|Year : 2022 | Volume
| Issue : 1 | Page : 15-20
Minimally invasive approach in appendectomy and cholecystectomy reduces risk for early but not late-onset Clostridioides difficile infection
Hugo Bonatti1, Tjasa Hranjec2, Robert G Sawyer3, Karim W Sadik4
1 Department of Surgery, University of Virginia Health Systems, Charlottesville, VA; Meritus Health, Meritus Surgical Specialists, Hagerstown, MD, USA
2 Department of Surgery, University of Virginia Health Systems, Charlottesville, VA; Division of Transplantation, Department of Surgery, Milton S. Hershey Medical Center, Hershey PA, USA
3 Department of Surgery, University of Virginia Health Systems, Charlottesville, VA; Department of Surgery, Western Michigan University School of Medicine, Kalamazoo, MI, USA
4 Department of Surgery, Division of Reconstructive Surgery, Guthrie Clinic, Sayre, PA, USA
|Date of Submission||20-Feb-2022|
|Date of Decision||10-May-2022|
|Date of Acceptance||11-May-2022|
|Date of Web Publication||17-Jun-2022|
Meritus Health, Meritus Surgical Specialists, Hagerstown, MD 21742
Source of Support: None, Conflict of Interest: None
Introduction: Clostridioides difficile-associated colitis (CDAC) may develop even after minor abdominal surgeries such as appendectomy and cholecystectomy. Minimally invasive techniques may reduce rates of postoperative CDAC due to less surgical trauma, shorter hospitalizations, and a lower incidence of certain complications.
Patients and Methods: This retrospective cohort study includes a total of 10,601 patients undergoing appendectomy (2529 laparoscopic and 2049 open) and cholecystectomy (3541 laparoscopic and 2482 open) at a single center between 1992 and 2011, who were diagnosed with CDAC and were followed for a minimum of 2 years.
Results: Cumulative CDAC rates were 2.3% after appendectomy and 4% after cholecystectomy (P < 0.0001) with 2.1% for all laparoscopic and 4.8% for all open procedures (P < 0.0001). The median time to CDAC onset was 76d after appendectomy and 122d after cholecystectomy (P < 0.05). Factors associated with the development of CDAC were older age (median 52 vs. 38 years, P < 0.0001), length of stay (median 8 vs. 2 days, P < 0.0001), development of non-C. difficile infections (23% vs. 7%, P < 0.0001), and having an open procedure (4.8% vs. 2.1%, P < 0.0001). Almost 40% of all patients developed their CDAC after 1 year and age, length of stay, and development of non-C. difficile infections or open surgical approach were not found to be risk factors.
Conclusion: Patients undergoing open appendectomy and cholecystectomy have a higher risk for early-onset CDAC when compared to their laparoscopic counterparts. Late-onset CDAC after these procedures is common and seems unrelated to perioperative factors.
Keywords: Appendectomy, cholecystectomy, Clostridioides difficile, laparoscopy
|How to cite this article:|
Bonatti H, Hranjec T, Sawyer RG, Sadik KW. Minimally invasive approach in appendectomy and cholecystectomy reduces risk for early but not late-onset Clostridioides difficile infection. World J Surg Infect 2022;1:15-20
|How to cite this URL:|
Bonatti H, Hranjec T, Sawyer RG, Sadik KW. Minimally invasive approach in appendectomy and cholecystectomy reduces risk for early but not late-onset Clostridioides difficile infection. World J Surg Infect [serial online] 2022 [cited 2022 Aug 8];1:15-20. Available from: https://www.worldsurginfect.com/text.asp?2022/1/1/15/347767
| Introduction|| |
Clostridioides difficile-associated colitis (CDAC) is mainly associated with exposure to antibiotic treatment causing alterations in the natural gut microbiome. Rates of CDAC after minor surgeries such as appendectomy and cholecystectomy are low and depend on multiple factors such as patient demographics and underlying comorbid conditions, surgical approach, and postoperative complications, especially infections among others., CDAC is associated with slower postoperative recovery and increases the length of hospitalization and costs.
