Introduction

As management of infections has become more sophisticated, the incidence of antibiotic associated colitis (i.e. Clostridium difficile colitis) has emerged as one of the leading hospital acquired infections [1]. Interestingly the incidence of community acquired C. difficile colitis (CDC) is increasing as well [2]. Antibiotic use results in diarrhea approximately five to 25% of the time depending on the antibiotic used [3]. Usually, the diarrhea is self limited and resolves upon completion of the antibiotic course. However, in approximately 10 to 20% of patients the diarrhea is a result of CDC and this rate appears to be increasing.[1][2][4]

Clostridium difficile is a gram positive, spore forming organism, which is both identifiable and treatable, but may lead to fulminant sepsis, with significant morbidity and mortality [3]. As discussed later many children are colonized but not infected with C. difficile presenting several diagnostic challenges in pediatric population [2]. First identified in 1935 by Hall and O’Toole in meconium cultures of healthy newborns, C. difficile was thought to represent a benign colonizer of the colon. As antibiotic use increased during the mid 1900s antibiotics became implicated in cases of pseudomembranous colitis, but C. difficile was identified as its etiology only recently [5]. In 1974, Tedesco et al linked pseudomembranous colitis to clindamycin use and showed that S. aureus was not its cause setting in motion a global search for the responsible agent [6]. In the 1980s studies carried out concurrently in England, Ann Arbor and Boston correctly identified C. difficile and its toxins as the causative factors [7]. Prior to these findings, the colitis was attributed to Staphylococcus aureus [7].

Today, C. difficile colitis is a major public health problem in both adult and pediatric population. In 2011, 450,000 cases of CDC were estimated in the United States, resulting in almost 30,000 deaths [8].  Each CDC incurs over $11,000 in associated costs [9]. While clindamycin is often associated with a risk of CDC, broad spectrum penicillins and cephalosporins are currently implicated in the majority of the infections [7]. Almost all antibiotics (including metronidazole and vancomycin) have been linked to CDC providing an additional case for strict antibiotic stewardship [10].

Epidemiology

C. difficile colitis (CDC) is increasing in the United States with rates of hospitalizations for treatment of CDC doubling between the years 2000 to 2010 [8]. In part this may be due to availability of more rapid testing which became accessible in the early 2000s and the emergence of more virulent strains, particularly the North American pulsed-field gel electrophoresis type 1 (NAP1) [11]. The NAP1 strain produces more toxin with a longer duration of effect than previous strains, leading to increasing morbidity and mortality. It has been implicated in hospital outbreaks around the world including Europe and Asia and North America [11]. Community acquired infections have also increased during this millennium - particularly among children [11]. Fortunately, children have not experienced increased rates of colectomy or death to the same degree as adults [12].

The epidemiologic studies in children are somewhat confounded by a high rate of colonization with C. difficile which is present in up to 70% of neonates compared to 3% of adults in the community and 20% in hospitalized patients [13][14]. In nonsurgical patients, clinical disease rarely occurs before age of two years due to a variety of proposed factors [13]. (see Presentation). Surgical patients, particularly infants with history of Hirschsprung disease, are at risk before their second birthday.[4]

In the United States, almost half a million patients were diagnosed with C. difficile infection by 2011 which accounts for approximately 30,000 deaths [8]. In children, the incidence of infection has risen from 4.4 to 6.5 per 10,000 patient days from 2001 to 2006 [12]. Antibiotic use remains the key risk factor for CDC, but use of , underlying bowel disease, gastrointestinal surgery, renal insufficiency and impaired humoral immunity have all been identified as risk factors [4]. Some of these characteristics are certainly markers of more fragile patients who are more frequently hospitalized and therefore at increased risk of contracting a CDC. [2][4] Since the transmission of C. difficile occurs by sporulation, suppression of gastric acid suppression may play a role in allowing spores to safely traverse the normally hostile stomach [10]. The C. difficile spores can persist in the environment for many months and are immune to heat, acid, alcohol and many disinfectants making them relatively easy to spread in hospital environments [13]. Hand hygiene, using chlorhexidine gluconate soaps rather than ethanol based solutions, the use of protective gowns and gloves in suspected cases of CDC and cleaning of surfaces with sodium hypochlorite solutions when CDC is suspected are important adjuncts in prevention of infection of other hospitalized patients [1].

