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Antibiotic-Associated Diarrhea and Clostridioides difficile Infection
Antibiotic-Associated Diarrhea
Etiology
Diarrhea is a common adverse effect of antibiotic use and can result from a variety of mechanisms. The most common type of diarrhea, often simply called antibiotic-associated diarrhea (AAD), is not associated with any specific pathogen and is, in fact, not the result of infection; it is believed to be caused by a disturbance of the normal colonic microbiota that leads to alterations in the bacterial metabolome. Such metabolic changes include alterations in the degradation of nonabsorbed carbohydrates, leading to osmotic diarrhea; decreased bile salt deconjugation by bacteria leading to stimulation of fluid secretion by the colonic mucosa; reduced bacterial degradation of bile salts, which increase intestinal permeability, increase cyclic adenosine monophosphate (AMP), activate mast cells, and stimulate colonic chloride secretion (see Chapter 101 ); stimulation of intestinal motility through the motilin-like effect of erythromycin; an allergic reaction; or infection with microorganisms other than C. (Clostridioides) difficile , including Clostridium perfringens type A, Staphylococcus aureus , and Salmonella enterica .
The genotype of C. perfringens that causes AAD is distinct from those that induce food poisoning. Type A strains isolated from patients with AAD carry the C. perfringens enterotoxin gene in a plasmid, whereas those that cause food poisoning have a chromosomal C. perfringens enterotoxin gene. S. aureus was identified as a cause of severe AAD and enterocolitis before CDI was identified. Since the advent of sensitive and specific testing for C. difficile , however, very few cases of S. aureus AAD have been confirmed, and the true role played by this pathogen in AAD is unclear. Klebsiella oxytoca is another pathogen that releases several potent toxins and causes AAD associated with right-sided hemorrhagic colitis.
AAD complicates 2% to 25% of antibiotic treatment courses, but the incidence varies depending on the antibiotic used; it is more common, for example, during therapy with ampicillin (5% to 10%), amoxicillin-clavulanate (10% to 25%), or cefixime (15% to 20%) and less common during therapy with fluoroquinolones (1% to 2%) or trimethoprim-sulfamethoxazole (<1%).
Most cases of AAD are mild, self-limited, and unaccompanied by fever. Pseudomembranous colitis is absent, and significant complications are rare. C. difficile (CDI) accounts for less than 10% of AAD cases but is an important pathogen to identify because it often requires specific antimicrobial therapy and can lead to life-threatening complications, as discussed later. A comparison between the clinical features of AAD caused by C. difficile and AAD from other causes is presented in Table 112.1 .
TABLE 112.1
Differences Between Antibiotic-Associated Diarrhea From C. difficile Infection and From Other Causes
From Bartlett JG. Clinical practice: antibiotic-associated diarrhea. N Engl J Med 2002; 346:334-9.
| Characteristic | C. difficile Infection | Other Causes |
|---|---|---|
| Most commonly implicated antibiotics | Clindamycin, cephalosporins, penicillins, fluoroquinolones | Clindamycin, cephalosporins, ampicillin, or amoxicillin-clavulanic acid |
| History | Usually no history of antibiotic intolerance | History of diarrhea with antibiotic therapy is common |
| Clinical Features | ||
| Epidemiologic pattern | May be epidemic or endemic in hospitals or long-term care facilities | Sporadic |
| Diarrhea | May be florid; evidence of colitis with cramps, fever, and fecal leukocytes is common | Usually mild-moderate in severity (“nuisance diarrhea”) without evidence of colitis |
| Findings on CT or colonoscopy | Evidence of colitis is common; pseudomembranes often are present | Usually normal |
| Complications | Hypoalbuminemia, anasarca, toxic megacolon; relapse can occur after treatment with metronidazole or vancomycin | Usually none; occasional cases of volume depletion |
| Results of assay for C. difficile toxin | Positive | Negative |
| Treatment | ||
| Withdrawal of implicated antibiotic | Condition can resolve but often persists or progresses | Condition usually resolves |
| Antiperistaltic agents | Relatively contraindicated | Often useful |
| Oral metronidazole or vancomycin | Prompt response | Not indicated |
Prevention and Treatment
Management of AAD consists of discontinuing the inciting antibiotic if possible. If the diarrhea is moderately severe or poorly tolerated, an antiperistaltic agent (e.g., loperamide) or bismuth subsalicylate may be used to relieve symptoms.