The majority of appendectomies and cholecystectomies in industrialized countries are done using a minimally invasive approach,,, which seems to reduce the incidence of postoperative CDAC due to shorter hospitalization, less surgical trauma, and lower rates of infectious complications. Whereas for several reasons, the appendectomy rates are decreasing, the epidemic of obesity has caused an increase in patients with symptomatic cholelithiasis requiring cholecystectomy.,,
During hospitalization, patients may become colonized with C. difficile, increasing the risk for late-onset CDAC when exposed to antibiotics; however, removal of the appendix or gallbladder may have a lasting impact on the risk for subsequent CDAC,, by changing the composition of gastrointestinal contents, especially bile, and the individual microbiome.,, Appendectomy has been associated with a more severe course of CDAC. CDAC may involve the appendix and has been isolated in cases of emphysematous cholecystitis from bile and pyogenic liver abscess in a patient with acute cholecystitis.,, As C. difficile may be a primary pathogen, appendectomy and cholecystectomy may increase the risk for this enteric disease even without antibiotic exposure.,,
The aim of this study was to compare the pattern of CDAC in patients who underwent laparoscopic and open appendectomy and cholecystectomy.,,,
| Patients and Methods|| |
This is retrospective cohort study from a large academic teaching hospital including all patients who underwent open and laparoscopic appendectomy (ICD: 44950, 44955, 44960, 44970, 47.0, 47.01, 47.1, 47.11, 47.19, 49315, 56315, A44950, A44955, A44960, A49315, and A56315) and open and laparoscopic cholecystectomy (ICD-9 code: 51.2, 51.21, 51.22, 51.23, 51.24, 54.21, and 64.41) between 1992 and 2011 who were diagnosed with CDAC (ICD: 008.45).
Patients received perioperative prophylaxis using various agents and protocols. For elective cholecystectomy, the preferred antibiotic was cefazolin intravenous single shot 2 g. Patients with acute cholecystitis were started on ampicillin/sulbactam (3 g q 8 h) or piperacillin/tazobactam (3.75 g q 8 h) and were operated on within 24–48 h. Patients with acute appendicitis were started on antibiotics in the emergency room (cefoxitin 2 g q8 h and ampicillin/sulbactam 3 g q 8 h) and were operated on according to operative room availability. In children, antibiotics were dosed based on weight, in patients allergic to penicillin, aminoglycosides, or fluoroquinolones were given and combined with clindamycin or metronidazole.
Surgical site infections and other infections were tracked using National Surgical Quality Improvement Program (NSQIP) since 1993, and implemented Surgical Care Improvement Project (SCIP) guidelines for perioperative antimicrobial use and other measures in 2006.
Diagnosis of C. difficile infection was based on ELISA testing for toxin in stool samples., No routine screening testing for C. difficile carriage was done at any time during the study period. Only positive tests were considered and patients with negative tests and those who were not tested were considered as a negative control.
Demographic, microbiological, and clinical data were retrieved from paper and electronic medical records and entered into an Excel database in a de-identified fashion. The institutional billing and operative databases were used to identify all appendectomies and cholecystectomies and cases of C. difficile infections were identified within the microbiology database. A large database created by the surgical infection group was used to confirm cases and non-C. difficile infections and additional demographic and clinical data were retrieved from this set. The open versus minimally invasive approach was identified from the operative database. The study was approved by the institutional review board (IRB). The minimal follow-up time for the study was 2 years.
Patients with CDAC 30 days before their operation were excluded as well as all immunocompromised individuals (transplant recipients, patients on steroids, HIV-positive individuals, etc.) and patients receiving anti-tumor necrosis factor agents.
Continuous variables are presented as a mean ± standard deviation and/or median with range and compared using the analysis of variance and/or nonparametric Kruskal–Wallis test. Categorical variables are displayed as percent of the parameter and were analyzed using a Chi-square or Fisher's exact test. Analyses were performed using SPSS Statistics for Windows, version 18.0 (SPSS Inc., Chicago, Ill, USA.
