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Introduction

Clostridioides difficile, previously known as Clostridium difficile, is a gram-positive, spore forming bacteria that causes diarrhea and colitis. Severe cases can cause sepsis, pseudomembranous colitis, toxic megacolon and multiorgan failure. According to the Centers for Disease Control and Prevention (CDC), C. difficile causes almost half a million infections in the US each year. 1 in 6 patients will become reinfected in 2 to 8 weeks. One in 11 people over age 65 diagnosed with a healthcare-associated CDI die within one month.1C. difficile was reported to be the leading cause of gastroenteritis-associated mortality causing approximately 12,800 deaths in 2017. There were 223,900 estimated cases in hospitalized patients contributing to $1 billion estimated attributable healthcare costs in 2017.2,3C. difficile is primarily spread via the fecal – oral route or hand-to-hand contact. There have also been reports of airborne environmental dispersal in healthcare facilities.3

Risk factors for developing a CDI include antibiotic use, acid-suppressing medications such as proton pump inhibitors or histamine-2 blockers, age > 65, recent hospitalizations, a weakened immune system potentially due to medications like chemotherapy, previous CDI or exposure to someone with active CDI.4 The number one risk factor for CDI remains antibiotic use. Symptoms of CDI usually develop shortly after antibiotic use, with risk persisting for up to 90 days. The highest risk of CDI occurs during and in the first month after antibiotic exposure. Extended antibiotic therapy and multiple courses of antibiotics further increases risk. As an unintended consequence of antibiotic use, people on antibiotics are 7-10 times more likely to get CDI due to the alteration in the composition of the gut microbiota and reduction in biodiversity.5 A study conducted in 2013 found an estimated 64% of patients received antibiotics 12 weeks before developing CDI.6 Persistent effects have been described, particularly following the use of fluoroquinolones. Changes observed following the use of penicillins include a decrease in both gram positive anaerobic and aerobic cocci as well as a decrease in enterobacteria. Cephalosporins, as well as broad spectrum penicillins such as piperacillin/tazobactam, also have been reported to decrease Clostridia, Lactobacilli and Bifidobacteria. Clindamycin decreases anaerobic bacteria, leads to a disappearance or a dramatic decrease in Bifidobacterium, Clostridium and some species of Bacteroides.5

The CDC publishes Antibiotic Resistance Threats in the United States, with the most recent updates from 2019. This report includes national death and infection estimates linked to antibiotic resistance. Eighteen antibiotic-resistant bacteria and fungi are categorized into three categories of concern: urgent, serious, and concerning. C. difficile is considered an urgent threat based on the detrimental impact it can have.7

C. difficile produces enterotoxin (toxin A) and cytotoxin (toxin B). Neutrophils are triggered as a result of toxin production and subsequently results in inflammation of the mucosal lining, cellular necrosis, and increased peristalsis and capillary permeability, contributing to diarrhea and colitis. The North American pulsed-field gel electrophoresis type 1 (NAP 1) strain of C. difficile has been linked to severe outbreaks in North America and Europe. NAP 1 is reported to produce binary toxin, 16 times more toxin A and 23 times more toxin B than other strains.8

Patients who have a CDI will present with diarrhea with loose, watery stools. According to the Infectious Diseases Society of America (IDSA) and Society of Healthcare Epidemiology of America (SHEA) guidelines, patients who present with unexplained and new onset >3 unformed stools in 24 hours should be tested for CDI. Frequent bowel movements will continue for several days accompanied by fever, stomach tenderness or pain, loss of appetite and nausea.9

CDC CDI Tracking

In 2009, the CDC launched the CDI surveillance program. It is conducted through the Emerging Infections Program (EIP) Healthcare-Associated Infections Community Interface (HAIC). The data can be utilized to measure CDI burden, identify strains of C. difficile, and monitor trends in the select 10 EIP sites across the US. As of December 2013, the sites include areas from California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, New York, Oregon and Tennessee.10 

For the purposes of tracking, case definitions have been set forth by the CDC. A CDI incident case is a positive C. difficile toxin assay or a positive C. difficile molecular assay of a stool specimen from a resident in the surveillance area who is > 1 years old. A stool specimen that is C. difficile positive greater than 8 weeks after the last positive specimen is a new case. Recurrent episodes are CDI cases with a positive specimen between 2 to 8 weeks after the last positive specimen. Duplicate episodes are cases with a positive specimen less than 2 weeks since the last positive specimen.10

