OVERVIEW: What every practitioner needs to know
Are you sure your patient has Clostridium difficile infection? What are the typical findings for this disease?
The clinical manifestations associated with Clostridium difficile infection (CDI) vary widely, ranging from asymptomatic carriage to fulminant colitis and death.
The most common manifestation of C. difficile disease is watery diarrhea, rarely with blood or mucus. Other signs and symptoms include fever, abdominal pain, lower quadrant tenderness, and leukocytosis.
Pseudomembranous colitis, associated with the formation of pseudomembranes in the colon, may be present in up to 50% of cases of C. difficile colitis.
Less common but severe presentations may include fulminant or complicated colitis (including toxic megacolon, ileus, or bowel perforation), renal failure, and hypotension/shock. Death may also occur.
Very rarely, C. difficile can cause extra intestinal infection, including bacteremia, necrotizing fasciitis, and musculoskeletal infections. In a recent study, CDI-associated reactive arthritis was reported as a potential underdiagnosed manifestation in children occasionally misdiagnosed as septic arthritis. This association needs to be further evaluated in larger prospective pediatric cohort studies.
Clostridium difficile is a spore-forming, gram-positive anaerobic bacillus that produces two major toxins, toxin A and toxin B, important in disease pathogenesis. It should be noted that there are some strains of C. difficile that do not produce toxins; these strains do not cause C. difficile infection.
Because C. difficile is an obligate anaerobe, the bacteria will die within minutes of exposure to air in its vegetative state. However, the ability of C. difficile to form spores enables the bacteria to survive in the physical environment for long periods, facilitating transmission. It is the most common cause of health care-associated diarrhea among adults in the United States and is associated with significant morbidity and mortality.
What other disease/condition shares some of these symptoms?
Mild forms of CDI may mimic viral gastroenteritis.
C. difficile colitis should be differentiated from other infectious causes of diarrheal disease, including Salmonella, Shigella, Campylobacter, and Yersinia.
The abdominal pain and tenderness associated with C. difficile colitis may mimic peritonitis; in particular, the signs and symptoms of CDI may overlap with appendicitis, intussusception, and ischemic bowel.
The presence of toxic megacolon in an ill patient should also raise the concern for Hirschsprung disease.
What caused this disease to develop at this time?
C. difficile is primarily a health care-associated pathogen. Previous antibiotic exposure is the single most important risk factor for the development of CDI. Although clindamycin and cephalosporins have been implicated most commonly, nearly all antimicrobials have been associated with the development of C. difficile disease (See Table I).
As many patients do not acquire C. difficile from the health care environment or remain asymptomatically colonized with the pathogen, there are additional factors at play that lead to the acquisition of C. difficile colonization and development of CDI. Among adults, these risk factors can be summarized using three major categories:
Host factors, including advanced age, underlying severity of illness, and immune status.
Increased exposure to C. difficile spores through prolonged hospital stays, contact with contaminated health care environments, or poor hand hygiene by hospital personnel.
Dedicated epidemiologic studies evaluating risk factors for the development of CDI among children are limited and often produce conflicting results. To date, exposure to antimicrobial agents (in particular ≥2 anti-infective agents), previous hospitalization, underlying complex medical conditions (including the presence of a gastrostomy or jejunostomy tube), and diapered status have been cited as risk factors for the development of CDI in children. However, additional data, including multicenter studies, are needed.
In particular, CDI has been described at increased rates among special populations of children, including those with malignancy or a solid organ transplant and those with inflammatory bowel disease. Patients with cystic fibrosis have higher rates of asymptomatic colonization.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
As C. difficile may cause asymptomatic colonization, stool testing should be performed only on unformed stool specimens from symptomatic patients. Thus, CDI is primarily a clinical diagnosis. In addition, it is imperative to be aware of the kind of C. difficile testing performed at a given institution and the limitations of each test.
The final clinical diagnosis of CDI should be based on the simultaneous presence of diarrhea and of C. difficile toxins in a diarrheal stool specimen unless ileus is suspected (for children > 1 year old). Diarrhea is defined as 3 or more loose stools that take the shape of their container in a 24-hour period, based on the WHO criteria.
Diagnosis of Clostridium difficile Infections in Children
There are two major categories of C. difficile testing:
Toxin testing: enzyme immunoassay (EIA) and tissue culture cytotoxicity.
Organism identification: glutamate dehydrogenase (GDH) EIA, stool culture, and nucleic acid amplification tests (i.e., polymerase chain reaction [PCR]).
