Clostridium difficile: Can you smell the new updates?

Clostridium difficile: Can you smell the new updates? Sunish Shah, Pharm.D. PGY-2 Infectious Disease Pharmacy Resident Yale-New Haven Hospital sshah1741@mail.usciences.edu

Learning objectives Recognize the epidemiology and virulence of Clostridium difficile infection Apply an appropriate treatment plan for a patient with Clostridium difficile infection based on presentation and severity of the infection Compare different treatment strategies for recurrent Clostridium difficile infection

History of CDI CDI associated with human disease + found to be the organism to cause the majority of antibioticassociated diarrhea 1977 NAP1/BI/027 induced outbreak 2002 1935 1978 2017 Clostridium difficile was first isolated from the stool of a healthy infant Metronidazole and vancomycin found to have activity against CDI Fidaxomicin approved for the treatment of CDI Heinlen et al. Am J Med Sci. 2010 Sep:247-52. McDonald et al. N Engl J Med. 2005 Dec: 2433-41.

Burden of CDI $ Rate of CDI hospitalizations has tripled from 5.6/ 1000 discharges in 2001 to 12.7/ 1000 discharges in 2011 Approximately $3.2 billion annually Up to $29,000 in attributable costs for nosocomial CDI CDI is associated with a 6% to 30% mortality rate Lessa et al. Clin Infect Dis. 2012 Feb:S65-70. Hota et al. Emerg Infect Dis. 2012 Feb:305-7.

Microbiology Gram-positive anaerobic bacillus Spore forming Toxin producing NAP1/B1/027 Increased toxin production Associated with severe disease Difficult to treat Associated with relapses Eze et al. J Glob Health. 2017 Jun:22-3.

NAP1 Worldwide distribution Canada 04 80% United States 05 69% Europe 08 6.2% Asia 06 < 1% McDonald et al. N Engl J Med. 2005 Dec:2431-41.

CDI Pathogenesis CDI spores and vegetative cells are ingested Spores Vegetative cells Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.

CDI Pathogenesis Stomach Only vegetative cells are killed in the acidic environment Spores Vegetative cells Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.

CDI Pathogenesis Small bowel Only vegetative cells are killed in the acidic environment Spores Vegetative cells Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.

CDI Pathogenesis B A B A A Colon Clostridium difficile multiplies and produces Toxins A, B and hydrolytic enzymes B B A B A B Toxin A Toxin B Spores Vegetative cells Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.

CDI Pathogenesis B B A A B A A B B WBC A B Toxins A + B Production of interleukins, increased vascular permeability, neutrophil and monocyte recruitment White blood cell Toxin A Toxin B Spores Vegetative cells Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.

CDI Pathogenesis H B H A H H B A H H H H B B Hydrolytic enzyme connective tissue degradation, leading to colitis, pseudomembrane formation and watery diarrhea WBC A B H White blood cell Toxin A Toxin B Spores Vegetative cells Hydrolytic enzymes Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.

Risk factors for CDI Advanced age Increased duration of hospitalization Antibiotics Clindamycin > 3-4 th generation cephalosporins > Fluoroquinolones Chemotherapy Manipulation of gastrointestinal tract Inflammatory bowel disease Solid organ transplantation Proton pump inhibitors Eze et al. J Glob Health. 2017 Jun:22-3.

Audience response Which of the following is true? A. Clindamycin is less likely to induce CDI compared to flouroquinolones B. CDI is associated with up to a 30% mortality rate C. The NAP1/B1/027 strain is associated with increased virulence and is common in the United States D. B + C only E. All of the above

Diagnostic testing Stool testing should only be performed on patients with unexplained new-onset diarrhea Test Method Molecular Target Characteristics EIA GDH Requires confirmation with toxin testing High sensitivity; Low specificity EIA Toxin A or Toxin B Used to confirm positive GDH test High sensitivity; Moderate specificity NAAT or PCR tcdb or tcdc gene Used when GDH and Toxin tests are discordant High sensitivity; Low specificity EIA: Enzyme immunoassay; GDH: Glutamate dehydrogenase; NAAT: Nucleic acid amplification test; PCR: Polymerase chain reaction Gupta et al. JAMA. 2016 Dec:2422-3.