Basic Science

The pathogenesis of C. difficile infection is multifactorial. Beginning with colonization symptomatic infection ultimately requires bacterial toxin production leading to cell necrosis [15]. The bacterium may exist in the gastrointestinal tract in its spore or vegetative form, the latter of which results in the actual infection [1]. In its vegetative form, C. difficile is highly susceptible to oxygen, necessitating sporulation, which explains its predisposition to the anaerobic environment of the colon [16]. When proper conditions, such as antibiotics use, develop germination and overgrowth of vegetative species begin [1]. The exact mechanism of this transition is still largely unclear. In 2008, Sorg and Sonenhein described the role of bile salts in germination expounding on the role of normal intestinal flora in prevention of CDC. The germination requires the presence of cholate and glycine derivatives of the primary bile salts [16]. In the colon, cholate is metabolized to deoxycholate by the native bacterial flora which in turn inhibits vegetative growth of C. difficile. They postulate that reduction of this metabolism occurs as the antibiotics deplete the native flora allowing for germination and propagation of C. difficile [16].

The virulence of C. difficile species requires presence of two toxins, A and B coded by the TcdA and TcdB genes respectively, responsible for the clinical findings of colitis. The strains of C. difficile which do not carry either of these toxins are typically nonpathogenic[17]. Until recently, much of the virulence was contributed to toxin A alone. Recently a clear role of toxin B has been recognized which in fact results in a 10 fold increase in toxicity [4][17][18]. Furthermore, in vitro and in rodents, TcdA +/TcdB– species have a much more attenuated disease course. In contrast, TcdA -/TcdB+ strains have become isolated with increased frequency in cases of CDC and are related to a higher disease severity and increased rates of fulminant colitis and colectomy [18].

The two toxins act independently to create an additive inflammatory effect, cell death and formation of pseudomembranes. Both are coded on the same pathogenicity locus, PaLoc, and their production is codependent [17]. It has been postulated that increased virulence results from increased toxin production, such as is seen with the NAP1 strain which contains 23 times more toxin B and 16 times more toxin A than the traditional strains [17]. In addition, deletion of toxin inhibitors adds to the virulence. The NAP1 strains isolated from United Kingdom and Montreal contain a deletion of TcdC locus known to regulate production of both toxin A and B [19]. The toxins disrupt normal colonocyte metabolism starting at the cell membrane but ultimately enter the cytosol setting in motion a series of mechanisms that lead to apoptosis and necrosis.

Of note, the most recent isolates of NAP1 strains have also been found to carry an additive binary toxin felt to contribute to its increased virulence. While its function has not been fully delineated, this toxin is known to facilitate binding of vegetative C. difficile to the intestinal epithelium [1].

Pathophysiology

The clinically apparent effects of both toxin A and B begin at the cellular level. Both toxins share a similar receptor binding and enzymatic domain - so much so that many believe the TcdB gene resulted from a TcdA gene duplication event [18]. The toxins enter the cell via a receptor mediated mechanism where they ultimately change the cell physiology by altering the actin cytoskeleton. While the targets within the cytoskeleton differ for each toxin, their end result is modification of Rho GTPases leading to actin condensation, bleb formation within the cell membrane, cell rounding and apoptosis [18]. Toxin B is more active in this sense than toxin A and its effects can be seen within two hours of endocytosis with cell death occurring within 24 hours [18]. rior to cell death, toxin A promotes disruption of tight epithelial cell junctions resulting in mobilization of neutrophils and cytokines, production of oxygen reactive species and overall initiation of a systemic inflammatory response syndrome[1][18]. TcdA can bind to neutrophils directly but it also promotes chemotaxis by an increase in macrophage inflammatory protein 2 (MIP-2) [18]. Neutrophils, macrophages, cytokines and the byproducts of cell necrosis make up the pseudomembranes which are the hallmark of the disease [1]. Diarrhea occurs as the fluid is mobilized into the colonic lumen and is further precipitated by malabsorption secondary to presence of pseudomembranes[18]. Further colonic distention and fluid sequestration may lead to toxic megacolon necessitating a colectomy.

toxic megacolon

Toxic megacolon with associated ischemia necessitating total abdominal colectomy in a 12 year old child with C. difficile colitis.

