Urinary tract infections following radical cystectomy with enhanced recovery protocol: A prospective study

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Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−6

Clinical-Bladder cancer

Urinary tract infections following radical cystectomy with enhanced recovery protocol: A prospective study Alireza Ghoreifi, M.D., Christine M. Van Horn, M.D., Willem Xu, M.D., Jie Cai, M.S., Gus Miranda, B.S., Sumeet Bhanvadia, M.D., Anne K. Schuckman, M.D., Siamak Daneshmand, M.D., Hooman Djaladat, M.D., M.S.* Institute of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA Received 13 May 2019; received in revised form 14 November 2019; accepted 23 December 2019

Abstract Objectives: Urinary tract infection (UTI) following radical cystectomy (RC) is a common complication associated with significant morbidity and risk of readmission. Recent literature has assessed the effect of perioperative antibiotic regimens on the rate of postoperative infections but not yet yielded with significant changes in UTI rates. Our study focused on the effect of postoperative suppressive regimens on the rate of UTI following radical cystectomy with Enhanced Recovery After Surgery (ERAS) protocol. Methods: We retrospectively reviewed 427 patients who underwent RC with ERAS protocol between May 2012 and January 2017 at our institution. The ERAS protocol infection prevention measures included 24-hr perioperative antibiotic followed by suppressive antibiotic until removal of catheter/stents. A patient was found to have a UTI if they had a positive urine culture and documented symptoms, positive urine culture with treatment per practitioner discretion, or negative or unavailable urine culture but the clinical presumption of UTI that got treatment. Urosepsis was defined if any of UTI episodes were associated with positive blood culture. Patients’ characteristics, UTI events, and urine culture sensitivities were reviewed for analysis. Results: The incidence of UTI and urosepsis was 36.1% and 7.13% within 90-days following RC, respectively. The median time to the first UTI was 13 days (IQR 8−35). Candida (25.57%) and Escherichia coli (22.16%) were the most commonly identified pathogens. UTI and urosepsis were significantly lower in patients who received suppressive fluoroquinolones compared to other antibiotic regimens (32.72% vs. 45.24%, P = 0.04 for UTI and 5.25% vs. 11.90%, P = 0.04 for urosepsis). In multivariable analysis, orthotopic neobladder and perioperative transfusion were significantly associated with increased UTI rate (OR = 2.3 and 1.71, p < 0.05, respectively). Conclusions: UTI is common following RC and urinary diversion with ERAS protocol. The most common isolated pathogens are candida and Escherichia coli. Orthotopic neobladder and perioperative transfusion are independent risk factors for postoperative UTI. The use of suppressive fluoroquinolones is associated with a significant decrease in UTI rate. Ó 2019 Elsevier Inc. All rights reserved.

Keywords: Radical cystectomy; Urinary diversion; Enhanced recovery; Urinary tract infections

1. Introduction Radical cystectomy (RC) with urinary diversion is the treatment of choice for muscle-invasive bladder cancer as well as high-risk noninvasive tumors. It is a complex procedure associated with high morbidity and potential Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *Corresponding author. E-mail address: [email protected] (H. Djaladat). https://doi.org/10.1016/j.urolonc.2019.12.021 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.

mortality. Complications can arise from any organ system, though commonly include gastrointestinal, renal or electrolyte-related, and infectious [1]. Attempts have been made to improve pericystectomy recovery with the use of Enhanced Recovery After Surgery (ERAS) protocols. These protocols typically involve avoiding bowel preparations, early feeding and mobilization, and perioperative antibiotics; some institutions have used postoperative suppressive antibiotics, as well [2,3]. While these protocols have shown overall improved perioperative

