Clostridium Difficile Infection: Considerations for the Contemporary Clinician

Clostridium difficileis a spore-forming, gram-positive bacteria spread by the fecaloral route. It is well established in the environment, often found in soil, water, meats, and an assortment of domesticated animals.^1-3An opportunistic pathogen,C. difficilecan overcome normal gastrointestinal (GI) tract flora, colonize the gut, and produce toxins (A and B) that may causeC. difficileinfection (CDI). This sequence of events triggers the most frequent reason for health care associated diarrhea and accounts for 15% to 25% of all antibiotic-associated diarrhea cases.^4-8

CDIs more than doubled from 2000 to 2009 and are close to eclipsing methicillin-resistantStaphylococcus aureusas the most common cause of health care associated infection in the United States.^3,4,6Part of this increase was due to a new hypervirulent strain, BI/NAP1/027, that delivers a third type of toxin (binary toxin) that is highly resistant to fluoroquinolones.^9-12In 2011, more than 450,000 CDI cases were diagnosed in the United States.⁹Since that time, CDI rates have smoothed out but remain historically high. Cost estimates vary, but these infections burden the health care system between $1.3 billion to $4.8 billion annually.¹³

Risk Factors

Known risk factors for CDI development include advanced age (older than 65 years), recent or multiple antibiotic use, numerous comorbidities diagnosis, extended hospitalization, and proton pump inhibitors use.^5,10,14,15Additional influences consist of previous GI surgery, enteral feeding, chemotherapy, immunosuppression,^3,6,9obesity, andC. difficileorganism exposure with the accompanying spread to other individuals.^1,7,11,16

Of the many identified risk factors, age and prior antibiotic use have special considerations. Chances of infection rise about 2% per year after age 18,17 and individuals older than 65 years have CDI rates 20 times larger compared with their younger counterparts.⁶As for antibiotics, even shortterm use raises the risk of infection.¹⁰The most common antibiotic groups that predispose an individual to CDI include cephalosporins, clindamycin, fluoroquinolones, and penicillins. Antibiotics groups that sometimes produce CDIs consist of macrolides, sulfonamides, and trimethoprim. The groups that rarely contribute to CDI involve aminoglycosides, chloramphenicol, metronidazole, tetracyclines, and vancomycin.^1,6

Etiology/Transmission

Many diverse native flora that occupy the GI tract promote and maintain normal GI functions, including food digestion and nutrient absorption. Under certain circumstances, such as antibiotic introduction or age-related physiological changes, the normal balance of flora is disturbed. This disruption can lead to dysbiosis, defined as reduction in the variety of the resident flora. As a result, the possibility exists forC. difficileto flourish and manufacture its toxins (A and B) and for CDI to develop.^1,3,10However, it is important to note that due to the defensive mechanisms of the native flora, exposure to and ingestion ofC. difficiledoes not necessarily cause symptoms or CDI.^11,12In addition,C. difficileisolates that are not found to generate either toxin A or toxin B do not cause disease.^3,10C. difficileis colonized in nearly 80% of normally developing infants and approximately 3% of healthy adults. Sources estimate that the number rises to 7% to 35% among hospitalized patients.^4,11,19Although an individual may be colonized, it does not mean that he or she will develop symptoms or become infected.^3,7,11

The most common method of transmission for CDI is the fecal-oral route, throughC. difficilespore ingestion.^1,3,12Nosocomial transmission was the primary way ofC. difficilecontact until fairly recently.C. difficilespores can last in the hospital environment for months; they have been found on communal equipment including stethoscopes, beside tables, thermometers, bed rails, commodes, and patients’ call lights. These spores may transfer through health care workers’ inadequate hand hygiene or inappropriate glove use. Patients themselves and visitors may also increase the risk with hand carriage of the spores.^{3,4,8,11,12,18}Lately, CDIs seem more likely to come from outside a hospital or an institution because these cases now account for more than half of all infections.^10,20

Clinical Presentation

Symptoms commonly appear 48 to 72 hours after infection with the toxigenicC. difficilespores.²¹The range of CDI symptoms is broad, with some individuals presenting at one end as asymptomatic carriers or having CDI with mild diarrhea, and patients on the other end having life-threatening pseudomembranous colitis or even dying.^1,3,8,10Patients often present with nonspecific signs and symptoms. Common sympwatery or semiformed, nonbloody diarrhea; tenderness in the lower abdomen; crampy abdominal pain; loss of appetite; dry mouth; and tachycardia.^3,7,12,19,22Patients may have 10 to 15 stools daily and are at risk for dehydration with electrolyte loss and water imbalance. If they present with fever, leukocytosis, and bloody diarrhea,C. difficilecolitis may be a concern.^1,3

