guideline : Guidelines for the Prevention, Diagnosis and Treatment of Clostridioides (Clostridium) difficile infection (CDI) in adults

Background

• Clostridioides (Clostridium) difficile is Gram-positive, spore-forming anaerobic bacillus.
• Development of CDI is related to an imbalance in normal colonic bacteria most often as a result of antibiotics in the previous 8-12 weeks.¹
• CDI is primarily a healthcare-associated infection where prevention is paramount and recognition and management is often complicated.
• Positive difficile in stool can have a wide range of clinical presentation.¹
  • Asymptomatic colonization (3-26% of hospital patients can be colonized)
  • Mild to moderate diarrhea
  • Fatal colitis with associated septic shock
• Elderly and immunocompromised patients are at highest risk for CDI. However, CDI should be considered in any patient presenting with a compatible clinical syndrome that includes recent antibiotic exposure.
• This document is meant to serve as a guide for inpatient CDI prevention, identification, diagnosis and treatment. When additional questions or concerns arise please call the Antimicrobial Stewardship Team pager at 1337 or the Infectious Diseases consultation service for additional guidance.

Prevention

1. Avoid Unnecessary Antimicrobials
   1. Although some antibiotics are especially high risk, any antibacterial agent (including agents difficile) could lead to CDI.
   2. Minimizing unnecessary antibiotics is the most important way you can protect your patients from CDI. When antibiotics cannot be discontinued, limit agents to the narrowest spectrum possible.
   3. For assistance with antimicrobial optimization, feel free to contact the AST pager or an ID fellow on call.

2. Avoid Hospital Spread
   1. difficile spores can easily be transmitted within the healthcare system and are difficult to kill, making infection control and prevention of CDI of paramount importance.
   2. Contact precautions should be implemented for patients with CDI. ¹
      1. Start contact precautions as soon as CDI is suspected.
      2. Contact precautions should be continued for a minimum of 48 hours after diarrhea has resolved. In most cases, contact precautions are extended for the duration of hospitalization due to the potential shedding of C. difficile spores after resolution of diarrhea.²

• Patients with CDI should be in a private room with a dedicated toilet to decrease transmission to other patients. If private rooms are limited, prioritize patients with stool incontinence for placement in private rooms.

1. Healthcare personnel must use gloves and gowns on entry to a room of a patient with CDI and while caring for patients with CDI.
2. Hand washing with soap and water instead of alcohol-based products is recommended to prevent the spread of C difficile.³Alcohol based hand sanitizers do not kill C. difficile spores.⁴
3. For up to date guidance on infection prevention measures for C. difficile infection, please refer to the Infection Prevention and Control manual or call the Office of Infection Prevention and Control at 40260.

3. Avoid Unnecessary Gastric acid suppression

Medications that suppress gastric acid, especially proton pump inhibitors, may increase a patient’s risk for developing CDI^5,6. Ensure that your patient has a defined clinical indication for these medications (See ICU guidelines for indications in critically ill). 

4. Patient Education

At the time of discharge, emphasize good hand hygiene (hand washing with soap and water instead of alcohol-based products) and encourage patients and families to use 10% bleach products to clean their home bathrooms after each bowel movement for 2 weeks. Use only paper towels (no cloth towels) and dispose of used paper towels after each use.

Diagnosis

1. Definition of CDI: Presence of ≥ 3 unformed stools within 24 hours in patients with reasonable suspicion for CDI, who have not been on laxatives and have a positive test for difficile or direct visualization of pseudomembranous colitis.

More than 99% of patients with CDI will have diarrhea. Testing is not typically indicated in patients requiring laxatives or with formed stool or constipation.

2. Testing: Computer clinical decision support is used to help ascertain a patient’s pre-test probability of difficile infection when ordering C. difficile testing.

1. Patients should have stool tested for CDI if:
   1. Patient has ≥ 3 unformed stools in 24 hours.

AND

1. Patient has other signs of colitis, such as fever, leukocytosis, or abdominal discomfort.

OR

Patient has risk factors for CDI (recent antibiotics, intra-abdominal surgery, or age over 60 years).

AND

• Patient has not received laxatives for past 48 hours.

AND

1. Increased volume and/or frequency of bowel movements- especially in the presence of other signs and symptoms or risk factors, in a patient with pre-existing diarrhea from other conditions, such underlying inflammatory bowel disease, intensive chemotherapy, or enteral tube feeding.