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A. Ghoreifi et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−6

recovery, complication rates are still as high as 70% to 78%, especially infectious ones [1,3]. Urinary tract infection (UTI) is a common complication following RC, increasing morbidity and readmission rate [1−3]. Patients can present with general symptoms like fever, nausea, fatigue or more specific symptoms like dysuria, suprapubic or flank pain. These infections can be polymicrobial, suggesting that broad antimicrobial coverage is prudent to treat and/or prevent them [4]. Much of the work to prevent postoperative UTIs has focused on changing the perioperative antibiotic regimen; however, this has not shown a significant reduction in UTI rate [5,6]. Some data suggest that antimicrobial prophylaxis use at the time of ureteral stent removal in patients with urinary diversion may prevent subsequent febrile episodes [7]. Our study aimed to assess the effect of postoperative suppressive antibiotics on the rate of UTI following RC in the context of an established ERAS protocol.

complications or symptoms, and records for follow-up from outside clinics were regularly obtained. 2.3. Data analysis

Using our institutional review board-approved bladder cancer database, we retrospectively reviewed the records of patients who underwent open RC for primary urothelial carcinoma of the bladder with curative intent and ERAS protocol with 1 of 3 urologic oncologists at our institution between May 2012 and January 2017. Patients with metastatic disease as well as those undergoing palliative or salvage radical cystectomy were excluded.

The incidence of postoperative UTI and urosepsis within 90 days following RC were evaluated. UTI was defined as: positive urine culture (>105 CFU/mL) with documented symptom/sign (fever, leukocytosis or dysuria), positive urine culture with antibiotic treatment per practitioner discretion following evaluation; or negative/unavailable urine culture with documented symptoms or clinical suspicion of UTI that got treatment [9]. Incidental positive urine cultures without documented clinical suspicion or treatment were not included as UTIs. Patients with signs of systemic inflammatory response syndrome (SIRS) and simultaneous positive blood and urine cultures for the same organism(s) were classified as having urosepsis. For each patient, antibiotics administered during the 90day follow-up period were identified and classified by type of use (perioperative and postoperative suppressive). We recorded the etiologic pathogens and their sensitivity for each UTI episode. Clinical and pathologic variables including age, sex, body mass index (BMI), diabetes mellitus, smoking, clinical/pathologic stage, neo-adjuvant chemotherapy, Charlson Comorbidity Index (CCI), American Society of Anesthesiologists (ASA) score, transfusion, type of diversion, operation time and hospital stay were assessed for association with UTI risk. Statistical software analysis package SAS, Version 9.4 (SAS Institute Inc., Cary, NC) was applied to all analyses in this study.

2.2. Surgical procedure and follow-up

3. Results

Patients underwent open RC, pelvic lymph node dissection and urinary diversion with the same previouslydescribed technique [8]. All patients were offered orthotopic neobladder (ONB) as the primary diversion type unless absolute contraindications were present, such as positive urethral margins or significant renal insufficiency, or patient preferred an alternative diversion. All patients received 24-hour perioperative intravenous antibiotics. All patients underwent a previously-described ERAS protocol that includes no preoperative bowel preparation, early enteral feeding and ambulation, and use of mu-receptor antagonist [2]. Following 24-hour perioperative antibiotic, all patients were switched to suppressive antibiotics until outpatient removal of their ureteral stents. Patients were followed q3-6 months in the first 2 years, every 6 months in the following year, and annually thereafter. Follow-up included physical examination, serum chemistry studies, and radiographic surveillance, mainly via the chest, abdomen, and pelvis CT scan. The majority of patients were visited (or contacted, if not) prospectively throughout the 90-day period to inquire about recent

427 patients who underwent RC with ERAS protocol between May 2012 and January 2017 were included in the study. Among these patients, UTI was recorded in 152 (36.1%), out of which 30 (19.7%) had documented urosepsis. 88 patients (57.9%) had more than 1 episode of UTI and 68 (44.7%) readmitted due to UTI within 90-days following surgery. The median length of stay (LOS) was higher in UTI compared to non-UTI patients (5 vs. 4 days, P = 0.02). The median time to the first UTI and stent removal was 13 and 20 days, respectively. 21.8% of the UTIs were in-hospital (index hospitalization), 45.07% between discharge and stent removal and 33.1% after stent removal up to 90-days, postoperatively. The clinical and pathologic features of the patients are shown in Table 1. Perioperative antibiotics: 80% of patients received cephalosporin (second generation) and 20% received other antibiotics including clindamycin, gentamicin, metronidazole or combination therapy. There was no significant difference in terms of the incidence of UTI and urosepsis between these 2 groups (34.8% vs. 40.48%, P = 0.37 for UTI and 7.47% vs. 4.76%, P = 0.48 for urosepsis).

