Clostridioidesdifficile is a Gram-positive anaerobic organism typically found as part of normal gut flora. Colonization with C. difficile is usually asymptomatic; however, an alteration in the intestinal microbiome and resulting overgrowth can result in C. difficile infection (CDI). While antibiotic exposure is the most common culprit for CDI, gastrointestinal surgery is also a well-described risk factor.[2,3] CDI is the second most common health-care-acquired infection (HAI) and the most common gastrointestinal HAI, with an estimated 365,200 cases reported by the CDC in 2017. While the incidence of CDI has seen a steady decline since 2011, it continues to remain a major cause of inpatient admission and utilization of health-care resources.
The exact incidence of periprocedural CDI with cystectomy is unknown, and the reported incidence of CDI in the literature varies widely.[6,7] Furthermore, nationwide database studies investigating CDI in cystectomy are lacking. One study utilizing the Nationwide Inpatient Sample (NIS) reported an incidence of 1.4%; however, due to a lack of follow-up data, this number is likely underreported. Given the significant impact of CDI on patients undergoing cystectomy, it is imperative to determine the true incidence of CDI in this patient population, as well as risk factors and outcomes.
We conducted an analysis of patients undergoing cystectomy using the ACS National Surgical Quality Improvement Program (NSQIP) to study the incidence, risk factors, and postsurgical outcomes associated with CDI following cystectomy. Developed by the American College of Surgery, this is a nationally validated, risk-adjusted, outcomes-based program designed to determine and improve the quality of surgical and postsurgical care.
The objective of the study was to determine the true incidence, risk factors, and outcomes of CDI in patients after cystectomy.
We conducted a retrospective study utilizing data from the NSQIP database. The NSQIP database includes perioperative variables from more than 500 institutions in the United States and is collected and maintained by trained surgical reviewers. Variables are included up to day 30 of admission, along with 30-day postdischarge readmission data. All reported cases are anonymous and de-identified.
CDI was included as a variable in the database for the years 2015, 2016, and 2017 only. Data from NSQIP from these 3 years were thus included in our study.
We included all adult patients from NSQIP in our study if: (a) they underwent a complete or partial cystectomy; as defined by the Current Procedural Terminology codes 51550, 51570, 51580, 51555, 51565, 51590, 51575, 51596, 51585, 51595, and 51597a, and (b) had data available for the postoperative CDI variable. As the variable was added in the latter half of 2015 in the database, some patients from 2015 have missing data for this variable; however, the risk of bias resulting from this is negligible as no specific subpopulation is at risk for missing data.
For all patients included in our study, patient age at the time of surgery, gender, race, body mass index (BMI), smoking status, preoperative comorbidities, hematocrit, albumin, creatinine, white blood cell count, source of admission, type of procedure (partial vs. radical cystectomy), American Society of Anesthesiologists classification, days from admission to procedure, and duration of procedure were included.
The incidence of CDI was the primary endpoint of the study. Secondary outcomes included independent predictors of CDI deduced by multivariable logistic regression analysis and the effect of CDI development on length of stay, readmission, and mortality.
Postoperative CDI data were included up to the 30th postoperative day in the NSQIP database. NSQIP notes the postoperative day of development of each complication. CDI was divided into predischarge and postdischarge categories by comparing the day of development of infection with the length of stay.
All statistical analyses were conducted using SPSS statistical software v. 23 (IBM, Armonk, New York, United States). Multivariable logistic regression analyses were conducted to assess independent associations. The final covariates were selected using backward stepwise logistic regression analyses; all variables noted in Table 1 were initially entered into the model, and the variables with the least significant association with CDI were successively eliminated to arrive at the final model. These final variables included in the model had significant independent associations with CDI.
Albumin was the only variable included in our analysis that had more than 10% missing values. The patients with missing albumin values were treated using the missing indicator method as described in previous studies on NSQIP database.[11,12] This approach to account for missing values has been supported over alternative approaches to account and adjust for missing values in this database by a study on missing data in NSQIP.
