Retrospective, single center evaluation of perineal prostate biopsy omitting antibiotic prophylaxis and omitting periinterventional screening for bacteriuria

doi:10.21203/rs.3.rs-4875283/v1

Purpose

The pursuit of effective and safe early detection methods for prostate cancer has led to advancements in non-invasive tools, yet the annual performance of one million prostate biopsies in the EU underscores the challenges. The transperineal approach, recommended by the EAU, offers reduced infectious complications compared to transrectal biopsies. The role of antibiotic prophylaxis in transperineal biopsies remains ambiguous, necessitating investigation due to concerns about antibiotic resistance and the impact on public health.

Methods

This retrospective study analyzed 636 patients who underwent transperineal prostate biopsies between January 2019 and August 2020. The primary endpoint was postinterventional infectious complications, with secondary endpoints including the general complication rate and associated risk factors.

Results

Among the cohort (median age 68), 12 complications were recorded, yielding a 1.9% complication rate. Infectious complications requiring hospitalization and antibiotic treatment occurred in 1.1% of cases. No identified risk factors were associated with infectious complications or post-interventional bleeding. Complications included gross hematuria, urinary retention requiring catheterization, and one case necessitating intensive care. Notably, the cohort did not systematically screen for bacteriuria, and patients with high risk for complications were not excluded. The complication rate appeared lower than reported for transrectal biopsies with antibiotic prophylaxis.

Conclusion

This study supports the safety of omitting antibiotic prophylaxis in transperineal prostate biopsies, showcasing a minimal infectious complication rate. The findings contribute to the ongoing discourse on antibiotic stewardship, emphasizing the need for judicious use to mitigate resistance.

Prostatic Neoplasms [MeSH]

Image-Guided Biopsy [MeSH]

Transperineal

Transrectal

Fusion biopsy

Intraoperative complications [MeSH]

The field of early prostate cancer detection has undergone substantial investigation to avoid unnecessary prostate biopsies, obtain accurate histopathological results and minimize morbidity. However, despite advances in non-invasive tools such as mpMRI, PSMA PET scan, risk calculators and ultrasound to determine the risk of prostate cancer, it is estimated that one million prostate biopsies are performed yearly in the EU[10].

Because of less infectious complications in the transperineal approach, it is considered the best practice according to the EAU guideline [10] s. While in transrectal biopsies, a peri interventional antibiotic prophylaxis seemed necessary due to contamination passing the unsterile digestive tube, the role of antibiotic prophylaxis in perineal biopsies remains unclear. Its effect has been assessed over the last years in many trials [5, 9, 11–14]. A prospective non-inferiority trial by Jazewicz et al. could meet its primary endpoint of non-inferiority concerning infectious complications while omitting antibiotic prophylaxis, using a non-inferiority threshold of 4%.[8] Two systematic reviews from 2022 could not show a significant difference in infectious complications using or not using peri-interventional antibiotics [1, 4].

The unreflective use of antibiotics and the growing cases of resistant organisms has become a significant public health issue. Hulscher et al. showed that indication of 20–50% of all antibiotic therapy was inappropriate[7]. Correct use of antibiotics is crucial for allowing further effective control of bacterial infection. If omitting antibiotic prophylaxis in a widely used procedure such as prostate biopsy is safe, its impact on public health could be of enormous importance[2, 3].

We analyzed the safety of omitting antibiotic prophylaxis in transperineal prostate biopsy without periinterventional screening for bacteriuria retrospectively. The primary endpoint is rate of postinterventional infectious complications. The secondary endpoint is general complication rate and risk factors.

2.1. Population

We retrospectively analyzed 650 consecutive patients who received transperineal prostate biopsies in our urology clinic between January 2019 and August 2020. Patients were eligible if they met the inclusion criteria, which included an indication for prostate biopsy due to suspicion of prostate cancer (pathological PSA value/dynamics, pathological DRE, or pathological MRI) and documented clinical data. Of the 650 patients, 636 met the inclusion criteria for perineal prostate biopsy with complete data (Fig. 1).

2.2. Biopsy procedure

Transperineal prostate biopsies were performed as outpatient procedures. Before completing the procedure, a short anamnesis was obtained, including operations of the genitourinary tract, indwelling catheter, family history, and existing diseases. A biopsy was not performed if the patient was under anticoagulant medications, except for platelet aggregation inhibitors such as aspirin. After excluding contraindications for prostate biopsy, general consent was obtained, and no blood or urine samples were taken before the intervention.

