Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95, 1 ORIGINAL PAPER pathologies beyond its common use in the management of renal stones (1). FURS can be used as a conservative treatment for urothelial tumors of the upper urinary tract (UTUC) and can be used in the follow-up after radical treatment of UTUC (2). However, the use of FURS is not without drawbacks. Significant complications, including urinary tract infection (UTI) and ureteric trauma, are fre- quently reported (3). In one study, febrile UTI was reported in 14.1% of patients submitted to flexible ureteroscopic lithotripsy (4). Unfortunately, prevention of postoperative UTI after FURS remains a debatable issue. Current practice lacks well-established clinical evi- dence based on randomized clinical studies and is main- ly based on retrospective studies (5). To standardize the periprocedural systemic antimicrobial administration, the American Urological Association best practice policy state- ment was developed (6). However, real-world practice is widely variable, and observational studies show relatively low compliance with these recommendations (5-7). To guard against post procedural infection, the most com- mon approach is single-dose antibiotic prophylaxis (8). On the other hand, some centers use more enhanced pre- cautions, including centralized collection and examina- tion of preoperative urine cultures, standardized antibiot- ic prophylaxis, and use of ureteral access sheath. Even with these precautions, postoperative UTI was encoun- tered in 6.7% of patients (9). The present randomized study aimed to compare the rate of post-procedural UTI in patients subjected to the standard antibiotic prophy- laxis alone versus enhanced prophylactic measures. PATIENTS AND METHODS A prospective randomized controlled study was conduct- ed at the Department of Urology, Armed Forces Hospital, Alhada, KSA, from March 2018 to July 2022. The study protocol was approved by the local ethical committee of the institution, and informed written consent was obtained from all patients before enrollment. The study included all patients subjected to FURS to manage ureter- Purpose: To compare the rate of post-flexible ureteroscopy urinary tract infection (UTI) in patients subjected to the standard antibiotic prophylaxis alone versus enhanced prophylactic measures. Methods: A prospective randomized controlled study included 256 patients subjected to flexible ureteroscopy (FURS) for ureteral or renal stones from March 2018 to July 2022. Treatment groups included the standard antibiotic prophylaxis group (group 1, n=128) and the enhanced prophylaxis group (group 2, n=128). Patients in group 1 were injected with intra- venous fluoroquinolone one hour preoperatively, and oral antibiotics were used for 24 h postoperatively. Patients in group 2 had urine culture ten days before the procedure; antibiotic- culture based was given for positive asymptomatic cases, while the procedure was deferred for active UTI. Results: The study groups were comparable regarding patient demographics, stone characteristics, operative time, and intra- operative complications. The overall hospitalization time was 1.68 ± 0.81 days. Postoperative, and overall complications were significantly higher in group 1 (15.6% vs. 6.3%, p = 0.04 and 26.6% vs. 17.2%, p = 0.047), respectively. Twenty patients (15.6 %) in the standard prophylaxis group were diagnosed with UTI in comparison to 8 patients (6.3 %) in the enhanced prophylaxis group (p = 0.047). Conclusions: Urinary tract infection after FURS could be reduced significantly by utilizing the suggested enhanced pro- phylactic approach. KEY WORDS: Antibiotic; Prophylaxis; Ureteroscopy; Urinary tract infect. Submitted 13 December 2022; Accepted 22 January 2023 INTRODUCTION Flexible ureteroscopy (FURS) has become one of the most reliable tools in upper urinary tract endourology. Thanks to creative ancillary instruments such as graspers and bas- kets, effective energy sources, and digital and robotic enhancements, FURS has expanded its diagnostic and therapeutic applications to many upper urinary tract Randomized comparison of effect of standard antibiotic prophylaxis versus enhanced prophylactic measures on rate of urinary tract infection after flexible ureteroscopy El-Sayed I. El-Agamy 1, Mohamed A. Elhelaly 1, Tamer A. Abouelgreed 2, Abdrabuh M. Abdrabuh 