The 2017 Annual Report for the EIP for CDI highlights the overall distribution of CDI by selected demographics including sex, age group, race and epidemiologic classification. As expected, based upon risk factors, the greatest number of cases occurred in those > 65 years old and more healthcare-associated CDI cases than community-associated CDI cases occurred in this age group. Based on sex, females had higher incidence than males for both community and hospital associated CDI. Based on race, white patients had more than 70% of cases for both community and hospital associated CDI. Other information provided included the percentage of CDI cases with first recurrences, hospitalization, and in-hospital death by age group and epidemiologic classification. For community-associated CDI cases, unfortunately for the age group > 65 years, they had the highest percentages of first recurrence, hospitalization and in-hospital deaths. For healthcare-associated CDI cases, the age group of 50 – 54 years old had the highest rates of first recurrence and hospitalization in 2017, but the age group > 65 years old still had the highest percentage of in-hospital deaths.11 

For acute care hospitals, the National Healthcare Safety Network (NHSN) is the nation’s most widely used healthcare-associated infection (HAI) tracking system. It provides facilities, states, regions, and the nation with data needed to identify problem areas, measure progress of prevention efforts, and ultimately eliminate healthcare-associated infections.

CDI must be reported to NHSN to fulfill Centers for Medicare and Medicaid Services’ (CMS) Hospital Inpatient Quality Reporting (IQR) requirements. The established CDI event categorizations are as follows12:

  • Community-Onset
    • Collected from an outpatient location in which the patient was not previously discharged from an inpatient location within the same facility ≤ 28 days prior to current date of specimen collection
    • Collected in an inpatient location ≤3 days after admission to the facility (days 1, 2, or 3 of admission)
  • Community-Onset Healthcare Facility-Associated
    • Collected from inpatient or outpatient location from a patient discharged from the facility < 28 days prior to current date of stool specimen collection. Previous discharge must have been from an inpatient location within the same facility
  • Healthcare Facility-Onset
    • Collected from an inpatient location > 3 days after admission (on or after day 4)

Diagnostic recommendations from IDSA/SHEA

When to test

Patients who present with a new onset of diarrhea, defined as 3 or more episodes of unformed stools in a 24-hour period, without any obvious explanations are candidates for C. difficile testing. This is particularly important in patients with relevant risk factors such as recent antimicrobial use, hospitalizations, advanced age (≥65 years old), and cancer chemotherapy. C. difficile testing should only be performed in patients presenting with acute diarrhea and suspecting CDI. Asymptomatic patients should not be screened for CDI since C. difficile carriers may yield a positive toxin result without having active disease. Stool samples that are sent to the laboratory should be soft, liquid stools that take the shape of the container in order to improve the specificity of C. difficile testing. Patients with suspected CDI should be placed on preemptive contact precautions while pending test results in order to decrease the transmission of C. difficile to other patients. Repeat CDI testing is not recommended as patients may remain positive for at least 6 weeks after the initial positive result.9

Comparison of laboratory analyses for CDI

There are a variety of laboratory stool testing that is available to support to the diagnosis of CDI. All these methods detect either one or both the major C. difficile toxins (A and B) or the C. difficile organism directly in the stool. Currently available laboratory tests for the diagnosis of CDI include toxigenic culture, nucleic acid amplification tests (NAAT), glutamate dehydrogenase (GDH) immunoassay, cell culture cytotoxicity neutralization assay, and toxins A and B enzyme immunoassays (EIA).

The latest clinical guidelines on CDI by IDSA/SHEA have two diagnostic testing recommendations based on specific institutional criteria. If the institution has pre-determined criteria where patients are screened carefully for clinical symptoms likely associated with CDI (at least 3 loose or unformed stools in ≤24 hours with history of antibiotic exposure and not taking a laxative), a highly sensitive test such as a NAAT alone or multistep algorithm may be used. If the institution does not have pre-determined criteria for patient stool submission, it is most appropriate to use a diagnostic approach that includes a test that is more specific for CDI. The use of a stool toxin test as part of a multistep algorithm rather than a NAAT alone for all specimens received in the clinical laboratory is preferred in this scenario. A multistep algorithm can be the following combination of testing: GHD plus toxin; GDH plus toxin arbitrated by NAAT, or NAAT plus toxin.9 An overview of each laboratory method will be discussed in the following section in the order of decreasing sensitivity.