The procedure was performed in lithotomy. The scrotum and penis were taped suprapubic (unsterile Leukoplast – Hypafix 15 cm x 20 m, Beiersdorf AG, Hamburg, Germany). The perineum was shaved when necessary, and gross dirt particles were removed. Antiseptic disinfection was completed with 7.5% Povidone-Iodine solution (Braunol 7.5% Povidon Iod, Braun, Germany). Two dedicated urologists performed the biopsies. Local anesthesia of the skin and periprostatic blockade were performed with a 20G needle (Sterican 20 G 70 mm, Braun, Germany) and 20 ml of Mepivicain 10mg/ml (Mecain, Eugia Pharma PUREN, Malta). Periprostatic block was achieved by finger guidance with the injection of mepivicain below the prostatic apex, bilaterally in the levator ani, and along the needle’s path. 5 to 10 minutes were given for the optimal effect of local anesthesia. Biopsies were performed with a disposable template grid (Template Grid 17/18GA, Civco, Iowa, United States of America). A 24 cm long 18-gauge needle with a hand fire system (CORAZOR, UROMED, Germany) was used for sample collection.

Systematic biopsies were performed under local anesthesia (periprostatic nerve block). In MRI Fusion biopsy procedures, we accompanied local anesthesia with sedation (midazolam and ketamine) to minimize the risk of movements during the procedure.

UroNav Philips Invivo (Amsterdam, Netherlands) with a template grid was utilized for fusion biopsy combined with the BK 3000, BK Medical (Nærum, Denmark) rectal ultrasound. Systematic biopsies were performed with five cores per half gland. MRI fusion biopsies complemented systematic biopsies with 3 to 4 biopsies per lesion, depending on lesion size and counts.

After checking for gross hematuria and the ability to void, the patient was dismissed.

2.3. Outcome variables

We chose the following categorical outcome variables: previous biopsy, under active surveillance, previous prostatitis, diabetes mellitus, diabetes mellitus medication, obesity (cut-off body mass index > 35), immunosuppression, anticoagulant therapy (aspirin clopidogrel, phenprocoumon, or a direct oral anticoagulant), indwelling catheter, previous surgery, DRE, performing urologist, type of anesthesia, ISUP grade group, type of complication. In addition, we chose the following continuous outcome variables: age (years), prostate volume (cc), number of MRI lesions, number of cores, and the number of positive cores.

2.4. Statisticsl methods

Statistical analyses were conducted using R (Version 4.0.5 for Windows). Non-parametric statistics were applied. Data were presented as raw values and percentages and medians with lower (Q1) and upper quartiles (Q3). We checked for risk factors using multivariate logistic regression. The threshold for a statistically significant difference was p < 0.05.

2.5. Data source

Data were collected between January 2022 and December 2022. We retrospectively obtained data from medical charts (i.e., categorical, and continuous outcome variables).

2.6. Bias

We encountered two types of bias:

Selection bias – the retrospective nature of the trial with 650 patients and less than 2% complications may be insufficient to provide a correct insight into the prevalence of infectious complications. A larger cohort may be necessary when analyzing complications and their risk factors with low incidence.
Follow-up bias: follow-up data were collected by chart review from charts of our clinic. No reported outpatient complication treatment (i.e., prescription of antibiotics in the postinterventional course) by another physician may have occurred. Higher-grade complications such as gross macrohematuria with the necessity of bladder irrigation and inpatient treatment with i.v. antibiotics should not have been missed, as our clinic is the only tertiary center in about a 75 km radius and all patients with complications are usually referred to our hospital.

Overall, 636 patients (median age 68 (62,73) years) with prostate cancer suspicion were included in this study. Demographics and biopsy results are highlighted in Tables 1, 2, and 3.