2. Material and methods 2.1. Patients

ARTICLE IN PRESS A. Ghoreifi et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−6 Table 1 Clinical and pathologic characteristics of patients. Variable

UTI/urosepsis (n = 152)

Sex, n (%) Male 123 (80.92%) Age (year) Mean (range) 70.5 (33−91) BMI (kg/m2) Median (range) 26.7 (17−26.8) ASA score, n (%) 1−2 26 (17.11%) 3−4 126 (82.89%) CCI, n (%) 0 55 (36.18%) 1 40 (26.32%) ≥2 57 (37.5%) Diabetes, n (%) 35 (23.03 %) Smoking, n (%) 106 (69.74%) NAChT, n (%) 56 (36.84%) Type of diversion, n (%) Orthotopic 99 (65.13%) Heterotopic 53 (34.87%) Transfusion, n (%) 67 (44.08%) Operation time (hour) Median (range) 5.5 (3−10.5) Hospital stay (day) Median (range) 5 (2−41) Pathologic stage, n (%) OC 95 (62.5%) EV 21 (13.82%) LN+ 36 (23.68%)

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Table 2 Multivariable logistic regression of risk factors for UTI.

No UTI/urosepsis (n = 269)

P value

95% CI

P value

0.79

0.46−1.38

0.41

0.51

0.31−0.85

0.01

1.15 2.30 1.71

0.46−2.97 1.44−3.77 1.10−2.67

0.55 0.01 0.02

0.69

0.81

CCD = continent cutaneous diversion; IC = ileal conduit; ONB = orthotopic neobladder.

212 (78.71%) 0.84 70 (34−92) 0.39 27.2 (13.7−26.8) 51 (18.96%) 218 (81.04%)

149 (55.39%) 120 (44.61%) 92 (34.2%)

Odds ratio

Perioperative antibiotics Cephalosporin vs. other regimens Suppressive antibiotics Fluoroquinolone vs. other regimens Type of diversion ONB vs. CCD ONB vs. IC Perioperative transfusion

0.71

104 (38.66%) 64 (23.79%) 101 (37.55%) 54 (20.07%) 196 (72.86%) 97 (36.06%)

Variable

0.53 0.50 0.92 0.06

0.04 0.15

5.2 (2.9−10.7) 0.02 4 (3−43) 0.35 159 (59.11) 52 (19.33%) 58 (21.56%)

ASA = American Society of Anesthesiologists; BMI = body mass index; CCI = Charlson Comorbidity Index; EV = extra-vesical; LN = lymph node positive; NAChT = neoadjuvant chemotherapy; OC = organ-confined.

Suppressive antibiotics: 79.41% of patients received fluoroquinolones as a suppressive antibiotic and 20.59% received other antibiotics including nitrofurantoin, sulfamethoxazole/trimethoprim, gentamicin or combination therapy. UTI and urosepsis were significantly lower in patients who received suppressive fluoroquinolones compared to other antibiotic regimens (32.72% vs. 45.24%, P = 0.04 for UTI and 5.25% vs. 11.90%, P = 0.04 for urosepsis). The mean number of UTI episodes was also lower in patients who received fluoroquinolones (0.8 vs. 1.1, P = 0.03 for UTI and 0.1 vs. 0.3, P = 0.03 for urosepsis). Table 2 shows the multivariable logistic regression analysis of possible UTI risk factors. Suppressive fluoroquinolones significantly decreased postoperative UTI incidence (OR = 0.51, CI 0.31−0.85, P = 0.01). Furthermore, perioperative blood transfusion and ONB were associated with UTI following RC (OR = 2.3 and 1.71, respectively). Reviewing available positive cultures in which 23.94% were multi-pathogen, the most common pathogens were candida species (25.57%) and E. coli (22.16%) (Fig. 1A). In 38% of cases, candida was found in combination with other known pathogens. Fig. 1B shows the sensitivity of the pathogens to different antibiotic groups. Among patients