Because AAD is believed to result from an alteration of the normal colonic microbiome, a variety of probiotic agents has been evaluated for its treatment and prevention (see Chapter 130 ). In a double-blind controlled clinical trial, oral capsules containing viable Saccharomyces boulardii , a nonpathogenic yeast, were coadministered with antibiotics; this combination treatment reduced the incidence of AAD in hospitalized patients from 22% in the placebo group to 9.5% in the S. boulardii group ( P = 0.04). Another randomized placebo-controlled trial, however, failed to demonstrate a beneficial effect for S. boulardii in an older adult population of antibiotic recipients. Lactobacillus species, in particular Lactobacillus rhamnosus GG, also have been studied in clinical trials of AAD. In one study of children being treated for respiratory tract infections, Lactobacillus GG was effective in reducing the incidence of AAD to 5% compared with a 16% incidence in the placebo group ; other clinical trials of Lactobacillus GG have yielded negative results. A meta-analysis examined the results of randomized double-blind placebo-controlled trials of probiotic therapy for AAD published between 1966 and 2000. Nine studies were analyzed, including 4 using S. boulardii and 4 using Lactobacillus GG. The combined odds ratio (OR) for AAD in the probiotic-treated groups was 0.37 compared with placebo (95% confidence interval [CI]: 0.26−0.53; P < 0.001). For S. boulardii, the OR in favor of active treatment over placebo was 0.39 (95% CI: 0.25−0.62; P < 0.001) and for lactobacilli the OR was 0.34 (95% CI: 0.19−0.61; P < 0.01). A recent systematic review and meta-analysis also examined the comparative efficacy and tolerability of probiotics for AAD. The authors found that L. rhamnosus GG (LGG) had the highest probability of being ranked best both in effectiveness (OR, 95% CI = 0.28 [0.17-0.47]) and tolerance (0.44 [0.23-0.84]) for prevention of AAD. In summary, the weight of published evidence suggests that probiotic agents such as LGG and S. boulardii , when used prophylactically in combination with antibiotics, reduce the risk for AAD. Such therapy may be especially advantageous in patients with a history of susceptibility to troublesome AAD.
Pseudomembranous Enterocolitis
Pseudomembranous enterocolitis was a rare entity in the medical literature before the widespread use of antibiotics. In recent decades, however, pseudomembranous colitis has emerged as a common complication of antibiotic use, with almost all cases caused by infection with toxin-producing strains of C. difficile .
A case report by Finney, published in 1893, is considered to be the first description in the medical literature of pseudomembranous enterocolitis. In that instance, fatal pseudomembranous inflammation of the small intestine followed surgery in a debilitated young woman with gastric outlet obstruction caused by peptic ulcer disease. The presence of an inflammatory pseudomembrane overlying intestinal mucosa characterizes pseudomembranous colitis (when the colon alone is involved) or pseudomembranous enterocolitis (when the small intestine also is involved). The pseudomembrane consists of inflammatory and cellular debris and forms distinctive patches of yellow or whitish-gray exudate that obscure the mucosa underlying them. In early lesions, a 1 to 2mm area of punctate ulceration may be visible. Grossly, pseudomembranes consist of ovoid plaques of 2 to 10 mm in diameter separated by areas of normal or hyperemic mucosa. Histologically, pseudomembranes can be seen to emanate from central areas of epithelial ulceration and erupt from the intestinal/colonic crypts in a “volcano-like” fashion. In more severe cases, the areas of ulceration and the overlying pseudomembranes coalesce to cover large areas of mucosa.
