J Gastrointest Surg (2015) 19:1363–1377 DOI 10.1007/s11605-015-2785-4

EVIDENCE-BASED CURRENT SURGICAL PRACTICE

Clostridium Difficile Infection from a Surgical Perspective Andreas M. Kaiser & Rachel Hogen & Liliana Bordeianou & Karim Alavi & Paul E. Wise & Ranjan Sudan & On behalf of the CME Committee of the SSAT

Received: 5 December 2014 / Accepted: 18 February 2015 / Published online: 28 April 2015 # 2015 The Society for Surgery of the Alimentary Tract

Abstract Background The incidence and the severity of Clostridium difficile infection (CDI) have increased significantly over the last decade, especially in high-risk populations such as patients with inflammatory bowel disease (IBD). Surgeons must be able to both identify and minimize the risk of CDI in their own surgical patients and determine which CDI patients will benefit from surgery. Purpose We sought to define the risk factors, compare the treatment options, define the surgical indications, and identify factors that affect surgical outcomes for CDI based on the currently available literature. Results Antibiotic use, exposure to the C. difficile bacteria, IBD, and higher levels of co-morbidity are all risk factors for CDI. The majority of CDI can be treated with antibiotics. Severe or fulminant colitis, however, has a high potential for poor outcome, Andreas M. Kaiser and Rachel Hogen are co-first authors. This article was submitted on behalf of the Continuing Education Committee of the SSAT. CME questions for this article available to SSAT members at http://ssat.com/jogscme/ Disclosure Information: Authors: Karim Alavi, M.D., MPH has nothing to disclose; Sook Yee Chan, M.D. has nothing to disclose. Paul Wise, M.D. has nothing to disclose. Andreas M. Kaiser, M.D. receives speaker fees from GI Health Foundation, and royalties from Uptodate and McGraw Hill Publisher. Ranjan Sudan, M.D. has nothing to disclose. Liliana Bordeianou, M.D. has nothing to disclose. Editors-in-Chief: Jeffrey B. Matthews, M.D., has nothing to disclose; Charles Yeo, M.D., has nothing to disclose. CME Overseers: Arbiter: Jeffrey B. Matthews, M.D., has nothing to disclose; Vice-Arbiter: Guilherme M. Campos, M.D., Ph.D., has nothing to disclose; Question Reviewers: Deepa Taggarshe, M.D. has nothing to disclose; I. Michael Leitman, M.D., has nothing to disclose. A. M. Kaiser (*) : R. Hogen Department of Surgery, Division of Colorectal Surgery, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 7418, Los Angeles 90033, CA, USA e-mail: [email protected]

P. E. Wise Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA

L. Bordeianou Department of Surgery, Colorectal Surgery Program Massachusetts General Hospital, Boston, MA 02114, USA K. Alavi Department of Surgery, UMass Memorial Medical Center, Worcester, MA, USA

R. Sudan Department of Surgery, Duke University Medical Center, Durham, NC, USA

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but experience and some data suggest a lower mortality rate with colectomy rather than with continued medical treatment. Open total abdominal colectomy with end ileostomy is typically the preferred surgical strategy. It is often difficult to determine which patients will fail medical management as some may not manifest clinical signs of severe infection. Surrogate parameters of failure of medical therapy include respiratory and/or renal insufficiency, age greater than 60 years, peripheral vascular disease, congestive heart failure, and coagulopathy, all of which have been associated with worse surgical outcomes. Evidence suggests that in appropriately selected patients, colectomy performed before the development of shock requiring vasopressors, respiratory failure, renal failure, multi-organ dysfunction, and mental status changes may reduce mortality of the most severe forms of colitis. For less severe or recurrent presentations, creation of a loop ileostomy with intra-operative colonic lavage, fecal microbiota transfer, and C. difficile vaccinations are being discussed but have only been studied in small case-controlled series. Conclusions Prevention, containment, and non-surgical treatment are the cornerstone of management for CDI. However, the most severe forms with toxic colitis benefit from involvement of a surgical team. Swift open total abdominal colectomy with end ileostomy in patients with severe or fulminant C. difficile colitis has the best chance to reduce mortality if it is not delayed until shock, end organ damage, vasopressor requirement, mental status changes develop. Less aggressive approaches may be appropriate for milder and refractory forms but require further study before their applicability can be determined. Keywords Clostridium difficile . Antibiotic-associated colitis . Antibiotic-associated diarrhea . Pseudo-membranous colitis . Toxic colitis . Total colectomy . Fecal microbiota transfer Abbreviations CDI Clostridium difficile infection EIA Enzyme immunoassay FDA Food and Drug Administration FMT Fecal microbiota transfer IBD Inflammatory bowel disease NAAT Nucleic acid amplification test PPI Proton pump inhibitor UC Ulcerative colitis WBC White blood cells

Introduction Clostridium difficile infection (CDI) is an important topic for any clinician but even more so for gastro-intestinal surgeons who are impacted not only by CDI as a complication of unrelated treatments but also when their judgment and surgical skills are most needed—for severe and life-threatening colitis. CDI is the leading cause of hospital-acquired diarrhea, and its prevalence has significantly increased over the last decade. The disease is most commonly caused by exposure to antibiotics, which alter the natural flora of the intestines.1 However, 43 % of community-acquired CDI patients do not have a known antibiotic exposure.2 In the hospital setting, gastrointestinal surgery, immuno-compromised status, exposure to peri-operative antibiotics, and possibly proton pump inhibitors (PPIs) contribute to increased risk of developing CDI , and come together specifically in the surgical population.3 4 The clinical presentation may have some overlap with unspecific antibiotic-associated diarrhea of which an estimated 20– 30 % are caused by C. difficile.5 The severity of true CDI

varies from mild diarrhea to fulminant toxic colitis. For the majority of cases, surgical management is not required be, cause the infection usually responds to antibiotic treatment.6 7 However, surgery may be necessary for more severe cases that progress despite antibiotic treatment.7 CDI presents a particular challenge to surgeons because the surgical options and their indications are not thoroughly studied or sufficiently well defined.