Finally, a multivariable linear regression model was applied to assess the length of stay between patients who developed postoperative CDI during index hospitalization and those who did not. Multivariable logistic regression analysis incorporating the same covariates was also conducted for 30-day mortality, unplanned readmission, and pulmonary embolism, to assess the impact of CDI on these outcomes.
Two-sided significance level of 0.05 was set for all analyses conducted for the purposes of this study.
A total of 7422 patients underwent cystectomy procedures during the period studied. Of these patients, 1185 patients were excluded due to missing data on CDI. Among the included patients, 489 (7.8%) patients underwent partial cystectomies with or without ureteral reimplantation, while 5748 patients (92.2%) underwent radical cystectomies with or without conduit or lymphadenectomy performed.
The mean age of participants was 67.45 years (standard deviation [SD]: 11.43), and 20.7% % of participants (1291 patients) were female. The mean BMI of the population was 28.68 (SD: 6.01), and 22% % of participants had a history of smoking within 1 year before the procedure.
Incidence of Clostridioides difficile infection
A total of 223 were diagnosed with CDI during the 30-day postsurgical period, which translated into an incidence of 3.6%. Of the patients with CDI, 42 patients (18.8%) developed infections after discharge from the hospital.
Predictors of Clostridioides difficile infection
Multivariable logistic regression was applied to deduce independent associations of preoperative, procedural, and postoperative factors with the development of CDI. Among preoperative factors, preoperative anemia (odds ratio [OR]: 1.397 and confidence interval [CI]: 1.021–1.912) and male gender (OR: 1.8 and CI: 1.282–2.528) were associated with the development of CDI. Table 2 shows the preoperative and procedure-related risk factors for CDI.
After adjusting for all factors mentioned above, among operative factors, nonelective nature of surgery was significantly associated with increased risk of CDI (OR: 2.56 and CI: 1.020–6.399). Complete cystectomy was associated with an increased risk of CDI when compared to partial cystectomy procedures (OR: 3.54 and CI: 1.212–10.322).
After adjusting for preoperative and procedure-related factors, postoperative organ space infections (OR: 1.95 and CI: 1.269–3.003), postoperative renal failure (OR: 2.38 and CI: 1.020–5571), postoperative sepsis (OR: 2.49 and CI: 1.621–3.828), and septic shock (OR 2.33 and CI 1.176–4.619) were independently associated with the development of CDI (all P < 0.05).
Among patients who developed CDI, 108 patients (48.4%) had preceding postoperative infections. The preceding infections included surgical site infections in 65 patients, pneumonia in 18 patients, and urinary tract infection in 25 patients, with 44 and 21 patients being diagnosed with sepsis and sepsis shock, respectively. Surgical site infections included superficial infections in 20 patients, deep incisional infections in 3 patients, and organ space infections in 42 patients.
Effect of postoperative Clostridioides difficile infection on patient outcomes
Patients who developed postoperative CDI during hospitalization had lengthier hospital admissions than those who did not develop a CDI after adjusting for preoperative, procedure-related, and postoperative factors (OR: 2.29 and CI: 1.780–2.938). Patients with CDI were more likely to be diagnosed with deep vein thromboses (OR: 2.48 and CI: 1.351–4.565).
There was no difference in the risk of 30-day mortality between patients who developed CDI and patients who did not. Development of CDI after hospital discharge was significantly associated with the risk of unplanned readmission (OR: 7.8; 95% CI: 3.4–17.9).