Risk factors for the development of pseudomembranous enterocolitis in the absence of CDI include intestinal surgery, intestinal ischemia, and other enteric infections. During the 1940s to the 1970s, most reported cases of pseudomembranous enterocolitis occurred following abdominal or pelvic surgery. Bartlett has identified descriptions of pseudomembranous enterocolitis in the medical literature associated with a wide variety of other intestinal disorders, including Shigella infection, Crohn disease, neonatal necrotizing enterocolitis, intestinal obstruction, Hirschsprung disease, and colonic carcinoma. Intestinal ischemia can result in histologic changes similar to those observed in severe C. difficile colitis, although classic pseudomembranes are uncommonly seen. Severe systemic insults including shock, advanced renal failure, spinal fracture, extensive burns, heavy metal poisoning, and hemolytic-uremic syndrome also have been associated with pseudomembranous enterocolitis. A potential common etiologic factor shared by many of these disorders is hypoperfusion of the intestinal mucosa with resultant ischemic necrosis and ulceration.
Infectious agents other than C. difficile have been implicated as causes of pseudomembranous colitis, most notably S. aureus . Before C. difficile was identified as the most common cause of pseudomembranous colitis, S. aureus often was identified in stool cultures of patients with postoperative pseudomembranous enterocolitis, and oral vancomycin proved to be effective therapy. In retrospect, however, it is difficult to ascertain whether the efficacy of vancomycin reflected its activity against staphylococcal infection or against unrecognized infection with C. difficile .
Clostridium difficile , recently reclassified as Clostridioides difficile , is an anaerobic, gram-positive, spore-forming, toxinogenic bacillus, first isolated in 1935 from the fecal flora of healthy neonates. The organism then passed into obscurity until 1978, when the association between toxins released by C. difficile and antibiotic-induced pseudomembranous colitis was first reported. Since that time, the incidence of CDI has increased dramatically, and the organism is now recognized as the primary cause of nosocomial infectious diarrhea in developed countries.
The reported incidence of CDI has risen substantially over the past 2 decades. For example, in the USA, the Agency for Healthcare Research and Quality identified 127,580 reported cases of CDI in hospitalized patients in 1997, 246,139 cases in 2004, and 346,805 cases in 2010. Reported deaths from CDI in the USA rose from 793 in 1999 to 7483 in 2008. Similarly, according to United Kingdom National Statistics, CDI as a primary or contributing cause of death rose from 13 per million population in 2001 to 83 per million in 2007. These observations prompted major efforts to reduce CDI in hospitals, and by 2011 the estimated number of C. difficile -related deaths in the United Kingdom had fallen dramatically to 19 per million population.
CDI also appears to be accompanied by heightened morbidity and mortality, owing in part to the emergence of increasingly virulent strains. One such strain was initially identified in the 1980s by restriction endonuclease analysis and named BI, but currently is referred to as North American Pulsed Field type 1 (NAP-1) or as PCR ribotype 027. The NAP-1 strain has led to severe outbreaks of CDI, with high mortality rates in both North America and Europe. The NAP-1 strain also produces binary toxin in addition to toxins A and B (see under “ C. difficile toxins”) and shows high level resistance to fluoroquinolones, making it more prevalent in patients receiving this class of antibiotics.
Epidemiology
Intestinal carriage rates of C. difficile in healthy adults are low (0% to 3% in American and European populations) and might represent intestinal transit without true colonization. In contrast, hospital inpatients treated with antibiotics have reported colonization rates of 10% to 21%. Acquisition from the hospital environment is a major source of CDI, not only from infected stool but also via environmental surfaces including floors, call buttons, soiled bedding, bedrails, bedpans, and toilet seats. One study demonstrated that spores persisted in toilets after flushing 24 times. The hands and stethoscopes of health care workers are also potential sources of nosocomial CDI. In one study, C. difficile was acquired, on average, in 3.2 days by patients who shared a room with a C. difficile -infected room-mate compared with 18.9 days by patients in single rooms or with room-mates whose stool cultures were negative for C. difficile . In the same study, C. difficile was cultured from the hands of 59% of hospital workers caring for patients with positive C. difficile cultures.