Prevention

As the prevalence of C. difficile infection (CDC) and its virulence rise, the emphasis on disease prevention becomes all the more paramount. This approach is two fold, focusing on both control of disease transmission and avoidance of iatrogenic infection by limiting the general use of antibiotics. CDC is transmitted via a fecal oral route, including the acquisition of spores from a contaminated environment [20]. If an infection is suspected, patients should be placed on contact precautions which may be removed once their diarrhea ceases [6]. Alcohol based solutions are not effective in cleaning the contaminated surfaces. Germicidal wipes and 10% sodium hypochlorite solutions should be used instead [4]. Protective gowns and gloves, in addition to hand washing with soap and water are superior to alcohol based solutions in decreasing spore transmission [4].

Antibiotic stewardship and avoidance of antibiotics, if possible, is another essential step in preventing new cases of CDC. Widespread antibiotic use has not only provided an environment for the germination of spores but has contributed to multidrug resistance of C. difficile strains. The recent isolates, including NAP1, are resistant to modern antibiotics, particularly fluoroquinolones, which is not the case with the historical controls [20]. Fluoroquinolones have been shown to contribute to the emergence of epidemic strains and limiting their use is essential in disease prevention [21].

Earlier studies had suggested that particular antibiotics, such as clindamycin, were mainly responsible for emergence of CDC. We now know that many antibiotics can be implicated including erythromycin, tetracycline, and rifampin. As new resistance patterns emerge multidrug resistant species are becoming a norm lending C. difficile an additional advantage over other susceptible intestinal flora [21]. Most C. difficile are susceptible to metronidazole and vancomycin although metronidazole-resistant strains are being reported in Europe [21] further stressing the importance of infection control and prevention.

Presentation

The majority of C. difficile colitis (CDC) begin with watery diarrhea which may remain the only prominent symptom. In some patients the disease progresses to advanced pseudomembranous colitis and toxic megacolon. The diagnosis may be delayed in up to 20% of patients who have minimal to no diarrhea and present with abdominal distention and ileus [1]. As is the case in sepsis due to other infectious etiologies, the spectrum of disease associated with C. difficile ranges from mild colitis to fulminant multiorgan failure and shock. It is still unclear why some patients experience more severe disease than others - even with the same strain of organism [1]. Classically, the diarrhea associated with CDC is watery but may turn bloody in cases of advanced colitis. Diarrhea, defined as stools that take the shape of their container and amounting to three or more episodes in 24 hours, in the setting of recent antibiotic use necessitates a work up for CDC[4]. In addition, patients report crampy abdominal pain, distention, emesis and fevers. A profound peripheral leukocytosis may be present with counts greater than 30,000. In severe cases, fluid resistant hypotension and peritonitis may develop necessitating an emergent colectomy [22][23]. The majority of pediatric CDC is of low to moderate severity with diarrhea and associated dehydration remaining the most prominent symptoms [24].

Children under two years of age and those with inflammatory bowel disease present a diagnostic challenge due to high carriage rates of C. difficile. Distinguishing between colonization and infection can be difficult in each of these groups and testing should be reserved for cases with a high index of suspicion for an infection [4].

Up to 37% of neonates and 30% of infants under six months of age are colonized with C. difficile [25]. This percentage decreases with age - down to 14% in infants who are between six and 12 months old [25] reaching adult levels of two to three percent by 24 months of life [2]. Breastfeeding appears to have a protective role, as only 14% of these babies are colonized in early infancy [25]. Despite a high rate of colonization, disease is rare in this population of children potentially due to their inability to bind and internalize toxins A and B [4]. According to the recent AAP Policy Statement, children under two years of age should not be tested for C. difficile unless they have a history of Hirschsprung disease, motility disorder or hospitalization in the setting of a C. difficile outbreak - each of which increases their risk for actual infection [25]. Furthermore, if tested as positive, alternative etiologies of diarrhea should be considered before making a diagnosis of CDC [25].

