Role of Prophylactic Antibiotics in Transperineal Prostate Biopsy: A Systematic Review and Meta-analysis

Take Home Message The likelihood of septic infections after transperineal prostate biopsy is similarly low with and without antibiotic prophylaxis. The omission of periprocedural antibiotics with this procedure stands to benefit patients by avoiding potential drug reactions associated with their use.


Introduction
Transrectal prostate biopsy is the current mainstay of prostate cancer diagnosis in most areas of the world [1,2]. Despite the use of targeted and/or augmented antibiotic regimens for periprocedural prophylaxis, transrectal prostate biopsy is associated with a significant risk of infectious complications, with the overall incidence in the range of 5-7% [3]. In contrast, transperineal prostate biopsy, which is performed percutaneously, thereby avoiding contact of the biopsy needle with the rectal mucosa, carries a risk of infectious complications that is approximately half of that of the transrectal approach. An analysis of the combined data from seven randomized trials comparing the two biopsy approaches with respect to overall infectious complications reported a risk ratio of 0.55 (95% confidence interval 0.33-0.92), favoring transperineal prostate biopsy [4]. When examining the risk of sepsis in particular, one metaanalysis, which included approximately 160 000 patients, placed the incidence of this complication at only 0.1% with the transperineal approach [5]. This figure was eight times higher (0.8%) than that with transrectal prostate biopsy.
As a result of the mounting data favoring transperineal prostate biopsy, recently the European Association of Urology (EAU) released a position paper as well as guideline recommendations that endorsed the use of this procedure whenever technically feasible in place of the transrectal approach [6,7]. This recommendation has been welcomed with open arms by the ''TRexit'' movement, which advocates for complete abandonment of transrectal prostate biopsy [8,9]. In fact, some have gone so far as to state that the safety profile of transperineal prostate biopsy warrants its widespread adoption without the use antibiotic prophylaxis. Proponents of this cite improved antibiotic stewardship as well as the elimination of antibiotic-related adverse events as the rationale for their view. Indeed, there is evidence of safely foregoing prophylactic antibiotics with transperineal prostate biopsy [10][11][12][13][14]. It is worth acknowledging, however, that much of the available data come from single-arm cohort studies without a comparison with the use of periprocedural antibiotics. With these questions in mind, we set out to perform a systematic review and meta-analysis with the primary aim of comparing the rates of infectious complications with these two competing practices.

Search strategy
This study was registered with PROSPERO, the international prospective registrar of systematic reviews (registration number: CRD42021228477), and followed the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement and Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews [15,16]. Comprehensive literature searches were conducted on December 29, 2020, in three databases for any publication types and reports of human studies after January 2000. The databases searched were MEDLINE (via PubMed), Embase (via OVID), and the Cochrane Library (via Wiley). Controlled vocabularies and text words were used in the development of the search strategies in all databases. Search results were combined in a bibliographic management tool (EndNote), and duplicates were removed both electronically and through a manual review. Our initial database search produced 1628 results, which were imported in Covidence (Veritas Health Innovation, Melbourne, Australia), a systematic review support tool, for further management and review, which included title/abstract screening and full-text screening phases. A focused update and manual review identified two additional articles for inclusion through April 30, 2021 [13,17].
The search terminology included four major concepts, all linked together with the AND operator: (1) transperineal, perineal, or perineum; (2) biopsy or biopsies including large and fine needle; (3) prostate cancer or prostatic neoplasia; and (4) infections including fever, sepsis, abscess, urinary tract infection (UTI), prostatitis, and others. Septic infections were identified as reported by authors of each study. To incorporate the gray literature perspective, publication types from Embase such as conference proceedings, technical and other reports, and theses/dissertations were screened. For a complete list of medical subject headings (MeSH) and keyword terms used in search strategy development, please refer to the MEDLINE search strategy accompanying this paper (Supplementary material).

Study criteria
A total of 1698 citations were screened by title and abstract against predetermined inclusion and exclusion criteria by two independent reviewers. Any discrepancies were resolved by consensus. A total of 587 articles were selected for full-text review, and 106 of these articles met the inclusion criteria for this study. Figure 1 outlines the study selection process. A careful exclusion of duplicates by institution and year was performed as feasible. Articles with overlapping cohorts were evaluated separately by two reviewers, and we included only the most comprehensive publications.