Table 1 Patient demographics and biopsy results
Age (years)	Missing	68 [62, 73] 0
PSA (ng/ml)	Missing	8.5 [6, 13.7] 9 (1.4%)
Prostate Volume (ccm)		52.0 [39, 72.3]
Indwelling catheter	Missing	8 (1.3%)
	No	598 (94.0%)
	Yes Missing	32 (5.0%) 6 (0.9%)
Active Surveillance
	No	601 (94.5%)
	Yes Missing	29 (4.6%) 6 (0.9%)
Biopsy technique
	MRI Fusion biopies	378 (59.4%)
	Random biopsies	255 (40.1%)
	Missing	3 (0.5%)
Total number of cores		13 [10, 16]
Prostate Cancer
	No Pca	267 (42%)
	ISUP 1	77 (12.1%)
	ISUP 2	90 (14.2%)
	ISUP 3	64 (10.1%)
	ISUP 4	73 (11.5%)
	ISUP 5 Missing	59 (9.3%) 6 (0.9%)

Results are shown as median, lower and upper quartiles.

Table 2 Prostate Cancer detection in Random biopsies
		n/N	(%)
ISUP score
	0	127/255	49.8%
	1	18/255	7.1%
	2	16/255	6.3%
	3	16/255	6.3%
	4	33/255	12.9%
	5	42/255	16.5%
	Missing	3/255	1.2%

ISUP grade group - International Society of Urological Pathology

Table 3 Prostate Cancer detection in MRI Fusion biopsies
		n/N	(%)
ISUP score
0	140/378		37%
1	59/378		15.6%
2	74/378		19.6%
3	48/378		12.7%
4	40/378		10.6%
5	17/378		4.5%
Missing	0/378		0%

ISUP grade group - International Society of Urological Pathology

In total, we recorded 12 complications, representing a complication rate of 1.9%. Details of Clavien Dindo grade are described in table 4. We found 1.1% (7/636) infectious complications needing antibiotic treatment (see table 5). One patient required treatment in the intensive care unit. Furthermore, four patients reported gross hematuria with bladder irrigation. And one patient needed catheterization due to urinary retention. The 11 patients who have been excluded from data analysis; no complications could have been identified in chart review.

Table 4 All complications
	n/N	(%)
Complications in total	12/636	1.90%
Clavien Dindo
Grade 1	0/636
Grade 2	11/636	1.70%
Grade 3	0/636
Grade 4	1/636	0.16%
Grade 5	0/636

Table 5 Infectious complications
		n/N	(%)
Infectious complications		7/636	1.10%
Type of infectious complication
Prostatitis	3/636		0.50%
Epididymitis	1/636		0.16%
Infection requiring hospitalization	2/636		0.30%
Urosepsis wit ICU	1/636		0.16%

We could not determine any risk factors for infectious complications (age p=0.44, diabetes mellitus p=0.23, indwelling catheter p=0.26, number of cores p =0.6, prostate volume p=0.44), post-interventional bleeding (age p=0.75, under anticoagulant agent p=0.5, number of cores p =0.14, prostate volume p=0.10). Table 6 highlights those patients who suffered from an infectious complication and their clinical details (see table 6).

4.1. Main Findings

Our study reported complications after transperineal prostate biopsy omitting peri-interventional antibiotic prophylaxis and not screening for bacteriuria in a single-center retrospective cohort of 632 patients.

Most trials do not mention if patients were excluded from the trial after performing urine analysis showing bacteriuria. In our cohort, patients were not systematically screened for underlying UTI/bacteriuria. As the transperineal route does not systematically injure the mucosa, there is no rationale for systematic bacteriuria screening. If there is clinical evidence of symptomatic UTI, we perform further diagnostics including urine microscopy and cultures, and biopsy is postponed after treatment of the underlying UTI.

Furthermore, we did not exclude patients with a "high risk for infectious complication after prostate biopsy." In our cohort, the only contraindication for prostate biopsy would have been a clinically evident underlying UTI. If the patient complained of pollacisuria with alguria and/or fever, we would collect a urine sample, and if deemed necessary, start an antibiotic therapy. However, in our cohort of 650 patients, we did not postpone any prostate biopsy due to UTI. High risk for infectious complication after prostate biopsy is not clearly defined. In the NORAPP trial, the following criteria were defined for high risk: indwelling urinary catheter, immunodeficiencies, high risk of infective endocarditis, or a history of thromboembolic disease.

