Clostridioides Difficile Infection

1 arec diffis oneofthecauses of dinah a CLOSTRIDIOIDES DIFFICILE INFECTION Catherine Van, PharmD, BCPS Assistant Professor, Pharmacy Practice West Coast University School of Pharmacy 3 Epidemiology o Most commonly recognized cause of infectious diarrhea in healthcare settings o Increasingly common in the community setting  Community acquired: estimated 28% of cases  Healthcare associated: 37%  Long-term care facilities: 36% o Increased morbidity and mortality associated with more severe disease, which may be linked to a hypervirulent strain, PCR ribotype 027 o Recurrent CDI poses up to a 33% higher risk of mortality compared to those who do not have a recurrence Dipiro Chapter 131 4 Etiology o Clostridium difficile (C. difficile)  Gram-positive, anaerobic, spore-forming, toxin-producing bacillus Spores resistant to heat, acid, and antibiotics  Officially renamed in 2016 to Clostridioides difficile  Spores transmitted by fecal-oral route  Potential reservoirs: asymptomatic carriers, infected patients, contaminated environment, and animal intestinal tract (canine, feline, porcine, avian)  Approximately 5% of adults and 15–70% of infants are colonized by C. difficile Czepiel J, Drozdz M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019; 38(7): 1211–1221. 5 Pathophysiology o Ability to sporulate and germinate essential to C. difficile virulence o Toxin proteins  Internalized by host cells through receptormediated endocytosis  Disrupt cytoskeletal architecture  Cell death  Loss of intestinal barrier integrity  Bacteria translocate into underlying tissues o Intestinal microbiota provides colonization resistance against CDI o Toxin-mediated damage to epithelium activates host inflammatory immune response  Overly robust inflammatory response can be damaging to host and contribute to disease pathology Abt MC, McKenney PT, Pamer EG. Clostridium difficile colitis: pathogenesis and host defense. Nat Rev Microbiol. 2016 Oct; 14(10): 609– 620. 6 Fehér C., Soriano A. Mensa J. A Review of Experimental and Off-Label Therapies for Clostridium difficile Infection. Infect Dis Ther 6, 1–35 (2017). 7 C. difficile Toxins TorinBisthedominantandpotent Toxin istheweakerone o Toxins A and B: enterotoxic and cytotoxic  Traditionally, toxin A named “enterotoxin A” and toxin B, “cytotoxin B”  Initial studies on animal models suggested that toxin A plays a dominant role, and the action of toxin B may occur only via the tissue damage caused by toxin A  In studies involving human colonic tissue, toxin B was a potent inflammatory toxin, whereas toxin A was even weaker, and both toxins were able to elicit CDI symptoms independently o C. difficile transferase (CDT; or binary toxin): third toxin produced by some C. difficile strains, including the epidemic PCR ribotypes 027 Czepiel J, Drozdz M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019; 38(7): 1211–1221. 8 CDI Key Risk Factors AAntibiotic exposure o  8- to 10-fold higher CDI risk during antimicrobial therapy and 2 4 weeks thereafter, and 3-fold higher in the next 2 months  Higher risk of CDI with Clindamycin Penicillins (Ampicillin & Amoxicillin) Cephalosporins (3rd & 4th Generation), carbapenems cofepem Fluoroquinolones o Older age (> 65 years)  Risk for CDI increased 5 to 10-fold, compared with < 65 years of age 3 o Hospitalization Czepiel J, Drozdz M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019; 38(7): 1211–1221. McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48 9 CDI Other Risk Factors u o Inflammatory bowel disease sista 5o Gastrointestinal surgeries/manipulation of the gastrointestinal tract, including tube feeding DTs caused by malignant 6o Immunological incompetence CKD neoplasms, transplantations, chronic kidney diseases, or immunosuppressant use 7 o Potentially those receiving acid suppressive medications  Although many studies have shown an association between C. difficile infection and acid suppressing medications, there is a need for prospective RCTs to confirm Dipiro Chapter 131 Czepiel J, Drozdz M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019; 38(7): 1211–1221. 