Epidemiology CDI has increased in incidence, severity, and mortality in the , USA over the last decade.6 8 Examination of death certificates in the USA revealed an increase in mortality secondary to CDI from 5.7 per million population in 1999 to 23.7 per million in 2004, which translates into a 35 % rate of increase per year.9 From 2006 to 2010, in comparison with the preceding 5 years, a 47 % increase in the rate of C. difficile colitis and a 32 % increase in the rate of colectomies were observed in the Nationwide Inpatient Sample.10 While a recent study of the Emerging Infections Program estimated that 97 % of cases of CDI are health care associated, there is some evidence that CDI is emerging in new populations such as inflammatory bowel disease (IBD) patients, pregnant women, and long, – term care facilities.5 11 15

Microbiology C. difficile is a gram-positive, spore-forming anaerobic bacterium.16 Spores of the bacteria are transmitted via the fecal-oral route, and bile acids induce their germination into vegetative bacteria within the intestinal tract. C. difficile produces a variety of toxins, including toxin A, toxin B, and binary toxin, that contribute to its pathogenesis but whose exact roles and pathomechnisms remain to be determined.

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Presence of toxins A and B appear to be necessary but not sufficient to cause CDI and have hence been used as surrogate markers in diagnostic tests. They are thought to cause glycosylation of cytoskeletal proteins of the enterocyte leading to loss of intercellular tight junctions and a secretory diarrhea, as well as variable degrees of an inflammatory response with cell , death.1 6 Over time, new strains of C. difficile have emerged. B1/NAP1/027 is a hyper-virulent strain identified within the last decade that causes hyper-production of toxin A and toxin B and has been responsible for multiple severe outbreaks of , – CDI across the world.1 17 19 Even though studies suggest that BI/NAP1/027 represents 28.1 % of CDI and the most common strain found in health-care facilities in the USA, there are numerous unnamed ribotypes, whose prevalence may have been underestimated by the research community because BI/ NAP1/027 causes more symptoms and thus gained greater recognition.20 The BI/NAP1/027 strain is known to be resistant to fluoroquinolones, and overuse of these antibiotics may have favored a selection advantage.21 Some reports noted a decreased susceptibility of B1/NAP1/027 isolates to vancomycin in the USA and Canada, and metronidazole may be , , , more effective in the treatment of this strain.1 6 21 22 Although no direct link between ribotype 027 and the severity of infection has been found, the evolution of antibiotic resistance and virulence in C. difficile has coincided with its rising preva– lence and worsening severity of CDI.23 26

Pathophysiology and Presentation The clinical presentation of CDI ranges from asymptomatic carrier status and self-limited diarrhea on the mild end of the spectrum to severe and potentially fatal fulminant/toxic colitis. The severity of the infection is thought to be a function of the virulence of the bacteria in relation to the host defense mechanisms.27 Five to fifteen percent of healthy adults, 10– 50 % of inpatients in health-care facilities, and 40–60 % of – neonates are estimated to be asymptomatic carriers.28 30 In long-term care facilities, the rates are even higher with up to 70 % of patients being asymptomatic carriers.31 Asymptomatic individuals are presumed to carry C. difficile without developing diarrhea or mucosal damage; however, this population is poorly delineated. Asymptomatic C. difficile usually occurs in individuals exposed to C. difficile in a health-care environment. The prevalence among health-care workers is unknown. There is evidence that asymptomatic carriers may have a degree of protective immunity in the form of IgG to toxins produced by C. difficile. It is believed that a robust, diverse intestinal microbiome and a healthy immune system at the time of exposure allow these individuals to develop antibodies that will grant them future protection against CDI.32 The same virulent, toxin-producing strains of C. difficile have been isolated in asymptomatic individuals and those with infection, and

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the majority of asymptomatic individuals have been found to carry toxigenic strains. Infants are suspected to acquire C. difficile in nurseries and neonatal intensive care units and remain asymptomatic because they lack C. difficile toxin receptors on their enterocytes Several studies have demonstrated transmission from asymptomatic individuals, suggesting that these individuals are an important reservoir for C. difficile outside the scope of CDI prevention programs.29 This important finding calls into question many of our basic tenets in diagnosing and preventing C. difficile. It also challenges the relevance of hospital isolation strategies and whether asymptomatic individuals warrant testing in certain health-care environments such as outbreaks and intensive care units. C. difficile accounts for approximately 20 % of antibiotic, , associated diarrhea.6 7 33 Disruption of the normal bacterial flora of the intestine appears to be the catalyst that allows C. difficile to colonize the colon and cause infection. Mild CDI causes diarrhea without macroscopic colitis or systemic symptoms. Mild C. difficile colitis is associated with nonspecific diffuse or patchy erythematous colitis without pseudo-membranes. This is associated with more severe diarrhea and mild systemic symptoms such as nausea, fever, leukocytosis, and malaise. Pseudo-membranous colitis represents the cytotoxic effects of the C. difficile toxins and is associated with moderate systemic symptoms and characteristic pseudomembranes on endoscopy. It should be noted, though, that pseudo-membranes are not specific for CDI. Other bacteria can cause pseudo-membranes, and in the pre-antibiotic era, Staphylococcus aureus was the most common cause. Chronic, smoldering CDI is associated with relatively mild systemic symptoms but persistent diarrhea and colonic inflammation. Severe fulminant colitis or toxic megacolon is life threatening and occurs in 3 % of patients with CDI. It is defined as colitis which progresses to segmental or total colonic distention in combination with signs of systemic toxicity such as fever, elevated WBC, abdominal distention, tenderness, hemodynamic instability, mental status changes, and other organ dysfunctions. It causes a paralytic ileus, which leads to a paradoxical decrease in diarrhea, and can progress to colonic perforation.33 Clinically, this may present as a colonic pseudoobstruction (Ogilvie syndrome) and should be in the differential diagnosis of patients with colonic dilation and decreased stool output.

