Clostridium difficile is the most common nosocomial

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1 SURGICAL INFECTIONS Volume 17, Number 3, 2016 ª Mary Ann Liebert, Inc. DOI: /sur The Surgical Management of Complicated Clostridium Difficile Infection: Alternatives to Colectomy Ben Kautza and Brian S. Zuckerbraun Abstract Background: Clostridium difficile is the most common nosocomial infection in the United States. There is a subset of patients for whom medical therapy fails or who progress rapidly to the development of complicated disease, often marked by critical systemic illness. Patients with complicated Clostridium difficile infection (CDI) who progress or fail to improve benefit from surgery. Results: This focused review highlights the importance of early surgical consultation for patients with complicated CDI, as well as emerging surgical therapy that does not involve resection of the colon but rather the creation of a loop ileostomy with colonic lavage, followed by antegrade vancomycin enemas into the colon during the post-operative period. Clostridium difficile is the most common nosocomial infection. In general, the disease manifests clinically as an acute diarrheal illness. Once the diagnosis is made, the infection can be treated with targeted antibiotic therapy. The major challenges in surrounding Clostridium difficile infection (CDI) include effective infection control and prevention, high recurrence rates and the possibility of chronic relapsing disease, and the 5% 10% of patients who develop complicated disease. Complicated disease is essentially those patients with CDI who progress to critical illness, end organ failure, severe abdominal distention, or substantial tenderness. This review focuses on the management of patients with complicated disease, with particular attention to the indications and timing of surgical management, as well as the optimal surgical management strategy. Clostridium difficile Infection Incidence/Prevalence Approximately 3% 6% of the U.S. population are asymptomatic carriers of C. difficile, although these rates may be greater in patients in long-term care facilities [1]. The overall prevalence of CDI ranges from 0.15% to 10% in hospitalized patients [2 5]. Rates of CDI have been increasing, and in the United States alone cases of CDI have more than doubled from 139,000 in 2000 to 336,600 cases in 2009 [6]. In a study from , the incidence of CDI in adults demonstrated increasing rates in all age ranges, with the most drastic increases in those older than 85 years in whom CDI doubled from 52 per 10,000 to 112 per 10,000 [7]. Since 2000, an epidemic strain has been characterized (NAP1/BI/027) [8]. This strain results in four times the endemic incidence and a five-fold increase in mortality. The NAP1/BI/ 027 strains have a greater rate of fluoroquinolone resistance, produce 16 times more toxin A, and 23 times more toxin B in vitro than other C. difficile strains [9]. Additionally, there is a greater recurrence rate after metronidazole therapy compared with infections caused by other C. difficile strains [10]. Disease Severity Classification One of the difficulties in the care of patients with CDI has been the lack of consensus definitions to stage the severity of disease. This is particularly relevant in patients with more severe manifestations and illness. According to recent guidelines provided by the American College of Gastroeneterology [11] (Table 1), the definition of mild CDI is C. difficile infection with diarrhea as the only symptom/sign. The definition of moderate CDI is C. difficile with diarrhea and additional symptoms/signs not meeting the definition of severe or complicated CDI. Severe CDI is C. difficile infection that presents with or develops during the course of the disease with any one of the following: A white blood cell count 15,000 cells/mm 3, hypoalbuminemia (serum albumin <3 g/dl), or abdominal tenderness. Complicated CDI is Department of Surgery and VA Pittsburgh Healthcare System, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Presented at the 33rd Annual Meeting of the Surgical Infection Society, Las Vegas, Nevada, April

2 338 KAUTZA AND ZUCKERBRAUN Table 1. Clostridium difficile Infection Severity Scoring System and Summary of Recommended Treatments Severity Criteria Treatment Mild Diarrhea Metronidazole 500 mg orally three times per day Moderate Diarrhea plus any additional signs or symptoms Metronidazole 500 mg orally three times per day not meeting severe or complicated criteria Severe Any two of the following: Vancomycin 125 mg orally every day - WBC 15,000 cells/mm 3 - Serum albumin <3 g/dl - Abdominal tenderness Complicated Any one of the following: Metronidazole 500 mg IV twice daily - Admission to intensive care unit for CDI + - Hypotension with or without required use Vancomycin 125 mg orally every day of vasopressors + - Temperature 38.5C Vancomycin 500 mg in 500 ml saline as enema - Ileus or substantial abdominal distention every day (if ileus or distended) - Mental status changes + - WBC 35,000 cells/mm 3 surgical consultation - Serum lactate levels greater than 2.2 mmol/l - End organ failure (mechanical ventilation, renal failure, etc) Adapted from Surawicz et al. [10]. WBC = white blood cell count; CDI = Clostridium dfficile