Antibiotic prophylaxis for transrectal needle biopsy of the prostate: a randomized controlled study
Dr N.P. Gupta, Department of Urology, All India Institute of Medical Sciences, New Delhi-110029, India.
Objectives To determine the effect of antibiotic prophylaxis on infective complications after transrectal needle biopsy of the prostate.
Patients and methods Between June 1996 and September 1998, 231 patients who satisfied the inclusion and exclusion criteria entered the study; the patients were randomized into three groups. Each patient underwent transrectal needle biopsy of the prostate after a cleansing enema at 06:00 hours. Patients in group 1 (75) then received a placebo tablet twice a day for 3 days; those in group 2 (79) were given a single dose of ciprofloxacin (500 mg) and tinidazole (600 mg), while those in group 3 (77) were given the same combination twice a day for 3 days. Urine cultures were obtained 48 h after the biopsy and blood cultures only from patients who developed fever. The complications (categorized as infective or noninfective) occurring in the three groups were compared using the chi-square test.
Results Noninfective complications included were lower urinary tract symptoms, rectal bleeding, haematuria and perineal pain. The infective complications included urinary tract infection and fever. There was no significant difference among the three groups in noninfective complications (27, 29 and 31 in groups 1–3, respectively) but the incidence of infective complications (19, six and eight, respectively) was significantly higher in group 1 (P = 0.003). However, the difference was significant only for urinary tract infection (P = 0.01) and not for fever.
Conclusions In selected patients a single dose of ciprofloxacin-tinidazole is adequate prophylaxis for transrectal needle biopsy of the prostate. The present urinary infection rate was higher if no antibiotics were used. Continuing the antibiotic prophylaxis for 3 days offered no benefit over single-dose prophylaxis.
Transrectal needle biopsy of the prostate (TNBP) is one of the commonest procedures performed by urologists, and although it is generally considered a safe procedure, complications secondary to biopsy are some of the most common adverse events encountered in practice. Currently, many urologists use prophylactic antibiotic therapy to minimize the infective complications after TNBP, but such therapy does not completely eliminate infection. The reported infection rate varies considerably in studies using different antibiotic regimens [1–10]. Hitherto, it has not been shown in a prospective randomized placebo-controlled study that the hazard of infection is significantly reduced by antibiotic prophylaxis. On the other hand, various studies using no antibiotic prophylaxis have also shown a varying incidence of infective complications [10–16].
At our institution we have been using a 3-day course of antibiotic prophylaxis for TNBP empirically for several years. The present prospective randomized placebo-controlled study was designed to determine the differences in infective complications with no antibiotics, single-dose antibiotics and a 3-day course of antibiotics. Although noninfective complications were also assessed, this assessment was peripheral to that of infective complications.
Patients and methods
The study was conducted between June 1996 and September 1998 at the outpatient clinic and included 231 patients who entered the study after giving informed consent. The inclusion criteria were: (i) a clinical suspicion of prostate cancer on DRE; (ii) age between 55 and 85 years; (iii) able to return for follow-up; and (iv) informed consent. The exclusion criteria were: (i) uncorrected bleeding diathesis; (ii) the presence of untreated UTI before biopsy; (iii) immunosuppressed patients; (iv) the presence of structural heart disease; and (v) an indwelling catheter.
The 231 patients were randomized into three groups, using computer-generated random numbers. No patient was excluded from the study after randomization. After a cellulose phosphate enema given at 06.00 hours, each patient underwent a digitally directed TNBP with an 18 G Trucut-type needle as an outpatient procedure 3 h later. Patients in group 1 (75, mean age 69 years, range 56–82) received a placebo tablet twice a day for 3 days, starting at 06:00 hours on the day of biopsy. In group 2, 79 patients (mean age 63 years, range 59–78) were given a single dose of ciprofloxacin (500 mg) and tinidazole (600 mg) orally at the same time, followed by placebo tablet twice a day for five more doses. In group 3, 77 patients (mean age 70 years, range 61–80) were given the same combination and dose but for 3 days.