Patient Case JZ is a 48 year old male with a past medical history of Chron s disease and living donor renal transplantation (2015) secondary to uncontrolled hypertension. He presents to the emergency department with right upper quadrant abdominal pain, fever and jaundice. He denies vomiting and has not had any bowel movements today. 138 103 3.8 25 17 0.9 95 8.9 15.1 43 240 CrCl= 130 ml/min BP HR RR SpO 2 Temp 101/80 98 22 96 101 F

Audience response Which of the following is true regarding JZ s case? A. The patient should be tested for CDI with GDH alone B. Given the patient s risk factor for Chron s disease and renal transplantation, CDI testing should not be performed and oral vancomycin should be started C. The patient should be tested for CDI with GDH. A positive GDH test should be confirmed with toxin testing D. The patient should not be tested for CDI at this time

Patient Case JZ was also found to have hyperbilirubinemia, elevation of biliary enzymes and elevation of liver enzymes. Endoscopic retrograde cholangiopancreatography is performed for the treatment of acute ascending cholangitis. He is discharged to finish a 7 day course of amoxicillin/ clavulanate. Ten days following discharge JZ returns to the emergency department complaining of diarrhea, fever and dizziness. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins. 138 103 2.9 25 17 3.2 95 29 15.1 43 240 CrCl= 24 ml/min BP HR RR SpO 2 Temp 90/72 98 22 96 104 F

Management of CDI

CDI Management Clinical diagnosis Non-severe CDI Severe CDI Fulminant CDI Recommended treatment Leukocytosis with a white blood cell count of 15 000 cells/ml and a serum creatinine level <1.5 mg/dl Leukocytosis with a white blood cell count of 15 000 cells/ml or a serum creatinine level >1.5 mg/dl Hypotension or shock, ileus, megacolon McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

CDI Management Clinical diagnosis Recommended treatment Quality of evidence Non-severe CDI Severe CDI Fulminant CDI VAN 125mg orally QID X 10 days FDX 200mg BID X 10 days Alternative: MDZ 500mg orally TID X 10 days VAN 125mg orally QID X 10 days FDX 200mg BID X 10 days VAN 500mg orally or via NG tube QID Ileus: Consider adding VAN rectal instillation Ileus: Consider adding intravenous MDZ High High High High High Moderate Low Moderate VAN: Vancomycin; FDX: Fidaxomicin; MDZ: Metronidazole; BID: Twice daily; QID: Four times daily; NG: Nasogastric McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

Treatment options Vancomycin Fidaxomicin Metronidazole Nitazoxanide Rifaximin Tigecycline Bacitracin Fusidic acid McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

Vancomycin mechanism of action NAG NAM NAG NAM NAG NAM NAM NAG NAM NAG NAM NAG D-Alanine D-Glutamate L-Lysine Pentaglycine chain Hammes et al. Antimicrob Agents Chemother. 1974 Dec:722-8.

Vancomycin mechanism of action NAG NAM NAG NAM NAG NAM Vanco Vanco Vanco Vanco Vanco Vanco Vanco NAM NAG NAM NAG Vanco NAM Vanco NAG Hammes et al. Antimicrob Agents Chemother. 1974 Dec:722-8.

Vancomycin mechanism of action NAG Vanco Vanco Vanco NAG Vanco NAM Vanco Vanco Vanco Vanco Vanco NAG Hammes et al. Antimicrob Agents Chemother. 1974 Dec:722-8.

Metronidazole mechanism of action Muller et al. Surgery. 1983 Jan:165-171.

Why is metronidazole not first line? Outcome Year Cure (%) RR (95% CI); P-value Reference Resolution of diarrhea at end of (10 days) treatment RCT Prior to 2000 RCT since 2000 All RCTs 95 (MTR) 98 (VAN) 75 (MTR) 85 (VAN) 78 (MTR) 87 (VAN) 0.97 (0.91-1.03); P= 0.40 Teasley et al Wenisch et al 0.89 (0.82-0.96); P=0.002 Zar et al Johnson et al 0.89 (0.85-0.96); P=0.0008 Outcome Year Cure (%) RR (95% CI); P-value Reference Resolution of diarrhea at end of treatment without CDI recurrence RCT Prior to 2000 RCT since 2000 All RCTs 85 (MTR) 84 (VAN) 59 (MTR) 70 (VAN) 63 (MTR) 73 (VAN) 1.0 (0.90-1.2); P= 1.0 Teasley et al Wenisch et al 0.84 (0.74-0.94); P=0.002 Zar et al Johnson et al 0.87 (0.79-0.96); P=0.003 McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

Zar et al Design Outcomes Controlled trial of adult patients with > 3 unformed stools and CDI toxin demonstrated in the stool or pseudomembranous colitis Patients randomly assigned to receive oral metronidazole (250 mg 4 times per day) or oral vancomycin (125 mg 4 times per day) for 10 days Cure rates for mild CDI Metronidazole (90%) vs Vancomycin (98%); (P=0.36) Cure rates for severe CDI Metronidazole (76%) vs Vancomycin (97%); (P=0.02) Zar et al. Clin Infect Dis. 2007 Aug:302-7.