Differential Diagnosis

A differential diagnosis needs to include other potential reasons for infectious diarrhea. Viruses, bacteria, and protozoa must be considered. Norovirus, rotavirus, adenovirus,Salmonella, andE. Coliare all known causes of diarrhea.¹⁸Viral symptoms may consist of nausea and vomiting, fever, generalized abdominal cramping, watery diarrhea, and intermittent headache. Bacterial drivers of diarrhea may trigger small volume stools, suprapubic pain, fever, and blood or mucous in the stool. Protozoal agents may produce loose stools, hyperperistalsis, itching of the perianal area, weight loss, rectal prolapse, wheezing, and tympanites. Inflammatory bowel disease, ischemic colitis, non-CDI antibiotic-related diarrhea, food poisoning, and traveler’s diarrhea should also be discerned.^3,12

Work Up

Diagnosing CDI correctly is essential for preventing transmission of the organism and deciding on appropriate treatment to reduce recurrence.²³Lab analysis should only be done on unformed stool samples from patients with clinically significant diarrhea. Although not validated, guidelines for clinically significant diarrhea can be defined as 3 or more loose stool episodes per day for 48 hours or more.^{1,4,12,13,18,24}

Lab Tests

Diagnostic test selection for CDI confirmation is controversial, as there is a variety of lab tests and a lack of standardized consensus for testing.²³CDI diagnosis is often completed through testing of stool samples.¹¹The stool culture has traditionally been the gold standard lab test for the identification ofC. difficile.^3,24Stool can be cultured forC. difficileand the recognition of its toxins (A or B). However, results take 4 to 5 days for confirmation, and the test does not detect if the sample has toxins (A or B) or not.¹The simplest test to distinguish whether toxins are present is the enzyme immunoassay. The results are accessible after 4 hours, but there are a large number of false-negatives.^3,12,24

Besides stool culture, several additional methods exist to help diagnose CDI. One test is the real-time polymerase chain reaction, which will detect if a sample has toxins. The test is quicker than a stool culture and has a high sensitivity and specificity; however, the diagnostic accuracy varies and relies on the prevalence of CDI.^25,26Another method is glutamate dehydrogenase (GDH) detection, which discovers ifC. difficileis present in the stoolsample, although it is not useful for showing if it is toxigenic. As a result, sensitivity is high and the specificity is low. Therefore, the GDH may show a large rate of false positives.¹¹

It is not recommended that repeat testing be completed during an ongoing CDI episode because it is of limited significance andC. difficilemay be measureable in the stool for weeks.^11,13,21,24If the CDI is more complicated and requires additional testing, a colonoscopy, endoscopy, and sigmoidoscopy can be advantageous in diagnosing complications.¹In advanced stages, an abdominal and pelvis computerized axial tomography scan may also be useful.^1,3

Complications

Complications are associated with severe CDI. A fulminating form may occur in 3% to 8% of patients, with a recent increase secondary to a hypervirulentC. difficilestrain that causes more systemic symptoms. Patients may have involuntary abdominal guarding, marked leukocytosis, anemia, and varied diarrhea that can lead to hypotension, shock, toxic megacolon, or ileus. Small intestine inflammation with CDI is quite rare, and appendicitis associated with CDI is even rarer. Any patient with these complications will likely require surgical intervention and hospitalization.^1,15,27

Treatment

Similar to CDI symptoms, treatment of an infection depends on its severity. Conservative treatments usually suffice for mild CDI, whereas surgery is reserved for severe CDI.^1,19Although tempting for patients to help with diarrhea, antiperistalsis medications, such as loperamide, should not be used in patients with CDI; however, evidence to support this claim is incomplete.¹²Probiotics have potential in CDI treatment. Although probiotics should not be used as the only treatment for an active CDI,¹¹they may be helpful for restoring native intestinal flora, increasing antimicrobial action, and providing additional intestinal barrier protection. More research is needed.

Two important principles should guide treatment. An essential first step is to have the patient stop taking the CDI-causing antibiotic. If that cannot happen, then it is necessary to switch to a commensurate antibiotic that is less likely to cause CDI. Second, prescribe antibiotics to patients with characteristic symptoms and a positive stool culture for CDI.¹

Antibiotics

For mild to moderate cases of CDI, oral metronidazole is typically the first choice; for more severe cases, oral vancomycin.^7,10,12Metronidazole impedes nucleic acid synthesis and disrupts protein synthesis in anaerobic bacterial DNA.¹⁰The dosage prescribed should be 250 mg 4 times per day by mouth or 500 mg 3 times per day by mouth for 10 to 14 days. The advantages of metronidazole include lower therapy cost and decreased spread of impervious bacteria strains such as vancomycin-resistant enterococci.^1,3A disadvantage of metronidazole is that the medication is systemically well absorbed, so little of it reaches the active site of infection.³¹