10 Clinical Presentation of CDI o Watery, non-bloody diarrhea o Abdominal pain, fever, nausea and vomiting, weakness, and loss of appetite o In most severe presentation: significant dehydration, Is abdominal distension, hypoalbuminemia with peripheral edema, and subsequent circulatory shock o Complications: toxic megacolon, colon perforation, intestinal paralysis, kidney failure, systemic inflammatory response syndrome, septicemia, and death Czepiel J, Drozdz M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019; 38(7): 1211–1221. 11 Diagnosis o CDI defined by  Presence of symptoms (three or more unformed stools in 24- hours) and either Stool test positive for C. difficile toxins or detection of toxigenic C. difficile, or Colonoscopic or histopathologic findings revealing pseudomembranous colitis o Optimal test for laboratory diagnosis remains controversial o Do not perform repeat testing (within 7 days) during the same episode of diarrhea and do not test stool from asymptomatic patients I 09N o Testing for cure should not be done on Dipiro Chapter 131 McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48 12 Diagnosis o Nucleic acid amplification tests (NAAT), such as PCR-based toxin testing  Should only be used in patients with acute diarrhea due to the test First possibility of detecting the toxins in asymptomatic patients y Noggins o Stepwise approach using screening for glutamate dehydrogenase (GDH) as the initial step  GDH assays detect common antigen present in all isolates of C. difficile, including nontoxigenic strains, thus requiring combination with another test (toxin test with or without NAAT) o Toxin enzyme immunoassay (EIA): incorporated into multi-step algorithms o Toxigenic culture or cell culture neutralization assays: limited due to delayed results and high cost o Use a NAAT alone or a multistep algorithm for testing Dipiro Chapter 131 McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48 13 Diagnosis McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48 14 Infection Prevention and Control I o Contact Precautions 2o Private room with a dedicated toilet to decrease transmission to other patients  Patients with suspected CDI if test results cannot be obtained on the same 3 day  At least 48 hours after diarrhea has resolved or until discharge if high rate of CDI o Healthcare personnel must use gloves and gowns 4o Hand hygiene with soap and water preferentially instead of alcohol based hand hygiene products before and after caring for CDI patients (increased efficacy of spore removal with soap and water) o Encourage patients to wash hands and shower to reduce the burden of spores on skin o Use disposable patient equipment when possible and ensure that reusable equipment is thoroughly cleaned and disinfected, preferentially with a sporicidal disinfectant s McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48 15 CDI Supportive Care I Is oAntibiotic Stewardship  Minimize frequency and duration of high-risk antibiotic therapy and number of antibiotic agents I  Implement an Antibiotic Stewardship Program 2  Antibiotics to be targeted based on local epidemiology and C. difficile strains; restriction of fluoroquinolones, clindamycin, and cephalosporins (except for surgical antibiotic prophylaxis) McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48 16 CDI Supportive Care 3o Discontinue is offending antimicrobial(s) as soon as possible ao Avoid use of antimotility agents (i.e. loperamide) if possible o Fluid and electrolyte replacement therapy if necessary 5o Discontinue unnecessary PPIs 6o Change to “low risk” antibiotic when continued antibiotic treatment is necessary (aminoglycosides, sulfonamides, macrolides, vancomycin) 7 o Antibiotic therapy for CDI should be started empirically for situations where a substantial delay in laboratory confirmation is expected, or for fulminant CDI McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48 17 Review What are key risk factors for CDI? Hospital 2 3 AntiBi Acidsuppressivemed a IBD 5 KD Immunocom 6 765ar 7 gastrointestinal surgies 18 CDI Treatment Fidatorticit Y Clinical Definition Supportive Clinical Data Initial episode, non-severe WBC ≤ 15K and • Preferred: FDX 200 mg PO BID x 10 days (W/M) SCr ≤ 1.5 • VAN 125 mg PO QID x 10 days (S/H) mg/dL • Alternative if above unavailable: Metronidazole (MTN) 500 mg PO