BackgroundAfter recommended restriction of the use of fluoroquinolones, the optimal antibiotic prophylaxis for transrectal prostate biopsy is still under debate. ObjectiveTo test the effectiveness of cefpodoxime as oral antibiotic prophylaxis for transrectal prostate biopsies and the complication rates relative to fluoroquinolones. Design, setting, and participantsAntibiotic prophylaxis for transrectal prostate biopsies at the Department of Urology at University Hospital Frankfurt was fluoroquinolones for 342 consecutive patients in January 2018 and December 2019 and cefpodoxime for 100 patients from January 2020 to July 2020. Data were prospectively evaluated and retrospectively analyzed. Patients were followed up according to clinical routine at 6 wk after biopsy at the earliest. Patients without follow-up (n = 98) and those receiving antibiotic prophylaxis other than cefpodoxime or fluoroquinolones (n = 15) were excluded. InterventionUse of cefpodoxime or fluoroquinolones as antibiotic prophylaxis for transrectal prostate biopsies. Outcome measurements and statistical analysisLogistic regression models were used to predict biopsy-related complications according to antibiotic prophylaxis. Results and limitationsOf 442 patients, 100 (22.6%) received cefpodoxime as antibiotic prophylaxis. Patient baseline and biopsy characteristics were comparable between the cefpodoxime and fluoroquinolone groups. Moreover, there were no differences in the number of prior prostate biopsies or the proportions of systematic vs. fusion biopsies (p > 0.05). There were no differences between the groups in infectious complications such as epididymitis and prostatitis after biopsy. Infectious complication rates were very low, at 2.0% in the cefpodoxime and0.9%fluoroquinolone group. Moreover, there were no differences between the groups in patient-reported complications, such as gross hematuria occurring at more than 5 d after biopsy, hematospermia, or rectal bleeding. In multivariable analyses, after adjustment for patient and prostate biopsy characteristics, cefpodoxime was not associated with higher complication rates than fluoroquinolones (p > 0.05). ConclusionsComplications after transrectal prostate biopsies are rare and cefpodoxime might be a sufficient choice as oral antibiotic prophylaxis and noninferior compared to fluoroquinolones. Patient summaryCefpodoxime might be a sufficient choice as an easily applicable oral antibiotic prophylaxis for transrectal prostate biopsy. The safety profile of cefpodoxime is comparable to the safety profile of fluoroquinolones.