CDI is primarily nosocomial in nature, associated with increased morbidity in surgical practice and considered an important hospital quality and reimbursement metric. It is previously known that although most urological procedures carry an inherently low risk of CDI, cystectomy procedures are associated with higher CDI rates. The data on CDI after cystectomy are primarily derived from small single-center studies that reported rates as high as 7%–8.8%. Large studies estimating CDI incidence and its predictors after cystectomy are lacking, and the only previous study available that estimated a rate of 1.4% was based on the NIS, a dataset that does not contain follow up data after discharge. Contrary to their estimation, we found an incidence rate of 3.6%. This is likely due to the fact that the more appropriate use of NSQIP database allowed us to include 30-day follow-up data, including data after discharge, and thus more accurately captured CDI that developed in the postoperative setting, especially cases that would have been missed in a study utilizing inpatient data alone. Given that most cases of CDI are reported within 1 month of alteration of gut flora, we believe that the 30-day follow-up interval used in our study is most appropriate. Our findings reaffirm the high rate of CDI in patients undergoing cystectomy and provide further insight into the incidence, risk factors, and outcomes of CDI following cystectomy.
It is worth discussing the role of antibiotics in the prevention of postoperative wound infections, as well as their impact on postoperative CDI. Antimicrobial prophylaxis is recommended by both the American Urological Association and the European Association of Urology for perioperative use in patients undergoing cystectomy and is routinely used in these patients.[18,19] In addition, when preparing patients for surgery, mechanical, antibiotic, or both kinds of bowel preparation are also employed. The effect of these antibiotic bowel preparations on CDI incidence is not yet clear, with studies showing conflicting results for noncolon surgery patients. In comparison, for patients undergoing colorectal surgery, some studies have found an increased risk of CDI with antibiotic bowel preparation. Interestingly, one previous retrospective study noted fewer cases of CDI after cystectomy if no bowel preparation was used in comparison to the use of mechanical bowel prep (2 vs. 11, P = 0.08). One limitation of our study is the inability to determine a difference between CDI rates based on the type of surgical preparation utilized. While NSQIP reports bowel preparation data for colorectal surgery, such data for urological interventions are not available at present. Additional studies are needed to further identify the role of bowel preparation in patients undergoing cystectomy.
This is the first study utilizing NSQIP to study the incidence, risk factors, and outcomes of CDI in a urological procedure. We found that preoperative anemia and male gender were associated with CDI. Anemia has been associated with CDI in the past.[22,23] Similarly, male patients have been found to be at increased risk of CDI in studies on other postsurgical populations. Postoperative infections have also been previously studied as risk factors for CDI in the postoperative setting. Based on our data, it appears that CDIs after cystectomy continue to remain a concern, and are associated with an increase in length of stay as well as a higher risk of readmissions. Therefore, it is imperative that quality improvement initiatives and interventions for reducing this burden continue to be tested and employed.
The main strength of our study is the high representative number of patients included in the study population, as well as the 30-day postoperative period of data accrual. One limitation to our study is the lack of bowel preparation data, as mentioned above. Second, we were not able to report the effect of CDI on inpatient cost. This is an important determinant of health-care resource use, as one previous study noted that over a 7-year period, $8.3 million in excess costs related to patients undergoing cystectomy could be attributed to postoperative CDI.
A sizable number of patients experience CDIs after cystectomy procedures in the USA, and CDI development is associated with an increase in length of stay and unplanned readmissions. Interventions and initiatives are needed to reduce this burden of disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al. Clinical practice guidelines for Clostridium difficile
infection in adults:2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431–55.
2. Wiström J, Norrby SR, Myhre EB, Eriksson S, Granström G, Lagergren L, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients:A prospective study. J Antimicrob Chemother 2001; 47:43–50.
3. Loo VG, Bourgault AM, Poirier L, Lamothe F, Michaud S, Turgeon N, et al. Host and pathogen factors for Clostridium difficile
infection and colonization. N Engl J Med 2011; 365:1693–703.
4. Control, C.f.D. and Prevention, Current HAI Progress Report: 2017 National and State Healthcare-Associated Infections Progress Report 2018.
5. Zhang D, Prabhu VS, Marcella SW Attributable healthcare resource utilization and costs for patients with primary and recurrent Clostridium difficile
infection in the United States. Clin Infect Dis 2018; 66:1326–32.