infection. C. difficile infection that presents with or develops during the course of CDI with at least one of the following signs/ symptoms: Admission to an intensive care unit, hypotension with or without required use of vasopressors, temperature 38.5 C, ileus or substantial abdominal distention, mental status changes, white blood cell count 35,000 cells/mm 3, serum lactate concentrations greater than 2.2 mmol/l, or any evidence of end organ failure. Symptoms of ileus include acute nausea, emesis, sudden cessation of diarrhea, abdominal distention, or radiologic signs consistent with disturbed intestinal transit. Although these criteria have not yet been validated, they define in more detail patients who should be considered to as having complicated disease. These criteria are based on signs and symptoms that have been negative prognostic indicators in multiple case series or other nonvalidated scoring indices [12 24]. We believe that it is important to adopt such a classification schema to be able to standardize care and treatment. This is particularly relevant in patients with complicated disease to ensure adequate escalation of care and timely involvement of surgical consultants in the care of these patients. Mortality in patients who are critically ill with CDI has been associated with delays in surgical consultation. Treatment of Complicated Clostridium difficile Infection This review will not focus on laboratory or diagnostic studies used to make the diagnosis of CDI. Central to making the diagnosis of CDI is consideration of the diagnosis in the first place. Additionally, in the setting of the clinical syndrome of CDI in patients who have risk factors (ongoing or recent antibiotic use or hospitalization), therapy should be initiated prior to confirmation of the diagnosis. However, the use of polymerase chain reaction based assays with high sensitivity and short turnaround times makes it more realistic to make rapid diagnoses. General management strategies that apply to all patients with CDI, regardless of the severity, include maintenance of good infection control practices, continued oral or enteral nutrition in the absence of an ileus, discontinuation of other antibiotics if no longer indicated or changing the antibiotic regimen from that which was incited CDI (if continued antibiotics are required for other infectious diseases), and initiation of targeted antibiotic therapy against CDI [11]. General antibiotic treatment strategies have utilized metronidazole (500 mg orally three times per day) for mild or moderate disease or vancomycin (125 mg orally four times per day) for severe disease. There are no randomized controlled trials of antibiotic therapy for the treatment of patients with complicated CDI. Recommendations are extrapolated from other data sets pertaining to recurrent CDI, and take into account impaired gastrointestinal motility and ileus that are present in some patients with complicated disease. Although there are no supportive data, most patients with complicated disease will be covered with both metronidazole (usually 500 mg intravenous three times daily) and vancomycin (500 mg orally each day). Additionally, in patients with ileus, many advocate the adjunctive use of vancomycin enemas to ensure delivery to the colon. A recent study by Kim et al. [25] suggested that more liberal use of vancomycin enemas in this patient population may be associated with decreased need for surgery. One essential feature of vancomycin enemas in a patient with an intact colon is that the volume must be sufficient to reflux far enough proximally to treat a substantial proportion of the length of the colon. Thus, the volume of each enema should be 500 1,000 ml. Recently, fidaxomicin has also been approved for use in CDI but has not been integrated into most typical treatment strategies [26]. For a further discussion on antibiotic therapy and CDI, see the recent guidelines from the American College of Gastroenterology [11]. Patients with complicated CDI disease have the highest mortality rates, ranging from 30% 80% [12,13,27]. Again, the criteria as to the definition of complicated disease has been

3 LOOP ILEOSTOMY/COLONIC LAVAGE FOR C. DIFFICILE 339 somewhat unclear. Nonetheless, based on the high mortality in this patient population, defining a clear set of criteria to upstage patients into the complicated category is aimed at decreasing mortality by enhancing aspects of care [28,29]. Most notably this enhanced bundle of care would include changing the antibiotic regimen and surgical consultation. A major challenge in the management of complicated CDI is the role of surgical management as a therapy. This includes the timely consultation of abdominal surgeons if the patient is on a medical service, and the lack of a consensus by surgeons on the indications of when to operate. In general, consideration for surgical therapy has only been as a salvage therapy. The only clear-cut indication for surgery in the past has been colonic perforation. However, this is quite rare and typically occurs very late in the disease process. Colonic perforation or ischemia is not inherent to this colonic infectious process, and usually will occur in the setting of abdominal compartment syndrome or non-occlusive mesenteric ischemia from