Toxigenic culture for C. difficile requires the isolation of the organism from fecal specimens using an anaerobic agar or broth culture with a selective medium. Although this method is highly sensitive, toxigenic culture is seldomly used in clinical practice as it is labor intensive, and results take several days to finalize. In addition, the use of a second test with EIA or NAAT is necessary to detect toxin production. Toxigenic culture is mainly used for epidemiologic studies.9, 13-14

NAATs, which include polymerase chain reaction (PCR), are highly sensitive laboratory tests that detect one or more genes specific to toxigenic C. difficile strains. Although this method is specific for toxigenic strains, NAAT is not capable of testing for active toxin production and can detect asymptomatic carriers of C. difficile. When using NAATs in clinical practice, it is important to only test stool samples from patients who are experiencing symptoms of active CDI in order to avoid the overdiagnosis of CDI and unnecessary treatment of patients with antibiotics. The results from NAAT can be available within as little as one hour.15-17

GDH immunoassays detect the essential antigen that is present in all isolates of C. difficile. This method has good sensitivity with a quick turnaround time in less than one hour. However, GDH testing lacks specificity because the GDH antigen can be found in both toxigenic and nontoxigenic strains of C. difficile. The clinical use of GDH must be combined with another test, usually the toxin EIA. In a multistep algorithm for diagnosing CDI, GDH testing is used as the initial screening step followed by a toxin test and or a molecular test for toxin gene detection. This multistep approach has allowed for rapid results and improved sensitivity compared with toxin EIA alone.9,18-19

Cell culture cytotoxicity neutralization assay was historically considered the gold standard for diagnosing CDI. This method has fallen out of favor and is not used in clinical practice because of its cumbersome and time-consuming procedures. Additionally, it lacks standardization, requires expertise in cell culture, and has a relatively slow turnaround time of 48 hours.9,13

Toxins EIA use monoclonal or polyclonal antibodies to detect C. difficile toxins. Since majority of C. difficile strains produce both toxins A and B or toxin B only, it is generally recommended that assays detect for both toxins A and B. There are several inexpensive commercial assays available with a quick turnaround time within hours.9,13,16 The sensitivity of EIA for toxins A and B is on average about 75 percent depending on the assay with high specificity up to 99 percent.20 High false-negative rates have been reported with EIA since 10 to 1,000 pg toxin must be present for detection.21 IDSA/SHEA recommends combining toxins EIA with GDH antigen testing and arbitrated with NAAT when necessary.

Determination of disease severity

Patients with CDI can present with a range of clinical manifestations from acute diarrhea to fulminant disease with toxic megacolon requiring hospital admissions to the intensive care unit or emergency surgery. The IDSA/SHEA guidelines use severity criteria based on white blood cell (WBC) count and serum creatinine to guide treatment decisions in CDI. Although several studies have evaluated potential factors for correlation with disease severity and treatment outcome21-23, current recommendations are based on expert opinion and further validation of these criteria is still needed. The IDSA/SHEA criteria for C. difficile disease severity are as follow:9

  • Non-severe CDI: Leukocytosis with a WBC count of ≤15,000 cells/mL and a serum creatinine level <1.5 mg/dL
  • Severe CDI: Leukocytosis with a WBC count of ≥15,000 cells/mL or a serum creatinine level >1.5 mg/dL
  • Fulminant CDI: Hypotension or shock, ileus, or megacolon