In the clinical setting, testing stool specimens for C. difficile toxins A and B by EIA is used commonly, and a wide variety of kits are available. They are rapid, specific, and relatively inexpensive to use. Assays that target detection of both toxins are preferable. However, the sensitivity of these tests varies (ranging from 70%-94%), and a negative test result may not rule out disease in the right clinical setting. As such, toxin testing by EIA is not recommended as a single modality for C. difficile testing.
Cytotoxicity assays were the gold standard before the more widespread introduction of EIA testing. However, they are expensive, require special equipment to perform, and have a slow turnaround time (24-48 hours).
EIA testing for C. difficile GDH are newer techniques in organism identification that are both rapid and sensitive. However, these tests are not specific for toxigenic strains of C. difficile and so require confirmatory testing with toxigenic culture or cytotoxicity assay.
In a recent pediatric study, 60% of patients with C. difficile diagnosed by PCR (136 cases) had no toxin detectable by ELISA revealing the present lack of laboratory criteria standardization for the diagnosis of CDI in children.
Stool culture remains the most sensitive method, but is not clinically practical because of its slow turnaround time (48-96 hours). Still, a combination of stool culture followed by identification of a toxigenic isolate (i.e., toxigenic culture) is the gold standard to which all other tests are compared and is essential for epidemiologic studies.
Other Issues in Testing
To overcome the lack of sensitivity of EIA testing, many laboratories use a two-step approach to C. difficile testing, including initial testing by EIA for GDH, followed by cytotoxicity assay or toxigenic culture on GDH-positive specimens.
When assessing the use of two-step testing algorithms for C. difficile infection, the following equations can be used:
Algorithm sensitivity = sensitivity(test1) × sensitivity(test2)
Algorithm specificity = specificity(test1) + [specificity(test2) × (1–specificity(test1))]
Of note, repeat testing during the same diarrheal episode, including “test of cure,” is not recommended.
Endoscopy can establish the diagnosis of pseudomembranous colitis. However, because of the high cost and risk to the patient, it should be reserved for special situations, such as when a patient has an ileus and stool specimens are not available or when other colonic diseases that can be diagnosed by endoscopy are being considered.
Would imaging studies be helpful? If so, which ones?
Imaging studies do not play a major role in the diagnosis of CDI. Abdominal computed tomography (CT) may be abnormal in up to 50% of patients with CDI, but is neither sensitive nor specific. Typical radiographic findings include segmental colonic wall thickening; however, these findings correlate poorly with clinical disease.
Among other diagnostic procedures, fecal levels of a bowel inflammation marker (calprotectin) has been recently associated with CDI severity.
If you are able to confirm the patient has C. difficile infection, what treatment should be initiated?
Approach to the First Episode of CDI
The first and most important step in treatment of CDI is to stop the inciting antimicrobial agent or agents as soon as possible. This is particularly important in preventing recurrence.
The mainstay of treatment of pediatric CDI is oral metronidazole (30 mg/kg/day in four divided doses, maximum 2 g/day) for 10 days. Metronidazole is effective when given orally or intravenously. Metronidazole remains the drug of choice for mild to moderate C. difficile infection in children as well as for the first relapse treatment.
A recent study comparing antibiotic-associated diarrhea (AAD) and CDI among adult and pediatric populations revealed that pediatric CDI responds better to metronidazole, while adult CDI responds better to vancomycin, while recurrent CDI is less common in children.
Oral vancomycin (40 mg/kg/day in four divided doses, maximum 500 mg, total daily dose 2 g/day) is also effective against C. difficile. Of note, vancomycin is only effective against C. difficile by the oral route. In pediatric patients, oral vancomycin or vancomycin administered with enema together with intravenous administration of metronidazole is recommended only for those who do not respond to metronidazole or for children with severe CDI defined as patients hospitalized in ICUs, with presence of underlying intestinal tract disease or with endoscopic confirmation of pseudomembranous colitis.
Additional supportive measures include fluid resuscitation and rehydration. Drugs that decrease intestinal motility should not be used.
Longer durations of therapy may be warranted if other antimicrobial agents cannot be discontinued.
The first recurrence of CDI is typically treated with the same medication as the initial episode.
The second recurrence can be treated with oral vancomycin in a tapered and/or pulsed regimen. Metronidazole should not be used beyond the first recurrence because of concerns for the development of neurotoxicity.
Treatment of subsequent recurrences are challenging and may require consultation with an infectious disease or gastroenterology expert with experience in treating recurrent CDI:
Cholestyramine (or other anion-exchange resins) and rifampin have been used in adults but have not been shown to decrease the likelihood of a subsequent recurrence. Of note, these resins also bind vancomycin, and so should not be used concurrently.