Risk Factors The two most common risk factors for CDI are exposure to antibiotics and exposure to the C. difficile bacteria, both of which are likely to occur in a health-care facility. Antibiotics are thought to disrupt the normal intestinal flora, allowing C. difficile to become more predominant. While most commonly associated with broad-spectrum antibiotics such as fluoroquinolones or clindamycin, any antibiotic exposure

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increases the risk for CDI. A single dose of antibiotics can cause CDI; however, an increased number of doses and/or duration of antibiotics have been shown to confer a greater risk. Patients are estimated to have a 7–10 times greater risk of CDI for 1 month and a twofold greater risk for 3 months after cessation of antibiotic therapy.34 Advanced age, greater co-morbidity, recent gastro-intestinal surgery, recent exposure to anti-neoplastic agents, IBD, and longer length of stay in health-care facilities , , , , – have also been shown to be independent risk factors.3 11 23 25 35 37 The literature regarding the effect of peri-operative antibiotics on the incidence of CDI is remarkably limited. Available data suggest a low incidence of CDI after peri-operative antibiotic exposure. For example, in a randomized controlled trial of patients undergoing elective colon surgery, the risk was estimated to be 1.7 % after a single peri-operative dose of ertapenem.4 One should caution though that the low incidence is potentially the result of underreporting but undoubtedly makes it difficult , , to determine a causal effect without very large studies.4 38 39 The association between PPIs and CDI is under debate and necessitates larger and randomized controlled trials to determine a cause-effect relationship. The concern that proton pump inhibitors (PPIs) are linked to an increased risk of CDI is largely based on retrospective case-control and cohort studies as well as meta-analyses that are limited by confounding patient variables, heterogeneous patient populations, and non, standardized PPI dosing.40 41 For example, a meta-analysis of 23 studies and 300,000 patients showed a 65 % increase in the Table 1

, ,

,

incidence of CDI among PPI users, but the analysis was limited in that the duration of PPI use was not defined.41 Nonetheless, this concern led the U.S. Food and Drug Administration (FDA) in 2013 to release a warning that CDI can be associated with use of PPIs.42 When the gastric acidity is reduced with PPIs, ingested vegetative organisms are presumed to more likely pass through the upper gastro-intestinal tract and to colonize the large intestine.43 However, our understanding of the role that PPIs play in the pathophysiology of CDI remains limited and does not fully explain all of our findings. For example, a recent study found a decreased risk of first time CDI recurrence with PPIs but increased risk for repeated recurrences associated with PPIs.44 There is also some evidence that , H2 blockers confer less increased risk than PPIs.43 45

Diagnosis CDI should only be investigated in patients with diarrhea. A myriad of laboratory tests can be used to diagnose CDI.46 Since non-toxin-producing strains are prevalent but clinically irrelevant, simple stool cultures are not indicated. Available diagnostic tools include enzyme immunoassays (EIA) for toxins, nucleic acid amplification tests (NAATs, aka polymerase chain reaction (PCR)) for C. difficile toxin genes, toxigenic cultures, or cell culture neutralization assays.46 Toxigenic culture is considered the gold standard but is too time –

Laboratory tests for the diagnosis of C. difficile infection1 3 29 47 53

Test

Method

Sensitivity

Specificity

Cost

Duration

Clinical availability and limitations

Toxigenic CD culture

Culture using selective media and demonstrate toxin production with EIA or CCA Inoculation of stool on culture medium with demonstration of cytopathic effect of CD using anti-toxin 24–48 h later Enzyme immunoassay for GDH (enzyme produced in larger quantities than toxins but produced by both toxigenic and non-toxigenic strains)

High

High

$22

5 days

Limited; resource intensive, long turnaround time

High (67–86 %)

High (97–100 %)

$15

24–72 h

Limited; resource intensive, long turnaround time

High (71–100 %)

Low (76–98 %)

$9

15–45 min

Toxin EIA

Enzyme immunoassay for both toxin A and toxin B

Low (15–99 %)

High (84–100 %)

$8

1h

Widely; high negative predictive value (NPV), but because GDH is produced by both toxigenic and non-toxigenic strains of CD, diagnosis must be confirmed with toxin EIA Widely; must detect both toxin A and toxin B; lower sensitivity, variable sensitivity

NAAT

PCR to detect toxin A and toxin B production genes

High (84–100 %)

High (94–100 %)

$25–49

45–180 min

CCNA

GDH EIA

Widely; more expensive; higher false positive rate

CCA cell culture cytotoxicity assay, EIA enzyme immunoassay, CCNA cell culture neutralization assay, GDH glutamine dehydrogenase, NAAT nucleic acid amplification test, PCR polymerase chain reaction

