COMPARISON OF OFLOXACIN AND NORFLOXACIN CONCENTRATION IN PROSTATIC TISSUES IN PATIENTS UNDERGOING TRANSURETHRAL RESECTION OF THE PROSTATE

Transcription

1 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, ofloxacin (OFLX) and norfloxacin (NFLX), in the prostate glands of patients who underwent transurethral resection of the prostate (TUR-P) after oral ingestion of both drugs for surgical prophylaxis. Methods: Ten patients with clinical symptoms of benign prostatic undergoing TUR-P received 200 mg of both drugs per os simultaneously 2 hours before surgery. The concentrations of the drugs in the serum and prostate at the time of surgery were measured by high performance liquid chromatography. Patients clinical characteristics were evaluated, including findings from transrectal ultrasonography of the prostate, prostate specific antigen concentration, renal function tests, and postoperative status. Results: Two hours after administration, the mean serum concentration of OFLX was 4.14 ± 0.64 mg/l (range ) and of NFLX was 1.10 ± 0.22 mg/l (range ). The concentration of ORLX in prostatic tissue was 4.10 ± 0.79 µg/g (range ) and of NFLX was 2.22 ± 0.57 µg/g (range ). 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 MIC 90 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 concentrations of both of these drugs exceeded the MIC for most gram-negative organisms. (J Formos Med Assoc 2001;100:548 52) Key words: ofloxacin norfloxacin prostatitis minimum inhibitory concentration prostatectomy Antibacterial chemoprophylaxis for urinary tract infection (UTI) during and after transurethral resection of the prostate (TUR-P) has long been controversial. Through administration of broad-spectrum antibiotics over a short preoperative period or as a single preoperative dose, the postoperative rates of UTI have decreased to less than 10% [1, 2]. The newer quinolones almost completely cover the spectrum of bacteria causing UTI and show good results in the treatment of uncomplicated and complicated UTI [3]. After preoperative administration of a single intravenous dose of pefloxacin (800 mg), prostatic tissue concentrations were found to be well above the MICs of pefloxacin for the bacteria commonly causing acute and chronic prostatitis [4]. Ofloxacin (OFLX) is a pyridonecarboxylic acid derivative with a broad spectrum of antibacterial activity in vitro and in vivo [5]. OFLX has been shown to be a good choice in the treatment of chronic bacterial prostatitis [6]. Norfloxacin (NFLX) is a lipid-soluble weak organic acid that binds to plasma proteins to a low Departments of Urology and 1 Pharmacy, College of Medicine, National Taiwan University, Taipei. Received: 16 January Revised: 5 February Accepted: 10 July Reprint requests and correspondence to: Dr. Jun Chen, Department of Urology, National Taiwan University, 7 Chung-Shan South Road, Taipei, Taiwan. 548

2 extent [7]. Because recurrent UTI in men was thought to be frequently associated with prostatic infection, Sabbaj et al compared the efficacy of NFLX to cotrimoxazole in male patients with recurrent UTI. They concluded that NFLX was more efficacious than cotrimoxazole in eradicating bacteria in the prostate (93% vs 67%) [7]. This study evaluated the extent of penetration of OFLX and NFLX, the two most widely used fluoroquinolones in Taiwan, in serum and prostatic adenoma tissue 2 hours after oral administration. The effectiveness of these agents in the prevention of postoperative UTI was also evaluated. Patients and Methods Sample collection Ten patients with benign prostatic were admitted to National Taiwan University Hospital (NTUH) to undergo transurethral resection of the prostate. None of the patients had received OFLX or NFLX within the preceding 72 hours. Every patient received a single oral dose of OFLX (200 mg) and NFLX (200 mg) simultaneously 2 hours before standard TUR-P was performed. Before administering these two drugs, 10 ml of venous blood was collected, and another 5 ml of blood was collected 2 hours after administration. Blood cell count (CBC), urinary analysis, blood urea nitrogen (BUN), and creatinine concentration (Cr) were measured before and 3 days after TUR-P. Prostate-specific antigen (PSA) concentration was measured once before surgery (TANDEMε PSA, Hybritech Inc, San Diego, CA, USA). Transrectal ultrasonography of the prostate (TRUS-P) was performed on every patient