with sepsis, again E. coli (40%) and candida species (20%) were the most common pathogens. 4. Discussion There is a lack of evidence regarding the effect of enhanced recovery after surgery (ERAS) protocols on UTI rates following RC including common pathogens and their antimicrobial sensitivities. This study reports a UTI rate of approximately 36% and the urosepsis rate of 7.13% within 90 days of surgery in a large cohort of RC patients with ERAS protocol. Candida species and Escherichia coli (E. coli) were the most commonly identified pathogens. Furthermore, we found that UTI and urosepsis were significantly lower in patients who received suppressive fluoroquinolones. Moreover, orthotopic neobladder (ONB) and perioperative transfusion were significantly associated with an increased UTI rate. The rate of UTI and urosepsis after RC has been reported between 9.5% to 39% and 12% to 36%, respectively [4,6,10−20]. Different factors may play a role in this wide range including heterogeneity of diversions, disparate antibiotic regimens and various definitions for UTI. The rate of UTI in our study was 36.1%, which is within the higher end of this range. The main reason for this high rate can be our broader definition of UTI compared to other studies; we included all patients who received antibiotic therapy for possible UTI, even if their urine culture was unavailable. However, there is no consistent definition of UTI and well-defined criteria to differentiate between infection and asymptomatic bacteriuria in this unique patient population [13]. Parker et al. defined UTI as the presence of symptoms in the setting of a urine culture ≥104 cfu. They reviewed 1,248 radical cystectomy patients and reported the 90-day postoperative UTI rate of 10% [4]. Using wider criteria, Wood et al. reported UTI rate of 39% following RC. They defined UTI as symptoms accompanied by a urine culture ≥104 cfu as well as the culture ≥105 cfu treated with antibiotics with or without symptoms [19]. A clear definition would help better identify patients with confirmed UTI and avoid unnecessary treatments.

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(A) Pathogens (%) 30 25 20 15 10 5 0

(B) Sensivity (%) 100 90 80 70 60 50 40 30 20 10 0

Fig. 1. (A) Frequency of common pathogens cultured from patients with UTI; (B) Percent sensitivity of postcystectomy UTI etiologies to various antibiotics.

The previous studies showed that enhanced recovery protocol decreased the LOS following RC from 9 to 11 to 4 days without increasing readmission rate. However, UTI remains the most common cause of ER visits and readmission even in ERAS era [1−3,10,11]. In our study, the 90day readmission rate was 44.7% and LOS was longer in UTI patients. Similar data from our institution on 1,133 non-ERAS cystectomy patients showed that 52% of UTI episodes led to readmission [13]. UTI increased LOS as well and this can be a challenge for both patients and healthcare providers in management of these patients. Median time to first UTI in our cohort was 13 days and most of the UTIs occurred before stent removal. This is similar to other studies which showed UTI is more common in the early postoperative course following RC [20,21]. Parker et al. also noted that 85% of their NB patients developed UTI while a catheter was still in place [4]. This may suggest possible role of foreign bodies (i.e., catheter and ureteral stents) in UTI development. In contrast, Abe et al. on their study on RC with ONB patients showed that UTI incidence may be associated with the time that patients start voiding training following stent removal [22]. Identification of clinical predictors may be helpful to prevent UTI after RC. In our study, perioperative blood transfusion was an independent risk factor for UTI (OR 1.71). However, other clinical factors including age, sex, BMI, CCI, ASA score, diabetes, smoking and neo-adjuvant chemotherapy were not associated with increased risk of UTI. Other studies have reported different results in this regard. In a large cohort of patients treated with RC at Mayo Clinic, Parker et al. found the development of a urine leak (OR 3.42), diabetes (OR 2.27) and perioperative blood transfusion (OR 1.58) to be associated with postoperative UTI [4]. In another study using the American College of Surgeons National Surgical Quality Improvement Project database, the same group found only operative time ≥ 480 min to be associated with the development of UTI after