Extracted variables and endpoint
Three independent investigators extracted data from all the selected studies. A standardized data extraction sheet defined a priori by the study team was utilized. Extracted data, where applicable, included study type (prospective vs retrospective and cohort vs randomized controlled trial [RCT]), country of senior author, number of participants, median/mean age, type of transperineal biopsy (ultrasound guided vs ultrasound/magnetic resonance imaging fusion), average number of biopsy cores, type of anesthesia (general, local, sedation, spinal, or combination), use of periprocedural antibiotics, duration and scheme of antibiotic prophylaxis if used, events of sepsis, and events of other infectious complications (fever, UTI, prostatitis, epididymo-orchitis, pyelonephritis, and unspecified infection). The primary outcomes of interest were septic and overall (septic plus nonseptic) infectious complications within 30 d after biopsy.

Statistical analysis
The two study groups of interest were patients who underwent transperineal prostate biopsy (1) with and (2) without prophylactic periprocedural antibiotics. Measures of central tendency (mean or median) as reported in individual studies were summarized as the median and interquartile range (IQR) across included studies for the variables of age and number of biopsy cores. The total proportions of postbiopsy infections (septic, nonseptic, and overall) were tabulated for each group with pooled samples compared by two-sample tests of proportions. One-sided p values of <0.05 were considered statistically significant to assess whether infectious complications were higher in the group that did not receive prophylactic antibiotics. A meta-analysis was conducted for the outcomes of septic, nonseptic, and overall infectious complications after biopsy using random-effect modeling. Freeman-Tukey dou-ble arcsine transformation was applied to stabilize variances for binomial data [18]. A subgroup analysis was conducted by stratifying the number of biopsy cores. Analyses were conducted using STATA version 15.0 (2017; STATA Corp, College Station, TX, USA).

2.5.
Risk of bias and strength of evidence assessment Risk of bias was assessed based on AHRQ guidelines, which suggest evaluation of design, enrollment/exposure, and outcome assessment for noncomparative single-arm studies [16,18]. Three investigators independently rated the included studies considering three items: design (specifying details on prostate biopsy template and antibiotic use), consecutive enrollment, and objective measurement of outcome (sufficient follow-up and method of assessment). If all three items were rated favorably, the study was considered to be of high quality. If one item was unfavorable or unclear, the study was considered to be of moderate quality.
If two or all three items were unfavorable or unclear, the study was considered to be of low quality. We graded the strength of evidence using the AHRQ EPC Methods Guide for Conducting Effectiveness and Comparative Effectiveness Reviews scheme [16].

Study design
From 1628 citations screened, we identified a total of 106 unique studies describing 112 cohorts of patients eligible for a quantitative analysis. Six (5.7%) studies described mixed cohorts of patients contributing to both study groups. There were 47 (44.3%) retrospective cohort studies, 45 prospective (42.5%) studies, and 14 (13.2%) RCTs. No randomized trials were focused on comparing antibiotic prophylaxis with no antibiotic prophylaxis for transperineal prostate biopsy. Twelve studies (11.3%) were multicenter. In total, 37 805 men from 98 patient cohorts received antibiotic prophylaxis. An additional 4772 men from 14 cohorts did not receive antibiotic prophylaxis (Fig. 1, Table 1, and Supplementary Table 1).

Pooled comparison and meta-analysis
Overall, two-sample tests of proportions did not demonstrate the rate of septic infections to be significantly higher in the groups with and without antibiotic prophylaxis (0.05% vs 0.08%, p = 0.2). Additionally, the rate of overall infections was similar between the two groups (1.35% vs 1.22%, p = 0.8). A meta-analysis of proportions across studies led to negligible effect sizes for sepsis events in either group (0.00 per 1000; Fig. 2 and Supplementary Figure 3). For men who received antibiotic prophylaxis, metaanalysis effect sizes for nonseptic and overall infections were 5.65 and 6.32 per 1000, respectively. In the group that Reasons for exclusion at data extraction level a -Overlapping patient cohorts among studies: 10 -Unable to ascribe complications: 5 Articles added Articles added after manual review in April 2021 (n = 2) a Reviewers did not need to agree on reason for exclusion  Fig. 1, 2, 4, and 5).

Subgroup analysis by number of biopsy cores
Given the higher number of biopsy cores taken among studies using antibiotic prophylaxis (median of 24 vs 18, p = 0.01), studies were stratified by the number of biopsy cores. We identified 42 (

Risk of bias assessment
Across the 106 unique studies that were evaluated, 31 (29.2%), 41 (38.7%), and 34 (32.1%) were identified as having a low, moderate, and high risk of bias, respectively (Fig. 3). The strength of evidence was rated to be moderate due to medium study limitations, direct outcome measurement, consistent but imprecise event rates, and an undetected reporting bias.