1. Stool testing for CDI: UVA Health uses an automated real-time PCR for the detection of toxin B gene (tcdB) with reflex enzyme immunoassay (EIA) for detection of free toxins ( difficile toxins A and B).
   1. Testing will not be performed on formed or semi-formed stools. Submit only watery or liquid stool that takes the form of the container.
   2. Interpretation of C. difficile PCR with Reflex EIA:

1. Repeat testing: Repeat testing is generally not recommended.
   99. If the first test is “negative”, do not send a second specimen for at least 7 days (negative predictive value of 99.8%). Requests for repeat testing within 7 days of an initial test must be approved by the Clinical Microbiology Director (pic 1221).
   100. If the first test result is “discordant” (PCR+/EIA-) in a patient for whom empiric treatment is withheld and with subsequent worsening symptoms, heightened concern for CDI should prompt reconsideration of treatment rather than repeat testing. Requests for repeat testing within 7 days of an initial test must be approved by the Clinical Microbiology Director (pic 1221).

• If the first test is “positive,” repeat testing during the same episode of diarrhea has no clinical utility.

1. Repeat testing is indicated if there is suspicion of recurrent CDI, i.e. recurrent diarrhea (in the presence of other signs and symptoms or risk factors) at least 7 days after a previous episode of appropriately treated CDI. Requests for repeat testing within 7 days after treatment of an initial test must be approved by the Clinical Microbiology Director (pic 1221).
2. Repeat C. difficile testing to document clearance, either as test of cure or determinant of duration of isolation, is not indicated.

Treatment:

1. General recommendations for all cases:
   • Discontinue non-CDI systemic antimicrobial therapy, if possible, as it may influence the risk of recurrence.
   • Avoid use of anti-peristaltic agents (e.g. loperamide), as this may obscure symptoms and precipitate toxic megacolon.
   • Cholestyramine not recommended as it may bind anti-C difficile therapies⁷.
   • Probiotic products (e.g. those containing Lactobacillus or Saccharomyces) are not recommended to prevent or treat CDI, as data are limited, with potential risk of bloodstream infection due to the probiotic agent, especially for patients with fulminant CDI, critically ill or immune-suppressed.
   • Recommend referral of patients treated for CDI to the Complicated difficile clinic (CCDC) for follow-up post-hospitalization for further patient education, coordination of care and prevention and management of future recurrences.

2. Classification of CDI cases by severity:

3. Treatment recommendations for specific CDI cases:

• Non-fulminant, initial episode:
  • Vancomycin 125 mg PO/NGT Q6H for 10 days
  • Alternatives:
    • Fidaxomicin 200 mg PO BID for 10 days, if vancomycin is not tolerated.
    • Metronidazole 500mg PO/NGT Q8H for 10 days in settings where access to vancomycin or fidaxomicin is limited and only for an initial episode of non-severe CDI. Avoid use in older patients. Repeated or prolonged courses may put patient at risk of cumulative and potentially irreversible neurotoxicity.

• Fulminant CDI:
  • Vancomycin 500 mg PO/NGT Q6H and metronidazole^9-10 500 mg IV Q8H

AND

• Rectal vancomycin if ileus present (Vancomycin 500 mg in 100 mL normal saline per rectum Q6H retention enema)

AND

• Recommend ID, GI and Surgery consultation
• Consider additional therapeutic options
  • Surgery: Call PIC (1305) for patients with any of the following related to CDI
• Abdominal complications
  • Acute abdomen
  • Megacolon
  • Colonic perforation
    • Septic shock and associated organ failure
  • Laboratory findings (WBC ≥ 25 k/µL, Lactate ≥ 5.0 mmol/L)
  • Renal failure
  • New onset ventilatory failure
  • Hemodynamic instability
  • Mental status changes
    • Fecal Microbiota Transplant (FMT): For select patients with CDI not responding to CDI therapy or in fulminant CDI, FMT could be considered in consultation with Infectious Diseases, Gastroenterology, and Surgery. (Please refer to protocol for inpatient FMT)
    • Fidaxomicin: Not studied in fulminant CDI, would not recommend.
    • Other interventions without convincing evidence for efficacy or benefits for fulminant CDI: IVIG, tigecycline, combination therapy with vancomycin and fidaxomicin, bezlotoxumab and high dose anti- difficile antibiotics. Use of these agents is not currently recommended and may only delay appropriate management of fulminant CDI.

• First recurrence:
  • Fidaxomicin 200 mg PO BID for 10 days (AST or ID consult approval required), if vancomycin was used for initial episode.