surgery [14]. Other risk factors including CCI > 2 (OR 1.7) [13] increased BMI [15], female gender [19] and urethral stricture (OR 5.93) [20] has also been reported as potential risk factors to UTI. In contrast, Mano et al. in their study of NB patients found that age, gender, intermittent catheterization, diabetes, perioperative chemotherapy, and bowel segment used for reconstruction were not associated with UTI [18]. Prospective studies are needed to address these conflicting results. Diversion type has also been considered as a possible predictor of UTI in some studies. In our study, a higher rate of UTI was seen in ONB compared to ileal conduit (IC) (OR 2.3) and continent cutaneous diversion (CCD) (OR 1.15). This is in line with what reported by the Swedish National Patient Registery showing a higher rate of UTI in ONB and CCD compared to IC (OR 1.21 and 1.11, respectively) [17]. Parker et al. also reported a higher 90-day UTI rate in patients with continent diversion (OR 2.17) [4]. In a review of 90-day complications of patients who underwent robotic RC and extracorporeal urinary diversion at City of Hope Cancer Center, Indiana pouch was associated with increased likelihood of UTI compared to IC or ONB (OR 7.30) [25]. In contrast, some studies showed no significant difference among different diversion types [13,23,24]. The association of ONB and UTI in our study may be mostly due to the prolonged urinary catheterization in this group. These findings are important for patient counseling before surgery. Furthermore, it can be helpful to optimize prophylactic therapies [4,17]. Understanding common types of pathogens is important in choosing the best treatment protocol. In our study, Candida species and E. coli were the most cultured pathogens followed by Enterococcus, Staphylococcus, and Klebsiella. The same pathogens have been reported in 2 other studies [6,13]. Interestingly, we found Candida species in about 25% of the urine cultures. Fungal UTI shows an increasing trend in recent years, ranging from 10% to 24% [4,6,13].

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This requires special attention and maybe a reflection of extensive antibiotic usages. Pariser et al. reported a significant decrease in the rate of Candida infections after their prophylactic antibiotic change [6]. Different factors may contribute to the high rate of fungal UTI after RC. The most likely hypothesis is the inappropriate use of broadspectrum antibiotics for presumed UTI which may also result in the increasing rate of poly-microbial and drugresistant UTIs [4,6]. Furthermore, foreign bodies (i.e., urinary diversion stents) can play a significant role [4]. The effect of underlying diseases (e.g., diabetes) has also been studied but has yet to be confirmed [13]. There is no randomized clinical trial on the use of antimicrobial prophylaxis in urologic surgeries involving bowel. The guidelines’ recommendations are mainly based on the non-urologic (i.e., colorectal surgery) meta-analyses. The American Urological Association recommends the 2nd/3rd generation of cephalosporins or aminoglycosides plus metronidazole/clindamycin as the prophylactic antibiotic of choice after cystectomy. It also considers ampicillinsulbactam or fluoroquinolones as the alternatives [26]. The recommendation is to not extend prophylaxis beyond 24 hours after surgery except for special situations. However, a recent study showed that 4-week suppressive antibiotic following RC is associated with a significant decrease in 30-day postoperative UTIs and readmissions for urosepsis without an increase in MDR organism or Clostridium difficile infection [27]. As a result, further prospective studies/randomized clinical trials are necessary for a better understanding of the microbiology of UTIs after RC. Pariser et al. showed that change in perioperative antibiotic prophylaxis from cefoxitin to ampicillin-sulbactam, gentamicin, and fluconazole resulted in significant decreases in postoperative overall as well as fungal infections after RC. However, the UTI rate remained unchanged [6]. In our study, the cultured pathogens were more sensitive to aminoglycosides followed by cephalosporins, similar to a previous report from our center [13]. Furthermore, our study demonstrated that the use of fluoroquinolones as a suppressive antibiotic significantly decreased the UTI and urosepsis, postoperatively. In the multivariate analysis, the incidence of UTI decreased by 50% in patients who received suppressive fluoroquinolones. However, different “perioperative” antibiotic regimens did not affect the postoperative rate of UTI/urosepsis. Our results are in line with data of similar studies confirming the importance of individual hospital’s colonization and resistance patterns awareness to optimize antibiotic regimens. It also suggests a benefit to altering antimicrobial prophylaxis with broad coverage and the potential utility of antifungals. It is worth mentioning that in light of the recent safety concerns surrounding fluoroquinolones, the risk-benefit ratio should be considered before prescription of this class of antibiotics. Since we used a broad definition for UTI diagnosis in our study, we did a confirmatory sub-group analysis of patients

