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Association between radical cystectomy prophylactic antimicrobial regimen and postoperative infection

Introduction: Infections are common after radical cystectomy. The objective of this study was to determine the association between antimicrobial prophylactic regimen and infection after radical cystectomy. Methods: A retrospective cohort study was performed on patients who underwent radical cystectomy at one tertiary Canadian center between January 2016 and April 2020. Patients received antimicrobial prophylaxis based on surgeon preference (cefazolin/metronidazole or ampicillin/ciprofloxacin/metronidazole or other). A univariable and multivariable logistic regression model was created to determine the association between antimicrobial regimen and postoperative infection within 30 days. The association between patient demographic factors, as well as preoperative and intraoperative variables and infection was also determined. Infection characteristics, including type, timing, and antimicrobial susceptibilities were reported. Results: One hundred and sixty-five patients were included. Mean age was 69.8 years, 121 (73.3%) were male, and 72 (43.6%) received orthotopic neobladder diversion. Ninety-six patients (58%) received cefazolin/metronidazole prophylaxis, 50 (30%) received ampicillin/ciprofloxacin/metronidazole, and 19 (11.5%) received another regimen. Fifty-four patients (32.7%) developed a postoperative infection (surgical site infection or urinary tract CUAJ – Original Research Ross et al Infection post-radical cystectomy


Introduction
Approximately 60% of radical cystectomy patients will develop a post-operative complication. [1][2][3][4] Infection, specifically urinary tract infection (UTI), surgical site infection (SSI), and postoperative Clostridium difficile (C. diff) infection, are amongst the most common, with reported rates of SSI up to 33%, UTI up to 36%, and C. diff up to 12%. 1,2,[4][5][6][7][8][9] The incidence of infection remains high in recent series and has been shown to negatively impact quality of life, prolong hospital stay, and increase health care related costs. 8,[10][11][12][13] Despite a high incidence of infection, there are few interventions proven to reduce rates after radical cystectomy. Previously, we reported a simple intraoperative intervention bundle with wound barrier that reduced SSIs by 80%. 14 Pre-operative prophylactic antimicrobials have been shown to reduce post-operative infection in surgery, however, cystectomy specific data are lacking. The American Urology Association (AUA) and European Association of Urology (EAU) recommend that patients undergoing radical cystectomy and diversion receive antimicrobial prophylaxis based on colorectal surgery data. [15][16][17][18] Further study is needed to characterize infections in patients undergoing radical cystectomy and determine the best methods of prevention.
The primary objective of this study was to determine the association between prophylactic antimicrobial regimens and infection (SSI/UTI) after cystectomy. Secondary objectives were to: characterize the incidence and timing of SSIs and UTI after cystectomy within 30 days, identify common causative organisms and antimicrobial susceptibilities, determine the incidence of post-operative C. diff infection, and identify patient and surgery risk factors for SSI/UTI. These data will be used to improve infection prevention protocols and to identify high-risk patients and settings requiring further study.

Study overview
A retrospective cohort study was performed on all patients who underwent radical cystectomy by one of four uro-oncologists at The Ottawa Hospital between January 1 st , 2016 and April 1 st , The Center for Disease Control definitions were used for SSI and UTI. 19 As per the CDC, SSIs are separated according to tissue layers involved and included superficial infections involving the skin and subcutaneous tissue, deep infections involving the facial and muscle layers, and organ space infections involving any space deep to the fascia that was disrupted during the operation. Patients meeting the criteria for infection for any tissue layer was included as an SSI event. UTI was defined as a positive urine culture in the presence of associated symptoms including fatigue, pressure, abdominal pain, foul smelling urine, cloudy urine, and/or fever. Sepsis related to the underlying infection was identified using the Systematic Inflammatory Response Syndrome (SIRS) criteria. 20 Time to infection was defined as the time from operation to positive culture result or clinical diagnosis of infection for SSI if no culture available.

Data collection
A prospective cystectomy database is maintained at The Ottawa Hospital. The cystectomy database includes patient, tumor, and operative characteristics. A single reviewer (JR) reviewed all medical records retrospectively for antimicrobial and infection related variables and outcomes. Patient variables collected included: sex, age, body mass index (BMI), smoking status, diagnosis of diabetes, and whether patient received neoadjuvant chemotherapy. Operative variables collected included operation date, operation time, pre-operative prophylactic antimicrobial regimen (cefazolin/metronidazole vs. ampicillin/ciprofloxacin/metronidazole vs. other), estimated blood loss (EBL), need for intra-operative blood transfusion, type of urinary diversion performed (ileal conduit vs. orthotopic neobladder vs. other), and pathologic stage. Post-operative variables collected included SSI, UTI, and C. Diff infection within 30-days of operation, culture results, antimicrobial susceptibilities of cultured bacteria, time to infection, readmission for infection, whether UTI was associated with catheter or stent removal, and incidence of sepsis from infection.