Discussion
In this meta-analysis, which included over 42 000 men across 106 unique studies, we found no significant differences in septic, nonseptic, and overall infectious complications after transperineal prostate biopsy in the presence or absence of periprocedural antibiotic prophylaxis. This trend held with respect to sepsis and after accounting for difference in biopsy core numbers between groups; however, we observed a higher risk of overall infections in the no antibiotic prophylaxis group. Although statistically significant, the absolute difference in terms of overall infectious complications was <1%, which may be considered clinically insignificant by most clinicians considering that sepsis rates were maintained at <0.1%. The similar rates of sepsis with and without antibiotics identified in this review suggest that antibiotics may have minimal impact on the prevention of serious infectious complications after transperineal biopsy. In light of this finding, we feel that consideration should be given to performing this biopsy procedure without antibiotic prophylaxis. This potentially stands to benefit antibiotic stewardship, as bacterial resistance to fluoroquinolones, the most commonly used antibiotic for transrectal biopsy prophylaxis, has risen steadily in recent decades [3]. More specifically, Cohen et al [119] reported that one out of every four men on prostate cancer active surveillance now harbors rectal flora resistant to fluoroquinolones. By eliminating the use of prophylaxis for transperineal prostate biopsy, less selective pressure should be placed on bacteria to develop a mechanism for antibiotic resistance. The exclusion of antibiotics when they are not beneficial is also cost effective. While the cost of commonly used antibiotics for prostate biopsy prophylaxis as well as rectal swabs is relatively low, considering the number of prostate biopsies performed annually, it becomes a significant burden for healthcare systems [120,121]. Additionally, the omission of unnecessary antibiotics for patients undergoing a transperineal prostate biopsy can spare patients from potential adverse drug reactions such as nephrotoxicity from aminoglycosides and musculoskeletal complications from fluoroquinolones [122,123]. Transitioning from general to local anesthesia for transperineal biopsy will also impact costs, although we found that only 36% of cases were currently performed with local anesthesia in the no antibiotics groups.
There has been considerable discussion in the literature about the number of biopsy cores taken and its association with infectious complications. When the transrectal approach is performed, the number of cores has no significant relationship with postbiopsy infection rates [5,124,125]. However, for the transperineal approach, we showed that the number of cores directly correlated with infection rates, such that there were more nonseptic infection events in the high biopsy core strata. Nevertheless, the rate of sepsis remained <0.1% and was not affected by the quantity of core samples obtained. It is possible that prior studies were limited by sample size and low event rates.

Summary of key findings
There is a growing interest in the use of transperineal prostate biopsy among the urological community. Unlike with the transrectal approach, it is unclear whether the use of periprocedural prophylactic antibiotics is warranted when performing transperineal prostate biopsy. Our metaanalysis of 106 different studies indicated that the rate of infectious complications for transperineal biopsy with and without antibiotics is around 1 with a <0.1% risk of sepsis. No statistically significant difference was found in the rate of septic infections between the two cohorts, indicating that there is likely limited benefit to providing patients with periprocedural antibiotics.

Limitations
This study is not without limitations. Most noteworthy is the fact that the majority of studies included in our analysis were retrospective and/or single arm in design, without any direct comparison between the two groups of interest. A second related limitation is the fact that studies of mixed methodological design were included in the analysis. This may have introduced a bias, as it is likely that data derived from RCTs and prospective studies had more intensive and reliable follow-up than data derived from retrospective reports. Given the greater proportion of patient data derived from studies of lower methodological quality in the no antibiotics group, it is certainly possible that the equivalence in outcomes was an artifact of this bias. It is reassuring, however, that the rate of infectious complications was overall low across studies regardless of methodological design, and therefore it is unlikely that this factor confounded our analysis. One final limitation is that our analysis did not take into account potential differences in patient-level data such as medical comorbidities, prior exposure to a transrectal biopsy, or number of prior prostate biopsies, all factors that can contribute to postprocedural infections [126,127]. For sepsis events, the susceptibility profile of the offending organism was not reported consistently. Again, the overall number of events in this study was low, and so it is unlikely that the knowledge of these factors would have impacted the results significantly.

Conclusions
In a meta-analysis with data from over 42 000 patients comparing the rate of infectious complications following transperineal prostate biopsy with and without periprocedural prophylactic antibiotics, we found no statistically or clinically significant differences in the rates of sepsis or overall infections between groups. In the low (<25) biopsy core stratum, there remained no significant difference in the rate of sepsis and a <1% absolute risk reduction for overall infections with prophylactic antibiotics. Given the low rate of infections, omission of periprocedural antibiotics stands to benefit antibiotic stewardship and avoidance of potential drug reactions. Clinical trials are deemed necessary to further validate our findings. Author contributions: Spyridon P. Basourakos had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Other: None. The remaining authors report no further disclosures related to this work.