Asymptomatic carriers rarely develop C. difficile –associated diarrhea, but they serve as an important reservoir of nosocomial infection. In one study, 29% of environmental cultures taken from the hospital rooms of symptom-free carriers were positive for C. difficile , compared with only 8% of cultures from rooms of patients who were culture-negative for C. difficile . In antibiotic-treated animals, the infective dose of toxigenic C. difficile may be as low as 2 organisms. If human susceptibility is similar, control of CDI in hospitals will continue to be a major challenge because up to 10 9 organisms per gram of stool are excreted in liquid feces. Highly resistant spores of C. difficile can persist for many months in the hospital environment and can result in infection if ingested by a susceptible host.
Although it is not possible to eradicate C. difficile and its spores from the hospital environment, certain control measures have been recommended to reduce the prevalence of C. difficile –associated diarrhea ( Box 112.1 ). Infected inpatients should be bedded in private rooms whenever possible to reduce patient-to-patient spread of C. difficile . Strict precautions including use of gowns and gloves and regular hand washing after patient contact should be observed. The use of alcohol-based hand gels may not be as effective as washing with soap and running water in removing C. difficile spores; hence, washing with soap and running water is recommended as an additional measure in an outbreak setting. A controlled trial of using vinyl disposable gloves during patient contact also reduced the transmission of infection. After discharge of infected patients, surface environmental disinfection is best performed with a cleaning agent (e.g., hypochlorite solution) that contains approximately 5000 ppm available chlorine (corresponding to a 1:10 dilution of household bleach). Ultraviolet light-based cleaning also has been shown to be effective against CDI spores and is being adapted in hospitals to clean patients’ rooms after discharge.
BOX 112.1
Proposed Checklist of Hospital Interventions to Decrease the Incidence and Mortality of Health Care–Associated CDI
Modified from Abbett SK, et al. Proposed checklist of hospital interventions to decrease the incidence of healthcare-associated Clostridium difficile infection. Infect Control Hosp Epidemiol 2009; 30:1062-9.
BM , Bowel movement; MD , medical doctor; NP, nurse practitioner; PA , physician assistant; RN , registered nurse; WBC , white blood cell count.
| CDI Prevention Checklist |
|---|
|
Hospital outbreaks of C. difficile –associated diarrhea are common and likely result from the close approximation of susceptible persons (older and infirm patients) who are taking antibiotics and who are then exposed to the pathogen either in the hospital environment or through direct person-to-person spread. Outbreaks of infection are seen with the emergence of virulent strains, which are highly toxinogenic and resistant to numerous antibiotics including fluoroquinolones. CDI is best prevented by avoiding the unnecessary use of broad-spectrum antibiotics, especially in hospitalized patients, and by careful attention to hand hygiene and environmental cleaning.
CDI may be hospital or community acquired. Hospital-acquired infections may have their onset of symptoms and signs of colitis develop in the hospital or after discharge to the community. The reported incidence of community-acquired CDI (8 to 12 cases per 100,000 person-years) is substantially lower than that of hospital-acquired CDI, but has increased in recent years. Community-acquired CDI is often diagnosed in patients who lack typical risk factors for the disease (e.g., recent antibiotic exposure). In a recent population-based study, community-acquired CDI accounted for 41% of total cases; patients with community-acquired disease were more likely to be younger women with less comorbidity and likelihood of antibiotic exposure compared with individuals who had hospital-acquired disease.
Pathogenesis
The pathogenesis of CDI usually requires alteration of the normal colonic microflora; oral ingestion of C. difficile spores; colonization of the large intestine; production and release of toxins A and B into the colonic lumen; binding and internalization of toxins by colonocytes and lamina propria inflammatory cells; and subsequent colonic damage (colitis). Several host factors, particularly the immune response to C. difficile toxins, determine whether a patient remains an asymptomatic carrier or develops colitis ( Fig. 112.1 ).
