathology results indicated operating theater to avoid contamination by urine. that almost all patients (9/10) also had focal inflamma- These specimens and blood samples were then stored tory cell infiltration, with pictures of chronic prostatitis at –70°C until use. Because all patients had indwelling (Table 1). Two patients (4 and 9) experienced leuko- Foley catheters after TUR-P with 24-hour normal saline cytosis (WBC = 23,200 and 12,900, respectively) after irrigation, postoperative infection was defined as eleva- TUR-P, which was resolved by additional parenteral tion of white blood cell count combined with shift-to- antibiotic treatment. Patients 7 and 10 had positive pre- left in differential count in the CBC of patients who had TUR-P urine culture results, but they recovered well fever during the postoperative period. after TUR-P. Patient 1 experienced gross hematuria and dysuria 1 month after TUR-P, and cystoscopy Measurement of drug concentration revealed bladder neck contracture. Although this Concentrations of OFLX and NFLX were measured patient recovered smoothly after the first operation, by high-performance liquid chromatography (HPLC). the pathology from the late bladder neck resection Approximately 1 g of prostatic tissue sample was placed revealed acute prostatitis. J Formos Med Assoc 2001 • Vol 100 • No 8 549 J. Chen, R.R.L. Chen, and H.S. Huang Table 1. The clinical characteristics of patients undergoing transurethral resection of the prostate (TUR-P) Patient Age BW Whole Adenoma Pathology PSA PSAD BUN Cr Outcome (kg) (g)* prostate (ng/mL) (mg/dL) (mg/dL) (g)* 1 73 63 22.4 7.5 Nodular 1.3 0.058 13.9 1.6 BN contracture hyperplasia + UTI 1 month later + prostatitis 2 62 68 26.2 14.4 Nodular 2.5 0.095 22 1.1 Smooth postoperative hyperplasia course + prostatitis 3 65 70 30.5 15.0 Nodular 3.7 0.121 24 2.2 Smooth postoperative hyperplasia course + prostatitis 4 58 73.5 51.0 43.5 Nodular 12.0 0.235 14.9 1.3 Leukocytosis after hyperplasia TUR-P + prostatitis 5 64 51.3 54.5 35.0 Nodular 5.6 0.103 11 1.0 Preoperative u/c: yeast-like hyperplasia organism; smooth postop- + prostatitis erative course 6 69 53 21.3 10.0 Nodular 3.8 0.178 17 0.9 Smooth postoperative hyperplasia course + prostatitis 7 52 84 21 11.5 Nodular 4.6 0.219 10.9 1.0 Preoperative u/c: E.
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