Rifaximin has resulted in cure in an uncontrolled case series of eight adult patients with recurrent CDI. However, C. difficile isolates were also noted to develop rising minimum inhibitory concentrations (MICs) against the drug during therapy.
Saccharomyces boulardii has been used with mixed results in adult patients, but may have benefit in preventing subsequent recurrences when used in combination with vancomycin. However, use of S. boulardii has been associated with the development of fungemia in immunocompromised adults, and so should be avoided in critically ill patients.
Fecal microbiota transplant (FMT) involves the instillation of stool from a healthy donor via enema or nasogastric tube, in an effort to replace the protective colonic microbiota. In a randomized controlled trial of FMT versus a standard vancomycin regimen, FMT was significantly more effective in the treatment of recurrent CDI in adult patients. Pediatric data are limited, but FMT has resulted in cure of recurrent CDI in uncontrolled cases in children > 7 years old with oral frozen FMT capsules. Contraindication for FMT is immunosuppression (severe neutropenia and prolonged administration of high dose corticosteroids etc).
Teicoplanin, a glycopeptide antibiotic similar to vancomycin, has been shown to be effective against C. difficile but is not available in the United States.
A novel macrolide antibiotic, fidaxomicin, is approved by the U.S. Food and Drug Administration for use in the treatment of CDI in adults. It had previously been shown not to be inferior to vancomycin in achieving clinical cure in randomized controlled trials; in addition, fidaxomicin was associated with a significantly lower rate of recurrence and may be superior to vancomycin in the face of concomitant antibacterial therapy. Pediatric studies are still pending.
Intravenous immunoglobulin has also been shown to be effective in nonrandomized case series in adult patients.
What are the adverse effects associated with each treatment option?
Adverse Events Associated with Major Treatment Options
The incidence of adverse effects with metronidazole is low.
Like any antibiotic, hypersensitivity reactions may occur.
Uncommon side effects include abdominal discomfort, nausea, vomiting, and metallic taste.
Cases of acute pancreatitis have also been reported.
Neurologic adverse events, namely peripheral neuropathy, have been reported, usually with prolonged treatment at high doses.
Reversible leukopenia and drug fever have also been reported.
Vancomycin is not systemically absorbed when administered orally. Therefore, limited side effects are reported.
Like any other medication, the possibility of a hypersensitivity reaction after administration remains.
What are the possible outcomes of C. difficile infection?
In most cases in children, C. difficile infection is cured without any complications or long-term sequelae.
Some believe that mild cases of CDI will resolve without therapy. In most cases, however, the risk of adverse effects of treatment is outweighed by the benefit of cure of the infection and prevention of C. difficile-associated complications.
Recurrence is the most important issue to discuss when counseling patients and their families. Recurrent episodes of CDI can be a major problem; up to 25% of patients may experience at least one recurrence. Other patients may continue to experience frequent recurrent episodes requiring retreatment. Recurrences may be related to relapse of infection with the original strain or reinfection due to exposure to a new strain. These two mechanisms are difficult to distinguish clinically.
Risk factors for recurrence include the administration of antimicrobial agents during or after the initial treatment of C. difficile infection as well as a defective immune response against toxin A. A recent study of risk factors for recurrent CDI in adults found additional modifiable risk factors, including use of certain antimicrobials following CDI treatment (fluoroquinolones) and gastric acid suppression. Another study identified malignancies and treatment with non-CDI antibiotics during CDI treatment as significant risk factors for recurrence in children.
What causes this disease and how frequent is it?
C. difficile is the cause of 20%-30% of cases of antibiotic-associated diarrhea among adults and is the most commonly identified cause of infectious diarrhea in health care settings.
Intestinal colonization rates are high among infants aged less than 1 year (up to 67% in some early studies). Colonization rates among healthy, older children are low, typically less than 5% for toxigenic strains; however, colonization rates have been reported up to 25% among hospitalized children.
A recent epidemiological study of CDI in children in the US reported for the period 2003-2012 a substantial increase from 24.0 to 58.0 per 10,000 discharges per year (P<0.001) among all age groups, while children 15 years and older presented the highest CDI rates.
The incubation period is unknown.
Historically, health care-associated diarrhea among children has been attributed to viral pathogens. However, C. difficile is increasingly recognized as an important pathogen among children in both community and hospital settings. Because C. difficile infection is not a reportable disease, surveillance data is limited. However, a large retrospective cohort study among 4895 hospitalized children at 22 US children’s hospitals demonstrated an incidence of 4.0 cases/1000 admissions. The median age of the children in this cohort was 4 years (interquartile range 1-11 years). The all-cause mortality rate among patients with CDI was 4%.