Alteration of the Colonic Microbiota
CDI usually follows antimicrobial therapy, other events such as treatment with chemotherapeutic agents, or association with certain diseases such as IBD, all of which have related perturbations in the colonic microbiota. A diverse and phylogenetically rich microbiota is protective against CDI, especially recurrent CDI (see later). The protective barrier provided by the normal intestinal microbiota is often referred to as colonization resistance ; its impairment by antibiotics and subsequent infection with C. difficile can be demonstrated in animal models. C. difficile also can colonize the intestines of germ-free mice but is eliminated after these animals are inoculated with feces from normal mice, clearly confirming the importance of the normal commensal organisms in preventing colonization and supporting the rationale for IMT (fecal microbiota transplantation) for prevention and treatment ; however, it should be noted that many patients with community-acquired CDI lack any clear history of exposure to antimicrobial agents.
Human neonates have poor colonization resistance because they have not yet developed a stable complex colonic microbiota. Colonization rates with C. difficile of 25% to 80% have been reported in healthy infants and children up to 24 months of age, who, despite large concentrations of toxins in the feces, rarely develop C. difficile –associated diarrhea. Absence of toxin receptor expression on the immature colonic epithelium has been suggested as a mechanism to explain the symptomless carrier state in infants and children.
Almost all antimicrobial agents can predispose to CDI; certain classes, specifically third- and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and clindamycin, currently carry the highest risks ( Table 112.2 ). Cancer chemotherapeutic agents or bowel preparation regimens (e.g., before colonoscopy or colonic surgery) rarely result in sufficient disturbance of the intestinal microbiota to allow subsequent colonization with C. difficile .
TABLE 112.2
Antimicrobial Agents That Predispose to CDI
Adapted from Kelly C, Lamont J. Treatment of Clostridium difficile diarrhea and colitis. In: Wolfe MM, editor. Gastrointestinal pharmacotherapy. Philadelphia: WB Saunders; 1993. p 199.
| Frequently | Sometimes | Rarely |
|---|---|---|
|
|
|
C. difficile Toxins
Pathogenic strains of C. difficile produce 2 structurally similar protein exotoxins, namely, toxin A and toxin B, which are the major known virulence factors. The genes encoding toxin A and toxin B reside in a 19.6-kb chromosomal region, the C. difficile pathogenicity locus, which contains the genes encoding toxin A ( tcdA ) and B ( tcdB ) as well as 2 putative regulatory genes ( tcdC and tcdD , also called tcdR ) ( Fig. 112.2 ). The tcdD gene product appears to up-regulate toxin transcription by complexing with RNA polymerase that binds to the toxin promoter regions. The tcdC gene is transcribed in the opposite direction to tcdA , tcdB , and tcdD , and its gene product appears to decrease toxin production. The 5th gene of the pathogenicity locus, tcdE , encodes a protein with sequence similarity to bacteriophage pore-forming holin proteins and mediates the secretion of C. difficile toxins across the bacterial cell membrane.
Toxins A (308 kd) and B (220 kd) are members of the large clostridial cytotoxin family; they share a number of structural features, and are 49% identical at the amino acid level. Both toxins carry an N-terminal enzymatic domain that mediates their toxic effects on mammalian cells, a central hydrophobic region that might act as a transmembrane domain to facilitate entry into the cytoplasm, and a C-terminal domain consisting of a series of repeated sequences that mediate toxin binding ( Fig. 112.3 ). A fourth domain also has been identified, which encodes an intrinsic peptidase that releases the N-terminal enzymatic domain into the cytosol.