Treatment recommendations from IDSA/SHEA

Initial episode

Treatment should be initiated in patients with a diagnosis or high suspicion of CDI where a substantial delay in laboratory confirmation is expected.9,15 Recommendations for the treatment of CDI is based on disease severity. In patients with non-severe or severe CDI, a standard course of vancomycin 125 mg orally four times a day or fidaxomicin 200 mg orally twice a day for 10 days can be used as first line treatment. Oral vancomycin achieves high levels in the colon due to its lack of systemic absorption.27 Intravenous vancomycin is minimally excreted into the colon hence it is not effective in CDI. Fidaxomicin demonstrated non-inferiority in clinical response rates compared to oral vancomycin.25,26 Oral metronidazole at a dose of 500 mg orally three times a day may be used as an alternative in the setting of non-severe CDI only where oral vancomycin and fidaxomicin is not available.9 Metronidazole is no longer recommended as first line treatment in CDI since clinical cure superiority was observed in patients with CDI treated with oral vancomycin compared with oral metronidazole.28,29

For fulminate CDI, oral vancomycin at a higher dose of 500 mg orally four times a day is recommended even though there is a lack of high-quality evidence to support this recommendation. If ileus is present, vancomycin may be administered rectally at a dosage of 500 mg in 100 mL of normal saline every 6 hours as a retention enema. Intravenous metronidazole 500 mg every 8 hours should be administered in addition to oral or rectal vancomycin, especially in the presence of ileus in order to ensure adequate antibiotic concentrations in the inflamed colon. Surgical intervention, such as a subtotal colectomy with preservation of the rectum, may be lifesaving for severely ill patients with rising leukocytosis (≥25,000 cells/mm3) or elevated lactate levels (≥5 mmol/L).9,30 Early surgical management has been linked to improved outcomes, such as increased survival rates.31

Recurrent episodes

Recurrent CDI is defined as an episode of symptom onset and positive diagnostic result following a confirmed episode of CDI within the previous 2 to 8 weeks.9 Management of recurrent CDI depends on the course of therapy prescribed during the initial episode. For patients with a first recurrence of CDI who were initially treated with oral metronidazole, treatment with a standard course of vancomycin for 10 days is appropriate. For patients with a first recurrence of CDI who were initially treated with a standard course of oral vancomycin, oral vancomycin tapered and pulsed therapy or a standard course of fidaxomicin are recommended. A tapered and pulsed oral vancomycin regimen consists of a stepwise decrease in dosage over time, usually over 12 weeks, and is based on a theory that the intermittent use of antibiotics facilitates a gradual restoration of the normal microbiota. An example of a tapered and pulsed oral vancomycin regimen is as follow: 125 mg four times a day for 10-14 days, 125 mg twice daily for 7 days, 125 mg once daily for 7 days, and then 125 mg every 2 or 3 days for 2 to 8 weeks.9

Antibiotic treatment options for patients with more than one recurrence of CDI include oral vancomycin therapy using a tapered and pulsed regimen as described above, a standard 10-day course of oral vancomycin followed by rifaximin 400 mg orally three times a day for 20 days, or fidaxomicin. The effectiveness of vancomycin followed by rifaximin was evaluated in a small randomized controlled trial which showed a decreased incidence of diarrhea compared to placebo.32 One potential concern for the use of rifaximin is resistance as the development of C. difficile strains with high minimum inhibitory concentrations (MICs) while on rifaximin treatment have been reported.19

Role of fecal microbiota transplant (FMT)

In patients with multiple recurrences of CDI despite repeated courses of appropriate antibiotics, fecal microbiota transplantation (FMT) may be considered as a viable alternative treatment approach.9 FMT consists of the instillation of processed stool collected from a healthy donor into the intestinal tract of patients with recurrent CDI via oral capsules, a nasogastric/nasoduodenal catheter, or into the colon through a colonoscopy or a rectal catheter.33,34 This process has shown to correct the intestinal dysbiosis brought about by repeated courses of antibiotics and is associated with high treatment success rates regardless of the route of administration. The highest success rates (80-100%) have been reported with instillation of feces via the colon.35-39 FMT has been well accepted by patients and it appears to have decent short-term safety data with mild to moderate self-limited post-FMT adverse events.9,40

Potential candidates for FMT include patients with their third or subsequent non-severe CDI recurrence.9 Once a candidate for FMT has been identified, an appropriate stool donor must be selected and carefully evaluated in accordance with recent recommendations in order to minimize the risk of iatrogenic infections. Detection of any of the following criteria should disqualify the individual from donating stool:9,41,42