Vancomycin interrupts the assembly of the cell wall in gram-positive bacteria through inhibition of essential peptides for crosslinking.¹⁰It should be prescribed orally at a dose of 125 mg every 6 hours for 10 to 14 days; higher doses of vancomycin (500 mg for the same period) do not shorten recovery time. Vancomycin’s primary strength is that the full dose of the medication makes it to the site of infection of the large intestine before absorption because the body does not otherwise take it in before that point.^1,3

Several sources, including randomized controlled trials, have demonstrated that both medications have been shown to display significant efficacy in CDI treatment.¹However, the antibiotic treatments’ effectiveness is hampered by lack of patient response in some individuals and the high rate of recurrence.¹⁰There is a newer microbial agent, fidaxomicin, approved for CDI treatment. Fidaxomicin interrupts protein synthesis through RNA inhibition. One advantage that initial evidence points to is decreased recurrence rates against the nonhypervirulent strains compared with treatment with vancomycin. A disadvantage is its expensive cost compared with metronidazole and vancomycin.^10,12

Relapse and Recurrence

CDI recurrence is the result of either relapse from the original infectious strain or re-infection from a new strain.¹⁴Despite accepted treatments, recurrence rates after the first CDI commonly range between 20% and 30%, and after the initial recurrence, the risk of subsequent recurrences can be as high as 50% after two.^{10,12,15,24,28,29}Recurrent infections are usually more severe than the first CDI, and patients are at a greater risk for complications.¹The first recurrence may be treated with the same antibiotic used for the primary CDI, but the second and third recurrence may be treated with a vancomycin taper or fidaxomicin. Metronidazole is not recommended for the second or third recurrence due to the risk for neuropathy development.^32,33

An alternative after the first recurrence treatment failure is consideration of fecal microbiota transplant (FMT). FMT is a newer solution to this problematic issue, with a success rate approaching 90%. This procedure is done by transplanting stool from a healthy donor to a patient with multiple recurrent CDI.^1,3,12The stool can be transferred via a nasogastric tube or an enema. The donor needs screening for communicable diseases before transplant.¹

Emerging Therapies

Several emerging therapies show promise in the treatment of CDI. One is CRS3123, an oral medication in early stage clinical trials. CRS3123 produces gram-positive coverage as a narrow-spectrum agent. Similar to oral vancomycin, it has limited systemic effects but a high tract concentration, so the medication can get to the active site of infection. Early research shows CRS3123 antimicrobial activity against allC. difficiletested strains in vitro.¹⁰Another is monoclonal antibodies. Monoclonal antibodies have also displayed potential in reducing recurrence rates; specific ones with toxin selectivity are being researched. Typically, monoclonal antibodies can only be delivered via intravenous administration, so their delivery is aimed primarily at inpatient settings. This is advantageous because sicker patients with CDI tend to be hospitalized. Monoclonal antibodies were even better at decreasing CDI recurrence rates in humans when paired with antibiotics (vancomycin or metronidazole) compared with antibiotic administration as the solo treatment.¹⁰Finally, several clinical trials are occurring for potential vaccines against CDI.^9,10,12

Prevention and Provider Considerations

Due toC. difficilespores’ ability to live in the environment for months, CDI is difficult to prevent; nevertheless, steps can be taken to decrease occurrence, recurrence, and transmission. An important factor gaining recognition in CDI prevention is proper environmental cleaning, especially with bleach.^5,11,13,30Adequate hand hygiene, particularly with soap and water, have also been well documented as effective at decreasingC. difficilespread, whereas alcohol hand foam or rubs have not been shown to killC. difficilespores.^{3,5,7,9,11-13,30}Gloves also help reduce CDI rates because they prevent spore adherence to hands.⁴As prescribers, antibiotic stewardship is essential.^{5,7,9,11-13,30}

Conclusion

CDI is a complex and ongoing major health issue. Prevention, diagnosis, and treatment can be challenging due to the rise in hypervirulent strains. As antibiotic prescription rates continue to increase, it seems natural that CDI levels will remain at high proportions. Many new promising treatments are currently in development, but it may take months or years before they become available to the general population. In the meantime, antibiotic stewardship, hand hygiene, appropriate diagnostic testing, and proper environmental cleaning are vital for keeping this tenacious infection under control.

Jenna Herman is the family nurse practitioner program coordinator and an assistant professor at the University of Mary in Bismarck, North Dakota. Her clinical practice as a nurse practitioner includes the emergency department of a level 2 trauma center and working as locum tenens in primary care clinics, nursing homes, and hospitals across rural North Dakota.

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