Johnson et al Design Outcomes Patients with CDI were randomly assigned in a 2:1:1 ratio to oral tolevamer, vancomycin 125 mg every 6 hours for 10 days, or metronidazole 375 mg every 6 hours for 10 days Overall clinical cure rates Tolevamer (44.2%) vs Metronidazole (72.7%) vs Vancomycin (81.1%); (P< 0.001) Cure rates for severe CDI Metronidazole (66.3%) vs vancomycin (78.5%); (P=.059). Johnson et al. Clin Infect Dis. 2014 Aug:345-54.

Other agents for primary CDI Agents with probable efficacy Agent Adult dose Side effects Supporting data Nitazoxanide Fusidic acid 500 mg PO bid 10 days 250 mg PO tid 10 days GI symptoms GI symptoms Small RCT comparison to vancomycin Modest RCT comparison to metronidazole Modest RCT comparison to metronidazole Small RCT comparison to vancomycin Nitazoxanide vs Vancomycin cure rates 74% (20/27) vancomycin vs. 77% (17/22) nitazoxanide Nitazoxanide vs Metronidazole cure rates 58% (19/33) metronidazole vs. 66% (25/38) nitazoxanide Fusidic Acid Not available in the United States Musher et al. Clin Infect Dis. 2006 Aug:421-7. Musher et al. Clin Infect Dis. 2009 Feb:e41-6. McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

Other agents for primary CDI Agents with limited efficacy Agent Adult dose Side effects Supporting data Tigecycline 50 mg IV bid 10 days Bacitracin 25,000 units PO qid 10 days Rifaximin 400 mg PO tid 10 days GI symptoms Minimally absorbed Minimally absorbed Small case series Two small RCT comparisons to vancomycin RCT for recurrent CDI Rifaximin vs Placebo CDI recurrence 31% (11/35) placebo vs. 77% (5/33) rifaximin (P=0.11) Garey et al. J Antimicrob Chemother. 2011 Dec:2850-5. McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

Patient Case JZ was also found to have hyperbilirubinemia, elevation of biliary enzymes and elevation of liver enzymes. Endoscopic retrograde cholangiopancreatography is performed for the treatment of acute ascending cholangitis. He is discharged to finish a 7 day course of amoxicillin/ clavulanate. Ten days following discharge JZ returns to the emergency department complaining of diarrhea, fever and dizziness. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins. 138 103 2.9 25 17 3.2 95 29 15.1 43 240 CrCl= 24 ml/min BP HR RR SpO 2 Temp 90/72 98 22 96 104 F

JZ is started on oral vancomycin 125mg every 6 hours before being admitted to the intensive care unit for norepinephrine administration. The following day, he still remains critically ill but he is having less frequent bowel movements. An abdominal X-ray is suggestive of paralytic ileus. Ultrasonography and computed tomography of the abdomen and pelvis identify colonic dilatation. How should JZ be managed? A. The oral vancomycin dose should be increased to 500mg every 6 hours B. Consideration should be given to additional rectal vancomycin C. Consideration should be given to additional oral metronidazole 500mg every 8 hours D. A+B E. All of the above Audience response

Patient Case JZ responds clinically to medical therapy and does not require surgery. He is discharged to home after finishing a 10 day course of therapy. Unfortunately, one month following discharge, JZ presents to the emergency department again with diarrhea and fever. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins. He is also found to have NAP1/B1/027 colonization. 138 103 3.4 25 17 1.5 95 17 15.1 43 240 CrCl= 43 ml/min BP HR RR SpO 2 Temp 124/82 98 18 96 102.1 F

Management of CDI recurrence

CDI recurrence After a first diagnosis of CDI, 10% 30% of patients develop at least 1 recurrent CDI episode The risk of recurrence increases with each successive recurrence NAP1/B1/027 McDonald et al Continuous use of PPIs was independently associated with a 50% increased risk for recurrence Re-exposure to antibiotics was associated with only a 30% increased risk McDonald et al. JAMA. 2015 Mar:784-91. McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

Management of CDI recurrence Clinical diagnosis Recommended treatment Evidence level First recurrence 2 nd or subsequent recurrence Initial MDZ use: VAN 125mg orally QID X 10 days Initial VAN use: FDX 200mg BID X 10 days Prolonged and tapered pulsed VAN regimen VAN in a tapered and pulsed regimen VAN 125mg orally QID X 10 days followed by rifaximin 400mg 3 times daily for 20 days FDX 200mg given twice daily for 10 days Fecal microbiota transplantation Low Moderate Low Low Low Low Moderate VAN: Vancomycin; FDX: Fidaxomicin; MDZ: Metronidazole; BID: Twice daily; QID: Four times daily McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.