We reported a low complication rate of 1.9% with 11 Clavien Dindo grade (CD) 2 complications and one CD 4 complication. The most common complications were infectious complications. The rate of infectious complications for the transperineal prostate biopsy without antibiotic prophylaxis in our cohort (ca. 1. %) seemed to be lower than for transrectal prostate biopsy with antibiotic prophylaxis (approx. 5%)[6]. The total number of low-grade complications may have been a little higher, as not all patients may have been referred back to our clinic and remember retrospectively if they have been prescribed an oral medication (i.e. antibiotics) by a private consultant. Higher-grade complications (Clavien Dindo Grade > 2) were likely not missed, as our tertiary medical care center comprises the only urological unit in a radius of about 75 km. Risk factors for infectious or bleeding complications did not meet statistical significance. This may have been due to our cohort's relatively low number of complications.

4.2. Findings of biopsy results

Histologically confirmed prostate cancer was more often found in fusion biopsy than in systematic biopsies (Tables 2 and 3). High-grade prostate cancer (ISUP > 3) was more frequently found in the group of systematic biopsies. An explanation could be that we did not perform upfront MRIs when there was a high risk for prostate cancer, such as PSA > 20 ng/ml or suspicious DRE. Therefore, systematic biopsies had a negative selection bias for ISUP grade compared to the group of MRI fusion biopsies.

4.3. Limitations

The main limitation of this study is that follow-up data has been collected with a retrospective chart review. Also, as mentioned, our tertiary referral clinic is the only hospital with a urology department in a radius of around 75 km, but other urologist/physician may have treated minor adverse events such as UTI without fever or a simple postoperative prostatitis two staged and some patients might not have recalled correctly afterwards.

Our report confirmed existing data showing a low number of infectious complications when using the transperineal route for prostate biopsies and omitting antibiotic prophylaxis. We did not assess systematically for underlying bacteriuria and still had a very low complication rate. Omitting antibiotic prophylaxis and omitting screening for bacteriuria seems to be safe in transperineal prostate biopsies.

Author Contributions: Conceptualization, methods, and investigation, F.L.,T.S.; Data mining, investigation and draft preparation was incorporated in academic formulation for a medical doctor thesis at the University Medical Center of the Johannes Gutenberg-University Mainz; formal analysis, F.L.; writing—original draft preparation, F.L.; writing—review and editing, F.L.,T.S., A.N.; visualization, F.L..; conceptualization and supervision, A.N.. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no funding.

Institutional Review Board Statement: This retrospective cohort study was conducted in accordance with the Declaration of Helsinki, and approved by our local ethics committee (Ethics Committee of the Mainz Medical Association (2022-16318)). Further, this study is reported in accordance with the STROBE statement guideline for cohort studies.

Informed Consent Statement: Patient consent was waived due to the retrospective nature of this study. Further, given the provided information, patients cannot be identified (including by the patients themselves).

Data Availability Statement: De-identified data is available upon request from the authors.

Acknowledgments: None.

Conflicts of Interest: All authors declare no conflict of interest.