For the purpose of the study, patients were divided into four groups (laparoscopic appendectomy (Group 1), open appendectomy (Group 2), laparoscopic cholecystectomy (Group 3), and open cholecystectomy (Group 4). We were unable to distinguish between patients with planned open surgeries and those who had a conversion from laparoscopic to open – the latter being allocated into the open groups.
| Results|| |
Demographics [Table 1]
There were 4578 patients in the appendectomy and 6023 patients in the cholecystectomy group (P < 0.0001). Appendectomy patients had a median age of 23 (range 0.5–89) years and cholecystectomy patients 48 (range 0.5–89) years. A male–female ratio was 46% versus 54% in the appendectomy and 34% versus 66% in the cholecystectomy group (P < 0.0001). In total 59% of cholecystectomy and 55% of appendectomy, cases were performed laparoscopically. The final study groups included 2529 laparoscopic, 2049 open appendectomies, 3541 laparoscopic, and 2482 open cholecystectomies. [Figure 1] displays the four groups according to the study timeline; [Figure 2] shows the decline in open and increase in laparoscopic appendectomies during the study period.
|Figure 1: Boxplot showing the onset of CDAC according to the four groups. CDAC: Clostridioides difficile-associated colitis|
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|Figure 2: Histogram displaying timeline of laparoscopic and open appendectomy|
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Hospital stay was median 2 days after appendectomy and 3 days after cholecystectomy patients (P = 0.006) and was significantly shorter for those undergoing laparoscopic surgery [Table 1].
Presurgical non-C. difficile infection rates including urinary tract infections (UTIs), pneumonias, and wound infections were 1% for the appendectomy group and 2% for the cholecystectomy group. Postsurgical non-C. difficile infection rates were 6% for the appendectomy and 9% for the cholecystectomy group, respectively. These infections were significantly more common in the open versus the laparoscopic groups (14% vs. 3%, P < 0.0001). Comparing open and laparoscopic procedures, rates of pneumonia were 4% versus 1% (P < 0.0001), rates of SSI were 5% versus 1% (P < 0.0001), and rates of UTI were 7% versus 2% (P < 0.0001). Patients with postoperative non-C. difficile infection were significantly older (median 51 vs. 37 years) and had longer LOS (median 12 vs. 2 days).
Clostridioides difficile associated colitis [Table 2]
|Table 2: Demographic and clinical data according to the presence of Clostridioides difficile-associated colitis|
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In total 345 patients were diagnosed with postoperative CDAC. The cumulative incidence of postoperative CDAC was 4.0% in the cholecystectomy group and 2.3% in the appendectomy group. The median time to CDAC was 76 days in the appendectomy group and 122 days in the cholecystectomy group. More than one-third of CDAC cases were diagnosed beyond 1 year after surgery both in the appendectomy and cholecystectomy groups. Patients with CDAC had a higher infection rate than those without CDAC (23% vs. 7%, P < 0.0001). Comparing patients with CDAC to those without CDAC, rates of pneumonia were 12% versus 2% (P < 0.0001), rates of SSI were 6% versus 3% (P < 0.002), and rates of UTI were 13% versus 4% (P < 0.0001). The increased rates of non-C. difficile infections and longer hospitalization were most pronounce in patients with CDAC onset within 1 year of surgery [Table 2].
Early CDAC recurrence rates were 4.3% after appendectomy and 1.2% after cholecystectomy (P = 0.06).
| Discussion|| |
The incidence of early postoperative CDAC following appendectomy and cholecystectomy in our cohort was approximately 3%, which is comparable to other studies., Most cases were observed during the immediate postoperative period; however, more than one-third of CDAC cases were diagnosed beyond 1 year after surgery but age, length of stay, and development of non-C. difficile infections or open surgical approach were not found to be risk factors.
Risk factors for CDAC are well-described and prolonged antibiotic exposure, use of proton-pump inhibitors and poor hospital hygiene are among the modifiable factors., However, changing demographics such as an increase in elderly surgical patients carrying significant comorbidities may be underestimated contributors. Indeed we found that CDAC patients were older and contributing factors were open surgery, increased length of stay, and secondary infections, which are associated with antibiotic exposure. These factors affected early-onset CDAC and not late-onset CDAC. Little data addressing the anatomical and functional changes following appendectomy and cholecystectomy that may contribute to the risk for late-onset CDAC are available.,,,,,
Our study has multiple limitations. This is a single-center study and only a historical surgical cohort was available; however, we aimed to include early cases of laparoscopic surgery and see how acceptance of this approach may impact the rates of CDAC after the two procedures. In addition, a significant number of patients may have been lost to follow up and there may be coding issues. False-positive and-negative test results need to be considered as a diagnosis was based on ELISA but adding later cohorts when newer more accurate tests were used would have added volatility to the dataset and was limited due to the IRB protocol. We have considered that the emergence of a hypervirulent C. difficile strain may have changed the pattern of CDAC; however, the annual number of CDAC cases was stable during the study period. All these limiting factors should have affected the four groups in a similar fashion.
