IBD, in full.

Confirm ulcerative colitis with endoscopy showing continuous colonic inflammation from the rectum plus histology, after excluding infection with two-step CDI testing. Treat mild-moderate disease with 5-ASA by route and extent (suppository for proctitis, enema for left-sided, oral plus rectal for extensive); if 5-ASA fails, treat as moderate-to-severe rather than stepping up gradually. Position advanced therapy by EFFICACY TIER, not by an anti-TNF-first rule. Advanced-therapy-naive, higher efficacy: infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, guselkumab; intermediate: golimumab, ustekinumab, tofacitinib, filgotinib, mirikizumab; lower: adalimumab. PREVIOUSLY TNF-EXPOSED, higher efficacy: tofacitinib, upadacitinib, ustekinumab; lower: adalimumab, vedolizumab, ozanimod, etrasimod - S1P modulators are weakest in exactly this group. Do not cycle within the anti-TNF class after primary non-response; switch mechanism. Apply treat-to-target (STRIDE-II) to endoscopic improvement (MES 0-1). Screen for acute severe UC by Truelove-Witts and admit for IV steroids. Begin CRC surveillance 8-10 years after DIAGNOSIS for extensive or left-sided disease; isolated proctitis follows average-risk screening.

Confirm ulcerative colitis with endoscopy showing continuous colonic inflammation from the rectum plus histology, after excluding infection with two-step CDI testing. Treat mild-moderate disease with 5-ASA by route and extent (suppository for proctitis, enema for left-sided, oral plus rectal for extensive); if 5-ASA fails, treat as moderate-to-severe rather than stepping up gradually. Position advanced therapy by EFFICACY TIER, not by an anti-TNF-first rule. Advanced-therapy-naive, higher efficacy: infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, guselkumab; intermediate: golimumab, ustekinumab, tofacitinib, filgotinib, mirikizumab; lower: adalimumab. PREVIOUSLY TNF-EXPOSED, higher efficacy: tofacitinib, upadacitinib, ustekinumab; lower: adalimumab, vedolizumab, ozanimod, etrasimod - S1P modulators are weakest in exactly this group. Do not cycle within the anti-TNF class after primary non-response; switch mechanism. Apply treat-to-target (STRIDE-II) to endoscopic improvement (MES 0-1). Screen for acute severe UC by Truelove-Witts and admit for IV steroids. Begin CRC surveillance 8-10 years after DIAGNOSIS for extensive or left-sided disease; isolated proctitis follows average-risk screening.

DIAGNOSIS: Use fecal calprotectin (cutoff >50-100 μg/g) to differentiate inflammatory from noninflammatory disease OF THE COLON (strong, moderate). Ileocolonoscopy with biopsies for suspected CD; biopsy uninvolved mucosa to define histologic extent; small bowel imaging is part of the initial workup (key concepts, ungraded). CT enterography is comparable to MR enterography for small bowel detection; MRE should be used PREFERENTIALLY in patients younger than 35 years and where serial examinations are likely, because of radiation avoidance, MRE is not a blanket first choice. Intestinal ultrasound is a radiation-free ADJUNCT to diagnosis and to monitoring treatment response (key concept, ungraded, not a graded recommendation). Perform routine endoscopic CRC surveillance in Crohn's colitis (strong, moderate). MILD-TO-MODERATE / LOWER PROGRESSION RISK: Recommend AGAINST oral mesalamine for induction or maintenance (strong, moderate); sulfasalazine should be considered ONLY for symptomatic mild COLONIC CD (key concept). Controlled ileal-release budesonide 9 mg daily for induction of symptomatic remission in mildly-to-moderately active ileocecal CD (strong, moderate), but recommend AGAINST ileal-release budesonide for MAINTENANCE (strong, low). MODERATE-TO-SEVERE / HIGHER RISK: SUGGEST AGAINST requiring failure of conventional therapy before initiating advanced therapy (conditional, LOW, a permission to skip step-up, not a mandate to start advanced therapy upfront). Oral corticosteroids for short-term induction only (strong, low). Recommend AGAINST azathioprine 1.5-2.5 mg/kg/d and 6-mercaptopurine 0.75-1.5 mg/kg/d for INDUCTION (strong, moderate), but SUGGEST the same agents and doses for MAINTENANCE after corticosteroid-induced remission (conditional, low). Check TPMT before starting azathioprine/6-MP (strong, low); measure NUDT15 variants in patients of East Asian ancestry and TPMT variants in all patients prior to thiopurine initiation (strong, moderate). Methotrexate up to 25 mg weekly IM/SC for maintenance after corticosteroid induction (conditional, low). Anti-TNF agents (IV infliximab, SC adalimumab, SC certolizumab pegol) for induction and maintenance (strong, moderate). Recommend COMBINATION IV infliximab + thiopurine over either agent alone in patients naive to both (strong, moderate). Vedolizumab IV for induction and maintenance of symptomatic remission (strong, moderate). Ustekinumab (strong, moderate); risankizumab (strong, moderate), and risankizumab over ustekinumab in prior anti-TNF exposure (conditional, low); mirikizumab (strong, moderate); guselkumab IV-then-SC or all-SC (strong, moderate). Upadacitinib for induction and maintenance in patients PREVIOUSLY EXPOSED TO ANTI-TNF (strong, moderate), the ACG does not endorse it as a first-line biologic-naive option. SC infliximab and SC vedolizumab are maintenance options in responders to IV induction (strong, moderate). PERIANAL FISTULIZING: infliximab for induction (strong, moderate); adalimumab (conditional, low); antibiotics added to infliximab or adalimumab (conditional, very low); vedolizumab, ustekinumab, upadacitinib each (conditional, VERY LOW). Drain perianal abscesses and place setons before escalating advanced therapy (key concept). POST-OPERATIVE: endoscopic assessment at 6-12 months after surgically induced remission over no monitoring (conditional, moderate); in LOW post-op recurrence risk, continued observation rather than immediate medical therapy (conditional, very low); imidazole antibiotics (metronidazole) 1-2 g/d after small intestinal resection (conditional, low); in HIGH-risk CD, anti-TNF to prevent endoscopic recurrence (STRONG, moderate) and vedolizumab (CONDITIONAL, low), these two are not co-equal. SURGERY/ABSCESS: intra-abdominal abscess >2 cm should be treated with antibiotics plus a drainage procedure, and immunosuppression HELD until drainage is achieved (conditional, low). DISEASE MODIFIERS: counsel active smokers to quit; use NSAIDs with caution; assess stress, depression and anxiety as part of comprehensive care (key concepts).