OR

• Vancomycin tapered regimen
  • Vancomycin 125 mg PO Q6H for 10-14 days
  • Vancomycin 125 mg PO Q2H for 1 week
  • Vancomycin 125 mg PO daily for 1 week
  • Vancomycin 125 mg PO every 2-3 days for 2-8 weeks
• Alternative:
  • If metronidazole used for initial episode, vancomycin 125 mg PO Q6H for 10 days
• Second recurrence:
  • Vancomycin tapered regimen
    • Vancomycin 125 mg PO Q6H for 10-14 days
    • Vancomycin 125 mg PO Q2H for 1 week
    • Vancomycin 125 mg PO daily for 1 week
    • Vancomycin 125 mg PO every 2-3 days for 2-8 weeks
  • Alternatives:
    • Fecal microbiota transplant (FMT) is recommended especially if patient had previously been on vancomycin tapered regimen for 1^st
    • Fidaxomicin 200 mg PO BID for 10 days may be used, but success rate decreases with increasing numbers of recurrences⁸. Fidaxomicin requires AST or ID consult approval.
  • Third or subsequent recurrence:
    • Recommend Infectious Diseases consult
    • Initiate vancomycin tapered regimen while awaiting FMT:
      • Vancomycin 125 mg PO Q6H for 10-14 days
      • Vancomycin 125 mg PO Q2H for 1 week
      • Vancomycin 125 mg PO daily for 1 week
      • Vancomycin 125 mg PO every 2-3 days for 2-8 weeks
    • Recommend fecal microbiota transplant (FMT)
      • Inpatient - Consult FMT team (Infectious Diseases and Gastroenterology) (see Inpatient FMT Protocol)
      • Outpatient - Referral to Complicated difficile Clinic (CCDC) for FMT.
    • Refractory CDI
      • Criteria for consideration:
        • Diagnosis of CDI per UVA/IDSA guidelines,
        • Treated with antibiotics effective against CDI for at least 72-96 hours, and
        • Non-improving signs and symptoms.
      • Recommend Infectious Disease and Gastroenterology consultations.

• Others:
  • There are insufficient data at this time to recommend extending the length of CDI treatment beyond the recommended treatment course or restarting CDI agents empirically for patients who require continued antibiotic therapy directed against the underlying infection or who require retreatment with antibiotics shortly after completion of CDI treatment, respectively.

References:

1. McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical Infectious Diseases. 2018 Mar 19;66(7):e1–e48.
2. Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Healthcare Quality Promotion (DHQP). FAQs for Clinicians about C. diff [Internet]. Available from: https://www.cdc.gov/cdiff/clinicians/faq.html#anchor_1533745437898
3. Oughton MT, Loo VG, Dendukuri N, Fenn S, Libman MD. Hand hygiene with soap and water is superior to alcohol rub and antiseptic wipes for removal of Clostridium difficile. Infect Control Hosp Epidemiol. 2009 Oct;30(10):939–944. PMID: 19715426
4. Clabots CR, Gerding SJ, Olson MM, Peterson LR, Gerding DN. Detection of asymptomatic Clostridium difficile carriage by an alcohol shock procedure. J Clin Microbiol. 1989 Oct;27(10):2386–2387. PMCID: PMC267032
5. Deshpande A, Pant C, Pasupuleti V, Rolston DDK, Jain A, Deshpande N, Thota P, Sferra TJ, Hernandez AV. Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis. Clin Gastroenterol Hepatol. 2012 Mar;10(3):225–233. PMID: 22019794
6. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012 Jul;107(7):1001–1010. PMID: 22710578
7. Taylor NS, Bartlett JG. Binding of Clostridium difficile cytotoxin and vancomycin by anion-exchange resins. J Infect Dis. 1980 Jan;141(1):92–97. PMID: 7365273
8. Spiceland CM, Khanna S, Pardi DS. Outcomes With Fidaxomicin Therapy in Clostridium difficile Infection. J Clin Gastroenterol. 2018 Feb;52(2):151–154. PMID: 28009682
9. Rokas KE, Johnson JW, Beardsley JR, Ohl CA, Luther VP, Williamson JC. The Addition of Intravenous Metronidazole to Oral Vancomycin is Associated With Improved Mortality in Critically Ill Patients With Clostridium difficile Infection. Clin Infect Dis. 2015 Sep 15;61(6):934-41. doi: 10.1093/cid/civ409. Epub 2015 May 29. PMID: 26024909.
10. Wang Y, Schluger A, Li J, Gomez-Simmonds A, Salmasian H, Freedberg D. Does Addition of Intravenous Metronidazole to Oral Vancomycin Improve Outcomes in Clostridioides difficile Infection? Clin Infect Dis. 2019 Nov 12:ciz1115. doi: 10.1093/cid/ciz1115. Epub ahead of print. PMID: 31714955.