TID for 10 days (W/H) Initial episode, severe WBC > 15K or SCr > 1.5 mg/dL Initial episode, fulminant Hypotension • VAN 500 mg PO or NG QID AND MTN 500 mg IV q8h or shock, ileus, • If ileus present: ADD rectal VANCO (i.e. VANCO megacolon PO/NG and rectal VAN and MTN IV) • Rectal VAN dose: 500 mg in 100 mL normal saline per rectum every 6 hours as retention enema (S/M for oral VAN; W/L for rectal VAN; S/M for IV MTN) VAN: vancomycin FDX: fidaxomicin Recommended Treatment (Strength of Recommendation: Strong or Weak/Quality of Evidence: High, Moderate, or Low) • Preferred: FDX 200 mg PO BID x 10 days (W/M) • VAN 125 mg PO QID x 10 days (S/H) McDonald LC et al., 2017 Update. Clinical Infections Diseases. 2018;66(7):e1-e48 Johnson S, et al. 2021 Focused Update. Clinical Infectious Diseases. 2021;73(5):e1029–e1044. 19 Agent Comparison Metronidazole • Fallen out of favor based on evidence showing it is significantly less effective than vancomycin or fidaxomicin • When used for prolonged or repeated courses, may lead to irreversible neurotoxicity McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48; Dipiro Chapter 131 20 Agent Comparison o When used for CDI, vancomycin must be administered orally because IV vancomycin does not achieve adequate gut lumen concentrations o When vancomycin has been compared to fidaxomicin: • Rate of initial cure was not significantly different between treatment groups • Fidaxomicin demonstrated a significant improvement in recurrence o Fidaxomicin (Dificid®) has not been studied in complicated or fulminant disease, therefore is not recommended McDonald LC et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clinical Infections Diseases. 2018;66(7):e1-e48; Dipiro Chapter 131 22 Medication Formulations Notes Metronidazole (Flagyl) • Tablet: 250 mg, 500 mg IV solution: has premixed bag (500 mg/100 mL) • Capsule: 125 mg, 250 mg Oral reconstituted solution: FIRVANQ – 25 mg/mL, 50 mg/mL; generic – 250 mg/5 mL • • Vancomycin (Vancocin, FIRVANQ) • Fidaxomicin (Dificid) • Tablet: 200 mg • Oral reconstituted suspension: 40 mg/mL (136 mL) Lexicomp • • • • Oral: Administer with food to minimize stomach upset Protect from light Contraindicated with use of alcohol or propylene glycol-containing products during therapy or within 3 days of therapy discontinuation Shake reconstituted oral solution well before each use Store oral solution at 2°C to 8°C prior to and following reconstitution; discard reconstituted why hazy or solution after 14 days or if appears contains particulates. Suspension: • Remove from refrigerator 15 minutes prior to each administration • Shake vigorously before use • Store reconstituted suspension at 2°C to 8°C for ≤12 days; discard after 12 days. Do not open pouch until time of use; store in original bottle. 23 Initial CDI – Monitoring oMonitor daily for resolution of  WBC count  Temperature  Diarrhea  Abdominal signs and symptoms  Overall clinical status oSymptomatic improvement within 1-2 days  Diarrhea resolution within 3-6 days 24 Question severe A patient is diagnosed with CDI (first episode) and has a WBC of 17,500 cells/mm3 (17.5 x 109/L). NKDA. Which regimens below would be appropriate selection for treatment, according to the most recent US guidelines for the treatment of CDI? Select all that apply. A. Metronidazole 500 mg orally every 8 hours B. Vancomycin 125 mg orally every 6 hours C. Fidaxomicin 200 mg orally twice daily 26 Iv no Bezlotoxumab (Zinplava®) i hadto gie Before lasIdose o Humanized monoclonal antibody that binds to and neutralizes toxin B o FDA approved in October 2016 as an adjunctive therapy to reduce recurrence of CDI o Dose: 10 mg/kg IV as a single dose during antibacterial treatment for CDI o Not an antibiotic and should not be used as monotherapy o In patients with history of congestive heart failure, reserved for use when benefit outweighs risk o For patients with recurrent CDI episode within the last 6 months, recommended as a co-intervention along with SOC antibiotics SOC: standard of care Dipiro Chapter 131 Johnson S, et al. 2021 Focused Update. Clinical Infectious Diseases. 2021;73(5):e1029–e1044. 