Children with inflammatory bowel disease (IBD) also have a high rate of colonization while being particularly vulnerable and susceptible to infection. In addition, many symptoms of IBD exacerbation mimic those of CDC creating further diagnostic dilemmas. While in adults concurrent CDC and IBD occur more frequently in ulcerative colitis (UC), in children the incidence is the same between UC and [26]. The rate of asymptomatic carriage of C. difficile in children with IBD is as high as 17% as opposed to three percnet in the general population. Symptomatic infection occurs in eight percent of pediatric IBD patients [26]. Interestingly, antibiotics exposure, immunosuppressant therapy, proton pump inhibitors and hospitalization, all of which are traditional risk factors for CDC, have not been shown to increase its risk in IBD patients. Instead, decreased biodiversity of intestinal flora and host genetic polymorphism associated with IBD are felt to increase both the risk for colonization and infection [26]. The presence of pseudomembranes on endoscopy is pathognomonic with C. difficile infection but are rarely seen in children with IBD raising arguments that, even when CDC is diagnosed, symptoms are due to IBD exacerbation, rather than infection [26]. Laboratory studies, discussed in the next module, may be positive in colonization alone. Given high rate of colonization with C. difficile in association with IBD, the CDC and AAP recommend testing and treatment only in truly symptomatic patients. The latter may be difficult to ascertain and differentiate and many pediatric gastroenterologists advocate a more aggressive approach including empiric treatment for IBD patients who test positive for C. difficile. This is particularly important as a concurrent CDC in patients with IBD increases rates of hospital readmission, length of hospital stay, need for parenteral nutrition and more frequent escalation of IBD therapy when compared to noninfected IBD patients. Currently, no prospective studies, consensus statements or guidelines are available for this population [26].

Assessment

Due to relatively high rate of colonization with C. difficile in children, testing should be reserved for patients with true diarrhea (see Presentation) or symptoms of colitis with history of antibiotic use. Commercially available tests essentially fall into two groups.

• those that assess for presence of the bacteria
• those that detect presence of the toxins in stool specimen of the host

The former either detects the presence of glutamine dehydrogenase (GDH) by using monoclonocal antibodies to C. difficile GDH or C. difficile specific genes using PCR methods - specifically nucleic acid amplification tests (NAATs) [2]. The GDH assay is nonspecific, detects both pathogenic and nontoxigenic C. difficle strains and is only recommended in multistep algorithms in which additional tests are used to confirm the diagnosis [2][4]. While colonization with C. difficile is common, the prevalence of actual infection is low in the general pediatric population resulting in a lower sensitivity and specificity of these tests [4]. The sensitivity of GDH assays is greater than 90% but may only identify carrier status.

The second group utilizes immunoassays to detect the presence of Tcd A and TcdB and are known as toxin EIAs[4]. These are inexpensive tests which provide rapid results and are therefore very useful clinically. As such, they were the preferred means of diagnosis in many microbiology labs until recently as they are being replaced with newer NAATs, specific to toxin A and B, which have significantly higher sensitivity (95%, compared to 35 to 50% for the EIA) and specificity nearing 100% [4]. These tests provide a rapid diagnosis and have significantly decreased number of repeat diagnostics [4].

If possible, diagnosis can be made or confirmed with endoscopy by identifying pseudomembranes. When present on endoscopy or histology, pseudomebranes definitively establish the diagnosis of C. difficile colitis [23]. Given the risks of colonic injury in the setting of active colitis, endoscopy is reserved for further evaluation of bloody stools or if the diagnosis remains in question.

pseudomembranes

CDI with associated pseudomembranes and toxic megacolon

In patients who are continuing to decline and develop changes in abdominal exam, plain abdominal radiographs are helpful in assessing for pneumoperitoneum and may additionally be helpful if pneumatosis or marked colonic distention are seen raising concerns for necrotizing changes or toxic megacolon. Plain radiographs are not specific for the latter findings and abdominal computerized tomography is more clinically helpful - particularly in patients with confounding history, such as inflammatory bowel disease or immunusupression. CT may show general findings of colitis, such as colonic wall thickening and pericolonic stranding but is also helpful in showing toxic megacolon (defined as a cecal diameter greater than twelve cm or transverse colonic diameter greater than six cm) [27]. The presence of toxic megacolon in the setting of clinical decline may necessitate a surgical intervention in addition to the medical management discussed in the next section.

computerized tomography

CT scan of a patient with CDI demonstrating extensive mucosal edema with hyperenahacment, colonic wall thickening and pericolonic stranding.