6. Miller R, Heinlen JE Reported rates of Clostridium difficile
following radical cystectomy in national datasets compared to individual institutions. Urol Oncol 2018; 36:526.e7–526.e11.
7. Liu NW, Shatagopam K, Monn MF, Kaimakliotis HZ, Cary C, Boris RS, et al. Risk for Clostridium difficile
infection after radical cystectomy for bladder cancer:Analysis of a contemporary series. Urol Oncol 2015; 33:22 e17-22.
8. Zhang S, Palazuelos-Munoz S, Balsells EM, Nair H, Chit A, Kyaw MH Cost of hospital management of Clostridium difficile
infection in United States –A meta-analysis and modelling study. BMC Infect Dis 2016; 16:447.
9. Skarsgard ED, Bedford J, Chan T, Whyte S, Afshar K ACS national surgical quality improvement program:Targeting quality improvement in Canadian pediatric surgery. J Pediatr Surg 2014; 49:682–7.
11. Greenblatt DY, Rajamanickam V, Mell MW Predictors of surgical site infection after open lower extremity revascularization. J Vasc Surg 2011; 54:433–9.
12. Bovonratwet P, Bohl DD, Russo GS, Ondeck NT, Nam D, Della Valle CJ, et al. How common-and how serious- is Clostridium difficile
colitis after geriatric hip fracture?Findings from the NSQIP dataset. Clin Orthop Relat Res 2018; 476:453–62.
13. Hamilton BH, Ko CY, Richards K, Hall BL Missing data in the American College of Surgeons National Surgical Quality Improvement Program are not missing at random:Implications and potential impact on quality assessments. J Am Coll Surg 2010; 210:125–39 e2.
14. Anderson PA, Bernatz J, Safdar N Clostridium difficile
infection:An orthopaedic surgeon's guide to epidemiology, management, and prevention. J Am Acad Orthop Surg 2017; 25:214–23.
15. Kim SP, Shah ND, Karnes RJ, Weight CJ, Frank I, Moriarty JP, et al. The implications of hospital acquired adverse events on mortality, length of stay and costs for patients undergoing radical cystectomy for bladder cancer. J Urol 2012; 187:2011–7.
16. Large MC, Kiriluk KJ, DeCastro GJ, Patel AR, Prasad S, Jayram G, et al. The impact of mechanical bowel preparation on postoperative complications for patients undergoing cystectomy and urinary diversion. J Urol 2012; 188:1801–5.
17. Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ Time interval of increased risk for Clostridium difficile
infection after exposure to antibiotics. J Antimicrob Chemother 2012; 67:742–8.
18. Wolf JS Jr, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, et al. Best practice policy statement on urologic surgery antimicrobial prophylaxis. J Urol 2008; 179:1379–90.
19. Grabe M, et al. Guidelines on Urological Infections NL-6803 AA ARNHEM, The Netherlands European Association of Urology 2015 182.
20. Heinlen JE, Salinas L, Cookson MS Clostridium difficile
infection in contemporary urologic practice. Urology 2018; 111:23–7.
21. Wren SM, Ahmed N, Jamal A, Safadi BY Preoperative oral antibiotics in colorectal surgery increase the rate of Clostridium difficile
colitis. Arch Surg 2005; 140:752–6.
22. Redelings MD, Sorvillo F, Mascola L Increase in Clostridium difficile
-related mortality rates, United States, 1999-2004. Emerg Infect Dis 2007; 13:1417–9.
23. Othman F, Crooks CJ, Card TR The risk of Clostridium difficile
infection in patients with pernicious anaemia:A retrospective cohort study using primary care database. United European Gastroenterol J 2017; 5:959–66.
24. Vaishnavi C, Gupta PK, Sharma M, Kochhar R Pancreatic disease patients are at higher risk for Clostridium difficile
infection compared to those with other co-morbidities. Gut Pathog 2019; 11:17.