Drug-microbiome-host interactions: antimicrobial effects of non-antibiotic compounds.

DIAGNOSIS. Test only individuals with symptoms suggestive of active CDI, defined as ≥3 unformed stools in 24 hours (key concept); testing of formed stool is rarely clinically indicated, and routine testing for cure in asymptomatic patients after treatment is not recommended. CDI testing algorithms should include both a highly sensitive and a highly specific testing modality to distinguish colonization from active infection (conditional, low quality); ACG's stated preferred method is a two-step algorithm, a highly sensitive NAAT or GDH first, then the more specific toxin EIA. Both positive = CDI reliably diagnosed; both negative = CDI unlikely; discordant (NAAT/GDH positive, toxin EIA negative) requires clinical evaluation and consideration of colonization or toxin below the limit of detection. Because no test is perfect, the diagnosis and decision to treat is a clinical one, and treatment should not be withheld where clinical suspicion is high. INITIAL NONSEVERE EPISODE. Either oral vancomycin 125 mg four times daily for 10 days (strong recommendation, low quality) OR oral fidaxomicin 200 mg twice daily for 10 days (strong recommendation, moderate quality), one agent as monotherapy, not the two given together, as co-equal first-line strong recommendations; ACG does not rank fidaxomicin above vancomycin. Oral metronidazole 500 mg three times daily for 10 days may be considered in low-risk patients, i.e. younger patients with minimal comorbidities (strong recommendation, moderate quality). SEVERE CDI. As initial therapy, vancomycin 125 mg four times daily for 10 days (strong recommendation, low quality); fidaxomicin 200 mg twice daily for 10 days carries only a conditional recommendation, very low quality. FULMINANT CDI. Medical therapy including adequate volume resuscitation plus oral vancomycin 500 mg every 6 hours for the first 48-72 hours (strong recommendation, very low quality); combination therapy with parenteral metronidazole 500 mg every 8 hours can be considered (conditional, very low quality); in patients with an ileus, the addition of vancomycin enemas 500 mg every 6 hours may be beneficial (conditional, very low quality). FMT is suggested for severe and fulminant CDI refractory to antibiotic therapy, particularly in poor surgical candidates (strong recommendation, low quality). Where surgery is required, either total colectomy with end ileostomy and stapled rectal stump or diverting loop ileostomy with colonic lavage and intraluminal vancomycin, depending on clinical circumstances and the surgeon's judgement. FIRST RECURRENCE. Tapering/pulsed-dose vancomycin for patients experiencing a first recurrence after an initial course of fidaxomicin, vancomycin, or metronidazole (strong recommendation, very low quality); fidaxomicin is recommended for a first recurrence after an initial course of vancomycin or metronidazole (conditional recommendation, moderate quality). ACG's strong recommendation here is the vancomycin taper, not fidaxomicin. SECOND OR FURTHER RECURRENCE. Treat with FMT to prevent further recurrences (strong recommendation, moderate quality), delivered by colonoscopy (strong, moderate) or capsules (strong, moderate), with delivery by enema suggested only if other methods are unavailable (conditional, low quality); repeat FMT is suggested for recurrence within 8 weeks of an initial FMT (conditional, very low quality), restarting anti-CDI antibiotics to control symptoms before repeat FMT. For patients with recurrent CDI who are not FMT candidates, relapsed after FMT, or require ongoing or frequent courses of antibiotics, long-term suppressive oral vancomycin, ACG suggests 125 mg once daily, may be used (conditional, very low quality). Oral vancomycin prophylaxis 125 mg once daily may be considered during subsequent systemic antibiotic use in patients with a history of CDI at high risk of recurrence, typically continued until 5 days after completion of the systemic antibiotics (conditional, low quality). BEZLOTOXUMAB. Suggested for prevention of CDI recurrence in patients at high risk of recurrence (conditional recommendation, moderate quality), given as a single weight-based IV infusion (10 mg/kg) during a course of anti-CDI treatment. ACG explicitly narrows this: given the drug's cost and minimal benefit in low-risk patients, it recommends bezlotoxumab be considered for patients aged 65 years or older WHO ALSO HAVE at least one of the following additional risk factors, experiencing their second episode of CDI within the past 6 months, immunocompromised, or severe CDI. ACG does not recommend bezlotoxumab in patients with a history of heart failure and advises it be used with caution in patients with severe underlying cardiovascular comorbidities. ADJUNCTIVE. ACG recommends against probiotics for primary prevention of CDI in patients being treated with antibiotics (conditional, moderate quality) and against probiotics for prevention of CDI recurrence (strong recommendation, very low quality). ACG suggests against discontinuation of antisecretory therapy (e.g. PPI) in patients with CDI provided there is an appropriate indication for its use (strong recommendation, very low quality). SPECIAL POPULATIONS. Test for C. difficile in patients with IBD presenting with an acute flare associated with diarrhea (strong, low quality); treat IBD with CDI using vancomycin 125 mg four times daily for a minimum of 14 days (strong, very low quality); immunosuppressive IBD therapy should not be held during anti-CDI therapy, and escalation may be considered if there is no symptomatic improvement; FMT should be considered for recurrent CDI in IBD (strong, very low quality). Vancomycin is recommended for pregnant, peripartum, and breastfeeding patients. Vancomycin or fidaxomicin is suggested first line in immunocompromised patients. SCOPE LIMIT. ACG 2021 addresses C. difficile infection specifically; it makes no recommendation on the management of non-C. difficile antibiotic-associated diarrhea, and it predates the FDA approvals of Rebyota (Nov 2022) and Vowst (Apr 2023).