The patients were requested to attend for follow-up 48 h and 7 days after the biopsy; they were also advised to return immediately if they had a complication. All patients were provided with a list of telephone numbers to call in an emergency. The follow-up visits were recorded according to a specified format. Urine cultures (for aerobic organisms) were obtained in all patients 48 h after the biopsy. Anaerobic urine cultures were obtained only in patients who had unexplained LUTS. All patients were instructed to record their temperature if they felt febrile. Blood cultures were obtained in patients who developed fever within 7 days after the biopsy. Telephone or letters were used to contact patients who defaulted on follow-up visits. Complications were recorded and categorized as noninfective or infective. The former included LUTS, rectal bleed, haematuria and perineal pain. LUTS were defined as the presence of frequency and/or urgency, and/or dysuria and/or suprapubic pain in the absence of detectable infection. Rectal bleed was defined as the passage of bright red blood rectally > 12 h after biopsy, or any bleed requiring active management irrespective of the time of occurrence. Haematuria was defined as that occurring or persisting for > 12 h or requiring active management irrespective of the time of occurrence. Perineal pain was defined as that occurring de novo after the biopsy and requiring analgesics to control it. The infective complications were UTI and fever; the former was defined as the presence of a positive urine culture irrespective of symptoms and the latter was defined as any temperature > 38°C in the first week after biopsy. The incidence of complications in the three groups was compared statistically using the chi-square test, with P < 0.05 considered to indicate significant differences.
The body mass index, findings on histology and noninfective complications in the three groups were comparable ( Table 1). The noninfective complications were self-limiting and none required intervention or transfusion. No patient developed urinary retention after the procedure. The overall incidence of infective complications was significantly higher in group 1 than in groups 2 and 3, but the difference was significant only for UTI and not for fever or bacteraemia ( Table 1). All infective complications in the three groups were caused by coliforms; there were no anaerobic infections. Of the 27 positive cultures (24 urine, three blood), 21 grew Escherichia coli, four grew Enterobacter spp. and two grew Klebsiella spp. All organisms were susceptible to ciprofloxacin on sensitivity testing. The occurrence of infective complications was compared with the presence of prostatitis on histology, with all histology specimens being examined by one pathologist. The criteria used to identify prostatitis  were: (i) areas of localized involvement of small groups of ducts and acini; (ii) distended lumina filled with secretions and a mixed inflammatory infiltrate; and (iii) a predominantly mononuclear infiltrate in the stroma with admixture of lymphocytes, plasma cells and histiocytes. Of the 231 patients, 17 had evidence of prostatitis on histology. However, only three of these developed an infective complication, whereas 30 of 33 patients who developed an infective complication had no evidence of prostatitis ( Table 1).
Table 1. Complications and correlation with histology
| LUTS||14|| 9||12|| 35|
| Rectal bleed|| 3|| 3|| 5|| 11|
| Haematuria|| 8||13||12|| 33|
| Perineal pain|| 2|| 0|| 0|| 2|
|Infective||19|| 6|| 8 *|| 33|
| UTI||14|| 4|| 6 *|| 24|
| Fever|| 5|| 2|| 2|| 9|
| With bacteraemia|| 2|| 0|| 1|| 3|
| No bacteraemia|| 3|| 2|| 1|| 6|
| Prostatitis|| 6|| 8|| 3|| 17|
| Infective complication||19|| 6|| 8|| 33|
| Prostatitis + inf. complication|| 2|| 1|| 0|| 3|
Although many urologists would prefer to administer antibiotics to patients undergoing TNBP there is no consensus on this issue. In the original description of TNBP, Astraldi  reported over 100 patients who had no antibiotic prophylaxis and no complications. Wendell and Evans  reviewed more than 4300 reported transperineal and transrectal biopsies, and found only 19 infective complications. Their series of 250 patients had an infective complication rate of only 0.8%. In a more recent prospective study, 415 patients underwent TNBP with no antibiotic prophylaxis and had an infective complication rate of 2.9%. However, Davison and Malament  reported a 36% incidence of fever and 24% incidence of positive urine cultures after prostatic biopsy with no antibiotics. However, with various antibiotics these decreased to 19% and 12%, respectively. In a prospective study of 48 patients, Crawford et al. showed a significant reduction in fever and UTI, but no significant difference in the bacteraemia rate with antibiotic prophylaxis. Thus there is significant variability in the reported infection rates after TNBP, irrespective of the use of antibiotics [1–16].