to measure the volume and estimate the weight of the whole prostate and adenoma (Bruel & Kjaer Model 8551 multiplane transducer). During TUR-P, we selected a portion of the resected prostatic adenoma strips (approximately 1 g) and washed them thoroughly with physiologic saline in the operating theater to avoid contamination by urine. These specimens and blood samples were then stored at 70 C until use. Because all patients had indwelling Foley catheters after TUR-P with 24-hour normal saline irrigation, postoperative infection was defined as elevation of white blood cell count combined with shift-toleft in differential count in the CBC of patients who had fever during the postoperative period. Measurement of drug concentration Concentrations of OFLX and NFLX were measured by high-performance liquid chromatography (HPLC). Approximately 1 g of prostatic tissue sample was placed Ofloxacin and Norfloxacin Concentrations in Serum and Prostate Adenoma in a homogenizer, to which was added 3 ml of 0.1 M phosphate buffered saline (PBS). The sample was then homogenized for 3 minutes. After centrifuging at 3000 rps for 10 minutes, the supernatant was used for analysis. A mixture of 200 µl of serum or tissue supernatant, 200 µl of internal standard solution (1.5 µg pipemidic acid dissolved in PBS), and 5 ml of dichloromethane were vortexed for 1 minute. The mixture was then centrifuged at 3,000g for 10 minutes, and 4 ml of the dichloromethane layer was transferred to a clean evaporative tube and evaporated under an 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 thermomixer and with ultrasound. Of the final sample, 20 µl was injected onto the HPLC column. A Hitachi F-1000 fluorescence-detector (Ibaragi, Japan) and a LoiChrosper 100 RP-18 (150 X 4.6 mm, 5 µm) column were employed for the analysis at a flow rate of 1 ml/minute at 30 C. The retention time for pipemidic acid (internal standard) was 3.4 minutes, for OFLX was 5.14 minutes, and for NFLX was 9.5 minutes. Concentrations of OFLX and NFLX obtained from the serum were expressed as mg per L and from prostatic specimens were expressed as µg per g of prostate tissue. Values were recorded as the mean of duplicate measurements for each specimen. Differences were assessed using a paired t-test, with a p value of less than 0.05 indicating statistical significance. Results The clinical characteristics of patients before and after TUR-P are listed in Table 1. The pathology of the prostatic adenoma showed nodular in all patients except patient 10, who had adenocarcinoma, though his PSA concentration was 1.0 and PSA density was Furthermore, pathology results indicated that almost all patients (9/10) also had focal inflammatory cell infiltration, with pictures of chronic prostatitis (Table 1). Two patients (4 and 9) experienced leukocytosis (WBC = 23,200 and 12,900, respectively) after TUR-P, which was resolved by additional parenteral antibiotic treatment. Patients 7 and 10 had positive pre- TUR-P urine culture results, but they recovered well after TUR-P. Patient 1 experienced gross hematuria and dysuria 1 month after TUR-P, and cystoscopy revealed bladder neck contracture. Although this patient recovered smoothly after the first operation, the pathology from the late bladder neck resection revealed acute prostatitis. 549

3 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)* Nodular BN contracture + UTI 1 month later Nodular Smooth postoperative Nodular Smooth postoperative Nodular Leukocytosis after TUR-P Nodular Preoperative u/c: yeast-like organism; smooth postop- erative Nodular Smooth postoperative Nodular Preoperative u/c: E. Coli Nodular Smooth postoperative Nodular Leukocytosis after TUR-P Adenocar Smooth postoperative cinoma ; cerebellar infarction 2 years later Mean SEM *Weight estimated by transrectal ultrasonography of the prostate. BW = body weight; PSA = prostate-specific antigen; PSAD = prostatespecific antigen density; BUN = blood urea nitrogen; Cr = creatinine concentration; BN = bladder neck; UTI = urinary tract infection; u/c = urine culture. The serum concentrations of OFLX and NFLX before oral administration were zero. Two hours after administration, the mean serum concentration of OFLX was 4.14 ± 0.64 mg/l and of NFLX was 1.10 ± 0.22 mg/l (Table 2). The concentrations of these two fluoroquinolones in prostatic tissues were 4.10 ± 0.79 µg/g for OFLX and 2.22 ± 0.57 