Changes in patient care during the study period affected the appendectomy group more than the cholecystectomy group. Laparoscopic cholecystectomy became standard earlier than laparoscopic appendectomy. More accurate diagnosis of appendicitis based on computed tomography (CT) scan (and/or ultrasound in selected patients) instead of clinical and laboratory parameters after a publication by Rao et al. has reduced negative appendectomy rates and led to the acceptance of nonoperative management of perforated appendicitis with antibiotics and percutaneous abscess drainage. CT scan is also the foundation of nonoperative management of early uncomplicated appendicitis. These recent developments in the management of appendicitis took mainly place after the study period. Thus far, no clear data on the rate of CDAC in patients treated with antimicrobial agents for acute appendicitis are available.
Little data addressing the anatomical and functional changes following appendectomy and cholecystectomy that may contribute to the risk for late onset CDAC are available.,,,,, Finding a model to study such an impact is difficult as large numbers of patients with a long follow up are needed. Franko et al and Wang et al were not able to show that patients with CDAC had high rates of appendectomy or cholecystectomy. We tried to ask the question if large cohorts of patients after appendectomy and cholecystectomy may be at increased risk for CDAC long-term but also this approach has many limitations as outlined above and we were not able to gather conclusive data.
Our data suggest that a laparoscopic approach for appendectomy and cholecystectomy may reduce the risk for early CDAC. Multiple factors seem to play a role and certainly the greater stress response with an open operation affecting the microbiome is involved as this indirectly should increase the pathogenicity of C. difficile. It should be noted that our data cannot be translated to the rural setting or developing countries, where a higher proportion of appendectomies and cholecytectomies are done in an open fashion.
| Conclusion|| |
Our data suggest that a laparoscopic approach for appendectomy and cholecystectomy may reduce the risk for early CDAC. Late-onset CDAC is common but independent from operative risk factors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Guh AY, Kutty PK. Clostridioides difficile
Infection. Ann Intern Med 2018;169:C49-64.
Baxter R, Ray GT, Fireman BH. Case-control study of antibiotic use and subsequent clostridium difficile-associated diarrhea in hospitalized patients. Infect Control Hosp Epidemiol 2008;29:44-50.
Theriot CM, Young VB. Interactions between the gastrointestinal microbiome and clostridium difficile. Annu Rev Microbiol 2015;69:445-61.
Zerey M, Paton BL, Lincourt AE, Gersin KS, Kercher KW, Heniford BT. The burden of Clostridium difficile in surgical patients in the United States. Surg Infect (Larchmt) 2007;8:557-66.
Metzger R, Swenson BR, Bonatti H, Hedrick TL, Hranjec T, Popovsky KA, et al.
Identification of risk factors for the development of clostridium difficile-associated diarrhea following treatment of polymicrobial surgical infections. Ann Surg 2010;251:722-7.
Ferris M, Quan S, Kaplan BS, Molodecky N, Ball CG, Chernoff GW, et al.
The global incidence of appendicitis: A systematic review of population-based studies. Ann Surg 2017;266:237-41.
Sirinek KR, Willis R, Schwesinger WH. Who will be able to perform open biliary surgery in 2025? J Am Coll Surg 2016;223:110-5.
Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: Cholelithiasis and cancer. Gut Liver 2012;6:172-87.
Jaschinski T, Mosch CG, Eikermann M, Neugebauer EA, Sauerland S. Laparoscopic versus open surgery for suspected appendicitis. Cochrane Database Syst Rev 2018;11:CD001546.
Sanders NL, Bollinger RR, Lee R, Thomas S, Parker W. Appendectomy and Clostridium difficile colitis: Relationships revealed by clinical observations and immunology. World J Gastroenterol 2013;19:5607-14.