Even amongst those who use antibiotic prophylaxis there is much variability in the type of antibiotic used and the duration of administration [6–10]. Most antibiotic use and duration has been empirical, and different studies have yielded different recommendations. There is also debate about which organisms play a major role in infection after biopsy, i.e. the anaerobes  or the coliforms . Even the timing of the administration of antibiotics differs in various studies. All these factors make direct comparisons among different series difficult and thus there is a need for prospective, randomized, placebo-controlled trials to address each of these issues.
The present study addressed two of these questions; whether antibiotic prophylaxis reduces the infection rate after TNBP and if so, whether a single dose is sufficient rather than prolonged administration. Other randomized controlled trials could be designed to determine the other issues, e.g. the predominant causative organism and optimal antibiotic to be used, i.e. a combination or a single drug.
The most common organisms causing infection after TNBP are the coliforms [6, 23], although anaerobic infection has also been reported [22, 24]. The commonest coliforms identified include E. coli, Enterobacter, Proteus and Klebsiella species , while the commonest anaerobes are reportedly Bacteroides, Peptococcus and Peptostreptococcus species . Gram-positive aerobes, including Enterococci and Staphylococcus saprophyticus, have also been reported . Ciprofloxacin  is a fluoroquinolone which acts by inhibiting the bacterial enzyme DNA gyrase. It has strong bactericidal activity against most Gram-negative organisms that cause UTI. Most anaerobes are resistant to the fluoroquinolones, except sparfloxacin. Ciprofloxacin is more active than norfloxacin against Pseudomonas aeruginosa and Enterococci. It is well absorbed after oral administration and widely distributed in body tissues; peak serum levels occur 1–3 h of an oral dose, although food intake may prolong the time to peak serum concentration. Concentrations in urine and prostatic tissue exceed serum levels, although the concentration in prostatic fluid is lower. Tinidazole  is a nitroimidazole similar to metronidazole and is useful for a variety of parasitic and anaerobic bacterial infections. It is highly effective against Bacteroides, Peptococcus, Peptostreptococcus, Clostridium, Fusobacterium and Veillonella species. Oral absorption is almost complete and peak serum levels are attained after ≈ 2 h. Its half-life of 12.5 h is longer than that of metronidazole, thus providing greater dosing convenience. About 16% of the oral dose appears unchanged in urine and the drug penetrates well into tissues of the urogenital tract. A combination of ciprofloxacin and tinidazole was used in the present study to cover both coliforms and anaerobes, which are likely to be the cause of infection in TNBP.
The incidence of noninfective complications was similar in the three groups and comparable to that in other reported series. Stringent exclusion criteria were applied with the intention of excluding all cases who were at high risk of infection or in whom infection could have serious consequences. It is likely that the real incidence of asymptomatic bacteraemia was much higher , but in otherwise healthy patients this should not be a cause for concern. All the infective complications in this study were caused by coliforms, with no infection attributable to anaerobic organisms; this suggests that coliforms are by far the most significant threat after TNBP. However, anaerobic urine cultures were conducted only for patients with unexplained LUTS, and blood cultures (both aerobic and anaerobic) were obtained only in febrile patients.
In conclusion, at least in selected patients, a single dose of ciprofloxacin-tinidazole is adequate prophylaxis for TNBP. The urinary infection rate was higher if no antibiotics were used and currently we recommend antibiotic prophylaxis. Continuing the antibiotic prophylaxis for 3 days offered no benefit over a single dose. This has considerable financial implications; at our centre alone, 350–450 TNBPs are performed each year and before this study all patients received a 3-day course of antibiotics, most often ciprofloxacin and metronidazole (or tinidazole). Although drug prices vary worldwide, the associated drug-related expenditure was reduced to one-sixth of its former value by using a single dose. Furthermore, this reduction in antibiotic use is likely to play a minor but useful role in retarding the rapid development of antibiotic resistance in the present era of antibiotic over-use.
M. Aron, MS, DNB, MCh, Senior Resident.
T.P. Rajeev, MS, Senior Resident.
N.P. Gupta, MS, MCh, Professor and Head.