Medical Treatment

Many C. difficile colitis (CDC) infections may be treated with cessation of antibiotic therapy alone which is the first step in management regardless of disease severity [4][23]. Resolution of diarrhea may be seen within two to three days in those with mild disease once antibiotics are discontinued [23]. In more moderate and severe cases, anticlostridial antibiotics should be started empirically as soon as the diagnosis is suspected. These include oral metronidazole , oral vancomycin and vancomycin enemas. Intravenous metronidazole is acceptable when oral forms are not tolerated [1]. What constitutes increased severity of disease in children has been debated, however, and studies are currently under way to define the criteria better. Diarrhea leading to dehydration or producing 10 or more stools a day should be considered at least moderate disease and treated accordingly [24]. Although seen rarely in children compared to adults, severe disease is defined as infection associated with complications including pseudomembrabous colitis, intestinal perforation, intensive care unit admission, severe leukocytosis, signs of end organ injury particularly or CDC related surgery [24].

Oral metronidazole is the drug of choice for management of mild to moderate CDC in children and is dosed at 30 mg/kg/day not to exceed 2 g/day. It is also recommended for the management of a first recurrence [4]. Oral vancomycin or vancomycin enemas should be added in severe disease and for management of a second recurrence. 40 mg/kd/day, divided every six hours, is the recommended vancomycin dose with a maximum of 2 g/day [4]. While newer antibiotics are currently under investigation and some have been approved for adults (e.g. rifaximin, nitazoxanide, and idaxomicin), their use in children is reserved for study protocols or with consultation with an infectious disease specialist. Vancomycin remains the only FDA approved drug for the treatment of CDC in children but has been replaced in practice by metronidazole following the emergence of vancomycin resistantenterococci in the 1990s [4]. The recommended duration of therapy for initial episode of moderate and severe disease is 10 days [28]. However, if no response is noted within five days, a change in therapy (typically from metronidazole to vancomycin) is encouraged.[28][29]

Adjuncts to antimicrobial therapy for the management of CDC include probiotics, luminal toxin binding resins such as cholestyramine and tolevamer and fecal bacteriotherapy for recurrent disease. The use of probiotics has increased over the last decade and has been beneficial in the prevention of antibiotic associated diarrheal disease, including CDC. Its use in infection treatment has not been well established. In hospitalized children, probiotics were found to reduce the incidence CDC by 65.9% [30] when given along with antibiotics [24]. The 2013 guidelines from the AAP do not recommend the use of probiotics as studies in children were not well controlled and the probiotics themselves have not been standardized [4]. More data has emerged since this statement and probiotics are now being encouraged by more authors [24].

Nonspecific, inert agents such as cholestyramine and colestipol have been advocated in management of CDC due to their ability to bind luminal toxins. In addition, olevamer was specifically designed to bind C. difficile toxins [1]. As monotherapy, all of these are agents are inferior to standard therapy, with some data suggesting more success when used as adjuncts to antibiotics [1]. Tolevamer interacts with and inactivates vancomycin and become less attractive in clinical practice [31]. At this time data is lacking to support the use of any of these agents.

In infected children, recurrent colitis occurs in up to 30% of patients due to re-activation of the same isolate or infection with a new strain [4]. The antimicrobial approach to these recurrences is outlined earlier in this section with metronidazole being the preferred agent for management of first recurrence. Due to possible neurotoxicity, prolonged use of metronidazole is not recommended [32]. Cure rates diminish with repeated therapy and fecal microbiota transplantation (FMT) has been increasingly applied in the pediatric management of recurrent CDC. Adult data have shown infection clearance in 92% of the refractory cases prompting extrapolation of protocols to pediatric patients [33]. Recent case studies from the European Society of Pediatric Gastroenterology and the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition have shown very promising results with infection resolution rates of 90 to 100% in small series of patients [33][34][35]. Generally, donor stool is collected from parents or siblings of the infected patients and administered endoscopically or via a nasogastric tube [33][35]. In two separate series of 10 and six patients, respectively, only one recurrence was identified two months following FMT (after the patient had received a new course of antibiotics) [33][34]. While this therapy is promising, current protocols for amount, type and administration of donor stool have not been well established.

Finally, antiperistaltic antidiarrheal agents, including loperamide and Lomotil® should not be used in CDC as they can lead to complications including toxic megacolon [1].

Indications for Surgery

Complicated C. difficile infection (CDC) that requires operative management are rare in children. Retrospective data indicate a low rate of colectomies, anywhere between 0.35 and 1.2% [36], compared to adult patients with up to a 20% to 50% rate of surgical intervention [29]. Of children who require an operation, a significant number have comorbidities such as inflammatory bowel disease or immunosuppression which further complicate data evaluation as it is unclear whether the primary disease or the CDC led to a surgical abdomen [36]. Nonetheless, some patients progress to fulminant colitis, colonic necrosis and perforation either within hours of disease onset or after days of appropriate therapy [37].