Analysis
Continuous and categorical baseline patient variables were organized by antimicrobial prophylaxis regimen used and were compared using t-tests and chi-squared tests, respectively. A composite outcome of infection (either SSI or UTI) was used for the primary analysis. Univariable and multivariable log binomial regression models were used to determine the association between antimicrobial prophylaxis regimen on post-operative infection. Models also determined the associations between other patient and operative factors with the primary outcome. Surgeon was included in the multivariable analysis as a cluster variable to adjust for random effect of surgeon specific factors. For each post-operative infection (SSI or UTI), urine, wound, and blood cultures were reviewed. For each positive culture, all microorganisms isolated were identified. For bacteria, antimicrobial susceptibility was recorded. Antimicrobial susceptibility results were limited to what was reported by the local microbiology laboratory. The percentage of bacteria that were resistant to each antimicrobial type tested was reported. Statistical significance was defined as p<0.05. All analysis was performed using SAS software, version 9.4 (SAS Institute Inc.).
In multivariable analyses, prophylactic antimicrobial regimen was not associated with overall infection (ampicillin/ciprofloxacin/metronidazol vs cefazolin/metronidazol; RR 0.99; 95%CI 0.50-1.99; Table 2). There was a non-statistically significant increased risk of infection for patients with higher BMI, patients with higher ASA, those who received an intra-operative transfusion, and those who received a neobladder urinary diversion ( Figure 3). Separate multivariable analyses were performed for the SSI outcome alone, and the UTI outcome alone. This was done because it is possible opposing directions of association for SSI and UTI could confound a clinically important association. Neobladder urinary diversion trended towards a decreased risk of SSI (RR 0.72; 95% CI 0.39, 1.33; p = 0.30) and an increased risk of UTI (RR
For bacteria isolated from all positive UTI or SSI cultures, resistance to antibiotics were frequently noted. Of the bacteria cultured, resistance to a combination of ampicillin/ciprofloxacin/metronidazole was seen in 22% and resistance to a combination of cefazolin/metronidazole was seen in 30% (Table 3). Twenty-one patients (21/54; 38.9%) had infections resistance to 2 antimicrobials. C. diff infection occurred in 9 patients (5.5%) (six patients for cefazolin/metronidazole and three for ampicillin/ciprofloxacin/metronidazole; RR 0.71, CI <0.001, 70.4; p=0.59; Table 2).

Discussion
Infection is a common sources of morbidity after cystectomy. 2,15,16 In this study, there was no association between the prophylactic antimicrobial regimen used and post-operative infections. Infection (SSI or UTI) occurred in 32.7% of patients, which is comparable to other institutions. 4,7,[21][22][23] Amongst patients with infection, there was a high rate of associated sepsis (48.5%) and hospital readmission (33.3%). 4,7,22 Possible reasons why infections are high include: insufficient antimicrobial coverage, duration, or timing, decreased susceptibility of bacteria to some antimicrobials, frequent presence of fungi, and a high number of patient and procedure specific risk factors.
This study did not identify an association between antimicrobial regimen and incidence of infection. Other studies have found reduced infections with broader antimicrobial coverage. One retrospective cohort study demonstrated a decreased risk of overall infection from 41% to 30% (p = 0.045) with use of ampicillin-sulbactam, gentamicin, and fluconazole compared to cefoxitin alone. 21 Another study found for patients receiving penicillin-based prophylaxis, the incidence of infection decreased with the addition of a beta-lactamase inhibitor. 2 All patients in this study received broad antimicrobial regimens with both aerobic and anaerobic coverage. This may have resulted in the lack of significant difference in incidence of infection between regimens.
The AUA recommends a single dose of prophylactic cefazolin pre-operatively with no direct recommendations for extending antimicrobials beyond this time period or use of prophylaxis at the time of catheter and stent removal. Prior studies have reported mixed results regarding UTI risk around the time of catheter and stent removal. One retrospective cohort study found that 37% of all UTIs post-cystectomy occurred within 24 hours of stent removal. 24 Another retrospective review found a significant decrease in UTI with administration of prophylactic antimicrobials at time of ureteric stent removal post-urinary diversion. 25 In contrast, two other retrospective studies did not find a benefit of extending antimicrobials beyond 24 hours. 2,4 In this study, patients were given antimicrobials for 24 hours post-operatively. Routine use of antimicrobials was not mandated at the time of catheter or stent removal, but patients may