Both toxins function as uridine diphosphate glucose hydrolases and glucosyltransferases, a requirement for their cellular toxic effects. Following internalization into the host cell cytoplasm, the toxins catalyze the transfer and covalent attachment of a glucose residue from uridine diphosphate glucose to a conserved threonine amino acid on small (20 to 25 kd) guanosine triphosphate-binding rho proteins. Rho proteins are part of the Ras superfamily, are expressed in all eukaryotic cells, and act as intracellular signaling molecules to regulate cytoskeletal organization and gene expression. The rho proteins, RhoA, Rac, and Cdc42, are substrates for both toxins A and B, whereas Rap is a substrate for toxin A only. , Glucosylation of rho proteins by the toxins leads to disordered cell signaling, disorganization of the cytoskeleton, disruption of protein synthesis, cell rounding, and cell death. Both toxins also activate nuclear factor-κB, mitogen-activated protein kinases, and COX-2 in target cells, leading to the release of proinflammatory cytokines including interleukin (IL)-1β, TNF-α, and IL-8. These cellular proinflammatory effects contribute to the marked intestinal inflammatory response evident in C. difficile –associated diarrhea and pseudomembranous colitis.
Toxin A initially was thought to be the only enterotoxin based on studies in animals, whereas toxin B, an extremely potent cytotoxin, appeared to have little independent enterotoxic activity in animals. This suggested that toxin B did not contribute to diarrhea and colitis in humans. This view was challenged by studies on human colon showing that, in fact, toxin B is 10 times more potent than toxin A in inducing in vitro colon injury. Furthermore, toxin A − /toxin B + strains of C. difficile have been isolated from patients with diarrhea and pseudomembranous colitis, confirming that toxin B is a major virulence factor in human disease.
A minority (≈15%) of C. difficile clinical isolates produce a third toxin—binary toxin—that is analogous to the iota toxin of C. perfringens and is encoded at a site distant from the pathogenicity locus that encodes toxins A and B. Binary toxin is composed of 2 parts: a 48-kd enzymatic protein and a 99-kd binding protein. Although binary toxin shows some enterotoxic activity in animal models, its role in the pathogenesis of C. difficile –associated diarrhea and colitis remains unclear. Most pathogenic strains of C. difficile lack binary toxin but nonetheless cause substantial colonic inflammation and injury. The NAP-1 strain is binary toxin positive, however, thereby raising renewed suspicion that this toxin might enhance the pathogenic effects of toxins A and B.
Immune Response to C. Difficile
Serum IgG and IgA antibodies against C. difficile toxins are found in >50% of healthy children and adults. Mucosal IgA antitoxin antibodies also are detectable in colonic secretions from >50% of humans and might inhibit receptor binding of toxin A. Immunization against C. difficile toxins protects animals from C. difficile colitis but does not protect against colonization—a situation that may be similar to the asymptomatic carrier state in humans.
High concentrations of antitoxin antibody in the serum are associated with protection against CDI, whereas recurrent CDI has been associated with low serum antitoxin antibody levels in children and adults. In one study, adult inpatients with C. difficile diarrhea and a low concentration of serum antitoxin had a 48-fold greater risk of recurrent disease after initial successful treatment compared with patients who had high antitoxin concentrations ( Fig. 112.4 ). High serum antitoxin concentrations also have been identified in asymptomatic carriers of toxinogenic C. difficile . In a prospective study of nosocomially-acquired C. difficile , 51% of infected patients who were asymptomatic carriers had serum IgG antitoxin A concentrations that were 3 times higher than those in patients with diarrhea (see Fig. 112.4 ). The immune response to toxin B has also been correlated with clinical outcomes, including risk of recurrence.