Indications for surgery in children with CDC may be classified into two groups.

• patients with an apparent surgical abdomen from peritonitis and bowel perforation
• patients with an uncontrolled source of sepsis, with or without toxic megacolon

Clearly, there is some overlap here, as bowel perforation may lead to sepsis and septic shock. The distinction is merely made to those for whom an operation is absolutely indicated from those with relative indication from a more complex clinical course. In the first group, the diagnosis is clinically apparent and supported with findings of pneumoperitoneum on imaging. The second group is somewhat more challenging, as delay in diagnosis clearly impacts outcomes and worsens both morbidity and mortality although children still fare better than adults [29][37]. Worsening abdominal distention and pain in the setting of severe leukocytosis, fevers, tachycardia and hypotension refractory to volume expansion are symptoms of poor source control. Hypotension necessitating inotropes indicates the onset of septic shock. Concomitant multiorgan failure may be present and necessitates an emergent laparotomy [29][37].

In addition to above, radiologic studies (either plain radiographs or computerized tomography) that demonstrate pneumatosis and severe colonic distention consistent with toxic megacolon with extensive pericolonic stranding and ascites all confirm severe disease that may require an operation [37]. CT can also demonstrate a “target” or an “accordion sign” in the setting of toxic megacolon. The target sign is seen with submucosal edema while the accordion sign results from thickening of colonic haustra[38].

As discussed in the subsequent module, if an intervention can be performed prior to the development of septic shock more surgical options may be available in addition to total abdominal colectomy with an ileostomy. The progression to severe disease may occur rapidly and these patients should be monitored closely in units with ability for prompt escalation of care. Studies in the adult population have shown better outcomes when these patients are managed on surgical services and in surgical intensive care units presumably due to earlier recognition of disease progression and need for operative management [37].

Surgical Decision Making

The traditional approach to surgical management of C. difficile colitis (CDC) includes an exploratory laparotomy with total abdominal colectomy and end ileostomy to address the pancolonic nature of the disease. Other options, including diverting loop ileostomy with colonic lavage, are becoming more acceptable with improving results over the last decade [39][40]. Segmental colectomy has typically yielded poor results. Surgical treatment of CDC should be considered an adjunct to medical management and medical therapy should be imitated as soon as an infection in suspected. An operation may be necessary if medical therapy fails resulting in a surgical abdomen or persistent septic source. A subset of patients may present with fulminant colitis and require an emergent operation before the diagnosis has even been established. These patients should receive immediate resuscitation and antibiotics while being prepared for the operating room with plans to continue medical therapy subsequent to the operation. As dictated by the emergent nature of the therapy, many of these patients are unstable through out the operation and remain in discontinuity with an open abdomen and plans for second look laparotomy [37].

Steps of the Procedure

The initial goal of the operation for C. difficile infection (CDC) is source control which typically requires a subtotal colectomy[28][37]. The bowel may be left in discontinuity or an end ileostomy created as dictated by patient stability. A generous exploratory laparotomy provides adequate exposure for prompt and efficient colectomy, while minimizing the potential for injury. On initial examination the colon may appear ischemic and significantly dilated. In some cases, however, the gross examination may reveal a relatively normal appearing serosa, prompting less than adequate resection or no resection at all. As C. difficile colitis begins as a mucosal based process, the degree of disease may not be apparent on the serosal surface, but the operation of choice is still colectomy [37]. If the diagnosis is unclear, intraoperative endoscopy can help establish the presence of pseudomembranes[28][37]. Colonic tissue may be thin, distended and friable and iatrogenic perforation with peritoneal contamination should be avoided [41]. Clamping the mesocolon at the beginning of the operation may help control the inflammatory response [37]. The colon is further mobilized along the white line of Toldt, followed by ligation of the mesocolon close to the antimesenteric border. The latter move limits dissection of edematous, inflamed tissues toward the root of the mesentery and minimizes unintentional injuries [37]. As this operation does not require an oncologic resection, complete mobilization and wide resection of the mesentery is not necessary. Care should be exercised with mobilization of the hepatic and splenic flexure to avoid injury to the duodenum and the spleen.