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consuming to be practical in a clinical setting.47 Enzymatic detection of glutamine dehydrogenase (GDH), EIA, and NAATs are often used in a clinical setting, NAATs for toxin genes are recommended over EIA and two-step algorithms involving EIA and GDH testing because they are more sensitive. Furthermore, the sensitivity of EIA and GDH testing can vary with strain and in the setting of outbreaks, whereas the , sensitivity of NAATs is much less variable29 47 Some studies report false positives associated with NAATs, but these are usually encountered when testing asymptomatic individuals, , which is not recommended (Table 1).29 47 Repeat testing within 7 days is generally not advised because it does not increase the testing sensitivity and increases the likelihood of false positive results. For example, repeat testing picks up less than 5 % of true positives with EIA and , about 1 % of true positives with PCR.54 55 Test for cure is also discouraged because patients may continue to test positive for several months despite resolution of symptoms or may continue to have diarrhea despite a negative lab result.3 Radiological studies such as CT scans are typically not needed to diagnose CDI, but they may serve as a general tool to guide clinical management of patients with advanced disease. CT does help determine the severity of the disease in patients with systemic signs of infection, distinguishes CDI from other differential diagnoses, and helps when reassessing an underlying non-C. difficile infection that was treated with antibiotics and triggered the development of CDI. CT scans can reveal colonic thickening or dilation, mucosal enhancement, peri-colonic stranding, and ascites but may be limited in patients with ileus or renal failure due to the inability to administer oral or intravenous contrast, respectively (see Figs. 1 and 2). Fulminant colitis is associated with loss of colonic muscular tone and can cause mucosal thumb printing with contrast trapped in the mucosal folds (see Fig. 3). Colonic distention greater than 6 cm in the setting of CDI indicates toxic megacolon. The early use of CT scan can be helpful in determining if patients have fulminant colitis.56 Radiological characteristics of colitis may be incidentally found on CT scans ordered for other purposes. While they are suggestive of CDI, the diagnosis of CDI should not solely rely on the imaging as it has a false negative rate in the range of 0–22 %.57 Endoscopy is generally used (a) when rapid confirmation of the suspected diagnosis is required, (b) if there is a strong

Fig. 1 CT scan with intravenous contrast. a Coronal view. b Axial view. c Magnified anteroposterior view. Arrows pointing to mucosal enhancement; single asterisk indicates colon wall thickening with loss of haustrations

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suspicion of CDI despite a negative laboratory result, (c) when stool is not available secondary to an ileus, or (d) when other colonic diseases are in the differential diagnosis (e.g., obstruction, ischemia, inflammatory bowel disease).58 Endoscopy can also be used for colonic decompression, but care must be taken not to cause iatrogenic injury in an inflamed, dilated colon.56 Adherent yellow plaques or pseudo-membranes on endoscopy strongly suggest the diagnosis and warrant empiric treatment (see Fig. 4). Flexible sigmoidoscopy is an appropriate initial test; however, it is estimated to miss 20 % of CDI cases in which the disease is localized proximal to the splenic flexure.33

Hospital Infection Control Measures Most hospitals have implemented infection control programs in response to CDI and other hospital-acquired infections.59 Antibiotic stewardship programs that encourage directed antibiotic use and minimization of clindamycin and fluoroquinolone use have been effective in reducing the incidence of CDI.60 C.Difficile has been shown to be present on the skin of infected individuals for on average up to 7 days after resolution of diarrhea.61 Thus, contact precautions should likely be implemented for at least 7 days after resolution of diarrhea. Hand hygiene is unquestionably an important factor in infection control. Gloves have been shown to significantly reduce CDI in one study from 7.7 per 1000 discharges to 1.5 per 1000 discharges. The prevalence of asymptomatic carriers was also reduced.62 Alcohol hand sanitizers are not effective in killing the spores of C.Difficile. Hand washing with soap and water or 4 % chlorhexidine should be mandatory, but there are differing reports of the efficacy of soap and water , , versus chlorhexidine.3 63 64 Gowns have not been well studied as a measure to reduce transmission in the CDI population.3 Given that asymptomatic carriers likely act as a reservoir of C.Difficile (as previously discussed), hand washing and/or glove use should be universally implemented in the hospital. However, other interventions to reduce transmission of resistant bacteria in intensive care units failed to show a benefit for other bacteria.65 If more aggressive contact precautions are indeed implemented, they should be employed for at least 7 days after diarrhea resolution. Disposable medical supplies,

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Fig. 2 Non-contrast CT. Diffuse colon wall thickening in transverse colon (a), ascending and descending colon (b), and pelvic entry (b). Also of note diffuse edematous changes involving abdominal wall

private or separated rooms, and effective cleaning of patient rooms have been recommended.3 However, further studies as to the efficacy of such measures and a cost-benefit ratio of disposable gowns are recommended.

Medical Treatment Antibiotics The first step in the management is to determine whether the antibiotics that incited the CDI can be discontinued. When there is a high clinical suspicion for CDI, specific treatment may be initiated before having the confirmation from lab results.3 Antibiotic therapy should be tailored to the severity of disease. The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America (SHEA/IDSA) has published guidance for the initial episode of CDI. As discussed later, however, the surgeons’ point of view—which is undoubtedly influenced by higher-risk inpatient populations—is to be more aggressive at each level of severity (see Table 2). The guidelines published by the American College of Gastroenterology in 2013 acknowledged that concern.3 Single antibiotic coverage is appropriate for mild to moderate disease, e.g., metronidazole 500 mg TID-QID per os (po) for 10–14 days or oral vancomycin 125–250 mg po QID for 10–14 days. Randomized controlled trials have demonstrated equivalent efficacy of oral metronidazole and oral vancomycin for mild cases of CDI with 90 and 98 % efficacy, , respectively.5 66 Metronidazole is rapidly absorbed by the small intestine, and thus, only a fraction will directly reach the colon, whereas IV metronidazole is dependent on biliary excretion to reach the gastro-intestinal tract. Vancomycin is not effective intravenously and must be administered by mouth or nasogastric tube (or less effective by rectal Fig. 3 CT scan with oral and rectal contrast only. Single asterisk indicates diffuse wall thickening with thumbprinting