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who had symptomatic UTI with positive cultures (data not shown). 81 patients (18.97%) met these “confirmed UTI” criteria. The same trend was seen in the univariate analysis of this group data. On the multivariate analysis, again the use of suppressive fluoroquinolones was associated with about 50% decrease in postoperative UTI rate following RC (OR 0.45, P = 0.01). Furthermore, postoperative blood transfusion was also associated with an increased UTI rate (OR 2.55, P = 0.001). The strength of this study is to present a large number of patients with bladder cancer who underwent homogenous surgery by a limited number of expert urologic oncologists and received similar perioperative care. The main limitation of our study has though been its retrospective nature and the absence of a control group. The urine cultures of all patients were not available, especially for patients who were followed up in local facilities. Furthermore, antibiotic sensitivity was not available for most of the fungal positive cultures. Finally, our current study is single institution and the microbiologic etiologies and antimicrobial sensitivity patterns may not be generalized to other centers. 5. Conclusions UTI is a common complication and cause of readmission following radical cystectomy and urinary diversion with enhanced recovery protocol. Suppressive fluoroquinolones are independently associated with decreased whereas ONB and perioperative transfusion with increased 90-day postoperative UTI rate. Candida and E. coli are the most common pathogens. Etiologic sensitivity for E. coli was best with aminoglycosides. References [1] Djaladat H, Katebian B, Bazargani ST, et al. 90-Day complication rate in patients undergoing radical cystectomy with enhanced recovery protocol: A prospective cohort study. World J Urol 2017;35 (6):907–11. https://doi.org/10.1007/s00345-016-1950-z. [2] Daneshmand S, Ahmadi H, Schuckman AK, Mitra AP, Cai J, Miranda G, et al. Enhanced recovery protocol after radical cystectomy for bladder cancer. J Urol 2014;192(1):50–5. https://doi.org/ 10.1016/j.juro.2014.01.097. [3] Altobelli E, Buscarini M, Gill HS, Skinner EC. Readmission rate and causes at 90-day after radical cystectomy in patients on early recovery after surgery protocol. Bladder Cancer 2017;3(1):51–6. https:// doi.org/10.3233/BLC-160061. [4] Parker WP, Toussi A, Tollefson MK, Frank I, Thompson RH, Zaid HB, et al. Risk factors and microbial distribution of urinary tract infections following radical cystectomy. Urology 2016;94:96–101. https://doi.org/10.1016/j.urology.2016.03.049. [5] Krasnow RE, Mossanen M, Koo S, Kubiak DW, Preston MA, Chung BI, et al. Prophylactic antibiotics and postoperative complications of radical cystectomy: A population based analysis in the United States. J Urol 2017;198(2):297–304. https://doi.org/ 10.1016/j.juro.2017.02.3340. [6] Pariser JJ, Anderson BB, Pearce SM, Han Z, Rodriguez JA 3rd, Landon E, et al. The effect of broader, directed antimicrobial prophylaxis including fungal coverage on perioperative infectious

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