C. difficile colitis is a pancolonic disease. If a colectomy is deemed necessary, most of the colon needs to be removed in order to achieve the best outcome. The rectum is typically preserved leaving a short Hartmann pouch at the recto-sigmoid junction.[37][41]

Once the colectomy is complete, an end iloestomy is matured and the abdomen is closed if the patient’s condition allows. If the patient continues to require cardiovascular support and has ongoing instability, the abdomen should be left open with plans for a second look laparotomy, abdominal washout and closure in 24 to 48 hours.

Intraoperative Decision Making

Recently, less aggressive surgical options, namely diverting loop ileostomy with colonic lavage have gained popularity in management of medically refractory C. difficile infection (CDC). Initially reported in 2011, this approach showed impressive results in a single center, which compared historical outcomes of total colectomy with prospective outcomes of ileostomy and lavage. Mortality alone was considered a secondary outcome, with 19% reported in those managed with an ileostomy compared to historical mortality of 50% following colectomy [40]. In addition, 79% of the patients underwent a successful ileostomy reversal within six months of ileostomy creation [40]. These results have since been difficult to reproduce in other institutions and more studies are recommended prior to full endorsement of the procedure.

In more stable patients, this approach does offer a less invasive operation, even if laparoscopy is not tolerated, with decreased stress to a critically ill patient and avoids the morbidity associated with a colectomy [37][39]. A standard loop ileostomy is performed, followed by intraoperative colonic lavage with 8L of polyethylene glycol solution and postoperative administration of antegrade vancomycin flushes [40],

In summary, the traditionally recommended operation involves a subtotal colectomy with a short Hartmann pouch and end ileostomy. If the patient remains critically ill throughout the operation, the abdomen may be left open and an ileostomy matured at a subsequent operation 24 to 48 hours later. More enthusiasm is emerging on use of loop ileostomy with colonic lavage and this may evolve into a more recommended approach as more robust data are acquired.

Postoperative Care

In a critically ill patient, postoperative care focuses on ongoing stabilization, restoration of intravascular volume and end-organ support as guided by the Surviving Sepsis Campaign and critical care principles. Antibiotics should be continued for at least 10 days and discontinued if there is clinical evidence of infection resolution [28]. Retesting for C. difficile is discouraged, as is the testing for cure, as these tests may remain positive for up to four weeks following resolution of disease symptoms [4][28]. Similarly, tests for recurrent C. difficile infection should not be done prior to four weeks from initial diagnosis [4]. In addition to antibiotics, nutritional support needs to be initiated as soon as clinically appropriate and continued until oral intake becomes sufficient to sustain the caloric needs.

The evidence is rather poor for continuation and duration of therapy following colectomy. In patients with an end ileostomy, therapy cannot reach the Hartmann pouch, which technically can harbor residual infection. Most societies recommend continuation of systemic thearpy with the addition of vancomycin enemas. The end point of therapy is not well defined, however, with low quality evidence supporting antibiotic use until the patient cinically improves [28]. Based on earlier evidence on the duration of systemic therapy, most protocols for diverting loop ilesotomy and colonic lavage have continued vancomycin irrigations for ten days [37][40].

Complications

Ongoing hemodynamic instability and septic shock, despite colectomy, lead to a high mortality in patients with fulminant C. difficile infection (CDC) with a 30 day mortality of over 50% in adults [29]. These statistics are better in children who overall experience less severe CDC. In addition, pelvic abscess due to Hartmann stump blow out or perioperative contamination can occur. Drainage of the stump with a Penrose drain or stump irrigation with Vancomycin enemas have been recommended but have not been shows to decrease rate of abscess [37].

As discussed in the previous section, a diverting loop ileostomy with colonic lavage, is being considered for more patients with surgical CDC. As this operation technically leaves the source of sepsis in situ, it may lead to ongoing instability. If the patient is not improving, a subsequent colectomy may be considered, although the success rate is unclear.

In infected children, recurrent CDC occurs in up to 30% of patients due to re-activation of the same isolate or infection with a new strain [4]. Metronidazole is the preferred agent for management of the first recurrence. Fecal microbiota transplant may be needed.

Finally, dehydration and electrolyte losses in patients with an ileostomy are common, necessitating frequent assessment of ostomy output, volume status, and need for electrolyte replacement.