severe dehydration and high-dose vasopressors. The other recommendation for surgical management has been clinical deterioration in critically ill patients for whom medical therapy is failing. Although this is an indication for surgical consultation, it is too subjective and vague to help guide practitioners. Multiple series have demonstrated that a decreased time from presentation to surgical management was associated with improved mortality [15,30,31]. Butala et al. [32] reviewed approximately 20 years of literature from 1989 to 2009 and concluded that earlier diagnosis and treatment with surgery reduced mortality associated with complicated CDI. Similarly, Sailhamer et al. [19] demonstrated a trend toward decreased mortality rates in patients who underwent surgery compared with those who did not. Moreover, this study illustrated that a shorter mean interval from admission to operation was associated with decreased mortality. Specifically, admission of patients with complicated CDI directly to the surgical service compared with admission to a non-surgical service correlated directly with earlier decision for surgical management and operation and improved outcomes. The recommendation for surgical consultation is any patient who meets the criteria for complicated disease (Table 1). Again, these criteria were developed based on factors that were repeatedly associated with mortality or the need for operative management across multiple single institution series. Upon surgical consultation, if there is not an immediate indication for surgical management, we advocate the use of computed tomography (CT) scanning of the abdomen and pelvis. This can be used as an adjunct to determine the severity and extent of disease. Several severity scoring systems have integrated CT scan findings in the past [14,33,34]. If renal function is not prohibitive, CT scans should be done with intravenous contrast to gain the most information. Concerning features on a CT scan include pancolitis, ascites, and megacolon. If a diagnosis of CDI has not been confirmed by diagnostic laboratory testing, CT scanning can be used to rule out other pathologic processes and help to determine the presence of ileus or perforation. A number of studies have evaluated risk factors for mortality in patients who underwent colectomy. Independent risk factors that have been found consistently among multiple studies include the development of shock, as determined by the need for vasopressors and increased lactate ( 5 mmol/l), mental status changes, and end organ failure. Such factors also include the need for pre-operative intubation and ventilation or renal failure [13,14,18]. Surgery for Complicated Clostridium difficile Infection The decision to operate for complicated CDI has varied substantially based on individual practices. Prior to the recent American College of Gastroenterolgy clinical practice guidelines, previous consensus statements have fallen short of making definitive recommendations for indications for surgery. These recent guidelines based the recommendations upon features that were associated with increased mortality (Table 2). Essentially, indications for immediate operation include any clinical signs of sepsis and organ dysfunction, if a patient requires intubation and mechanical ventilation and this is not attributed to any other process, or if the patient is developing renal failure. Another immediate indication for surgical management is if a patient requires the support of vasopressors and has been resuscitated adequately. Laboratory values that have been associated with high mortality and immediate consideration for operation include extreme white blood cell counts 50,000 cells per microliter or serum lactate 5.0 mmol/l. Of course, there is no substitute for clinical acumen. Patients who satisfy the criteria for complicated disease and have been receiving appropriate therapy who then demonstrate an exacerbation on clinical examination should also be considered candidates for surgical management prior to the development of sepsis. The standard of care for operative management had been subtotal colectomy. This was based on relatively small studies comparing subtotal colectomy to patients who underwent segmental colectomy [17,35,36]. This makes sense because the disease often involves a pancolitis, and intraoperative assessment of the health of the colon is difficult because the appearance of the colon from the serosal surface Table 2. Indications for Operative Management in Patients with Clostridium difficile Infection A diagnosis of Clostridium difficile colitis as determined by one of the following: 1. Positive laboratory assay 2. Endoscopic findings 3. Computed tomography scan findings consistent with C. difficile colitis (pancolitis ascites) Plus any one of the following criteria: 1. Peritonitis 2. Perforation 3. Sepsis 4. Intubation 5. Vasopressor requirement 6. Mental status changes 7. Unexplained clinical deterioration 8. Renal failure 9. Lactate >5 mmol/l 10. WBC count 50,000 cells/ml 11. Abdominal compartment syndrome 12. Patients on maximal therapy for complicated CDI who fail to improve within 5 days as determined by resolving symptoms and physical examination, and WBC/band count CDI = Clostridium dfficile infection; WBC = white blood cell.