3, Mohamed F. Elebiary 3, Adel Elatreisy 3, Osama M. Ghoneimy 3, Basem A. Fathi 3, Mohamed Zamra 4, Khalid Kutub 5 1 Department of Urology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt & Department of Urology, Armed Forced Hospital, Alhada, KSA; 2 Department of Urology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt & Gulf Medical University, UAE; 3 Department of Urology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 4 Department of Urology, AlQasemi Hospital, Sharjah, UAE; 5 Department of Urology, Al Aharq Jospital, Fujairah, UAE. DOI: 10.4081/aiua.2023.11084 Summary Archivio Italiano di Urologia e Andrologia 2023; 95, 1 El-Sayed I. El-Agamy, Mohamed A. Elhelaly, Tamer A. Abouelgreed, et al. al or renal stones. Exclusion criteria were symptomatic UTI, use of rigid ureteroscope, and antegrade ureteroscopy. Preoperatively, all patients were subjected to careful history taking, thorough clinical examination, and non-contrast computed tomography scan to evaluate the stone characteristics. Patients were equally and ran- domly allocated into one of the two treatment groups, including the standard antibiotic prophylaxis group and the enhanced prophylaxis group. The sample size was calculated utilizing the G-power software program for statistical power 80% and type II statistical error 20%. The total number of patients was 256, equally divided into the two groups (each group included 128 patients). Patients in the standard antibiotic prophylaxis group were injected intravenously with fluoroquinolone one hour preoperatively, and oral antibiotics were used for 24 hours postoperatively. Patients in the enhanced prophy- laxis group had urine culture ten days before the proce- dure. Patients with sterile cultures received standard antibiotic prophylaxis. In contrast, patients with polymi- crobial preoperative urine culture (defined by a urine cul- ture isolating at least three microorganisms, of which none is predominant) were treated with ceftriaxone from 48 hours before the procedure until one day after surgery. Patients with positive urine culture were contacted to assess if they had symptoms of UTI. In asymptomatic cases, according to the specific pathogens identified, a full course of antibiotics was started five days before surgery until 48 h after the intervention (Figure 1). For those hav- ing a clinically significant infection, the intervention was deferred. In addition to the antibiotic prophylaxis, hydrophilic- coated ureteral access sheaths were systematically used in all cases. The primary outcome of the study was the occurrence of postoperative UTI within 30 days from treatment. Postoperative UTI was defined as the occurrence of a temperature higher than 38 °C associated with pyuria Figure 1. Flow chart of the study population. Archivio Italiano di Urologia e Andrologia 2023; 95, 1 Antibiotic prophylaxis for urinary tract infection after flexible ureteroscopy and/or bacteriuria without any other focal infectious sites. In a symptomatic patient, no routine urine culture was requested. Statistical analysis Data obtained from the present study were presented as number and percent or mean and standard deviation (SD). Numerical data were compared using a t-test, while cate- gorical data were compared using the chi-square test. Logistic regression was used to identify predictors of out- come. All statistical operations were computed using SPSS 25 (IBM, USA), and a p-value less than 0.05 was considered statistically significant. RESULTS In total, 256 patients were included in the study; the mean age in years ± SD was 46.8 ± 12.9, the male to female ratio was 178/78, and all patients underwent FURS for stone disease with laser lithotripsy. The mean stone number ± SD of the entire cohort was 2.5 ± 1, and the largest stone diameter was 2.1 ± 0.78. The stones were recurrent in 50% of patients and were associated with moderate hydronephrosis in 21.9% and mild hydronephrosis in 48.4%, whereas no hydronephrosis was associated in 29.7%. Regarding the stone location, it was in the proxi- mal ureter in 35.2%, in the kidney in 36.7%, and com- bined in 28.1%. Pre-FURS internal double J ureteric stents were placed in 26.5% of patients who presented with proximal ureteric obstructing stones and slight acute renal impairment, which was normalized after ureteric stenting. Group 1 included patients subjected to the standard antibiotic prophylaxis protocol (n = 128). Group 2 includ- ed patients subjected to the enhanced prophylaxis proto- col (n = 128) who had sterile urine culture in 66 cases (51.6%), polymicrobial positive urine culture in 41 cases (32%), and isolated organism in 21 (16.4%). There were no significant differences between the study groups regarding patient demographics and stone characteristics, as illustrated in Table 1. The overall hospitalization time was 1.68 ± 0.81 days, comparable between groups 1 and 2 with no significant difference (p = 0.35) (Table 1). We reported an overall complication rate of 21.9% (56 cases). Intraoperative complications were comparable between the study groups. Conversely, postoperative, and overall total complications were significantly higher in group 1, as shown in Table 2. All the reported complications were MCCS grades I and II that were managed conservatively. Regarding post-FURS urinary tract infection, 20 patients (15.6%) in the standard prophylaxis group were diag- nosed with UTI in comparison to 8 patients (6.3%) in the enhanced prophylaxis group with statistically significant difference (p = 0.047) (Table 2). Hospital readmission was mandatory in 10 cases (3.9%) for UTI and urosepsis. In these cases we collected urine and blood samples for cul- ture and started with empirical intravenous meropenem (1 gram every 8 hours). Urine culture showed E. coli in 8 cases and Klebsiella pneumonia in two, all sensitive to meropenem, and all patients were discharged after ten days of antibiotic course after confirmation of sterile urine. Using binary logistic regression analysis, female gender [OR (95% CI): 0.09 (0.018-0.46) and operative time [OR (95%CI): 0.97 (0.94-0.99)] were significant predictors of postoperative UTI at univariate analysis. However, only female sex remained significant at multivariate analysis [OR (95% CI): 0.09 (0.017-0.49)] (Table 3). Table 1. Comparison between the studied groups regarding the preoperative, operative, and postoperative data. Parameters Standard prophylaxis Enhanced prophylaxis P value Group 1 (n = 128) Group 2 (n = 128 Age (years) mean ± SD 47.4 ± 11.8 46.1 ± 14.3 0.67 Male/female n 86/42 96/36 0.52 BMI (Kg/m2) mean ± SD 30.4 ± 4.8 29.4 ± 4.2 0.42 Associated morbidities n (%) Hypertension 38 (29.9%) 34 (26.7%) 0.66 Diabetes mellitus 62 (48.4%) 56 (43.8%) 0.45 Previous stone operation n (%) 59 (45.3%) 70 (54.7%) 0.26 Preoperative ureteral stent n (%) 36 (28.3%) 32 (25 %) 0.72 Preoperative hydronephrosis n (%) None 36 (28.1%) 40 (31.3%) 0.52 Mild 66 (51.6%) 58 (45.3%) Moderate 22 (20.3%) 30 (23.4%) Stone location n (%) Kidney 44 (34.4%) 50 (39.1%) 0.7 Ureter 50 (39.1%) 40 (31.2%) Combined 34 (26.6%) 38 (29.7%) Stones number mean ± SD 2.6 ± 1.1 2.4 ± 1 0.43 Largest stone size (cm3) mean ± SD 2 ± 0.9 2.2 ± 0.7 0.31 Operative time (min.) mean ± SD 117.4 ± 26.2 114.8 ± 22.7 0.63 Hospitalization time, days 1.53 ± 0.7 1.63 ± 0.8 0.34 Table 3. Predictors of postoperative UTI in the studied groups. Univariate analysis Multivariate analysis OR 95% CI p value OR 95% CI p value Age 0.99 0.94-1.03 0.54 - - - Sex 0.09 0.018-0.46 0.004 0.09 0.017-0.49 0.005 Diabetes 0.53 0.14-2.02 0.36 - - - Stone size 0.82 0.55-1.24 0.35 - - - Operative time 0.97 0.94-0.99 0.032 0.97 0.95-1.01 0.063 Type of prophylaxis 0.22 0.044-1.09 0.063 0.19 0.033-1.14 0.069 Table 2. Complications rate among studied groups. Parameters Total Group 1 Group 2 P value (n = 256) (n = 128) (n = 128) Overall complications 56 (21.9%) 34 (26.6%) 22 (17.2%) 0.04 Intraoperative complications 28 (10.9%) 14 (10.9%) 14 (10.9%) 0.89 Postoperative complications 28 (10.9%) 20 (15.6%) 8 (6.3%) 0.047 MCCS grading of complications GRADE 1 Ureteric mucosal injury 12 (4.7%) 6 (4.7%) 6 (4.7%) 0.98 Hematuria 16 (6.3%) 10 (3.9%) 6 (4.7%) 0.34 GRADE 2 UTI 28 (10.9%) 20 (15.6%) 8 (6.3%) 0.047 Readmission (within 8 weeks) 10 (3.9%) 8 (6.3%) 2 (1.7%) 0.038 Archivio Italiano di Urologia e Andrologia 2023; 95, 1 El-Sayed I. El-Agamy, Mohamed A. Elhelaly, Tamer A. Abouelgreed, et al. DISCUSSION Urinary tract infections after FURS are commonly seen in clinical practice. Even in the absence of microbial inva- sion, the surgical procedure elicits a significant systemic inflammatory response related to the procedure's dura- tion and can predispose to infectious complications (10). The present prospective study assessed the value of stan- dard antibiotic prophylaxis versus enhanced prophylax- is in preventing UTIs after FURS. Postoperative UTI was diagnosed in twenty patients (15.6%) in the standard prophylaxis group versus eight patients (6.3%) in the enhanced prophylaxis group (p = 0.047). The beneficial effects of enhanced prophylaxis are attributed to addi- tional measures included in the protocol, namely the preoperative culture and treatment of identified infec- tions and use of coated ureteral access sheaths. The relation between positive preoperative culture and postoperative UTI in patients submitted to FURS was discussed by the study by Senocak et al. (11). In their paper, positive preoperative urine culture with mul- tidrug resistance isolates was recognized as an independ- ent risk factor of postoperative UTI. Of note, none of our patients had such isolates. Also, in the study of Alezra et al. (12), positive day-1 culture was a significant predic- tor of severe UTI. In addition, the study of Auge et al. (13) highlighted the value of ureteral access sheath (UAS) in the reduction of postoperative UTI after FURS. Similar conclusions were reported by the randomized study of Özkaya et al. (14). They noted that using UAS in impacted mid-upper ureteral stones was related to fewer infectious complications. The UAS reduces the irrigation pressures transmitted to the renal pelvis and parenchyma (13). Moreover, appro- priate UAS selection is essential to optimize the renal blood flow during FURS. Adequate renal blood flow is critical to maintain local immune defensive mechanisms (15). In our study, logistic regression analysis identified the female sex as an independent risk factor of postoperative UTI. This finding conforms with the study of Baboudjian et al. (9). Their study showed preoperative polymicrobial urine culture and increased operative time as predictors of postoperative UTI. Our conclusions are also supported by the recent meta- analysis of Ma et al. (16). In contrast, the study of Baseskioglu et al. (17) recognized preoperative infection history, comorbidity score, and residual fragments as sig- nificant predictors of UTI after FURS, while the relevant risk factors in the study of Ozgor et al. (18) were longer operation time, presence of renal abnormality and age ≤ 40 years. CONCLUSIONS Urinary tract infection after flexible ureteroscopy and laser lithotripsy could be reduced significantly by utiliz- ing the suggested enhanced prophylactic approach. The female sex factor is the only independent predicting fac- tor for the occurrence of post-FURS urinary tract infec- tions. REFERENCES 1. Alenezi H and Denstedt JD. Flexible ureteroscopy: Technological advancements, current indications and outcomes in the treatment of urolithiasis. Asian J Urol. 2015; 2:133-141. 2. Cho SY. Current status of flexible ureteroscopy in urology. Korean J Urol. 2015; 56:680-688. 3. Osther PJS. Risks of flexible ureterorenoscopy: pathophysiology and prevention. Urolithiasis. 2018; 46:59-67. 4. Kim JW, Lee YJ, Chung JW, et al. Clinical characteristics of post- operative febrile urinary tract infections after ureteroscopic lithotrip- sy. Investig Clin Urol. 2018; 59:335-341. 5. Greene DJ, Gill BC, Hinck B, et al. 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Urolithiasis. 2019; 47:481-486. Correspondence El-Sayed I. El-Agamy, MD abuamr1978@yahoo.com Mohamed A. Elhelaly, MD elhelalymohammed@yahoo.com Department of Urology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt & Department of Urology, Armed Forced Hospital, Alhada, KSA Tamer A. Abouelgreed, MD (Corresponding Author) dr_tamer_ali@yahoo.com tamerali.8@azhar.edu.eg Department of Urology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt. & Gulf Medical University, UAE Abdrabuh M. Abdrabuh, MD abdo197871@yahoo.com Mohamed F. Elebiary, MD dr_elebiary@yahoo.com Adel Elatreisy, MD dr_adelelatreisy@yahoo.com Osama M. Ghoneimy, MD elgendyosama787@gmail.com Basem A. Fathi, MD basemhara@gmail.com basemabdalla.8@azhar.edu.eg Department of Urology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt Mohamed Zamra, MD mohamedzomrah@gmail.com Department of Urology, AlQasemi Hospital, Sharjah, UAE Khalid Kutub, MD abanis35@gmail.com Department of Urology, Al Sharq Hospital, Fujairah, UAE Conflict of interest: The authors declare no potential conflict of interest.