  • Detection of any transmissible microbial pathogen, including SARS-COV-2 for stools donated after December 1, 2019
  • Treated with an antibiotic during the preceding 3 months of donating stool
  • Pre-existing medical conditions such as IBD, malignant diseases, chronic infections, active autoimmune illness, recipient of immunosuppressive medications
Figure 1. IDSA/SHEA Diagnostic Recommendations for CDI9
1NAAT: Nucleic acid amplification test
2EIA: Enzyme immunoassay
3Multistep algorithm: Glutamate dehydrogenase (GDH) plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin
Table 1. IDSA/SHEA Treatment Recommendations for Initial Episodes of CDI in Adult Patients9
CDI Disease Severity Treatment Recommendation
Non-severe

(WBC ≤15,000 cells/mL, SCr <1.5 mg/dL)		 · Vancomycin 125 mg PO 4 times a day for 10 days OR
· Fidaxomicin 200 mg PO twice daily for 10 days
· If above agents are not available: Metronidazole 500 mg PO 3 times day for 10 days
Severe

(WBC >15,000 cells/mL, SCr >1.5 mg/dL)		 · Vancomycin 125 mg PO 4 times a day for 10 days OR
· Fidaxomicin 200 mg PO twice daily for 10 days
Fulminant

(Hypotension or shock, ileus, megacolon)		 · Vancomycin 500 mg PO/NG 4 times a day
· If ileus: vancomycin 500 mg in 100 mL of normal saline every 6 hours as rectal retention enema PLUS metronidazole 500 mg IV every 8 hours
Table 2. IDSA/SHEA Treatment Recommendations for Recurrent CDI in Adult Patients9
CDI Recurrence Treatment Recommendation
First recurrence · If metronidazole was used for initial episode: Vancomycin 125 mg PO 4 times a day for 10 days
· If standard course of vancomycin was used for initial episode: Vancomycin tapered and pulsed regimen (125 mg 4 times a day for 10-14 days, 2 times daily for 7 days, once daily for 7 days, then every 2 or 3 days for 2-8 weeks) OR
· Fidaxomicin 200 mg PO twice daily for 10 days
Second or subsequent recurrence · Oral vancomycin tapered and pulsed regimen (125 mg 4 times a day for 10-14 days, 2 times daily for 7 days, once daily for 7 days, then every 2 or 3 days for 2-8 weeks)
OR
· Vancomycin 125 mg PO 4 times a day followed by rifaximin 400 mg PO 3 times daily for 20 days OR
· Fidaxomicin 200 mg PO twice daily for 10 days
· Fecal microbiota transplantation

Prevention: Role of Probiotics

Although several studies suggest the role of probiotics for primary prevention of CDI, IDSA/SHEA do not recommend the administration of probiotics in this setting due to insufficient data. Many limitations exist in the published literature including the differences in probiotic formulations studied, duration of probiotic administration, definitions of CDI, duration of study follow-up, and inclusion criteria of study participants.9 There is also the potential for the organisms in probiotic formulations to translocate into the bloodstream of hospitalized patients, resulting in bacteremia and sepsis.43-45

Prevention: Role of Bezlotoxumab

Since publication of the latest updates of IDSA/SHEA’s clinical guidelines for CDI, a new therapeutic agent was approved by the Food and Drug Administration (FDA). Bezlotoxumab is a monoclonal antibody directed against C. difficile toxin B. It is FDA indicated to reduce recurrence of CDI in patients 18 years of age or older who are receiving antibiotic treatment for CDI and are at high risk for CDI recurrence. Bezlotoxumab is not indicated for the treatment for CDI and should only be used in conjunction with antibiotic therapy of CDI. 46,47

Prevention: Infection Control Procedures

The CDC identifies core strategies for prevention of CDI in acute care facilities consisting of the following48:

Isolate and Initiate Contact Precautions for Suspected or Confirmed CDI

Recommendations include to create protocols to allow for rapid isolation of patients with suspected or confirmed CDI. Patients suspected to have CDI should be evaluated quickly. Contact precautions should be in place and the patient should be in a single room with a toilet. Contact precautions should remain for at least 48 hours after diarrhea has resolved or for the duration of hospitalization. Use of patient-care equipment like blood-pressure cuffs, stethoscopes, should only be used on the patient or disinfected appropriately if shared. Patients should shower daily with soap and water and those who come in contact with an infected patient should practice hand hygiene. When transferring a patient between units or facilities, notification is important so that contact precautions may be maintained.