4 340 KAUTZA AND ZUCKERBRAUN is often quite bland and unrevealing. Once again, rarely is this disease associated with colonic necrosis. Interest has developed in other operative strategies that do not involve resection of the colon if it is viable and there is no colonic perforation [11,24,28,29,37]. The largest series comes from our institution [37]. This was a case controlled series that demonstrated that loop ileostomy, intra-operative colon lavage with polyethylene glycol 3350/balanced electrolyte solution, and post-operative antegrade colonic vancomycin flushes via the ileostomy led to colon preservation in more than 90% of patients and improved survival compared with historic control groups who had undergone colectomy (19% versus 50% mortality). There were no significant difference in demographics, APACHE II scores, and presence of immunosuppression between these two groups. Most cases were performed using a minimally invasive surgical approach and more than 80% of patients who were followed long-term had restoration of gastrointestinal continuity. We believe there are several advantages to adopting this operative approach, most notably, the willingness to consider surgical management prior to clinical demise, given the decreased short-term and long-term consequences of preservation of the colon. The operation is of smaller magnitude and may be tolerated better by patients who often have substantial comorbidities. Although there were no differences in physiologic criteria between patients in our before and after case controlled series as determined by APACHE-II criteria, we believe that this does not necessarily reflect other aspects of the patient s clinical condition, most notably, the temporal aspects related to care of these patients. With our recent strategy, the mean time from admission to surgical consultation, and mean time from surgical consultation to operative management were both reduced by more than 50% compared with our control groups. Again, this underscores the importance of early surgical consultation and management. Figure 1 highlights our recommended surgical management. There are several important considerations to keep in mind in the management of patients when adopting this nonresection approach. Although many patients will demonstrate immediate improvement in their clinical condition, some patients have taken several days to improve. We hypothesize that this is based on the fact that although the inciting bacterial overgrowth and infection with associated toxin production should be addressed immediately by this therapy, the inflamed colon is left in place and may continue to drive a systemic inflammatory response, which may take days to resolve. Repeat CT scanning in our patient population has often demonstrated that the colon remains thickened and inflamed in appearance for many days, even in patients who have shown near-immediate resolution of their clinical condition. Additionally, we have observed the development of abdominal compartment syndrome in the post-operative FIG. 1. Operative management strategy for complicated Clostridium difficile infection (CDI).

5 LOOP ILEOSTOMY/COLONIC LAVAGE FOR C. DIFFICILE 341 period in a small number of patients (approximately 5%). This was likely secondary to concurrent renal failure in these patients, ongoing high-volume intravenous fluid requirements, and the production of ascites. For this reason, we have adopted the placement of an intra-peritoneal drain if ascites is found at the time of operative exploration, as well as observation for the development of abdominal compartment syndrome in the post-operative period. Another consideration is that if a patient deteriorates in the post-operative period, this operation does not preclude subsequent colectomy. We believe the only absolute contraindications to this approach include the findings of perforation or necrosis, again these being relatively infrequent findings. A relative contraindication that has evolved is the finding of abdominal compartment syndrome at the time of initial exploration. Although we have managed these patients successfully with exploratory laparotomy to relieve the abdominal compartment, creation of loop ileostomy and colonic washout with resection followed by subsequent closure of the abdomen, we now use colectomy with end ileostomy in this patient population. This allows for a single operation in this acute period with definitive management. Time will determine if this surgical strategy is widely applicable. The most important management in patients with complicated disease is involvement of the surgical team and lowering the threshold for an operation prior to physiologic decompensation. Author Disclosure Statement No competing financial interests exist. References 1. Clabots CR, Johnson S, Olson MM, et al. Acquisition