µg/g for NFLX (Table 2). OFLX concentrations were significantly higher than those of NFLX in both serum and prostatic tissue (p < 0.001). The ratio of the prostatic tissue concentration (P) to serum concentration (S) was 2.11 for OFLX and 5.71 for NFLX. However, the difference in P/S ratio between OFLX and NFLX was not statistically significant (p = 0.175). The P/ S ratios in Patients 7 and 10 were considerably different from those in other patients. If we deleted these outlying 550 data from the mean, the P/S ratio would have been 1.45 ± 0.16 for NFLX and 0.72 ± 0.04 for OFLX, reaching significance (p < 0.001). At the same time, the mean plasma concentrations would be 1.13 ± 0.21 mg/l for NFLX and 4.99 ± 0.35 mg/l for OFLX (p < 0.001), and the concentrations in prostatic tissue would be 1.91 ± 0.41 µg/ g for NFLX and 3.61 ± 0.40 µg/g for OFLX (p = 0.009). Discussion The degree of transference of antimicrobial agents into prostatic fluid is influenced by several characteristics of the drug, and better penetration is seen after

4 Ofloxacin and Norfloxacin Concentrations in Serum and Prostate Adenoma Table 2. Individual and mean (± SEM) ofloxacin (OFLX) and norfloxacin (NFLX) concentrations in the plasma and in prostate tissue 2 hours after the oral administration of these two drugs Patient Prostatic tissue (µg/g) Plasma (mg/l) Prostate/serum concentration NFLX OFLX NFLX OFLX NFLX OFLX Mean* Range ( ) ( ) ( ) ( ) ( ) ( ) SEM* p p < 0.01 p < p = *Mean and SEM are calculated without the data from Patients 7 and 10. Differences between NFLX and OFLX in prostatic tissue, plasma, and prostate/serum ratio were assessed using a paired t-test. administration of lipid-soluble bases with high pka values, such as co-trimoxazole (pka = 7.4) and newer fluoroquinolones (NFLX: pka 1 = , pka 2 = ; OFLX: pka 1 = 5.74, pka 2 = 7.9) [8]. Reviewing the literature, the concentration of OFLX demonstrable in prostatic tissue varied between 0.41 and 8.02 mg/kg, and the concentration of NFLX was between 0.75 and 7.58 mg/kg [3, 8]. The concentration of OFLX (3.61 ± 0.40) was significantly higher than that of NFLX (1.91 ± 0.41 µg/ ml) after deleting the two extreme data points (Patients 7 and 10). The mean concentration of OFLX (3.61 ± 0.40 mg/g; range µg/g) in the prostate obtained in this study was in excess of the OFLX minimum inhibitory concentration (MIC) for most pathogens responsible for a large percentage of prostatic infections: E. cloacae (MIC 90, 0.78 µg/ml), E. coli (MIC 90, 019 µg/ml), and Proteus mirabilis (MIC 90, 0.39 µg/ml) [9]. Although the mean concentration of NFLX (1.91 ± 0.41 µg/ml; range µg/ml) also exceeded the MIC for E. cloacae (MIC 90, 0.78 µg/ml), E. coli (MIC 90, 0.39 µg/ml), and P. mirabilis (MIC 90, 0.39 µg/ml), the prostatic concentrations of NFLX in Patients 7 and 9 were not above the MIC 90 for E. cloacae [3]. With respect to gram-positive organisms, OFLX was present at concentrations above the MIC 90 for Staphylococcus epidermidis (0.78 µg/ml) and Streptococcus faecalis (3.13 µg/ml), two of the most common causes of prostatitis [10, 11]. However, the NFLX concentration in prostate did not exceed the NFLX MIC 90 for S. epidermidis (3.13 µg/ml) and S. faecalis (50 µg/ml). The pseudomonads were not well covered by either drug in this study. According to reports by Paton & Reeves and Aagaard, maximum serum concentration can be generally observed 1 to 3 hours following administration of NFLX and 1.1 to 1.4 hours following administration of OFLX [12, 13]. Therefore, oral administration of antibiotic 2 hours before surgery should be adequate to achieve maximal serum concentrations of these two drugs. Reviewing our results (Table 2), the plasma concentrations of OFLX and NFLX were, indeed, elevated to the expected levels (except in Patients 7 and 10) [3], but two patients (Patients 4 and 9) still experienced postoperative leukocytosis with fever. Postoperative urine and blood cultures were examined for these two patients but failed to find any pathogen. Although chemoprophylaxis for UTI during and after TUR-P has been reported by preoperative administration of a single oral dose of ciprofloxacin (500 mg) and the results have been promising [4], the success rate of the present study was only 80%. Fluoroquinolones used in this study have a relatively short mean serum half-life (about 3 to 7 hours for NFLX and 5 to 7 hours for OFLX). A further 5 days of treatment with these fluoroquinolones has been suggested by Grabe et al to further reduce perioperative UTI rates [14]. Furthermore, adjusting the dosage according to the body weight may be necessary as shown by Patients 7 (84 kg) and 10 (80 kg), who had lower plasma concentrations of NFLX and OFLX. Another possible reason why single preoperative NFLX and OFLX administration was unable to prevent infection after TUR-P in this study was that 90% of patients had chronic prostatitis (confirmed by their 551