instillation). It is not absorbed but stays within the lumen at high concentrations while avoiding the systemic side effects. For more severe disease or insufficient response, dual antibiotic coverage is advisable even if there have not been any systematic studies. Oral vancomycin 250–500 mg QID (po) is recommended either by mouth or via nasogastric tube (or less effective by rectal instillation), in combination with metronidazole 500 mg TID-QID per os or intravenously. While metronidazole has been shown to be equally effective as vancomycin in treating mild disease, prospective randomized double-blind controlled trials have shown it to be inferior in , severe CDI with 76 versus 97 % efficacy, respectively.5 66 In patients with a significant ileus or non-colonic abdominal distention, direct vancomycin instillation via enema, colonoscopy, or rectal tube may be added. The recommended dosing is 500 mg of vancomycin in 500 mL QID per rectum in the hopes that larger volumes will increase the likelihood that the medication will reach the more proximal colon.3 From a surgical perspective, the biggest variance from the SHEA/IDSA guidance relates to patients with severe complicated disease as defined by the presence of hypotension, shock, ileus, or megacolon. As discussed in the later section on surgical management, this combination of prognostic red flags does not allow for delay and represents the key moment for a difficult decision towards surgery. Despite the immediate efficacy of vancomycin and metronidazole, relapse rates are frequent and reach 19 % after the first and 35–38 % after subsequent infections.67 Furthermore, an estimated 50–65 % of patients with recurrent CDI go on to , develop chronic relapsing CDI.68 69 Recently, several new antibiotics have been investigated for the treatment of CDI. Nitazoxanide is a broad spectrum, anti-parasitic agent. It was shown in two small double-blinded randomized controlled trials to have comparable efficacy to vancomycin and metronidazole. The sample sizes of these studies were too small to draw significant conclusions, but

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Fig. 4 Endoscopic appearance of pseudo-membranous colitis: severe (a), mild (b)

,

nitazoxanide warrants further investigation.70 71 Fidaxomicin is a promising new antibiotic with a narrow spectrum against C. difficile and gram-positive organisms but minimal activity against gram-negative organisms. It is poorly absorbed from the gastro-intestinal tract and thus has minimal side effects. In a randomized controlled trial comparing fidaxomicin with vancomycin in the treatment of CDI, fidaxomicin was found to have equivalent cure rates of 88–92 and 85–89.8 %, respectively, for all C. difficile strains but significantly lower recurrence rates (7.8 vs. 25.5 %, respectively) in the non-B1/NAP1/ 027 strains.72 Among B1/NAP1/027 strains, recurrence rates were 24.4 % with fidaxomicin and 23.6 % with vancomycin.72 Fidaxomicin has not been studied in severe CDI. Guidelines about treatment of recurrent CDI remain sparse. The first recurrence of mild to moderate CDI can be treated with the same antibiotic regimen used to treat the initial infection. Severe first recurrences should be treated with vancomycin as described for severe initial infections.5 While a first episode is typically treated for 10–14 days, recurrent and refractory-appearing CDI may need antibiotics over a substantially longer period of time, for example for 4–6 weeks. Alternatively, vancomycin in a pulsed or tapered regimen or fidaxomicin is recommended to treat subsequent recurrences , , (Table 3).3 69 80 Table 2

Probiotics for Treatment or Secondary Prevention Probiotics have been the focus of hope that they could reshape the bacterial balance in the intestine by increasing the diversity of the microbiome. Probiotics are live microbial stock that consists of non-pathogenic yeast and bacteria such as saccharomyces and lactobacillus species. These organisms are found naturally in the intestine but are not the predominant species. Unfortunately, probiotics failed to show a benefit in the treatment of active CDI. In regard to secondary prevention, a recent review found their impact to be limited. They were shown to reduce the incidence of C.Difficile diarrhea but not CDI in – patients taking antibiotics.81 83 There have also been anecdotal cases of bacterial translocation causing systemic disease in immuno-compromised individuals.80 Immunoglobulins and Vaccines The use of intravenous immunoglobulins (IVIG) has not been well studied and should only be used as adjunctive therapy in the general population. IVIG may be a more important treatment modality in immuno-suppressed transplant patients with hypo-gammaglobulinemia. Production of higher levels of anti-toxin antibodies has been associated with shorter disease , duration and lower recurrence rates.84 85 This has fostered

Surgeons’ modifications of SHEA/IDSA guidelines for inpatients with CDI5

Severity of CDI infection

Clinical characteristics defining CDI severity

SHEA/IDSA recommended treatment

Surgical recommendation

Mild or moderate

WBC 1.5 times baseline level

Vancomycin 125 mg QID po × 10–14 days

Severe complicated

Hypotension, shock, ileus, megacolon

Vancomycin 500 mg QID po or NGT plus metronidazole 500 mg TID po/IV; add rectal vancomycin in setting of ileus

Metronidazole 500 mg TID-QID po × 10–14 days or vancomycin 125–250 mg QID po × 10–14 days Vancomycin 250–500 mg QID po or NGT, plus metronidazole 500 mg TID-QID po/IV; add rectal vancomycin in setting of ileus Surgery

SHEA/IDSA Society for Healthcare Epidemiology of America/Infectious Diseases Society of America, po per os, IV intravenous, NGT via nasogastric tube, TID three times daily, QID four times daily

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,

–

Antibiotics used in the treatment of CDI66 70 72 78 Costa

Antibiotic

Dose

Vancomycin

125–250 mg PO QID × 10–14 days Cure: 74–100 %; relapse: 7–33 % $433–2600

Metronidazole 500 mg PO (or IV) TID-QID × 10–14 days Fidaxomicin a

200 mg PO BID × 10–14 days

Efficacy

Side effects/limitations

Minimal side effects; cost; difficulty reaching colon in ileus; B1/NAP1/027 resistance in the USA; possibility for VRE Cure: 65–94 %; relapse: 17–38 % $11–67 Side effects: nausea, vomiting, taste disturbances, peripheral neuropathy; difficulty reaching colon in ileus Cure: 88–92 %; relapse: 7–24 % $3170–4119 Expensive; not well studied in severe CDI

