The effect of rectal swab culture-guided antimicrobial prophylaxis in men undergoing prostate biopsy on infectious complications and cost of care: A randomized controlled trial in the Netherlands.

PROBLEM, RELEVANCE AND RESEARCH QUESTIONS Transrectal ultrasound-guided prostate biopsy (TRUS-PB) is a well established procedure to obtain tissue for the diagnosis of prostate cancer. In The Netherlands, TRUS-PB is performed in approximately 40.000 patients annually. Due to the transrectal approach of the procedure, it may be accompanied by infectious complications, including urinary tract infections (UTI), acute prostatitis, and sepsis. Ciprofloxacin has been recommended for TRUS-PB prophylaxis in American, European and Dutch guidelines, although no clear recommendations are made on the duration of prophylaxis. In The Netherlands, therefore, various prophylactic ciprofloxacin schedules are used, of which 2 to 3 day regimens are most common. Due to increasing fluoroquinolone (FQ) resistance in gram negative bacilli (currently more than 20% in E. coli), a significant increase up to 6% in infective complications after TRUS-PB procedures was recently noticed. Antibiotic treatment of these infections and hospitalization may account for increased health care associated costs and will contribute to the further development of antibiotic resistance. Directed prophylaxis based on resistance data of individual rectal cultures may help to reduce infectious complications after TRUS-PB. Previous studies already showed promising results but had retrospective designs, did not use control groups, used unclear screenings techniques, or were underpowered. In addition, expensive and time-consuming bacterial culture methods were performed. Moreover, the majority of these studies used intravenously antibiotics in case of FQ resistance. Oral alternatives to FQ, if available, are preferred over intravenous prophylaxis, because they are cheaper and more comfortable for the patient. This study aims to assess the effectiveness and cost-effectiveness of rectal culture-guided antimicrobial prophylaxis to reduce infectious complications after TRUS-PB. Also, duration of antibiotic prophylaxis will be reduced from 72 to 24 hours, thereby controlling further development of resistant bacteria. To facilitate future implementation of targeted prophylaxis into daily clinical practice, a guideline will be developed that not only includes recommendations on appropriate targeted antimicrobial prophylaxis but also how to implement the approach. STUDY DESIGN AND POPULATION We aim to perform a prospective non-blinded randomized controlled trial to investigate the value of a personalized rectal culture-guided oral antibiotic prophylaxis approach for adult men aged 30-90 years undergoing TRUS-PB for diagnosis of prostate cancer. Patients will be randomized into two groups of 666 patients each: a control group receiving routine empirical prophylaxis with oral ciprofloxacin and an intervention group receiving rectal culture-guided oral antibiotic prophylaxis. INTERVENTION The antibiotics used in the intervention group are ciprofloxacin, trimethoprim/sulfamethoxazol (SXT), fosfomycin or pivmecillinam/augmentin. These antibiotics were chosen because they can be administered orally and their potential effectiveness for prophylaxis has been shown in previous studies. Based on the amount of evidence, ciprofloxacin remains our first choice of prophylaxis, in case of FQ-resistant rectal flora, SXT will be second choice, followed by fosfomycin and pivmecillinam/augmentin. For the screening of resistant rectal flora, we developed a simple and rapid phenotypic culture method to guide the use of prophylactic antibiotics. Rectal swabs will be taken within 2 weeks before TRUS-PB and cultured on 4 selective agar plates containing concentrations of the oral antibiotics used in this study. This method obviates full susceptibility testing of cultured colonies. HYPOTHESIS Our hypothesis is that the targeted prophylaxis group will have a 2.2% reduction of post-biopsy infectious complications compared to the control group. Primary endpoints are any registered clinical infectious complication within 7 days after TRUS-PB and cost of care 30 days post-TRUS-PB. CLINICAL IMPLEMENTATION If the culture-guided approach investigated in our study is superior to the current empirical prophylaxis with ciprofloxacin and is proven to be cost-effective, a national prophylaxis guideline on behalf of the Dutch Association of Urology (NVU) will be developed based on the results of our study. To facilitate adherence, this guideline will include recommendations on how to address potential determinants in the organization and performance of the culture-guided approach. Information from semi-structured interviews and/or focus groups among future users will be used to translate a generic determinant framework into a tailored questionnaire. A survey to assess determinants will be performed among Dutch hospitals. Also, study results will be submitted to high impact scientific journals and presented at (inter)national conferences and a national symposium will be organized on this topic.