Antibiotic therapy in patients with high prostate-specific antigen: Is it worth considering? A systematic review

ABSTRACT Objective: To address the question of whether antibiotic therapy can obviate the need for prostate biopsy (PBx) in patients presenting with high prostate-specific antigen (PSA) levels. Methods: With the increase in unnecessary PBx in men with high PSA levels, a systematic review was performed according to the Cochrane Reviews guidelines and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Results: The literature search yielded 42 studies, of which 11 were excluded due to irrelevance of data. Most of the studies were retrospective, nine studies were randomised controlled trials, and there were seven prospective non-randomised trials. The age range of the patients was 51–95 years. Antibiotics, predominantly ofloxacin or ciprofloxacin, combined with a non-steroidal anti-inflammatory drug (NSAID) or not, were prescribed for 2–8 weeks. All studies focussed on PSA levels ranging from ≤ 4 to ≥ 10 ng/mL. Furthermore, antibiotic therapy normalised PSA levels by a wide variety of percentages (16–59%), and the PSA level decrease also varied widely and ranged from 17% to 80%. For patients who had unchanged or decreased PSA, carcinoma was found in 40–52% and 7.7–20.3%, respectively. No cancer was detected if the PSA level decreased to < 4 ng/mL. Conclusion: Antibiotic therapy is clinically beneficial in patients with high PSA levels. PSA reduction or normalisation after medical therapy, either antibiotic and/or NSAID, for ≥ 2 weeks can avoid unnecessary PBx. Antibiotic therapy is more beneficial when the PSA level is < 20 ng/mL. Abbreviations: EPS: expressed prostatic secretion; PBx: prostate biopsy; (%f)(f/t)(t)PSA, (percentage free) (free/total) (total) serum PSA; PSAD: PSA density; RCT: randomised controlled trial; VB3: voided bladder urine 3


Introduction
In daily practice, some urologists often prescribe antibiotics before prostate biopsy (PBx) to men with a newly increased PSA to decrease inflammation-induced PSA elevation and help to reduce unnecessary PBx. However, others have reported that antibiotic treatment has no significant effect on the PSA level and that a lowered level of PSA after antibiotic treatment does not mean a decreased risk of prostate cancer [1].
PBx is a potentially morbid procedure. Prostatitis is commonly reported on needle biopsies and 65-70% of patients with abnormal PSA levels do not have cancer on prostate needle biopsy. After a 2-year clinical and biochemical follow-up of symptomatic men who had a high PSA level and a normal DRE, and normal repeat PSA level, PBx can be safely avoided [2].
In the present review we aimed to address the controversy of whether antibiotic treatment can exclude inflammation in the differential diagnosis of PSA elevation and thus can avoid unnecessary PBx. We considered patients with LUTS, normal DRE and normal urine analysis, and elevated PSA levels.

Search strategy and study selection
The systematic review was performed according to the Cochrane Reviews guidelines and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [3].
The search strategy was conducted to find relevant studies from the Medical Literature Analysis and Retrieval System Online (MEDLINE; 1966-2018), Excerpta Medica dataBASE (EMBASE; 1980-2018), Google Scholar, and individual urological journals. The search was conducted in January 2018.
Terms used included: 'prostate', 'biopsy', 'high PSA', and 'antibiotic therapy'. All language papers were considered if reporting on PSA reduction after antibiotic therapy. References of searched papers were evaluated for potential inclusion. Authors of the included studies were contacted whenever the data were not available or not clear.

Inclusion criteria
(1) All studies reporting on antibiotic therapy in patients with high PSA levels.
(2) Studies published in the English language over the period 1980-2018.

Exclusion criteria
(1) Animal studies and case reports.
(2) Studies on patients with high PSA levels without documented antibiotic therapy.
Two reviewers (D.T. and O.M.A.) identified all studies that adhered to the inclusion criteria for full review.
Each reviewer independently selected studies for inclusion. Disagreement between the extracting authors was resolved by consensus or referred to a third author (A.A.S.).

Data extraction and analysis
The objectives were to evaluate the efficacy and safety of using antibiotic therapy in PSA reduction resulting in the avoidance of unnecessary PBx. The variables extracted from each study were: patient demographics, antibiotic type, antibiotic duration, NSAID use with antibiotic or not, PSA reduction level after antibiotic therapy, and rate of PBx after antibiotic therapy.

Characteristics of the included studies
The 31 included studies were published between 1995 and 2018, and included 4682 patients with an age range between 51 and 95 years.  The type and duration of antibiotic use Concerning the duration of antibiotic use, some studies prescribed antibiotics for 2-4 weeks , whilst others prescribed for 6-8 weeks [4,7,[28][29][30].

Effect of antibiotic use
There was no significant difference in the mean change in PSA level between the levofloxacin and ciprofloxacin groups [9].
Shtricker et al. [10] compared 135 patients who received antibiotics (65) with those who did not (70). The PSA levels decreased by 60% in both groups and at PBx prostate cancer was found in 25% of patients in both groups. In both groups, 40% of the patients had no decrease in PSA levels; however, prostate cancer was found in only two patients (12%) who received antibiotics, and in eight (42%) who did not receive antibiotic. PSA levels tend to fall when measurement is repeated after 45 days, regardless of antibiotic use [6].
In the Lee et al. [7] study of 413 patients, 215 (52%) patients had positive findings on expressed prostatic secretion (EPS) or voided bladder urine 3 (VB3) tests. After 8 weeks of quinolone antibiotic therapy, 53 of these 215 men avoided PBx due to of normalisation of their PSA levels.