Estimated local prices at Los Angeles Pharmacies79

interest in IVIG treatments and vaccinations against C.Difficile. IgG to anti-toxin A is thought to play the biggest protective role. The efficacy and role of IVIG for the treatment of CDI would need to be investigated more systematically, however. There are a small number of largely retrospective, non-randomized, case series that suggest a benefit in refractory cases of severe CDI, whereby the use of monoclonal antibodies appears to achieve the strongest response.85 A phase II randomized, controlled trial testing monoclonal antibodies against toxin A and toxin B in the treatment of CDI did show a decrease in recurrence rates in the patients with only a single previous episode of CDI but did not significantly shorten the duration of the active infection. These patients were all also treated with either metronidazole or vancomycin. The antibiotics were not standardized or controlled, which is a potentially confounding factor.86 Patients with hypo-gammaglobulinemia such as immuno-suppressed transplant patients may represent a special population in which IVIG may play a more important role. In a study by Munoz et al. in heart transplant patients, hypogammaglobulinemia was the only independent risk factor found for CDI and was associated with a fivefold increase in the CDI risk. In this setting, IVIG was efficacious in decreasing the risk of both primary and recurrent CDI.87 A vaccine containing epitopes of toxins A and B is currently under investigation by several large pharmaceutical companies. In combination with antibiotics, it was effective in three patients treated for recurrent CDI.88 The vaccine was shown to produce elevated levels of anti-toxin A and anti-toxin B immunoglobulins in a phase II clinical trial by a European drug company. At the present time, it is being further investigated in a phase III clinical trial.89

there is no clinical evidence to support its efficacy in the treatment of CDI. While a clinician could be tempted to give it anyway, it should be noted that it also binds vancomycin and thus could reduce the true intestinal bioavailability of that therapeutic drug. Hence, in order to avoid interference with vancomycin, cholestyramine dosing must be staggered in the interval between vancomycin dosing.90 Tolevamer is an anionic polymer that sequesters toxin A and toxin B and was found to be moderately efficacious in treating CDI. However, with a cure rate of only 42–46 %, randomized controlled trials found it to be significantly inferior to metronidazole or vancomycin with 72–73 and 81 %, respectively.67 The production of tolevamer was therefore halted.

Surgery Surgical Strategy Surgery successfully eliminates the majority of the disease and the trigger of the systemic inflammatory response.91 While the majority of CDI are manageable with conservative

Toxin Binders Toxin binders represent potential adjunctive therapies or future avenues of treatment. CDI is a toxin-mediated disease, and thus neutralizing the toxins would seem to be an effective way of treating it. There are several toxin binders that have been utilized to this end, including cholestyramine and tolevamer. Cholestyramine is a bile acid sequestrant that has anecdotal evidence likely because it causes constipation, but

Fig. 5 Resection specimen (total abdominal colectomy): diffuse edema and pseudo-membranes are notable

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measures, surgery should be considered without delay in all patients with severe or fulminant CDI. The most evidence-based surgical procedure is a total abdominal colectomy with end ileostomy with the goal to rapidly eliminate diseased colon without the challenge of a pelvic dissection (see Fig. 5). The rectal stump typically also harbors disease, but the risks associated with a procto-colectomy outweighs the benefits, and the rectum commonly clears the C. difficile with or without supportive vancomycin enemas. A segmental colectomy is considered an inferior choice as it leaves substantially more inflamed tissue behind.57 It has been estimated that approximately 15.9 % of patients need reoperation after a segmental colectomy to further reduce infected bowel.92

Identification of Surgical Patients The decision to proceed with surgery is challenging because it requires balancing the risk of proceeding too late with the risk of unnecessarily removing a colon that could have recovered with non-surgical measures. Determining the timing and indications for surgical treatment in studies has been limited by small sample sizes, retrospective design, and variable definitions for severe or fulminant.3 The mortality rates reported for total colectomy in patients with fulminant CDI have been invariably high in the range of 30–50 %.93 The poor outcomes are likely the result of delays in proceeding with surgery but need to be viewed in light of the high overall mortality rate associated with fulminant colitis in general, estimated to be up to 80 %.57 Earlier surgical intervention and identification of the patient population that will fail medical management are the keys to improving surgical outcomes. The ability to determine the severity of CDI is limited, and Bolder and sicker^ patients do not necessarily equate to more severe disease. A study by Dudukgian et al. looked at 398 cases of C. difficile colitis in a single institution from 1999 to 2006: higher APACHE II score, higher ASA class, preexisting pulmonary and renal disease, use of steroids, evidence of toxic megacolon, WBC >20, and clinical signs of organ dysfunction were all found to be associated with higher mortality in patients with C. difficile colitis.93 However, older age, immuno-suppression after transplantation, or chemotherapy were not associated with higher mortality, and 87.8 % of the patients who died were not offered surgery. This group of patients was found to have more medical co-morbidities but also found to have fewer clinical signs of severe infection, suggesting a masking of severe infection, which might have benefited from earlier surgical intervention. However, 68 patients with an ASA >4 were medically treated and survived.93 Thus, the ability to determine the severity of infection and which patient’s will respond to medical therapy versus surgical therapy is still limited.