DIAGNOSIS: Use fecal calprotectin (cutoff >50-100 μg/g) to differentiate inflammatory from noninflammatory disease OF THE COLON (strong, moderate). Ileocolonoscopy with biopsies for suspected CD; biopsy uninvolved mucosa to define histologic extent; small bowel imaging is part of the initial workup (key concepts, ungraded). CT enterography is comparable to MR enterography for small bowel detection; MRE should be used PREFERENTIALLY in patients younger than 35 years and where serial examinations are likely, because of radiation avoidance, MRE is not a blanket first choice. Intestinal ultrasound is a radiation-free ADJUNCT to diagnosis and to monitoring treatment response (key concept, ungraded, not a graded recommendation). Perform routine endoscopic CRC surveillance in Crohn's colitis (strong, moderate). MILD-TO-MODERATE / LOWER PROGRESSION RISK: Recommend AGAINST oral mesalamine for induction or maintenance (strong, moderate); sulfasalazine should be considered ONLY for symptomatic mild COLONIC CD (key concept). Controlled ileal-release budesonide 9 mg daily for induction of symptomatic remission in mildly-to-moderately active ileocecal CD (strong, moderate), but recommend AGAINST ileal-release budesonide for MAINTENANCE (strong, low). MODERATE-TO-SEVERE / HIGHER RISK: SUGGEST AGAINST requiring failure of conventional therapy before initiating advanced therapy (conditional, LOW, a permission to skip step-up, not a mandate to start advanced therapy upfront). Oral corticosteroids for short-term induction only (strong, low). Recommend AGAINST azathioprine 1.5-2.5 mg/kg/d and 6-mercaptopurine 0.75-1.5 mg/kg/d for INDUCTION (strong, moderate), but SUGGEST the same agents and doses for MAINTENANCE after corticosteroid-induced remission (conditional, low). Check TPMT before starting azathioprine/6-MP (strong, low); measure NUDT15 variants in patients of East Asian ancestry and TPMT variants in all patients prior to thiopurine initiation (strong, moderate). Methotrexate up to 25 mg weekly IM/SC for maintenance after corticosteroid induction (conditional, low). Anti-TNF agents (IV infliximab, SC adalimumab, SC certolizumab pegol) for induction and maintenance (strong, moderate). Recommend COMBINATION IV infliximab + thiopurine over either agent alone in patients naive to both (strong, moderate). Vedolizumab IV for induction and maintenance of symptomatic remission (strong, moderate). Ustekinumab (strong, moderate); risankizumab (strong, moderate), and risankizumab over ustekinumab in prior anti-TNF exposure (conditional, low); mirikizumab (strong, moderate); guselkumab IV-then-SC or all-SC (strong, moderate). Upadacitinib for induction and maintenance in patients PREVIOUSLY EXPOSED TO ANTI-TNF (strong, moderate), the ACG does not endorse it as a first-line biologic-naive option. SC infliximab and SC vedolizumab are maintenance options in responders to IV induction (strong, moderate). PERIANAL FISTULIZING: infliximab for induction (strong, moderate); adalimumab (conditional, low); antibiotics added to infliximab or adalimumab (conditional, very low); vedolizumab, ustekinumab, upadacitinib each (conditional, VERY LOW). Drain perianal abscesses and place setons before escalating advanced therapy (key concept). POST-OPERATIVE: endoscopic assessment at 6-12 months after surgically induced remission over no monitoring (conditional, moderate); in LOW post-op recurrence risk, continued observation rather than immediate medical therapy (conditional, very low); imidazole antibiotics (metronidazole) 1-2 g/d after small intestinal resection (conditional, low); in HIGH-risk CD, anti-TNF to prevent endoscopic recurrence (STRONG, moderate) and vedolizumab (CONDITIONAL, low), these two are not co-equal. SURGERY/ABSCESS: intra-abdominal abscess >2 cm should be treated with antibiotics plus a drainage procedure, and immunosuppression HELD until drainage is achieved (conditional, low). DISEASE MODIFIERS: counsel active smokers to quit; use NSAIDs with caution; assess stress, depression and anxiety as part of comprehensive care (key concepts).

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).