5 pathology). Failure of antibiotic therapy in chronic bacterial prostatitis was due to the difficulty of eradicating protected bacterial microcolonies within an infectioninduced altered microenvironment deep within the prostate gland [15]. These protected small bacterial colonies might be released from the prostate during TUR-P, and result in infection after TUR-P. Furthermore, the MIC 90 s of NFLX and OFLX for Klebsiella pneumoniae, E. cloacae, Staphylococcus aureus, and S. epidermidis were shown to be at least four- to eight-fold higher in Taiwan than in other countries [16]. Although we could not find these pathogens in the pre- and/or postoperative cultures, the development of resistance strains in Taiwan, where antimicrobial drugs are used with little restriction, may also play a role in post-tur-p infection. In conclusion, it is not surprising that OFLX reached significantly higher concentrations in serum and prostatic adenoma tissues than NFLX for the same dose, because oral bioavailability is estimated to be 90% for OFLX and 35% to 45% for NFLX [12]. However, NFLX has a higher P/S ratio than OFLX. Both exceeded the MICs for most gram-negative organisms but some individuals may only achieve lower prostatic concentrations against E. cloacae. The results of this study show that the success rate for eradication of postoperative infection after a single administration of OFLX (200 mg) and NFLX (200 mg) orally was 80%. Comparing these results with the rate of postoperative UTI and septic complication after a single dose of ciprofloxacin (less than 5%), it appears that a longer of OFLX or NFLX treatment after TUR-P may further lower the complication rate. ACKNOWLEDGMENTS: We gratefully acknowledge Mr. Kau Yeong-Shun for his excellent technical assistance. References 1. Childs SJ, Wells WG, Mirelman S: Antibiotic prophylaxis for genitourinary surgery in community hospitals. J Urol 1983;130: Naber KG: Antibakterielle Chemoprophylaxe bei transurethaler Resektion der Prostasta. Aktuelle Urologie 1987;18: Cunha BA: The fluoroquinolones for urinary tract infections: a review. Adv Ther 1994:11: Giannopoulos A, Koratzanis G, Giamarellos-Bourboulis EJ, et al: Pharmacokinetics of intravenously administered pefloxacin in the prostate; perspectives for its application in surgical prophylaxis. Int J Antimicrob Agents 2001;17: Seibert G, Limbert M, Klesel N: Comparison of the antibacterial in vitro and in vivo activity of ofloxacin (HOE 280, DL 8280) and nalidixic acid analogues. Eur J Clin Microbiol 1983;2: Aagaard J, Knes J, Madsen PO: Prostatic tissue levels of ofloxacin. Urology 1991;38: Sabbaj J, Hoagland VL, Cook T: Norfloxacin versus cotrimoxazole in the treatment of recurring urinary tract infections in men. Scand J Infect Dis Suppl 1986;48: Boerema JB, Bach D, Jol C, et al: Penetration of rufloxacin into human prostatic tissue and fluid. J Antimicrob Chemother 1991;28: Sato K, Inoue Y, Fujii T, et al: Antibacterial activity of ofloxacin and its mode of action. Infection 1986;14(Suppl 4):S226 S Wedren H: On chronic prostatitis with special studies of Staphylococcus epidermidis. Scand J Urol Nephrol 1989; 123: Doble A: Chronic prostatitis. Br J Urol 1994;74: Paton JH, Reeves DS: Fluoroquinolone antibiotics microbiology, pharmacokinetics and clinical use. Drugs 1988;36: Aagaard J: Ofloxacin in prostatitis. Drugs 1993;45 (Suppl): Grabe M, Hellsten S, Forsgren A. The effects of a short and a prolonged perioperative of ciprofloxacin in TUR compared to a control group without antibiotics. International Symposium on New Quinolones, Geneva, [abstract no. 179] 15. Nickel JC, Downey J, Clark J, et al: Antibiotics pharmacokinetics in the inflamed prostate. J Urol 1995;153: Chen YC, Chang SC, Hsu LY, et al: In vitro antimicrobial activity of fluoroquinolones against clinical isolates obtained in 1989 and J Formos Med Assoc 1993;92: