ENDOUROLOGY AND STONE DISEASE Risk Factors of Infectious Complications after Flexible Uretero-renoscopy with Laser Lithotripsy Cagri Senocak,1* Cihat Ozcan,1 Tolga Sahin,1 Gulden Yilmaz,2 Ekrem Ozyuvali,1 Selcuk Sarikaya,1 Berkan Resor- lu,3 Ural Oguz,1 Omer Faruk Bozkurt,1 Ali Unsal,4 Oztug Adsan1 Purpose: To determine the perioperative risk factors for postoperative infections among patients undergoing flex- ible uretero-renoscopy with laser lithotripsy (FURSLL). In addition, the resistance patterns of pathogens isolated from positive preoperative urine cultures were investigated. Materials and Methods: We retrospectively reviewed data from 492 consecutive patients who had undergone FURSLL for stone disease in our department. Postoperative infection was defined as fever (≥ 38°C) with pyuria (≥ 10 white blood cells per high power field), or systemic inflammatory response syndrome, or sepsis. Pre-operative and intra-operative characteristics between patients with and without postoperative infectious complications were compared using univariate analyses. Significant variables on univariate analyses were included in a multivariate logistic regression analysis to evaluate risk factors associated with postoperative infection following FURSLL. Results: 42 (8.5%) of 492 patients had postoperative infectious complications after FURSLL. 59 (12%) of 492 pa- tients had a positive preoperative urine culture. 19 (32.2% of 59) patients had multidrug resistance (MDR) isolates recovered from positive preoperative urine cultures. 75% (9/12 cultures) of the positive preoperative urine cultures of patients in whom a postoperative infectious complication developed consisted of gram-negative pathogens. On multivariate analysis positive preoperative MDR urine culture (OR:4.75;95%CI:1.55-14.56; P = .006) was found to be significant with the dependent variable as the postoperative infectious complications despite appropriate preoperative antibiotic therapy. Conclusion: We found that positive preoperative MDR urine culture is a significant risk factor for infectious complications after FURSLL. Our findings point to the need for further research on assessment of risk factors for MDR infections to reduce the rate of postoperative infectious complications. Keywords: nephrolithiasis; ureteroscopy, laser lithotripsy; urinary tract infections; multi-drug resistance. INTRODUCTION With the improvement in technology, minimally invasive flexible uretero-renoscopy with laser lithotripsy (FURSLL) has been recently touted as a tool to improve the outcomes of uretero-renal stone surgery. FURSLL has become an increasingly favorable op- tion even for patients with renal and proximal ureteral stones less than 20mm.(1,2,3) For these stones, the stone- free rates of FURSLL are up to 94.1% with 28% overall risk of perioperative complications.(4,5,6) As experience with FURSLL has grown, one of inter- esting topic is the increasing rate of infectious com- plications associated with FURSLL. Infectious com- plications rates including fever and sepsis in patients undergoing FURSLL have been reported to vary from 2% to 28% and from 3% to %5, respectively.(4) How- ever, risk factors of infection after FURSLL have been investigated by limited number of studies and warrant further investigation.(7,8,9) We, therefore, aimed to iden- 1Department of Urology, Kecioren Training and Research Hospital, Ankara, Turkey 2Department of Infectious Diseases and Clinical Microbiology, Ankara University School of Medicine, Ankara, Turkey. 3Department of Urology, Ondokuz Mayis University School of Medicine, Samsun, Turkey. 4Department of Urology, Gazi University School of Medicine, Ankara, Turkey. *Correspondence: Department of Urology, Kecioren Training and Research Hospital, 06380, Ankara, Turkey, Phone: +90 530-926-9784, E-mail: senocakcagri2010@gmail.com. Received May 2017 & Accepted September 2017 tify possible risk factors for postoperative infection af- ter FURSLL in this study. We also aimed to evaluate the prevalence and resistance patterns of pathogens iso- lated from preoperative urine cultures and appropriate empiric therapy for postoperative infections of patients undergoing FURSLL. MATERIALS AND METHODS Study Design and Population After institutional review board approval, we retrospec- tively analyzed the collected data from 506 consecu- tive patients treated with FURSLL for either intrarenal or proximal ureteral stones between January 2010 and October 2014 at the Urology Department of Anka- ra Kecioren Training and Research Hospital. Patients with missing data for the clinical baseline records, or without a preoperative urine sample sent for culture, or with postoperative fever due to other potential source of infection were excluded from the study. Kidney-ure- Endourology and Stone Diseases 158 ter-bladder radiography with or without the use of a contrast medium and ultrasonography/noncontrast-en- hanced computed tomography was used for preopera- tive imaging variables. Four urological surgeons expe- rienced with FURSLL performed the procedures with modifications according to each surgeon’s preferences and experience. A 7.5 F Storz Flex-X2 was used for flexible URS. A hydrophilic coated ureteral access sheath (9.5/11.5F or 12/14F) was placed under fluoro- scopic guidance to maintain low intrarenal pressure and to facilitate extraction of stone fragments. A manual ir- rigation pump was used to improve visualization during surgery. Postoperatively, a double-j stent was placed based at the surgeon’s discretion and removed within two to three weeks. Midstream clean catch urine spec- imens were obtained for each patient. Preoperatively, a 7-day appropriate course of antibiotic therapy based on the culture sensitivity was given to the patients with positive preoperative urine culture, and FURSLL pro- cedures were performed only after achieving a negative urine culture just prior to the procedure. As for intraop- erative antibiotic prophylaxis to minimize the potential infectious complications following FURSLL, a single dose of first generation parenteral cephalosporin antibi- otic (cefazolin) was given to the patients with negative preoperative urine cultures during anesthetic induction, while among those with positive preoperative urine cultures, a dose of antibiotic was given intraoperative- ly based on preoperative antimicrobial susceptibilities. Postoperative urine analysis and culture within 30 days following surgery was collected in the presence of fever (≥ 38 °C) or SIRS. Chest radiography, blood tests and physical examination were performed postoperatively on patients with fever to help rule-out other possible causes of infection. Outcome assessment A positive preoperative urine culture was defined as ≥ 50,000 CFU/ml of a pathogenic organism within 30 days before index procedure. The preoperative urine specimen was assumed to be contaminated where there was a mixed culture (growth of more than one isolate), and then a repeat culture was obtained. Multidrug resist- Table 1. Perioperative characteristics of total cohort and by postoperative infectious complications Variable Total cohort (n = 492) Cases (n = 42, 8.5%) Controls (n = 450, 91.5%) P Age in years, median (IQR) 42 (32-54) 39.5 (25-58) 42 (32-54) 0.333 Gender, female, % 43.7 54.7 42.6 0.131 Body-mass index, kg/m2 (IQR) 26.4 (24.4-28.2) 26.3 (24-29.5) 26.4 (24.5-28.1) 0.943 Diabetes mellitus, % 11.8 21.4 10.9 0.043 Stone size, mm, median (IQR) 13 (10-16) 15 (12-21) 12 (10-15) < 0.001 Stone number, median (IQR) 1 (1-2) 1 (1-2) 1 (1-2) 0.536 Stone location, % 0.656 Upper ureteral 18.0 12.0 18.6 Renal pelvis 39.2 40.5 39.1 Inferior calyx 26.0 26.2 26.0 Upper/Mid calyx 16.6 21.4 16.2 History of previous stone treatment, % 0.392 None 49.4 64.2 48.0 Extracorporeal shock wave lithotripsy 35.5 28.5 36.2 Ureterorenoscopy 4.7 2.3 4.9 Percutaneous nephrolithotomy 1.4 - 1.5 Open surgery 2.5 - 2.7 Multiple modalities 6.5 4.7 6.7 Renal anatomical anomaly, % 4.7 7.1 4.4 0.428 Hydronephrosis, % 0.600 None or mild 70.7 64.3 71.3 Moderate or severe 29.3 35.7 28.7 Preoperative double-j stent, % 22.3 21.4 22.4 0.880 Positive preoperative non-MDR urine culture, % 8.1 16.7 7.3 0.034 Positive preoperative MDR urine culture, % 3.9 12.0 3.1 0.005 Operation time, minutes, median (IQR) 57 (46-70.5) 65 (55-95) 56 (46-70) 0.001 Use of ureteral access sheath, % 0.422 None 6.9 9.5 6.6 9.5/11.5F 66.4 71.4 66.0 12/14F 26.6 19.0 27.3 Postoperative double-j stent, % 74.8 76.2 74.7 0.828 Hospitalization time, days, median (IQR) 1 (1-2) 5 (4-7) 1 (1-2) < 0.001 Presence of residual fragments, % 18.7 19.0 18.7 0.952 Abbreviations: IQR, interquartile range; MDR, multidrug resistant. Isolated pathogens All isolates n=59 MDR isolates n=19 Non-MDR isolates n=40 P Gram-negative, % Escherichia coli 50.8 42.0 55.0 0.355 Klebsiella pneumoniae 15.2 22.2 12.5 0.580 Pseudomonas aeruginosa 8.5 10.5 7.5 0.697 Proteus mirabilis 3.4 5.5 2.5 0.823 Gram-positive, % Enterococcus species 17.0 21.0 15.0 0.563 Staphylococcus species 5.0 0.0 7.5 0.472 Table 2. Distribution of pathogens with and without multidrug resistance (MDR) isolated from 59 positive preoperative urine culturesa Infection after RIRS-Senocak et al. Vol 15 No 04 July-August 2018 159 ance (MDR) gram-negative pathogens in urine cultures were defined as resistance to at least one antibiotic in at least three of the following antibiotic categories (antibi- otics used in the analysis given in parenthesis): cephalo- sporins (ceftriaxone), fluoroquinolones (levofloxacin), penicillins with beta-lactamase inhibitors (amoxicillin/ clavulanate), aminoglycosides (gentamicin or amik- acin), carbapenems (meropenem), trimethoprim-sul- famethoxazole, and nitrofurantoin.(10) MDR analysis of gram-positive pathogens with the same criteria was performed for four antibiotic categories: aminoglyco- sides (gentamycin), fluoroquinolones (levofloxacin), penicillins (ampicillin), glycopeptides (vancomycin). Positive MDR culture was defined as any evidence of MDR pathogens in positive urine cultures. Positive urine cultures that did not meet the criteria were consid- ered to be positive non-MDR cultures. Stone size was determined by measuring the longest diameter on pre- operative radiologic investigation; in cases of multiple calculi, stone size was defined as the sum of the longest diameter of each stone. Hydronephrosis was graded as either none/mild or moderate/severe using the Society of Fetal Urology grading system.(11) The operative time was calculated from the time of ureteroscope insertion to the end of placing a double-j stent. SIRS was defined as the occurrence of at least two of the following crite- ria: fever ≥ 38 °C or hypothermia ≤ 36.0°C, tachycardia > 90 beats/minute, tachypnea > 20 breaths/minute, leu- cocytosis > 12,000/µL or leucopoenia < 4,000 µL and sepsis was defined as culture-proven postoperative uri- nary tract infection together with SIRS.(12) In the present study, we used kidney-ureter-bladder radiography and ultrasonography that was performed on the second post- operative day for the assessment of residual fragments (3 mm <). The main outcome of the present study was postoper- ative infectious complication and was defined as fever (≥ 38 °C) with pyuria (≥ 10 white blood cells per high power field), or SIRS, or sepsis. Results of concern in- cluded the prevalence and resistance patterns of patho- gens in urine cultures of patients undergoing FURSLL and risk factors for postoperative infectious complica- tions. Statistical Analysis Perioperative characteristics between patients with and without postoperative infectious complications were compared using univariate Mann-Whitney test, Chi- square or Fisher’s Exact test. All significant factors associated with postoperative infectious complications following FURSLL on univariate analyses (variables with P < .05) were then included in a multivariate logistic regression analysis with a backward stepwise approach to select the significant ones. STATA version 11.0 (StataCorp, USA) was used for analysis with a two-sided alpha level of < 0.05 being considered statis- tically significant. RESULTS The collected data included patient, stone, and treat- ment parameters. Data also included bacterial species and bacterial resistance to antibiotics used to treat pre- operative urine cultures. 4 patients were excluded from the study due to having postoperative fever because of chest infection (n = 2) and tonsillitis (n = 2). We also excluded patients due to missing data on preoperative urine culture (n = 7) and body-mass index (BMI, n = 3). After these exclusions, we obtained 492 patients with complete data to identify predictors of postoperative infectious complications following FURSLL. Of the included 492 patients, 42 patients had the postoperative infectious complications (case group) and other 450 pa- tients did not develop postoperative infection (control group). Cohort characteristics of patients with vs. with- out postoperative infectious complications are shown in Table 1. Patients in the case group had larger median stone size compared to patients in the control group, though this difference was small and median stone size for both groups was 13mm (P < .001). Preoperative double-j stents (n = 110, 22.3% of 492) were inserted in 2 patients with evidence of pyonephrosis, in 3 patients with severe hydronephrosis, and were inserted in the re- maining majority (n = 105) to allow for passive ureteral dilation to facilitate the passage of the ureteral access sheath. Postoperative double-j stents were inserted for the purpose of facilitating passage of stone fragments in 307 cases (62.4% of 492), while double-j stents were required in all cases with intraoperative complications (n = 61, 12.4% of 492) including mucosal injury of ure- ter (n = 26, 5.28%), ureteral perforation (n = 4, 0.81%), and mucosal bleeding (n = 31, 6.3%). Patients in the case group were more likely to be having a positive pre- operative non-MDR urine culture (16.7 vs. 7.3%, P = .034) and MDR urine culture (12 vs. 3.1%, P = .005). Overall, 42 (8.5%) patients had postoperative infectious complications after FURSLL. Of the 42 patients with an infectious complication, 14 (33.3%) had fever with pyuria, 23 (54.8%) had SIRS, and 5 (11.9%) had sep- Table 3. Antibiotic resistance rates among gram-negative and gram-positive pathogens with and without multidrug resistance (MDR) isolated from 59 positive preoperative urine cultures Antibiotic resistance rates among gram-negative pathogens Antibiotics All isolates n = 46 MDR isolates n = 15 non-MDR isolates n = 31 P Amoxicillin-clavulanate 39.1% 80.0% 19.3% < 0.001 Ceftriaxone 21.7% 60.0% 3.2% < 0.001 Meropenem 0.0% 0.0% 0.0% - Levofloxacin 24.0% 53.3% 9.7% 0.001 Amikacin 2.2% 6.7% 0.0% 0.146 Gentamicin 28.3% 66.7% 9.7% < 0.001 Trimethoprim-sulfamethoxazole 47.8% 86.7% 29.0% < 0.001 Nitrofurantoin 15.2% 33.3% 6.4% 0.017 Antibiotic resistance rates among gram positive pathogens Antibiotics All isolates n = 13 MDR isolates n = 4 non-MDR isolates n = 9 P Ampicillin 38.4% 100.0% 11.1% 0.002 Gentamicin 46.1% 100.0% 22.2% 0.009 Levofloxacin 38.4 % 100.0% 11.1% 0.002 Vancomycin 0.0% 0.0% 0.0% - Infection after RIRS-Senocak et al. Endourology and Stone Diseases 160 sis. 59 (12%) of 492 patients had a positive preopera- tive urine culture. 19 (32.2% of 59) patients had MDR isolates recovered from positive preoperative urine cultures. The distribution of the pathogens in patients with and without MDR preoperative urine cultures is shown in Table 2. We did not identify any fungal iso- lates from preoperative urine cultures. Gram-negative pathogens were isolated more often than gram-positive ones in the preoperative urine cultures and the majority of pathogens were Escherichia coli and Enterococcus species. Antibiotic resistance rates among gram-nega- tive pathogens with MDR from positive preoperative urine cultures were significantly greater than those with non-MDR, while all of the isolates were carbapenems susceptible and 97.8% of the isolates were susceptible to amikacin (Table 3). Postoperative infectious complications after FURSLL were seen in 30 of 433 (6.9%) patients with negative preoperative urine cultures, 7 of 40 (17.5%) patients with preoperative non-MDR urine cultures, and 5of 19 (26%) patients with preoperative MDR urine cul- tures. Specifically, 75% (9/12 cultures) of the positive preoperative urine cultures of patients in whom a post- operative infectious complication developed consisted of gram-negative pathogens. Of the 42 patients with an infectious complication, 12 (28.6%) had a positive postoperative urine culture. In the 12 patients with a positive postoperative urine culture, 7 patients had a positive preoperative urine culture while 3 of 7 were positive for different pathogens. 5 patients experienced sepsis. Patients with sepsis were treated on an intensive care unit in collaboration with the infectious diseases specialists. On multivariate analysis positive preoperative MDR urine culture (OR: 4.75, 95% CI: 1.55-14.56; P=.006) was found to be significant with the dependent varia- ble as the postoperative infectious complications after controlling for diabetes mellitus, stone size, operative time and positive preoperative non-MDR urine culture (Table 4). DISCUSSION We examined a single-institution contemporary series of patients undergoing FURSLL for the management of intrarenal and upper ureteral calculi. Infectious complications rate after FURSLL in the current study was 8.5%, which is in line with the previously report- ed rates ranging from 2% to 28%.(4) The prevalence of overall MDR pathogens in positive urine cultures prior to FURSLL was 32.2%. High rates of MDR pathogens in patients with urinary tract infections have also been reported in numerous studies worldwide.(13) Unsuita- ble use of broad-spectrum antibiotics and unnecessary prescription of antibiotics may be responsible for these high rates. In univariate analyses, positive preoperative non-MDR and MDR urine cultures were both associated with higher risk of postoperative infectious complications. After adjusting for clinical and intraoperative signifi- cant variables based on multivariate analysis, there was a statistically non-significant but strong trend for asso- ciation of positive preoperative non-MDR urine cul- tures with higher risk of postoperative infectious com- plications. One might think that it would be easy to be accepted that positive preoperative urine cultures itself is a risk factor of postoperative infection after FURSLL whether the bacteria are MDR or non-MDR. In ac- cordance with this point, very recent published studies demonstrated that a positive preoperative urine culture was the most powerful predictor of postoperative infec- tion in patients undergoing FURSLL.(8,9) Furthermore, we identified positive preoperative MDR urine culture as independent risk factor associated with a 4.75-fold increased risk of postoperative infectious complication after FURSLL in patients suffering from stone disease despite receiving appropriate preoperative antibiotic therapy. Another article highlighting the importance of positive preoperative MDR urine culture in a subset of patients with infectious complications after endoscop- ic surgery for renal stone disease, PCNL, was recently published by Patel et al.(14) Their finding that a positive preoperative MDR culture before PCNL increases the risk of development a postoperative infectious compli- cation by 4.89-fold therefore has strong clinical impor- tance and warrants extra caution to postoperative care by urologists. These relevant findings are particularly important because infections caused by MDR patho- gens require timely and appropriate treatments includ- ing both empirical and definitive antibiotic therapy to reduce postoperative morbidity and costs outcomes. We found that 12 patients with positive preoperative urine cultures still developed postoperative infection complications despite receiving appropriate preopera- tive antibiotic therapy. We also demonstrated that out of 12 patients with postoperative infectious complications, 3 patients had discordant culture results between posi- tive preoperative and positive postoperative urine cul- tures. These findings correspond with those of Margel et al.(15) who found that 19 of 75 (25%) PCNL-treated patients with a positive stone culture had sterile urine, and the sensitivity of urine culture to predict stone colo- nization was only 30%. Furthermore, antibiotic prophy- laxis used in this study failed to eliminate the risk of in- fection after FURSLL in 30 of 433 (6.9%) patients with negative preoperative urine cultures. Indeed, Martov et al.(16) showed in the Clinical Research Office of the Endourological Society (CROES) ureteroscopy (URS) Global Study that in patients with a negative baseline urine culture undergoing URS for ureteral stones (n = 1141) or renal stones (n = 184), rates of postoperative Table 4. Multivariate logistic regression analysis of variables associated with postoperative infectious complications after flexible urete- ro-renoscopy with laser lithotripsy OR 95% CI P Multivariate Analysis Diabetes mellitus 1.99 0.85-4.64 0.110 Stone size 1.03 0.96-1.10 0.331 Operation time 1.01 0.99-1.03 0.094 Positive preoperative non-MDR urine culture 2.27 0.88-5.86 0.088 Positive preoperative MDR urine culture 4.75 1.55-14.56 0.006 Abbreviations: MDR, multidrug resistant; OR, odds ratio; CI, confidence interval. Infection after RIRS-Senocak et al. Vol 15 No 04 July-August 2018 161 urinary tract infection and fever were not reduced by preoperative antibiotic prophylaxis. Possible explana- tions for these findings might be that cultures obtained from bladder may not accurately reflect the pathogens responsible for the infection found in upper urinary tract urine or in infected stones and antibiotics may not be able to penetrate properly into the infected stone.(17) We found that gram-negative pathogens were isolated more often than gram-positive pathogens among preop- erative urine cultures of patients with postoperative in- fectious complications. Similar results in preoperative urine cultures were found by Gutierrez et al.,(18) examin- ing 5,354 patients undergoing PCNL. They demonstrat- ed that the prevalence of fever among PCNL-treated pa- tients with a positive preoperative urine culture varied markedly depending on which pathogens were found in their urine cultures. These findings suggest that the risk of infection depends on the predominant pathogens identified in urine cultures of patients undergoing en- dourological procedures for the treatment of nephrolith- iasis including FURSLL and PCNL. One of the significant findings of our study is the im- portance of identifying patients with risk factors for infection after FURSLL in order to select empirical antibiotic therapy. We found that both cephalosporins and fluoroquinolones, types of antibiotics that are com- monly used for treating urinary tract infections, cannot be recommended for the empirical treatment of postop- erative infections after FURSLL based on the findings from our local resistance data given the high overall re- sistance rates among gram-negative pathogens (nearly 25%). Furthermore, all tested antibiotics in this study, except carbapenems and amikacin, were not suitable for empiric treatment among patients with a postoperative infectious complication, given that in our study we ob- served a nearly 5 times risk of postoperative infection in patients with a positive preoperative MDR urine culture and 79% of positive preoperative MDR urine culture consisted of gram-negative pathogens. It is well estab- lished that carbapenems has a favorable and acceptable safety profile.(19) Amikacin use, however, has been limited due to concerns regarding its toxicity includ- ing ototoxicity and nephrotoxicity.(20) Our data suggest that choices for empiric antibiotic treatment in patients with postoperative infectious complications should be based on prompt evaluation of common uropathogens relevant to the disease and on local resistance data, giv- en that susceptibility results will take at least 48 hours after a urine culture is reported as positive. Although the choice of empiric initial antibiotic therapy for pa- tients with infectious complication will be very much dependent on preoperative cultures and on local resist- ance data, carbapenems may be appropriate empiric therapy while awaiting the urine culture result in the treatment of postoperative infectious complications for FURSLL-treated patients. Limitations Our study has some built-in limitations. First, this is a retrospective observational study in a subset of patients who received FURSLL. Second, our recommendation for empiric antibiotic treatment (carbapenems) in pa- tients with infectious complications after FURSLL is based on local resistance patterns using our institution- al antibiogram that may not be generalizable to other centers where antibiotic resistance patterns may differ. Third, no complete data on stone composition, stone culture and upper urinary tract urine culture were avail- able. Lastly, we did not consider the possible effect of intraoperative irrigation pressure on postoperative in- fectious complications, although we observed no differ- ence between patients with and without postoperative infectious complications in ureteral access sheath use which may be helpful for maintaining low intrarenal pressure. CONCLUSIONS We found that positive preoperative MDR urine culture is a significant risk factor for infectious complications after FURSLL. Our findings point to the need for fur- ther research on assessment of risk factors for MDR infections to reduce the rate of postoperative infectious complications. The necessity for well-designed pro- spective studies is therefore urgent to answer clinical questions of how to treat and for how long to mitigate the infectious complications in the setting of positive preoperative MDR urine culture, such as dosing and du- ration of antibiotic therapy and the possible benefit of antibiotic combinations versus monotherapy. 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