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Increasing consensus suggests that early surgical intervention in appropriately selected individuals with an otherwise reasonable prognosis reduces the mortality associated with fulminant colitis. A systematic review and meta-analysis by Stewart et al. demonstrated that patients with fulminant C. difficile colitis were more likely to survive with emergent colectomy than continued medical treatment.94 The literature regarding this topic is limited, and the included studies consistently failed to identify indications for surgery as well as criteria for determining non-surgical candidates. Furthermore, this metaanalysis was largely limited to short-term 30-day outcomes.94 Based on current evidence, colectomy should be performed prior to the development of shock and vasopressor requirement, end organ failure, and mental status changes in order to , , , minimize the risk of mortality.57 92 93 95 A meta-analysis by Bhangu et al. examined predictors of post-operative mortality. This study found that shock requiring vasopressors, preoperative intubation, acute renal failure, and multi-organ failure were all associated with increased mortality.92 While age greater than 75 years was also associated with increased risk of death, WBC, pre-existing renal failure, and higher Charlson comorbidity score were interestingly not associated with increased post-operative mortality.92 There is also some evidence that patients who are cared for by a surgical team have shortertime interval to operation, more operations, and lower mortality rates (12.8 vs. 39.3 %).96 In a recent retrospective nationwide study of 19,374 cases of C.Difficile colitis requiring colectomy by Halabi et al., shorter-time interval to colectomy was associated with lower mortality.10 Patients who underwent colectomy on hospital day 0–2 had the lowest mortality when compared to undergoing colectomy on hospital days 3–8 with a higher mortality and after hospital day 8 with the highest mortality. Patients that progressed to end organ renal or respiratory failure also had a higher mortality, again supporting that earlier colectomy is beneficial.10 The variation of relevant parameters and patient characteristics that predict unfavorable outcomes from these largely retrospective data illustrates the difficulty of drawing reliable and unbiased conclusions. However, a number of factors such as respiratory insufficiency, renal insufficiency, age greater than 60 years, peripheral vascular disease, congestive heart failure, and coagulopathy have been associated with worse , , , , surgical outcomes in various studies.10 92 93 95 97 These factors do not represent contraindications to surgery but rather should be taken into consideration when weighing the risks and benefits of surgery. Despite improved in-hospital outcomes with colectomy for fulminant colitis, there is limited data on long-term prognosis. A retrospective study of 61 patients who underwent colectomy for fulminant colitis at Mount Sinai Medical Center estimated a mean survival of 18.1 months. However, patients with fulminant C. difficile colitis are often elderly with multiple medical problems and potential other causes for death.

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Unfortunately, the authors were unable to identify the cause of death in these patients and thus, could not directly attribute it to CDI or colectomy for CDI.98 Surgical Standard Technique Total abdominal colectomy with end ileostomy is the recommended standard approach.92There are numerous reasons to perform this in an open rather than laparoscopic fashion: (1) to minimize the duration of the surgery in patients who are often unstable and coagulopathic; (2) because the colon is often enlarged and edematous, making it very heavy and difficult to handle; and (3) because fulminant C. difficile colitis and megacolon can prompt abdominal compartment syndrome, which is relieved by an open operation but can be aggravated by gas insufflation. If possible, the operation should aim at an early devascularization of the colon to shut off the systemic inflammatory response—an observation frequently seen but hard to prove in an objective fashion. The major vascular stalks are quickly identified, freed up, and devascularized with clamping and transsection. The entire colon is then mobilized from its retroperitoneal attachments starting at the ileocecal junction. The bowel is transsected with a linear stapler at the terminal ileum and at the rectosigmoid junction. An end ileostomy is created. The rectal stump may be tagged for later identification. Given that the inflammation commonly also affects the rectum, there is a risk of a rectal stump blow-out, i.e., leak from the staple line. Efforts to reduce that risk have not been studied but include a rectal washout with povidone-iodine solution or continued decompression of the blind Hartmann pouch for the first few days by means of a larger diameter rectal tube. Alternatively, the proximal end of the rectosigmoid can be brought out as a mucous fistula to the abdominal skin. Vancomycin enemas can be instilled in the rectal tube if there is a concern for continued infection in the rectum.33 Surgical Alternatives Less invasive surgical options are being explored in hopes of improving the morbidity and mortality associated with severe CDI. A recent case-controlled study at the University of Pittsburgh compared cases of fulminant colitis treated with creation of a loop ileostomy to be used for intra-operative colonic lavage with warmed polyethylene glycol 3350/electrolyte solution and post-operative ante-grade vancomycin flushes to historical controls treated with total colectomy and end ileostomy.99 This novel treatment strategy, which in the majority of cases was done laparoscopically, was performed in 42 patients and compared to 42 immediately preceding historical controls. It resulted in reduced mortality of 19 versus 50 %, respectively, and preserved the colon in 39/42 patients; the mean time to resolution of WBC was 6 days. Three patients

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in the study subsequently required a total abdominal colectomy, either for abdominal compartment syndrome or for continued sepsis. The author recommended caution in patients with abdominal compartment syndrome. The impressive series led the authors to state that this approach was beneficial in that the various teams would be less hesitant to proceed with surgery earlier in the disease course due to the lesser invasiveness and higher chance to avoid a permanent ileostomy. It may represent a future treatment avenue for earlier in the disease course. However, the study warrants a critical examination as it has significant limitations which currently hinder broad application of its conclusions: the small study cohort, the retrospective comparison to historical controls, and the lack of randomization. As the patients were not randomly assigned, a selection and management bias cannot be ruled out even though by numbers the two groups appeared comparable. In fact, the authors themselves admit using this method earlier than colectomy because it is less invasive, suggesting that their cohort of patients was healthier than those undergoing colectomy.99 The 2015 practice parameter of the American Society of Colon and Rectal Surgeons considers the evidence on this surgical approach weak and recommends caution when contemplating its application.7