CDI can occur in both endemic and epidemic settings. Cases often appear in clusters or outbreaks within institutions. A study among adult hospitals in Quebec also suggests the possibility of CDI seasonality; however, additional studies are needed to elucidate this further.
Mode of Transmission
C. difficile can be isolated from soil and is commonly present in the environment. Transmission occurs mainly through the fecal-oral route through contact with C. difficile spores on external sources in health care environments. Many studies have implicated contamination of the hands of health care workers caring for patients with CDI as a primary mode of transmission; one study revealed a hand contamination rate of 59% among health care workers caring for patients with CDI, regardless of any direct patient contact.
C. difficile is also an important pathogen among several animal species; however, the role of transmission of C. difficile from animals to humans has not been established.
Genetics and CDI
Failure to produce serum antibodies to C. difficile toxin A has been shown to be associated with more severe and recurrent cases of CDI among adults.
More recently, a common single nucleotide polymorphismin the 251 region of the IL8 gene has been shown to be associated with increased susceptibility to CDI as well as an independent predictor of recurrent CDI. IL-8 secretion is associated with neutrophil recruitment and hypothesized to play a role in the pathogenesis of CDI. IL-8 has also been identified in stool specimens from patients with other forms of infectious or inflammatory diarrhea, including Shigella, Cryptosporidium, and enteroaggregative Escherichia coli.
It should be noted that these studies have been conducted in adult patients only; it is unclear whether or how these genetic polymorphisms play a role in CDI among children.
Changing Epidemiology of C. difficile Infection
The epidemiology of CDI has changed dramatically in recent years, including a rise in both the incidence and severity of disease. This change has occurred in parallel to the emergence of a hypervirulent strain of C. difficile, referred to as the North American pulsed-field gel electrophoresis type 1 (NAP1), restriction-endonuclease analysis group type B1, and PCR ribotype 027 (B1/NAP1/027), or NAP1 strain. The NAP1 strain is fluoroquinolone-resistant and capable of producing an extra toxin (binary toxin) as well as increased levels of toxin A and toxin B. In addition, NAP1 strains have been shown to have a mutation on a regulator gene (TcdC), which functions to downregulate the genes coding for toxin A and toxin B. Other studies have shown increased sporulation rates among NAP1 strains.
The first epidemic cases caused by the NAP1 strain were reported between 2000 and 2002 from the United States and Quebec, Canada, where the hypervirulent strain was associated with a dramatic increase in morbidity and mortality among affected patients, including higher rates of sepsis, toxic megacolon, bowel perforation, and death. From 2000-2001, the rate of hospital discharge diagnoses of CDI in the United States increased by 26% nationally.
Of note, many of these epidemic cases occurred in populations previously believed to be at “low risk,” including healthy peripartum women and persons in the community without traditional risk factors for CDI. Recent estimates from the CDC’s National Healthcare Safety Network have reported that 52% of cases of CDI are present on admission. Numerous studies have evaluated risk factors for “community-associated” CDI and have found that many patients lack previous exposure to antimicrobial agents. However, many of these studies were retrospective and used differing definitions for community-associated disease, such that additional studies are needed to better characterize community-associated CDI.
Since these early reports, the NAP1 strain has been identified throughout the United States, Canada, the United Kingdom, continental Europe, and Asia.
Less is known about the epidemiology of CDI among pediatric patients. However, several studies have noted a rise in cases of CDI among children in both community and hospital settings. From 2010-2011, active population- and laboratory-based surveillance for CDI in children by the Emerging Infections Program found that 71% of cases were community-associated. The highest CDI incidence was among 1 year olds, with similar disease severity across age groups.
The NAP1 strain also has been identified in children but less commonly than in adults.
The antibiotic susceptibility of pediatric C. difficile isolates revealed predominance of susceptible strains compared with adults’ as follows: 122 pediatric and 74 adult isolates: metronidazole, 0% and 0%; vancomycin, 0% and 8% (P = 0.003); rifaximin, 1.6% and 6.7% (P = 0.11); clindamycin, 18.9% and 25.3% (P = 0.29); and moxifloxacin, 2.5% and 36% (P = <0.0001).
How do these pathogens/genes/exposures cause this disease?
The pathogenesis of CDI involves three major steps:
Alteration of colonic microbiota (by antibiotic exposure, medications, or surgery), acquisition of C. difficile colonization (through the fecal-oral route), and growth of C. difficile and elaboration of toxins.
The major inciting event for CDI is disruption of the normal intestinal microbiota through exposure to either antibiotics or antineoplastic agents with antibacterial activity.