Perform Environmental Cleaning to Prevent CDI

Daily and terminal cleaning protocols should be in place for patient-care areas and equipment. CDI patient rooms should be cleaned daily with a C. difficile sporicidal agent like an Environmental Protection Agency (EPA) List K agent which can be found here https://www.epa.gov/pesticide-registration/list-k-epas-registered-antimicrobial-products-effective-against-clostridium. The patient-care environment should be cleaned and disinfected daily as should any shared patient equipment. Terminal cleaning is needed after CDI patients are transferred or discharged. Any contaminated areas that a patient with CDI may have been during transient visits should also be cleaned with a C. difficile sporicidal agent.

Develop Infrastructure to Support CDI Prevention

With the goal of CDI prevention in mind, a multidisciplinary workgroup can help to identify strategies and follow results of interventions. Monitoring facility CDI rates, evaluating units with high incidence and reviewing cases to develop an intervention for modifiable risk factors will help to decrease CDIs. Education, proper training of personnel on prevention practices for CDI, routine audits of hand hygiene, contact precautions and room cleaning all help with prevention. 

Engage the Facility in Antibiotic Stewardship Program

Pharmacists can assist with appropriate prescribing of antibiotics that pose highest risk for CDI like fluoroquinolones and cephalosporins. Treatment guidelines for common infections can help clinicians select appropriate antibiotics and limit use of other options linked to CDI. Utilizing the shortest effective duration of antibiotic therapy needed is also helpful to decrease unnecessary antibiotic exposure. 

Patient Counseling and Support

Pharmacists can play a vital role by providing patient counseling and education to patients and family members. Knowing that C. difficile can easily spread from person to person most commonly via the fecal oral route, when a patient infected with C. difficile does not clean their hands with soap and water, they put others at risk for developing CDI. Washing with soap and water is the best way to prevent the spread of C. difficile. 

When patients are home, they should:

  • Wash hands with soap and water every time they use the bathroom and always before eating
  • Remind relatives and friends who care for the patient to wash hands as well
  • Try to use a separate bathroom especially when having diarrhea
  • If a separate bathroom is not available, the bathroom should be well cleaned before others use it
  • Take showers and wash with soap to remove difficile germs on the body

To kill C. difficile at home, one can mix 1 part bleach to 9 parts water. This cleaning solution can be used to disinfect high touch surfaces like

  • Doorknobs
  • Electronics
  • Refrigerator handles
  • Cups
  • Toilet flushers and toilet seats

Laundry such as bed linens, towels, household linens and clothing like underwear should be washed well. Any laundry items that have visible fecal matter should be rinsed prior to washing. Chlorine bleach can be used if safe on the items. Using the safest, hottest water setting is advisable.49 

The C. diff Foundation introduced the C. diff Nationwide Community Support (CDNCS) program in 2015 as there was a lack of professional support groups. The community support group allows patients and families impacted by CDI to decrease anxiety and stress surrounding the disease by connecting with each other. Their website provides resources for patients. They host an annual international C. diff conference and health EXPO. The year 2021 will mark the first time the organization hosts a patient and family C. diff community symposium which will feature healthcare professional keynote speakers and patients.50 

Pharmacist's Role in Prevention and Management

Pharmacists are in a unique position to help prevent and manage CDI. With antibiotic use being the most common risk factor for developing CDI, pharmacist led antimicrobial stewardship interventions can decrease the unnecessary and inappropriate use of these agents. Institutional guidelines, protocols, and policies can be developed to aid in the prevention and management of CDI. Some examples include criteria for CDI testing, infection control measures for CDI, treatment options for CDI, and restrictions on antimicrobial agents. Prospective audit and feedback is an effective antimicrobial stewardship strategy where pharmacists can review patients on antibiotics to identify opportunities for de-escalation and discontinuation. Active surveillance of acid suppressing agents such as proton pump inhibitors can also contribute to decreasing the risk of CDI. Education and training for healthcare professionals, patients and family members are essential in promoting the prudent use of antibiotics to prevent the unintended consequences of these agents such as C. difficile. Education and training on appropriate infection control measures is also necessary to reduce the spread of C. difficile.

References

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