Fidaxomicin Macrocylic antibiotic with activity against C. difficile Produced by Dactylosporangium aurantiacum Mechanism of action Inhibits bacterial RNA polymerase at transcription initiation Demonstrated to inhibit toxin A and B production Resistance has been reported rpob and rpoc Reduced incidence of VRE and Candida Zhanel et al. Can J Infect Dis Med Microbiol. 2015 Dec:305-12.

Louie et al Prospective, multicenter, double-blind trial Patients randomized to 200 mg of fidaxomicin q12h with intervening matching doses of placebo or 125 mg of vancomycin q6h X 10 days Inclusion Exclusion 16 years of age or older Fulminant CDI Diarrhea with CDI toxin Prior fidaxomicin exposure Ulcerative colitis or Crohn s disease CDI within prior 3 months Louie et al. N Engl J Med. 2011 Feb:422-31.

Baseline demographics Characteristic Fidaxomicin (N=265) Vancomycin (N=283) Age (yr) 59.9 + 17.1 62.7 + 17.0 Female sex (%) 57.4 54.8 Unformed stools/day (no.) 8.2 + 4.3 8.4 + 5.5 Inpatient (%) 55.1 57.2 Prior CDI episode, n (%) 16.2 17.0 BI/NAP1/027 strain* (%) 35.3 36.4 *Based on the 415 patients who had a strain type that could be evaluated Louie et al. N Engl J Med. 2011 Feb:422-31.

Patients (%) Results Fidaxomicin Vancomycin P=0.004 P=0.006 100 80 92 90 78 67 60 40 24 20 13 0 Clinical Cure Recurrence Global Cure Clinical cure Defined as the resolution of diarrhea Global cure Defined as the resolution of diarrhea without recurrence Recurrence NAP1: 24.4% fidaxomicin vs. 23.6% vancomycin (p=0.93) Non-NAP1: 7.8% fidaxomicin vs. 25.5% vancomycin (p<0.001) Louie et al. N Engl J Med. 2011 Feb:422-31.

Cornely et al 45 sites in Europe; 41 sites in Canada and the United States Patients randomized to 200 mg of fidaxomicin q12h with intervening matching doses of placebo or 125 mg of vancomycin q6h X 10 days Inclusion Exclusion 16 years of age or older Fulminant CDI Diarrhea with CDI toxin Prior fidaxomicin exposure Ulcerative colitis or Crohn s disease CDI within prior 3 months Cornely et al. Lancet Infect Dis. 2012 Feb:281-9.

Results Characteristic Fidaxomicin Vancomycin P-value Clinical Cure All 221/252 (87.7%) 223/257 (86.8%) 0.754 Europe 89/100 (89.0%) 82/98 (83.7%) 0.275 USA and Canada 132/152 (86.8%) 141/159 (88.7%) 0.621 Recurrence All 28/221 (12.7%) 60/223 (26.9%) 0.0002 Europe 8/89 (9.0%) 19/82 (23.2%) 0.011 USA and Canada 20/132 (15.2%) 41/141 (29.1%) 0.006 Sustained Response All 193/252 (76.6%) 163/257 (63.4%) 0.001 Europe 81/100 (81.0%) 63/98 (64.3%) 0.008 USA and Canada 112/152 (73.7%) 100/159 (62.9%) 0.041 Cornely et al. Lancet Infect Dis. 2012 Feb:281-9.