Outcomes

Rates of antibiotic associated and C. difficile colitis (CDC) continue to rise in the era of modern medicine. In addition, the emergence of more virulent strains and an increase in community acquired infections have made previous low risk groups, including healthy children, more susceptible to serious disease. Children with comorbidities, such as inflammatory bowel disease, remain a high risk population whose infections are becoming more difficult to treat. While the outcomes in children are more promising than in adults, with lower rates of morbidity and mortality, the rates of complicated and recurrent CDC are on the rise necessitating constant evolution in our treatment strategies. Of those, antibiotic stewardship and timely cessation of antimicrobial therapy, when one is indicated, remain on the forefront of disease prevention.

CDC portends worse outcomes in hospitalized children, including an increased length of stay and in hospital mortality, transfer to an intensive care unit, increasing rates of colectomy and more frequent need for discharge to a care facility [42]. Most recent reviews indicate a stay of up to six days for children with CDC, compared to two days for those without. Rates of colectomy range anywhere between 0.3 to 1.2% and all cause mortality in children with CDC is on the rise with a reported rate of 0.5 to 4% [12][36][42]. In addition, even when accounting for other comorbidities, CDC appears to be an independent risk factor for mortality [12][42].

Recurrent infections contribute to compounding costs, repeated hospitalizations and overall increased morbidity. Up to 30% of children develop a recurrent infection, necessitating multifactorial therapy, including fecal microbiota transplant [4]. The latter has shown improved clearance rates with reported rate of 90 to 100% in refractory cases [33][34][35].

As noted earlier, rates of colectomy for fulminant C. difficile colitis are rare in children, compared to adult rates of surgical intervention of up to 51%.[29] Mortality following colectomy for CDC in adult patients is as high as 57% [29] but is difficult to ascertain in children due to low rates of surgery. Nonetheless, presence of an ileostomy and ultimate need for further operations (such as ileostomy reversal) come with independent risks of both repeated hospitalization and interventions.

Follow-Up

The majority of patients with C. difficile infection require no specific follow-up therapy as their diarrhea responds to the cessation of antibiotics and/or treatment with appropriate anticlostridial therapy. Repeated testing for cure is discouraged [2][4][28]. The recommended duration of therapy for initial episode of moderate and severe disease is 10 days [28]. However, if no response is noted within five days, a change in therapy (typically from metronidazole to vancomycin) is encouraged [28][29].

Research and Future Directions

As rates of CDC and its associated morbidity and mortality continue to increase research into development of newer antibiotics and immunotherapy are under way. Following exposure to C. difficile toxins, patients develop humoral immunity and have higher circulating levels of IgG and IgA [1][43]. Higher levels of these antibodies appear to be protective against active disease. Conversely, Kyne and colleagues demonstrated that patients with low levels of anti-TcdA IgG antibodies had a higher rate of symptomatic infection [43] and increased severity of disease [1][44]. Consequently, monoclonal antibodies to both toxin A and B have been used in recent studies in an attempt to improve therapy response. These have been added to standard antibiotic therapy with a reported significant reduction of recurrent infection.[1] In a randomized, double blinded, placebo controlled study by Lowy and colleagues, antibodies to both toxins were given to 101 patients and compared to 99 patients who received placebo therapy [45]. They showed a seven percent recurrence rate in the treatment group compared to 25% rate in the placebo group which is comparable to the recurrence rates in general population [45].

In addition to monoclonal antibody therapy, efforts have been directed toward development of an anti-C. difficile vaccine. The initial results were inconclusive but more recent data from a Phase I clinical trial appear much more promising. The study administered a vaccine to healthy adult volunteers between 18 and 65 years of age with no reported serious side effects [46]. The study is still in progress, but preliminary results show development of high antibody titers toward both TcdA and TcdB[46]. Finally, newer antibiotics, including rifaximin, nitazoxanide, idoxamicin and tinidazole are currently studied as alternatives to standard antimicrobial therapy for CDC. To date, all of these agents appear to have similar results to metronidazole and vancomcyin [47]. As antibiotic use remains the major inciting event in emergence of CDC, development of newer antibiotics may seem somewhat counterproductive, but remains necessary as newer, more virulent strains emerge. This is another argument for appropriate use of antibiotics in general with prompt cessation when therapy is no longer indicated in addition to strict infection control practices to minimize spread of the organism.

Perspectives and Commentary

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Discussion Questions and Cases

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References