Fecal Microbiota Transfer (FMT) Fecal Microbiota Transfer (FMT) is the transfer of stool from a healthy donor to a sick recipient to cure a disease related to the altered microbiome. Parenthetically, it should not be called a fecal transplantation as no human tissue or DNA is incorporated into the host. Fecal transfer remedies the decreased colonic diversity that is thought to drive CDI.100 This therapy has shown remarkable efficacy in pilot series. Currently, it is under investigation with FDA oversight for the treatment of recurrent CDI and pseudo-membranous colitis. Relatives can donate stool, or frozen, thawed, or fresh fecal preparations from standard donors can be instilled.83 Instillation can be done via colonoscopy, EGD, or nasogastric tube. One review estimated a 92 % resolution of CDI with fecal transfer in patients with recurrent C.Difficile and those with pseudomembranous colitis. Lower GI tract rather than upper GI tract stool instillation was associated with better results. The limits of this study are that it did not define or stratify the severity of disease treated.101 Mattila et al. performed a retrospective review of 70 patients with recurrent C.Difficile colitis who underwent fecal transfer and found that the infection resolved in 89 % of patients with strain 027 as well as in all patients without the more virulent strain. The four non-responders in the study with strain 027 died of colitis but had long-standing diarrheal disease or significant co-morbidity.68 Despite these promising early results, long-term follow-up after fecal transfer has not been well studied. The longest published follow-up

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was 3 months in 77 patients with a 91 % cure rate.60 Furthermore, there are concerns that fecal transfer could transmit infection or incite autoimmune reactions as seen in four of the 77 patients.60 The appropriate levels of fecal screening and the safety of fecal transfer require further study. A solution recently published focused on using oral, capsulized, and frozen FMT samples from pre-screened unrelated donors.102 Furthermore, the severity of disease in which fecal transfer would be appropriate still needs to be determined. So far, most studies published on fecal transfer and several randomized controlled trials currently underway focus on patients with recurrent C. difficile colitis, while there have been fewer studies on acute and severe pseudo-membranous colitis.60 Currently, the FDA has approved FMT as an Investigational New Drug (IND) for use in refractory or recurrent CDI after failure of standard treatment regimens. The IND categorization, which was announced in May 2013, requires providers to submit an application before using FMT. Since that time, the FDA has continued to investigate FMT and made evolving statements on the degree to which they will enforce the IND requirements. In February 2014, the FDA announced that it would use discretion in enforcing the IND requirements as long as the patient is consented appropriately for FMT and informed that FMT is an investigational treatment, the donor is known to the patient or physician, and the stool and donor are tested under direction of the physician.103

Inflammatory Bowel Disease and CDI The incidence of CDI in IBD patients with colonic disease is rising, be it due to an absolute increase or due to increased awareness.104 Undoubtedly, IBD colitis is associated with an increased risk for acquiring a superimposed infection with C. difficile, and the recurrence rates are higher than in the general population.105 CDI on top of IBD, particularly ulcerative colitis (UC), has been associated with a higher morbidity, , , mortality, and need for colectomy.11 106 107 Contributing factors include corticosteroids and possibly PPIs, whereas infliximab and other immuno-modulators have not been confirmed.108 CDI should be suspected and/or ruled out in patients with clinical signs of a disease flare-up regardless of a possible antibiotic exposure, which may be absent in up to 40 % of , , IBD patients.11 109 110 Twenty percent of patients with relapsing IBD were found to have positive stool tests for C. difficile.111 It should be noted that morphological changes of the colon and mucosa may be rather different in the setting of IBD and may lack pseudo-membranes due to the underlying chronic colonic inflammation.112 Numerous authors reported adverse outcomes of IBD patients with CDI but

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focused their concerns primarily on adjustments to conserva, , tive management.106 112 113 However, superimposed C. difficile and cytomegalovirus infections in IBD patients should be interpreted as a poor prognostic sign with a high probability of failure with medical management. A curative proctocolectomy should be discussed and its indication reevaluated by interdisciplinary team members. UC patients that develop CDI may benefit from proactive treatment.114 Despite early reports of success with fecal microbiota transfer as treatment for CDI in IBD patients, FMT should be avoided in such patients because it has been associated with disease flares.105 CDI in the overwhelming majority of cases is limited to the large intestine. However, there are two situations in which C. difficile can affect the small bowel: (A) it rarely causes enteritis in patients with an ileostomy, resulting in highvolume watery ileostomy output as well as an ileus-type clinical picture;11 (B) C. difficile has been associated with up to 10–18 % of cases of recurrent pouchitis in patients after procto-colectomy and ileal pouch-anal anastomosis (IPAA).115 In both situations, a specific antibiotic treatment will need to be initiated (metronidazole, vancomycin, fidaxomycin) to control the symptoms.

Summary The incidence and severity of CDI has seen a dramatic increase over the last decade in both the general population as well as in surgical patient populations, and CDI is becoming particularly more prevalent in high-risk groups such as IBD patients. High-density health care, new bacteria strains, and antibiotic resistance may contribute to these trends. Wide use of PPIs and steroids has also been implicated in the rising prevalence of the disease. Surgeons are affected by the disease in two ways: (1) triggering the disease by unrelated interventions and antibiotic use and (2) when the disease requires surgical expertise. Surgical treatment is needed only for a fraction of all patients but should not be delayed when the disease is severe or fulminant. The decision making remains a clinical challenge because of the difficulty in determining the severity of disease and predicting the patient’s response to medical versus surgical therapy. There is consensus that early surgical treatment, i.e., before evidence of multiorgan failure, is associated with better outcomes, but more studies are needed to determine which patient populations will benefit most from an operation, much less which operation they should have and when they should have it. There are many novel treatment strategies emerging, but sound conclusions about the safety and efficacy of these treatments are limited because they have not been thoroughly studied.

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