Clostridioides Difficile Infection: a Comprehensive Review for Primary Providers

Clostridioides difficile infection: a comprehensive review for primary providers PEDRO CORTÉS1, YAN BI2, FERNANDO STANCAMPIANO1, JOSE R. VALERY1, JANE H. COOPER1, DANA M. HARRIS1 1 Division of Community Internal Medicine, Mayo Clinic, Jacksonville, FL, 32224 2 Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, 32224 Clostridioides difficile infection (CDI) is an issue of great concern due to its rising incidence, recurrence, morbidity and impact on healthcare spending. Treatment guidelines have changed in the last few years, and new therapies are being considered. This is a practical review for the primary care practitioner of the latest guidelines for CDI diagnosis, treatment, and emerging therapies. Key words: Clostridioides difficile, eradication, recurrent infection, fecal microbiota transplantation. Abbreviations: CD: Clostridioides Difficile, C. difficile; CDI: Clostridioides Difficile infection ; CDI: recurrent Clostridioides Difficile infection ; FMT: Fecal microbiota transplantation ; GDH: Glutamate dehydrogenase; NAAT: Nucleic acid amplification test. INTRODUCTION treatment of initial CDI, remained unchanged [5]. Notably, up to 25% of patients experience rCDI Clostridioides difficile (CD) was discovered within 30 days of initial treatment [6]. in 1978 and identified as the main etiology Antibiotic usage is the most critical risk of antibiotic-associated pseudomembranous factor for acquisition of CDI [7–9] but advanced colitis [1]; it was known as Clostridium difficile age, hospitalization, and severe comorbid until 2016 when it was reclassified based illness play a role as well [9]. Additional risk on molecular information as Clostridioides factors include enteral feeding [10], difficile [2]. CD is a gram-positive, toxin- inflammatory bowel disease [11], cirrhosis producing anaerobic bacterium, that causes an [12] and gastric acid suppression [9]. estimated $4.8 billion in healthcare expenditure Risk factors for rCDI include age older than 65 in the United States [3]. Approximately 453,000 years [13–14], severe comorbidities [13–14], cases of CDI are diagnosed each year in the use of antibiotics during treatment United States, with 83,000 being recurrences and of CDI [13–14], serum creatinine ≥ 1.2 mg/dL 29,300 resulting in death [3]. Prevalence of CDI [13–14] and lack of antibody-mediated increased in the United States and Europe from immune response to toxin B [15–16]. Risk 2003 to 2006 as a result of the NAP1/BI/027 factors for severe complications, such as death, hypervirulent strain that spreads more rapidly admission to the ICU, toxic megacolon, and causes more severe illness [3,4]. However, perforation or colectomy, include older age, between 2011 and 2017, the incidence of CDI leukopenia with white blood cell (WBC) count has declined from 154.9 to 143.6 per 100,000 < 4 x 109/L or leukocytosis with≥ 20 x 109/L, persons [5]; this in-hospital decline has been decreased albumin < 2.5 g/dL, elevated blood primarily driven by reductions of nosocomial urea nitrogen > 19.6 mg/dL, increased infections and application of antibiotic inflammatory marker C-reactive protein ≥ 150 stewardship, while community-acquired infec- mg/L, heart rate > 90/minute, and respiratory tions have remained steady [5]. Recurrent CDI rate > 20/minute [17]. Most importantly, CDI (rCDI), defined by recurrence of diarrhea within may also occur in the absence of any apparent two to eight weeks following successful risk factor [18]. ROM. J. INTERN. MED., 2021, 59, 3, 262–269 DOI: 10.2478/rjim-2021-0010 2 C. difficile review 263 Whom/How to test Alcohol-based hand sanitizers are not 1. Patients with acute diarrhea, defined as ≥ 3 recommended because they are not effective loose stools, should be tested if there is no other C difficile sporicides, although they are effective clear etiology [6, 19–21]. in killing the CD non-spore forms [24]. 2. Two-step testing for the presence of toxin and 6. Evidence to place asymptomatic patients on organism should be performed, and includes [6]: contact precautions remains inconclusive [6]. a. Stool glutamate dehydrogenase (GDH) 7. There is insufficient evidence to discontinue enzyme immune assay (EIA) and toxin testing proton pump inhibitors to decrease CDI incidence [6]. b. GDH EIA and toxin, to be determined by nucleic acid amplification testing (NAAT) How to treat initial CDI when the test result is inconclusive Management of CDI relies on assessing disease c. NAAT plus toxin testing severity to determine treatment [6, 19–21]. CDI is 3. Avoid re-testing within the first 7 days of categorized as mild/moderate (non-severe), therapy [6]. severe, and fulminant. There are several schemas 4. Testing asymptomatic patients is not to determine disease severity and treatment, recommended [6]. including guidelines from the American College 5. Do not test to document cure in patients who of Gastroenterology (ACG) [19], the Infectious have completed treatment and are asymptomatic, Diseases Society of America (IDSA) [6] and the as more than 60% of cases remain CD positive European Society of Clinical Microbiology and despite resolution of diarrhea [22]. Infectious Diseases (ESCMID) [20-21]. Table 1. The IDSA updated its treatment recommendations How to prevent transmission from patients in 2017 given new evidence of vancomycin being with CDI superior to metronidazole for preventing rCDI, 1. Provide for patients a private room and and fidaxomicin being as efficacious as toilet, if possible [6, 19–21]. vancomycin for treating CDI and superior for 2. Use contact precautions consisting of gloves preventing rCDI [6]. The guidelines removed and gowns during encounters [6, 19–21]. metronidazole as treatment of mild or moderate 3. Implement contact precautions pending disease and included fidaxomicin as treatment of diagnosis confirmation [6, 19–21]. mild, moderate, and severe CDI and for the 4. Continue isolation precautions for 48 hours treatment of rCDI. Guidelines from ACG and after diarrhea has resolved [6]. ESCMID are older and still recommend metronidazole for mild or moderate disease; 5. Wash hands with soap and water after taking ESCMID recommends fidaxomicin for rCDI off gloves in order to remove spores [23]. Table 1 Classification of CDI Severity from 2017 IDSA and 2014 ESCMID1 Classification of CDI Severity 2017 IDSA Classification 2014 ESCMID Classification [37] Non-severe • WBC < 15 x 109/L • Stool frequency < 4 times daily • Creatinine < 1.5 mg/dL • No signs of severe colitis Severe • WBC > 15 x 109/L • Severe colitis OR • Creatinine > 1.5 mg/dL • Complicated course with shock Fulminant • Hypotension • Need for ICU admission • Ileus • WBC > 15 x 109/L • Megacolon • Albumin < 3 g/dL • Creatinine > 1.3 mg/dL or 1.5 times above baseline WBC: White Blood Cells ICU: Intensive Care Unit 1 2014 ESCMID classification of non-severe and severe Because CDI is a dysbiosis, the most important Replenishing the microbiota is also the rationale aspect of treatment and prevention of recurrence behind the successful treatment of FMT. IDSA is the discontinuation of the inciting antibiotic(s) recommendations for treating a first episode of in addition to providing supportive care [6]. CDI are summarized in Table 2. Table 2 Treatment of initial episode of CDI Treatment of initial episode of Clostridium difficile infection Classification Recommended Treatment Strength of Recommendation/ Quality of Evidence Non-severe PO VAN 125 mg QID for 10-14d, or Strong/High PO FDX 200 mg BID for 10d, or Strong/High PO MTZ 500mg TID for 10 or 14d Weak/High Severe PO VAN 125 mg QID for 10d, or Strong/High PO FDX 200 mg BID for 10d Strong/High Fulminant PO VAN 500 mg QID, or Strong/Moderate PR VAN 500 mg/100 mL NS enema Q6H Weak/Low and IV MTZ 500 mg Q8H with VAN Strong/Moderate VAN: Vancomycin FDX: Fidaxomicin MTZ: Metronidazole QID: four times daily BID: twice daily TID: three times daily NS: normal saline 1. For non-severe cases, one of the following AND regimens may be used: • IV Metronidazole 500 mg every 8 hours • PO Vancomycin 125 mg four times daily for concurrently 10 days OR 4. For surgical management of acute abdomen, • PO Fidaxomicin 200 mg twice daily for 10 megacolon, colonic perforation, or septic shock days OR with organ failure, a subtotal colectomy with • PO Metronidazole 500 mg three times daily rectum preservation is preferred. An alternative for 14 days, if vancomycin or fidaxomicin are approach for colonic preservation is a diverting not available loop ileostomy with colonic lavage followed by 2. For severe cases, treatment with oral antegrade vancomycin flushes [6]. vancomycin or oral fidaxomicin, as above, is • Early surgical intervention may be indicated recommended. Metronidazole should be avoided in selected patients with a rising WBC count for severe CDI. (≥ 25 x 109/L) or lactate (≥ 5 mmol/L) [6]. 3. For fulminant cases, the following regimen is recommended: How to treat rCDI • PO Vancomycin 500 mg four times daily OR The number of recurrences of CDI and the regimen • PR retention enema Vancomycin 500 mg in used for the initial episode of CDI determine the 100 mL normal saline every 6 hours if ileus is treatment for rCDI [6]. Recommendations for rCDI present are summarized in Table 3. ROM. J. INTERN. MED., 2021, 59, 3, 262–269 4 C. difficile review 265 1. For an initial recurrence of CDI, the o PO vancomycin 125 mg twice daily for following regimens may be used: 7 days, followed by • PO Vancomycin 125 mg four times daily for o PO vancomycin 125 mg once daily for 7 days, 10 to 14 days if metronidazole

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