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Basourakos SP, Alshak MN, Lewicki PJ, Cheng E, Tzeng M, DeRosa AP, Allaway MJ, Ross AE, Schaeffer EM, Patel HD, Hu JC, Gorin MA (2022) Role of Prophylactic Antibiotics in Transperineal Prostate Biopsy: A Systematic Review and Meta-analysis. Eur Urol Open Sci 37:53–63. doi: 10.1016/j.euros.2022.01.001
Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M (2014) A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis 14:1–25. doi: 10.1186/1471-2334-14-13
Bootsma AMJ, Laguna Pes MP, Geerlings SE, Goossens A (2008) Antibiotic Prophylaxis in Urologic Procedures: A Systematic Review. Eur Urol 54:1270–1286. doi: 10.1016/j.eururo.2008.03.033
Castellani D, Pirola GM, Law YXT, Gubbiotti M, Giulioni C, Scarcella S, Wroclawski ML, Chan E, Chiu PKF, Teoh JYC, Gauhar V, Rubilotta E (2022) Infection Rate after Transperineal Prostate Biopsy with and without Prophylactic Antibiotics: Results from a Systematic Review and Meta-Analysis of Comparative Studies. Journal of Urology 207:25–34
Ding X fei, Luan Y, Lu S ming, Zhou G chen, Huang T bao, Zhu L yong, Guo C hao (2021) Risk factors for infection complications after transrectal ultrasound-guided transperineal prostate biopsy. World J Urol 39:2463–2467. doi: 10.1007/s00345-020-03454-y
Guo LH, Wu R, Xu HX, Xu JM, Wu J, Wang S, Bo XW, Liu BJ (2015) Comparison between Ultrasound Guided Transperineal and Transrectal Prostate Biopsy: A Prospective, Randomized, and Controlled Trial. Sci Rep 5:1–10. doi: 10.1038/srep16089
Hulscher ME, Grol RP, van der Meer JW (2010) Antibiotic prescribing in hospitals: a social and behavioural scientific approach. Lancet Infect Dis 10:167–175. doi: 10.1016/S1473-3099(10)70027-X
Jacewicz M, Günzel K, Rud E, Sandbæk G, Magheli A, Busch J, Hinz S, Baco E (2022) Antibiotic prophylaxis versus no antibiotic prophylaxis in transperineal prostate biopsies (NORAPP): a randomised, open-label, non-inferiority trial. Lancet Infect Dis 22:1465–1471. doi: 10.1016/S1473-3099(22)00373-5
Kohl T, Sigle A, Kuru T, Salem J, Rolfs H, Kowalke T, Suarez-Ibarrola R, Michaelis J, Binder N, Jilg CA, Miernik A, Grabbert MT, Schultze-Seemann W, Gratzke C, Porres D (2021) Comprehensive analysis of complications after transperineal prostate biopsy without antibiotic prophylaxis: results of a multicenter trial with 30 days’ follow-up. Prostate Cancer Prostatic Dis 1–5. doi: 10.1038/s41391-021-00423-3
Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, Fanti S, Fossati N, Gandaglia G, Gillessen S, Grivas N, Grummet J, Henry AM, van der Kwast TH, Lam TB, Lardas M, Liew M, Mason MD, Moris L, Oprea-Lager DE, van der Poel HG, Rouvière O, Schoots IG, Tilki D, Wiegel T, Willemse PPM, Cornford P (2021) EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer—2020 Update. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 79:243–262. doi: 10.1016/j.eururo.2020.09.042
Pepdjonovic L, Tan GH, Huang S, Mann S, Frydenberg M, Moon D, Hanegbi U, Landau A, Snow R, Grummet J (2017) Zero hospital admissions for infection after 577 transperineal prostate biopsies using single-dose cephazolin prophylaxis. World J Urol 35:1199–1203. doi: 10.1007/s00345-016-1985-1
Sigle A, Suarez-Ibarrola R, Pudimat M, Michaelis J, Jilg CA, Miernik A, Grabbert MT, Schultze-Seemann W, Gratzke C, Schlager D (2021) Safety and side effects of transperineal prostate biopsy without antibiotic prophylaxis. Urologic Oncology: Seminars and Original Investigations 39:782.e1-782.e5. doi: 10.1016/j.urolonc.2021.02.016
Sigle A, Suarez-Ibarrola R, Pudimat M, Michaelis J, Jilg CA, Miernik A, Grabbert MT, Schultze-Seemann W, Gratzke C, Schlager D, Pepdjonovic L, Tan GH, Huang S, Mann S, Frydenberg M, Moon D, Hanegbi U, Landau A, Snow R, Grummet J, Baba K, Sekine Y, Miyazawa Y, Syuto T, Nomura M, Koike H, Matsui H, Shibata Y, Ito K, Suzuki K (2017) Safety and side effects of transperineal prostate biopsy without antibiotic prophylaxis. World J Urol 39:1199–1203. doi: 10.1007/s00345-016-1985-1
Xiang J, Yan H, Li J, Wang X, Chen H, Zheng X (2019) Transperineal versus transrectal prostate biopsy in the diagnosis of prostate cancer: A systematic review and meta-analysis. World J Surg Oncol 17:1–11. doi: 10.1186/s12957-019-1573-0

No competing interests reported.

Retrospective, single center evaluation of perineal prostate biopsy omitting antibiotic prophylaxis and omitting periinterventional screening for bacteriuria

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials and Methods

2.1. Population

2.2. Biopsy procedure

2.3. Outcome variables

2.4. Statisticsl methods

2.5. Data source

2.6. Bias

3. Results

4. Discussion

4.1. Main Findings

4.2. Findings of biopsy results

4.3. Limitations

5. Conclusions

Declarations

References

Additional Declarations

Status:

Version 1