Seretis C, Seretis F, Goonetilleke K. Appendicectomy and clostridium difficile infection: Is there a link? J Clin Med Res 2014;6:239-41.
Wang Y, Li J, Zachariah P, Abrams J, Freedberg DE. Relationship between remote cholecystectomy and incident Clostridioides difficile
infection. Clin Microbiol Infect 2019;25:994-9.
Sorg JA, Sonenshein AL. Chenodeoxycholate is an inhibitor of clostridium difficile spore germination. J Bacteriol 2009;191:1115-7.
Fehervari Z. What is the point of the gallbladder? Nat Immunol 2017;18:1189.
Randal Bollinger R, Barbas AS, Bush EL, Lin SS, Parker W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J Theor Biol 2007;249:826-31.
Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: From the natural environment to infectious diseases. Nat Rev Microbiol 2004;2:95-108.
Joshi T, Elderd BD, Abbott KC. No appendix necessary: Fecal transplants and antibiotics can resolve clostridium difficile infection. J Theor Biol 2018;442:139-48.
Clanton J, Subichin M, Drolshagen K, Daley T, Firstenberg MS. Fulminant clostridium difficile infection: An association with prior appendectomy? World J Gastrointest Surg 2013;5:233-8.
Brown TA, Rajappannair L, Dalton AB, Bandi R, Myers JP, Kefalas CH. Acute appendicitis in the setting of clostridium difficile colitis: Case report and review of the literature. Clin Gastroenterol Hepatol 2007;5:969-71.
Ulger Toprak N, Balkose G, Durak D, Dulundu E, Demirbaş T, Yegen C, et al.
Clostridium difficile: A rare cause of pyogenic liver abscess. Anaerobe 2016;42:108-10.
Papavramidis TS, Michalopoulos A, Papadopoulos VN, Paramythiotis D, Karadimou V, Kokkinakis H, et al.
Emphysematous cholecystitis: A case report. Cases J 2008;1:73.
Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Sferra TJ, et al.
Community-associated clostridium difficile infection and antibiotics: A meta-analysis. J Antimicrob Chemother 2013;68:1951-61.
Franko J, Ferrel B, Pierson P, Raman S, Frankova D, Rearigh LM, et al.
Influence of prior appendectomy and cholecystectomy on Clostridioides difficile
infection recurrence and mortality. Am J Surg 2020;220:203-7.
Viscidi R, Laughon BE, Hanvanich M, Bartlett JG, Yolken RH. Improved enzyme immunoassays for the detection of antigens in fecal specimens. Investigation and correction of interfering factors. J Immunol Methods 1984;67:129-43.
Lee SD, Turgeon DK, Ko CW, Fritsche TR, Surawicz CM. Clinical correlation of toxin and common antigen enzyme immunoassay testing in patients with Clostridium difficile disease. Am J Gastroenterol 2003;98:1569-72.
Napolitano LM, Edmiston CE Jr. Clostridium difficile disease: Diagnosis, pathogenesis, and treatment update. Surgery 2017;162:325-48.
Yong FA, Alvarado AM, Wang H, Tsai J, Estes NC. Appendectomy: A risk factor for colectomy in patients with clostridium difficile. Am J Surg 2015;209:532-5.
Carignan A, Allard C, Pépin J, Cossette B, Nault V, Valiquette L. Risk of clostridium difficile infection after perioperative antibacterial prophylaxis before and during an outbreak of infection due to a hypervirulent strain. Clin Infect Dis 2008;46:1838-43.
Rao PM, Rhea JT, Novelline RA, Mostafavi AA, McCabe CJ. Effect of computed tomography of the appendix on treatment of patients and use of hospital resources. N Engl J Med 1998;338:141-6.
Marin D, Ho LM, Barnhart H, Neville AM, White RR, Paulson EK. Percutaneous abscess drainage in patients with perforated acute appendicitis: Effectiveness, safety, and prediction of outcome. AJR Am J Roentgenol 2010;194:422-9.
Huston JM, Kao LS, Chang PK, Sanders JM, Buckman S, Adams CA, et al.
Antibiotics versus appendectomy for acute uncomplicated appendicitis in adults: Review of the evidence and future directions. Surg Infect (Larchmt) 2017;18:527-35.
[Figure 1], [Figure 2]
[Table 1], [Table 2]