No effect of antibiotic on PSA level
Inflammation had no significant influence on total serum PSA (tPSA) level or the percentage free PSA (% fPSA) [26]. The tPSA, %fPSA, and free/total PSA ratio (f/tPSA) alterations before and after antibiotic therapy did not show any statistically significant difference (P > 0.05) [22]. There is no advantage in administering antibacterial therapy with initial PSA levels of 4-10 ng/mL, without overt evidence of inflammation [10].
The majority of studies addressed the effect of antibiotics on the acutely inflamed prostate, whilst some of the other studies reported on documented chronic inflamed type [4,7,9,18,20,21,25,29].
Three studies did not use antibiotics but assessed the degree of inflammation after prostatectomy [33][34][35].
In the Dirim et al. [28] study, PSA levels decreased after antibiotic treatment in 47 of 85 patients. The f/tPSA ratio decreased or remained unchanged in 21 of these 47 cases and increased in 26. There were 38 patients who had increased PSA levels after antibiotic therapy. The f/tPSA ratios decreased or remained unchanged in 20 of these 38 cases and increased in 18. In the Toktas et al. [12] study, there were significant changes in the values of PSA and its derivatives in the antibiotic treatment group, from 5.31 to 4.69 and 4.58 ng/mL, consecutively. In the Kyung et al. [30] study, the PSA density (PSAD) after antibiotic treatment was normalised (< 0.15 ng/mL/mL) in 23 of the 40 patients with a high PSAD before treatment.

Rate of carcinoma and pbx avoidance
As regard patients who had unchanged or decreased PSA levels, carcinoma was found in 40-52% and 7.7-20.3%, respectively. No cancer was detected if the PSA level decreased to < 4 ng/mL or by > 70% [10,17,27,28]. However, the possibility of prostate cancer in patients with a PSA level of < 2.5 ng/mL is still present [18].
With regard to PSA levels, Azab et al. [4] reported that of their 142 patients treated with antibiotic and NSAIDs for 6 weeks, prostate cancer was detected in 12% (three of 25 patients) with PSA levels of < 2.5 ng/mL, 12.7% (six of 47 patients) with PSA levels of ≥ 2.5-< 4.0 ng/mL, and in 30% (21/70 patients) with PSA levels ≥ 4.0 ng/mL. Shtricker et al. [10] studied the cancer detection rate in patients with PSA levels of 4-10 ng/mL, who received antibiotic therapy (65 patients) vs those who did not (70 patients). The cancer detection rate at PBx in patients who did not have a PSA level decrease was 12% (two of 17 patients) after antibiotic therapy vs 42% (eight of 19 patients) in those no antibiotic therapy [10]. Similarly, Kaygisiz et al. [27] reported that prostate cancer was found at PBx in 10.8% of the patients with PSA levels between 4 and 10 ng/mL, but in none with PSA levels <4 ng/mL.
In the Yoo et al. [32] study, PBx was performed in 50 of 237 patients (21.1%), and only a single case (2%) of prostate cancer was diagnosed. In the Baltaci et al. [13] study, in 17% of the men the tPSA after treatment was < 4 ng/mL and of these five (29.4%) had prostate cancer at PBx.
In the Lee et al. [7] study, the total prostate cancer detection rate was 20.7% in the patients with negative findings on EPS or VB3 tests and 3.3% in the patients with positive findings.

Discussion
Although there is controversy surrounding the value of antibiotics in reducing higher PSA levels, some urologists in daily practice often prescribe antibiotics before PBx to men with a newly increased PSA level. PSA level reduction after antibiotics might identify those patients in whom PBx can be avoided.
Some researchers have found that antibiotic treatment can decrease inflammation-induced PSA elevation and help to reduce unnecessary PBx. Conversely, others have reported that antibiotic treatment has no significant effect on the PSA level, and a lowered PSA level after antibiotic treatment does not mean a decreased risk of prostate cancer [1].
The evidence for inflammation should be addressed before trying antibiotic therapy in patients with high PSA levels. The proof of inflammation can be delineated via EPS [7], symptoms of acute or chronic prostatitis [4,7,9,18,20,21,25,29], and detection of the degree of inflammation after prostatectomy [33,34].
The PSA level in focus for antibiotic therapy ranges from 4 to 10 ng/mL. Some studies assessed PSA levels <4 ng/mL [6,18], whilst others assessed levels >10 ng/ mL [9,16,19,21]. In patients with PSA levels higher than the threshold value, definitive treatment should be not postponed for preliminary antibiotic therapy.
The f/tPSA ratio rather than tPSA appears to be more helpful in suggesting prostate cancer in cases receiving antibiotic therapy for high PSA levels [12,28,30].
PBx should be considered without trying antibiotic therapy in patients with high PSA values, if a suspicion of prostatitis does not exist [22].
Carcinoma was found in 40-52% of patients who did not have a PSA decrease. Conversely, a detection rate of 7.7-20.3% was found in patients who had a PSA decrease in comparison with the pre-treatment values [10,17,27,28].

Conclusion
Antibiotic therapy is clinically beneficial in patients with high PSA levels. PSA reduction or normalisation after medical therapy, either antibiotic and/or NSAID, for ≥2 weeks can avoid unnecessary PBx. Antibiotic therapy is more beneficial when the PSA level is <20 ng/mL, especially when the evidence for inflammation is not overt.

Disclosure statement
No potential conflict of interest was reported by the author(s).