Among healthy children and adults, the indigenous microbiota of the gut provides an essential host defense mechanism against the colonization and overgrowth of C. difficile and other potential pathogens, known as “colonization resistance.” Antimicrobial therapy disrupts these defenses by exerting selective pressure on the microbiota and facilitating overgrowth of potential pathogens, an effect that may last days to weeks.
Once colonization with C. difficile is established, the virulence of the organism is related to the production of two major toxins: toxin A (an enterotoxin) and toxin B (a cytotoxin). Once these toxins undergo endocytosis by intestinal epithelial cells, they cause irreversible damage to the cells’ guanosine triphosphate binding proteins, leading to cytoskeletal derangement, and ultimately cell death.
Higher levels of toxin are associated with more severe episodes of colitis. Strains producing both toxins are common, occurring in 65% of cases. Toxin B is produced by 97% of C. difficile strains.
Not all persons who are colonized with C. difficile go on to experience disease, suggesting that there are additional factors involved that lead to the development of CDI. These factors include the virulence of the organism (i.e., epidemic strains), as well as host factors, including severity of underlying illness or the patient’s immune response (i.e., preexisting protective antibodies against toxin A).
What complications might you expect from the disease or treatment of the disease?
Complications associated with CDI are uncommon in children but may occur in cases of C. difficile colitis. They include toxic megacolon, bowel perforation and peritonitis, and hypovolemia, hypoalbuminemia, and hypokalemia with myopathy.
Are additional laboratory studies available; even some that are not widely available?
Nucleic acid amplification tests, PCR techniques, have been shown to be rapid, sensitive, and specific in detection of C. difficile. These tests work by detecting the gene for C. difficile toxin and so identify the organism directly. PCR is becoming increasingly available in many clinical laboratories and may ultimately replace current methods of testing because of the lack of sensitivity of other modalities.
How can C. difficile infection be prevented?
Limiting Antibiotic Use
CDI can be prevented by minimizing the frequency and duration of antimicrobial therapy as well as limiting the number of antimicrobial agents used. This objective can be supported in the inpatient setting through the implementation of an antibiotic stewardship program.
Preventing Transmission in the Hospital
The transmission of C. difficile can be mitigated in the hospital setting through the proper use of hand hygiene as well as the implementation of contact precautions, including the use of gowns and gloves, by health care workers and visitors on entry to the hospital room of a patient with CDI. Of these measures, the use of gloves has been shown to be the most critical in disrupting the transmission of C. difficile.
For hospitalized patients with CDI, contact precautions should be maintained for 48 hours after the resolution of diarrheal symptoms. In addition, environmental surfaces should be cleaned with chlorine-containing or other sporicidal agents.
Because of the inherent lack of activity of alcohol against C. difficile spores, the widespread use of alcohol-based hand rubs (ABHRs) have undergone scrutiny as a means for facilitating the transmission of C. difficile. However, there are very limited in vivo data to support this theory; in fact, there have been numerous published studies that have shown no association between ABHRs and increase in CDI. Furthermore, given that the use of ABHRs is convenient for both health care workers and visitors, the benefit of increased hand hygiene compliance through the use of ABHRs is likely outweighed by the risk of resistance of C. difficile spores to alcohol.
Classification of CDI
Healthcare facility–associated disease (HA-CDI) is considered when CDI symptom onset occurs during hospitalization (48 hours after admission), or up to 4 weeks after discharge. If symptom onset appears between 4 and 12 weeks after discharge, CDI is classified as“ indeterminate” disease. It is recommended that these need not be differentiated from community-associated CDI (CA-CDI) defined as symptom onset in the community or during the first 48 hours of admission and no prior admission to a healthcare facility in the last 12 weeks for surveillance purposes.
CDC revised CDI definition Jan 2017
Clostridium difficile infection must meet at least one of the following criteria:
Positive test for toxin-producing C. difficile on an unformed stool specimen (conforms to the shape of the container).
Patient has evidence of pseudomembranous colitis on gross anatomic (includes endoscopic exams) or histopathologic exam.
The date of event for CDI criterion 1, will always be the specimen collection date of the unformed stool, i.e., not the date of onset of unformed stool. A positive test for toxin-producing C. difficile and an unformed stool specimen is a single element and both are required to meet criterion 1.
There are limited data to support the use of probiotics to prevent the incidence of C. difficile infection and thus it is not routinely recommended.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has Clostridium difficile infection? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- If you are able to confirm the patient has C. difficile infection, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of C. difficile infection?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause this disease?
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can C. difficile infection be prevented?