27 Recurrent CDI Treatment Clinical Definition Recommended Treatment (Strength of Recommendation: Strong or Weak/Quality of Evidence: High, Moderate, Low, or Very Low) First recurrence • Preferred: FDX 200 mg PO BID x 10 days, or BID for 5 days followed by once every other day for 20 days (W/L) • Alternative: VAN 125 mg PO QID x 10 days (W/L)  Consider if metronidazole was used for treatment of the first episode • Alternative: VAN PO in a tapered and pulsed regimen (W/L) • Adjunctive treatment: Bezlotoxumab 10 mg/kg IV once during administration of SOC antibiotics (W/VL)  Data when combined with fidaxomicin limited VAN: vancomycin, FDX: fidaxomicin SOC: standard of care McDonald LC et al., 2017 Update. Clinical Infections Diseases. 2018;66(7):e1-e48 Johnson S, et al. 2021 Focused Update. Clinical Infectious Diseases. 2021;73(5):e1029–e1044. 29 Recurrent CDI Treatment Clinical Definition Recommended Treatment (Strength of Recommendation: Strong or Weak/Quality of Evidence: High, Moderate, Low, or Very Low) Second or subsequent recurrence • FDX 200 mg PO BID x 10 days, or BID for 5 days followed by once every other day for 20 days (W/L) • VAN PO in a tapered and pulsed regimen (W/L) • VAN 125 mg PO QID x 10 days followed by rifaximin 400 mg PO TID x 20 days (W/L) • Fecal microbiota transplantation (FMT) (S/M)  Appropriate ABX treatments for at least 2 recurrences (ie, 3 CDI episodes) should be tried prior to offering FMT • Adjunctive treatment: Bezlotoxumab 10 mg/kg IV once during administration of SOC antibiotics (W/VL) VAN: vancomycin, FDX: fidaxomicin SOC: standard of care McDonald LC et al., 2017 Update. Clinical Infections Diseases. 2018;66(7):e1-e48 Johnson S, et al. 2021 Focused Update. Clinical Infectious Diseases. 2021;73(5):e1029–e1044. 30 Fecal Microbiota Transplantation (FMT) oMultiple RCTs have shown efficacy of FMT with resolution rates of 80% to 90% in most studies oRebyota (fecal microbiota, live – rectal) and Vowst (fecal microbiota spores, live – oral)  Approved for prevention of CDI recurrence in patients ≥18 years of age following antibiotic treatment of recurrent CDI  Not indicated for treatment of CDI Dipiro Chapter 131; Lexicomp 31 Therapy Dosing Rebyota (fecal microbiota, live – rectal) 150 mL (contents of Administration: 1 bag) as a single • Prior to use, thaw completely by placing dose, administered carton in refrigerator (2°C to 8°C [36°F to 24 to 72 hours after 46°F]) for ~24 hours; do not thaw using a completion of C. heat source (eg, microwave, hot water) difficile treatment • Administer via gravity flow using provided regimen administration set • Do not allow administration tube to sag or loop (may prevent entire dose from being delivered) • Do not squeeze the bag to deliver product (may cause patient discomfort) • Do not hang bag from an IV stand • Some product will remain in tube after administration is complete ADRs: • GI: abdominal distention (4%), abdominal pain (9%), diarrhea (7%), flatulence (3%), nausea (3%) Lexicomp Notes 32 Therapy Dosing Notes Vowst (fecal microbiota spores, live – oral) 4 capsules once daily for 3 consecutive days, beginning 2 to 4 days after completion of C. difficile treatment regimen Administration: • Swallow capsules whole; do not open, crush, dissolve, or chew • First dose: administer a bowel prep according to manufacturer's directions and do not eat or drink, except small amounts of water, for ≥8 hours prior to first dose • Subsequent doses: administer on an empty stomach before the first meal of the day ADRs: • GI: abdominal distention (31%), constipation (14%), diarrhea (3% to 10%), flatulence (4%), nausea (3%) • Nervous system: chills (11%) Lexicomp 33 Question According to current US guidelines, a patient diagnosed severe with first-episode CDI that is determined to be critically ill (has systemic symptoms including hypotension) should be treated with which regimen below for C. difficile infection? Patient is also on vancomycin IV for MRSA bacteremia with NKDA. No ileus noted. A. Add metronidazole orally to current ABX regimen B. Add vancomycin rectally to current ABX regimen C. Vancomycin intravenously adequate D. Add fidaxomicin orally to current ABX regimen E. Add metronidazole intravenously + vancomycin orally F. Add metronidazole intravenously + vancomycin rectally G. Add metronidazole intravenously to current ABX regimen