Other Risk Factors For CDI
In addition to antimicrobial therapy and inpatient care, increasing age and increased comorbidity are important risk factors for CDI. The U.S. Agency for Healthcare Research and Quality has reported an overall CDI rate in hospitalized patients of 110 per 100,000 population. Age was a major risk factor for infection, with rates of 1089 per 1,000,000 population in those aged 85 or older compared with 486 per 1,000,000 for those 65 to 84 years of age, 101 per 1,000,000 for those 45 to 64 years of age, and 28 per 1,000,000 for those 18 to 44 years of age. Older adults are particularly predisposed to infection with C. difficile because of increased nosocomial antibiotic exposure and reduced innate and adaptive immune function. In one study of antibiotic recipients, patients with severe underlying disease at the time of hospital admission were 8 times more likely to develop CDI compared with patients who were less severely ill. Other reported risk factors for CDI include the use of an NG tube, GI procedures that are associated with bowel cleansing, ileus or both, ICU stay, and length of hospital stay. The strengths of the associations of these risk factors with C. difficile vary from study to study. These factors are often markers of disease severity, older age, or both, and the significance of their association with C. difficile can decline or be lost after controlling for these confounding variables.
There is a dose-dependent association between acid suppression and risk for C. difficile –associated diarrhea. Although many studies have confirmed this association, others have found that the initial apparent association was lost after adjusting for confounding variables, and meta-analyses disagree as to the strength of evidence for a primary association between PPI use and risk for CDI and whether or not a cause-effect relationship might exist. C. difficile spores are acid resistant; hence, potential effects of PPI use on CDI risk more likely results from microbiota alterations.
Patients undergoing cytotoxic chemotherapy for malignancy are at risk for CDI because of frequent antibiotic use, nosocomial exposure to C. difficile , and severe comorbidity. Even in the absence of antibiotic use, antineoplastic chemotherapy predisposes to CDI, reflecting the ability of these drugs to alter the colonic microbiota and reduce C. difficile colonization resistance. C. difficile –associated diarrhea also has been reported in patients undergoing immunosuppressive therapy in the setting of solid organ or bone marrow transplantation.
Infection with a broad range of enteric pathogens including C. difficile , Campylobacter , and Salmonella species can precipitate or mimic disease relapse in IBD. Patients with HIV infection are at risk for C. difficile –associated diarrhea because of multiple risk factors, including frequent prophylactic and therapeutic antibiotic use, hospitalization, and immunodeficiency. C. difficile colitis behaves the same in HIV-infected patients as it does in control groups, and testing for C. difficile should be a routine part of the diagnostic evaluation in patients with diarrhea and a history of current or recent antibiotic treatment.
CDI in IBD
Another nonantibiotic risk factor for CDI is IBD. C. difficile is the most commonly identified specific pathogen in IBD patients in North America and Europe, and is present in as many as 5% to 19% of patients with relapse of colitis in some case series. Patients with Crohn disease or UC remain at an increased risk of primary and recurrent CDI even in the absence of antibiotic or immunosuppressant therapy, likely caused by an underlying microbial dysbiosis associated with colitis. Patients who present with a flare of IBD should routinely be tested for CDI. IBD patients with CDI should be treated as having severe CDI even in the absence of severity markers such as leukocytosis or elevated creatinine; hence, they should be treated with vancomycin or fidaxomicin instead of metronidazole. Because CDI in IBD is associated with an increased risk of several adverse events including hospitalization, surgery, escalation of IBD therapy and mortality, one should consider hospitalization for monitoring and for the aggressive management for IBD patients with CDI who have profuse diarrhea, severe abdominal pain, a marked leukocytosis or evidence of sepsis. It may be prudent to postpone escalation of glucocorticoids and other immunosuppressive agents during acute CDI until therapy for CDI has been initiated because glucocorticoid escalation may be associated with worse outcomes. The decision to withhold, continue or escalate immunosuppression in IBD patients with CDI should be individualized because there is insufficient existing robust literature to guide firm recommendations. Like other patients with CDI, if diarrhea or other symptoms of colitis persist or return after antibiotic treatment, patients should be tested again for CDI. It may be hard to distinguish colonization from active infection if sensitive nucleic acid amplification testing (NAAT) is used owing to the possibility of more than one cause of symptoms, and it may be better to use a 2-step testing approach that includes a toxin assay in this situation. Lastly, IBD patients with recurrent CDI should be offered IMT because this treatment has been shown to be safe and effective to treat CDI in this patient population (see later).