Results Clinical cure Fidaxomicin (n=252) Vancomycin (n=257) p-value Non-BI/NAP1/027, n (%) 120/131 (91.6%) 106/121 (87.6%) 0.297 Concomitant antibiotics, n (%) 46/51 (90.2%) 33/45 (73.3%) 0.031 Recurrence Fidaxomicin (n=221) Vancomycin (n=223) p-value Non-BI/NAP1/027, n (%) 11/120 (9.2%) 29/106 (27.4%) 0.0003 First episode, n (%) 21/184 (11.4%) 49/191 (25.7%) 0.0004 Sustained Response Fidaxomicin (n=252) Vancomycin (n=257) p-value Non-BI/NAP1/027, n (%) 109/131 (83.2%) 77/121 (63.6%) 0.0004 Severe, n (%) 44/63 (69.8%) 29/61 (47.5%) 0.012 Cornely et al. Lancet Infect Dis. 2012 Feb:281-9.

Bezlotoxumab Monoclonal antibody with high binding affinity for Toxin B Binding prevents attachment to colonic mucosal cells No binding affinity to Toxin A Actoxumab with activity against Toxin A Approved as adjunct therapy for recurrent CDI No evidence of resistance Navalkele et al. Biologics: Targets & Therapy. 2018 Jan:11-21.

Wilcox et al Two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II Participants received an infusion of bezlotoxumab (10mg/kg), actoxumab plus bezlotoxumab (10mg/kg each), or placebo Inclusion Diarrhea with toxigenic CDI Standard CDI therapy receipt Exclusion Surgery for CDI within 24 hours Saccharomyces reciept Chronic diarrheal illness Pregnant or beast-feeding Wilcox et al. N Engl J Med. 2017 Jan:305-17.

Pooled baseline demographics Characteristic A + B (N=773) B (N=781) Placebo (N=773) Metronidazole, n (%) 366 (47.3) 365 (46.7) 353 (45.7) Vancomycin, n (%) 366 (47.3) 370 (47.4) 372 (48.1) Fidaxomicin, n (%) 25 (3.2) 30 (3.8) 30 (3.9) > 2 prior CDI episodes 103 (13.3) 100 (12.8) 126 (16.3) Immunocompromised 163 (21.1) 178 (22.8) 153 (19.8) BI/NAP1/027 76 (15.9) 89 (18.2) 100 (20.6) Wilcox et al. N Engl J Med. 2017 Jan:305-17.

Patients with infection recurrence through week 12 (%) Results 40 35 30 25 20 15 10 5 0 A +B B Placebo P< 0.001 P< 0.001 P< 0.001 P< 0.001 28 P< 0.001 26 27 17 16 17 16 15 15 P< 0.001 Modify I Modify II Pooled data Wilcox et al. N Engl J Med. 2017 Jan:305-17.

Fecal Microbiota Transplantation Restoration of normal gastrointestinal flora with live enteric bacteria from a donor How is it done? Nasogastric tube Nasoduodenal (ND) tube Esophagogastroduodenoscopy Capsulized frozen sample Colonoscopy Retention Enema

Does it work? van Nood et al Randomized trial of patients with a recurrence of CDI Primary end point Resolution of CDI without relapse after 10 weeks Oral vancomycin X 14 days followed by bowel lavage (BL) and ND donor feces (n=16) 81.3% success rate Oral vancomycin X 14 days (n=13) 30.8% success rate Oral vancomycin X 14 days and BL (n=13) 23.1% success rate Youngster et al Phase 1 safety and efficacy study Patients with recurrent CDI Fifteen capsules from unrelated donors administered X 2 days Resolution of diarrhea: 14/20 (70%) van Nood et al. N Engl J Med. 2013 Jan:407-15. Youngster et al. JAMA. 2014 Nov:1772-8.

Patient Case JZ responds clinically to medical therapy and does not require surgery. He is discharged to home after finishing a 10 day course of therapy. Unfortunately, one month following discharge, JZ presents to the emergency department again with diarrhea and fever. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins. He is also found to have NAP1/B1/027 colonization. 138 103 3.4 25 17 1.5 95 17 15.1 43 240 CrCl= 43 ml/min BP HR RR SpO 2 Temp 124/82 98 18 96 102.1 F

Audience response Which of the following is true regarding JZ s case? A. The patient can be treated with oral vancomycin for 10 days; bezlotoxumab can be used adjunctively B. The patient can be treated with fidaxomicin or an oral vancomycin taper; bezlotoxumab can be used adjunctively C. The patient can be treated with bezlotoxumab alone D. Fidaxomicin would be preferred over bezlotoxumab to prevent subsequent recurrence

Conclusion CDI is associated with a high mortality rate and an increasing incidence Oral vancomycin and fidaxomicin are the drugs of choice Strategies to prevent CDI recurrence include prophylactic bezlotoxumab and treatment with fidaxomicin

Questions B H A H H B A H H H H B B H