of Clostridium difficile by hospitalized patients: Evidence for colonized new admissions as a source of infection. J Infect Dis 1992;166: Samore MH, DeGirolami PC, Tlucko A, et al. Clostridium difficile colonization and diarrhea at a tertiary care hospital. Clin Infect Dis 1994;18: McFarland LV. Renewed interest in a difficult disease: Clostridium difficile infections Epidemiology and current treatment strategies. Curr Opin Gastroenterol 2009;25: McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320: Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372: Centers for Disease Control and Prevention (CDC). Vital signs: Preventing Clostridium difficile infections. MMWR Morb Mortal Wkly Rep 2012;61: Zilberberg MD, Shorr AF, Kollef MH. Increase in Clostridium difficile-related hospitalizations among infants in the United States, Pediatr Infect Dis J 2008; 27: McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005;353: Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005;366: Hubert B, Loo VG, Bourgault AM, et al. A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Quebec. Clin Infect Dis 2007;44: Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108: Dudukgian H, Sie E, Gonzalez-Ruiz C, et al. C. difficile colitis Predictors of fatal outcome. J Gastrointest Surg 2010;14: Lamontagne F, Labbe AC, Haeck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007;245: Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: An underappreciated and increasing cause of death and complications. Ann Surg 2002;235: Byrn JC, Maun DC, Gingold DS, et al. Predictors of mortality after colectomy for fulminant Clostridium difficile colitis. Arch Surg 2008;143: Greenstein AJ, Byrn JC, Zhang LP, et al. Risk factors for the development of fulminant Clostridium difficile colitis. Surgery 2008;143: Perera AD, Akbari RP, Cowher MS, et al. Colectomy for fulminant Clostridium difficile colitis: Predictors of mortality. Am Surg 2010;76: Pepin J, Vo TT, Boutros M, et al. Risk factors for mortality following emergency colectomy for fulminant Clostridium difficile infection. Dis Colon Rectum 2009;52: Sailhamer EA, Carson K, Chang Y, et al. Fulminant Clostridium difficile colitis: Patterns of care and predictors of mortality. Arch Surg 2009;144: Gujja D, Friedenberg FK. Predictors of serious complications due to Clostridium difficile infection. Aliment Pharmacol Ther 2009;29: Lungulescu OA, Cao W, Gatskevich E, et al. CSI: A severity index for Clostridium difficile infection at the time of admission. J Hosp Infect 2011;79: Bauer MP, van Dissel JT, Kuijper EJ. Clostridium difficile: Controversies and approaches to management. Curr Opin Infect Dis 2009;22: Fujitani S, George WL, Murthy AR. Comparison of clinical severity score indices for Clostridium difficile infection. Infect Control Hosp Epidemiol 2001;32: Carchman EH, Peitzman AB, Simmons RL, Zuckerbraun BS. The role of acute care surgery in the treatment of severe, complicated Clostridium difficile-associated disease. J Trauma Acute Care Surg 2012;73: Kim PK, Huh HC, Cohen HW, et al. Intracolonic Vancomycin for Severe Clostridium difficile Colitis. Surg Infect 2013;14: Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2001;364: Synnott K, Mealy K, Merry C, et al. Timing of surgery for fulminating pseudomembranous colitis. Br J Surg 1998;85: Nassour I, Carchman EH, Simmons RL, Zuckerbraun BS. Novel management strategies in the treatment of severe Clostridium difficile infection. Adv Surg 2012;46: Olivas AD, Umanskiy K, Zuckerbraun B, Alverdy JC. Avoiding colectomy during surgical management of fulminant Clostridium difficile colitis. Surg Infect 2010;11:

6 342 KAUTZA AND ZUCKERBRAUN 30. Markelov A, Livert D, Kohli H. Predictors of fatal outcome after colectomy for fulminant Clostridium difficile colitis: A 10-year experience. Am Surg 2011;77: Ali SO, Welch JP, Dring RJ. Early surgical intervention for fulminant pseudomembranous colitis. Am Surg 2008;74: Butala P, Divino CM. Surgical aspects of fulminant Clostridium difficile colitis. Am J Surg 2010;200: Kirkpatrick ID, Greenberg HM. Evaluating the CT diagnosis of Clostridium difficile colitis: Should CT guide therapy? AJR Am J Roentgenol 2001;176: Lipsett PA, Samantaray DK, Tam ML, et al. Pseudomembranous colitis: A surgical disease? Surgery 1994;116: Medich DS, Lee KK, Simmons RL, et al. Laparotomy for fulminant pseudomembranous colitis. Arch Surg 1992;127: Koss K, Clark MA, Sanders DSA, et al. The outcome of surgery in fulminant Clostridium difficile colitis. Colorectal Dis 2006;8: Neal MD, Alverdy JC, Hall DE, et al. Diverting loop ileostomy and colonic lavage: An alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg 2001;254: Address correspondence to: Dr. Brian S. Zuckerbraun University of Pittsburgh Medical School 200 Lothrop Street F1200 PUH Pittsburgh, PA zuckerbraunbs@upmc.edu