Clinical Features
Clinical manifestations of CDI range from asymptomatic carriage to mild or moderate diarrhea to life-threatening pseudomembranous colitis with toxic megacolon. Asymptomatic carriage of C. difficile is common in hospitalized patients. Several large epidemiologic studies indicate that 10% to 21% of hospital inpatients receiving antibiotics in high-risk units are carriers. Although most of the C. difficile isolates from carriers are toxin producing, carriers do not develop symptomatic disease, perhaps as a result of adaptive protective immunity.
In patients who develop diarrhea with C. difficile , symptoms usually begin soon after colonization. The incubation period is usually less than a week, with a median time of onset of approximately 2 days. Colonization can occur during, or for up to 2 or even 3 months after, antibiotic treatment.
C. difficile diarrhea is typically associated with the frequent passage of loose or watery bowel movements. Some patients present with fever, leukocytosis, and cramping abdominal pain. Mucus or occult blood may be present, but melena or hematochezia is uncommon and, if present, suggests IBD, colon cancer, or another source of bleeding. Because C. difficile is not an invasive pathogen, extraintestinal manifestations of CDI such as septic arthritis, bacteremia, or tissue abscess are extremely rare. An oligoarticular, asymmetrical, nondeforming large-joint arthropathy, similar to that seen in other infectious colitides, is sometimes seen.
Patients with more severe disease can develop colonic ileus or toxic dilatation and present with minimal or even no diarrhea. In the absence of diarrhea, the only clues to the diagnosis may be high fever, moderate or marked (e.g., leukemoid) polymorphonuclear leukocytosis, lower or diffuse abdominal pain, tenderness, and distention.
Abdominal plain films might reveal a dilated colon, toxic megacolon, or small bowel ileus with air-fluid levels mimicking intestinal obstruction or ischemia. In such cases, a CT scan of the abdomen may reveal nonspecific features common to ischemic, infectious, and inflammatory colitides ( Fig. 112.5 ). Radiologic features of pseudomembranous colitis include mucosal edema, a thickened colonic wall, pancolitis, and pericolonic inflammation with or without ascites, and usually without small bowel involvement other than ileus; one notable exception is in patients with a mature ileostomy or ileal pouch where C. difficile can infect the colon-like altered ileal mucosa. Flexible sigmoidoscopy or colonoscopy is sometimes indicated to identify pseudomembranous colitis when the diagnosis remains unclear after initial evaluation (see later).
Complications of severe C. difficile colitis include dehydration, hypoalbuminemia, ascites, electrolyte disturbances, renal failure, hypotension, toxic megacolon, systemic inflammatory response syndrome, bowel perforation, and death.
Diagnosis
The diagnosis of CDI is based on the presence of diarrhea plus other evidence of acute colitis, and demonstration in stools of C. difficile toxins or toxinogenic C. difficile . Although a history of recent antibiotic use is common, it is not a requirement for diagnosis as CDI is often seen without recent antibiotic exposure.
Whom to Test?
The diagnosis of CDI should be considered in a patient with acute diarrhea, especially if they had antibiotic exposure within the previous 2 to 3 months. Most, but not all, cases occur during or after hospitalization, although a significant proportion are community acquired. Approximately 40% of patients with CDI at tertiary referral centers are symptomatic on admission; most have had a recent hospitalization.
Recent CDI testing guidelines recommend that if there are pre-specified institutional criteria to test only stools from patients with unexplained and new onset diarrhea (3 or more unformed stools in 24 hours), then a NAAT can be used alone ( Fig. 112.6 ). If these testing criteria are not in place, then a 2-step test starting with glutamate dehydrogenase (GDH) enzyme immune-assay (EIA) or NAAT followed, if positive, by toxin testing (e.g., by EIA) is recommended (see later).
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