CUAJ -Original Research
Ross et al Infection post-radical cystectomy 7 © 2021 Canadian Urological Association have received antimicrobial prophylaxis at the discretion of their treating surgeon. In total, four patients (4/165; 2.4%) developed UTIs associated with catheter or stent removal.
In this study, higher BMI, female sex, higher ASA score, and intra-operative transfusion were associated with increased risk of infection. Similar to other studies, patients receiving continent urinary diversion appeared to have a higher risk of UTI compared to ileal conduit. 4,24,26,27 Active infection at time of cystectomy has been associated with increased risk of post-operative infection. 24 In this study, patients with a positive pre-operative urine culture had less infections. We hypothesize this could be because patients with positive pre-operative culture may have received targeted pre-operative antimicrobials which sterilized their urinary tract prior to surgery, making the treatment more directed and effective. The incidence of post-operative C. diff was low in this study at 5.5% and prophylactic antimicrobial regimen was not associated with increased risk of C. diff.
E. coli was the most common cause of UTI (29.0% of UTIs) and Klebsiella sp. was the most common cause of SSI (31.4% of SSIs). Other studies have identified E. coli and Enterococcus as a common cause of UTI and Enterococcus, Klebsiella, and Coagulase Negative Staphylococcus as common causes of SSI in this population. 1,[4][5][6][7]21,28,29 Fungal infections have also been reported in up to 23% of cystectomy patients. 1,7,21 Candida was isolated in 15% of SSI or UTI cultures in this study with no difference noted between prophylaxis regimens given. Frequently, cultured bacteria were not susceptible to some of the antimicrobials used, for example 22% of cultures isolated a bacteria that was resistant to the ampicillin/ciprofloxacin/metronidazole regimen, and 30% of cultures identified a bacteria resistant to the cefazolin/metronidazole regimen. While some of the susceptibility/resistance patterns identified may be the result of antimicrobial pressures from the prophylaxis, these resistance patterns illustrate the challenge posed by patients with frequent antimicrobial exposures. Other studies have also demonstrated high incidence of resistant organisms including vancomycin-resistant enterococcus in up to 12.8% and methicillin-resistant staphylococcus in up to 63.6%. 1,24 This high level of antimicrobial resistance highlights the importance of adherence to institution specific antibiograms when making decisions regarding antimicrobial coverage. Furthermore, promotion of antimicrobial stewardship and development of non-antimicrobial solutions to reduce infection is required. These approaches may include identification of highrisk populations and modifying procedure and patient risk factors perioperatively when possible.
The proportion of bacteria that were resistant (not susceptible) to specific antimicrobials was reported (Table 3). These results are meant to provide insight into interventions that may reduce infections in this population. It is not meant to represent a local antibiogram, because resistance to antimicrobials identified in this study may be a consequence of antimicrobials used during prophylaxis, and therefore may not accurately represent true susceptibilities prior to surgery. Otherwise stated, the antimicrobial prophylactic regimen may have induced resistances. While this is a limitation of the study design, results do suggest that common infective organisms  (Table 3). Other studies have also reported low resistance rates to nitrofurantoin (21%), suggesting it may warrant further study in this population. 26 Nitrofurantoin is concentrated in the urinary system and is associated with fewer changes in local bacterial flora and less induction of antimicrobial resistance. 30 The results of this study provide a comprehensive overview of infection post-radical cystectomy at our institution. Because a majority of infections occurred greater than seven days post-operatively, we hypothesize that longer duration of prophylaxis may reduce infections. Furthermore, most bacteria isolated from positive cultures in this study were sensitive to nitrofurantoin and nitrofurantoin is generally considered to have a favorable side effect profile compared to most antimicrobials. Further study is planned to test if routine use of low dose daily nitrofurantoin for 2-3 weeks post op is effective and safe.
Limitations of this study include that this was a single center, retrospective study, therefore generalizability to other centers may not be possible. Lack of randomization may have led to differences between groups. This being said, we adjusted for important patient and treatment variables in the multivariable analysis to reduce confounding. Furthermore, the single physician reviewer was not blinded to prophylactic regimen representing a potential source of bias. There was no protocol for antimicrobials around time of catheter or stent removal. Because outpatient prescribing data is not routinely recorded in the electronic medical record, we were unable to determine which patients may have received antimicrobials at the time of catheter or stent removal. If differences in post-operative antibiotic use existed between patient groups this could bias results in a manner which we could not completely control for. We however attempted to adjust for any possible differences in practice patterns like these by including surgeon as a cluster variable in the multivariable analysis. Some UTIs may have been missed if a urine culture was not drawn or if drawn but negative because antimicrobials had already been initiated. We opted to include only culture proven UTIs to avoid including patients with symptoms unrelated to infection. Finally, the resistance rates to antimicrobials presented in this study may have been influenced by many factors including past exposures to hospitals and antimicrobials prior to and at the time of the cystectomy. The resistance patterns reported are not meant to serve as a formal antibiogram.

Conclusions
Infection is common after radical cystectomy. There was no association between prophylactic antimicrobial regimen and post-operative infection. Based on the results, further study which includes increasing duration of prophylaxis as well as the use of more widely-sensitive antimicrobials based on local resistance patterns, is being planned to help reduce incidence of infection in this population.