Confronting Challenges in the Management of C difficile: Recurrent Infection and Hypervirulent Strains Faculty and Disclosures Ciarán P. Kelly, MD Professor of Medicine Department of Medicine Harvard Medical School Attending Physician Division of Gastroenterology Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Ciarán P. Kelly, MD, has disclosed that he has received consulting fees from Artugen, Merck, and Vedanta; fees for non-CME/CE services from Biocodex; and funds for research support from Institut Merieux. Program Overview Burden of Disease Diagnosis in 2018 Initial Management Management of Recurrent Disease Prevention of Recurrence Burden of Disease CDI: An Opportunistic Infection Antibiotic therapy Disturbed colonic microbiota C difficile exposure and colonization Toxin A and toxin B Symptomless carriage Kelly. NEJM. 2008;359:1932. Diarrhea and colitis Slide credit: clinicaloptions.com CDI: Incidence and Mortality > 450,000 CDI cases annually[1] 29,000 CDI-related deaths annually[1] CDI designated by the CDC as urgent threat to public health[2] Rate per 1000 Discharges ‒ 60% are hospital-associated infections CDI-Related US Hospitalizations, 2001-2013[3] 20 15 10 5 0 Yr Observed 1. Lessa. NEJM. 2015;372:825. 2. CDC. Antibiotic resistance threats in the US. 2013. 3. Healthcare Cost and Utilization Project. Report 2012-01. Projected Slide credit: clinicaloptions.com Contributing Factors to Increased CDI Incidence Host factors Age Immune response Underlying disease C difficile bacterial factors Environmental factors Virulence Sporulation Antibiotic resistance Antibiotic use PPI use Burden of C difficile spores Kelly. NEJM. 2008;359:1932. Bauer. Clin Microbiol Infect. 2009;15:1067. Cohen. Infect Control Hosp Epidemiol. 2010;31:431. Slide credit: clinicaloptions.com “Hypervirulent” Strains of C difficile Emerged in the US, Canada, and Europe in the early 2000s[1-4] ‒ Ribotypes 027 (& 078) Associated with[1-3]: ‒ High-level fluoroquinolone resistance ‒ Increased spore formation Approaches to diagnosis and management are the same as for other C difficile strains[6] ‒ Multiple disease outbreaks ‒ High toxin production ‒ Increased disease severity and mortality rates 1. Loo. NEJM. 2005;353:2442. 2. McDonald. NEJM. 2005;353:2433. 3. Yakob. Sci Rep. 2015;5:12666. 4. Pepin. Clin Infect Dis. 2005;41:1254. 5. CDC. Tracking Clostridium difficile infection. 2015. 6. McDonald. Clin Infect Dis. 2018;66:987. Slide credit: clinicaloptions.com Diagnosis in 2018 Principles of CDI Diagnosis and Management Suspect CDI based on clinical signs Discontinue nonessential antibiotics Confirm presence of toxin-producing C difficile by stool testing (usually NAAT or EIA) Treat CDI if laboratory-confirmed diagnosis* *Empiric treatment best avoided unless high clinical index of suspicion and either expectation of substantial delay (> 24 hrs) in laboratory confirmation or fulminant disease. McDonald. Clin Infect Dis. 2018;66:987. Slide credit: clinicaloptions.com IDSA-SHEA Guideline Recommendations for Diagnostic Testing Clinical signs of CDI: ‒ Diarrhea, defined as ≥ 3 unformed stools in 24 hrs ‒ New onset Difficulties : ‒ Not induced by laxatives 4% of healthy adults are colonized by Cl. difficile 20-25% of the C.difficile strains may be non-toxigenic McDonald. Clin Infect Dis. 2018;66:987. Slide credit: clinicaloptions.com Commonly Used Stool Tests for CDI Test Nucleic acid amplification test Accuracy Cost Highly sensitive High but falling Specific but not highly sensitive Low Rapid Potential concerns: sensitivity moderate (~ 85%); frequent false-negative results Sensitive but not specific Low Rapid Used as a “triage” step Potential concerns: frequent false-positive results; confirmation with another assay required eg, PCR-based assays Stool toxin EIA test Enzyme immunoassay Glutamate dehydrogenase test “C difficile antigen” Comments Rapid Increasingly used (in place of toxin test) Potential concerns: may detect bacteria or spores in the absence of toxin or disease Other stool tests for CDI include anaerobic bacterial culture and tissue culture cytotoxicity Cohen. Infect Control Hosp Epidemiol. 2010;31:431. Surawicz. Am J Gastroenterol. 2013;108:478. Slide credit: clinicaloptions.com CDI Diagnosis: IDSA-SHEA–Recommended Approach Option A GDH antigen plus stool toxin tests Option B NAAT Both tests positive: consistent with CDI Positive: consistent with CDI* GDH negative/stool toxin test positive: consistent with CDI Negative: not consistent with CDI GDH positive/stool toxin test negative: inconclusive; consider NAAT (see right column) Both tests negative: not consistent with CDI *Consider stool toxin EIA if clinical characteristics of CDI are not clearly present. Note that > 10% of patients in hospital receiving antibiotics without diarrhea will test positive by NAAT (ie, asymptomatic carriers). McDonald. Clin Infect Dis. 2018;66:987. Surawicz. Am J Gastroenterol. 2013;108:478. Slide credit: clinicaloptions.com Initial Management Vancomycin vs Metronidazole for Treating CDI ‒ Patients stratified by disease severity* CDI Cure Rate† 100 98 Vancomycin Metronidazole 97 90 90 Cure (%) Prospective, double-blind study in which patients with CDI were randomized to receive vancomycin 125 mg QID or metronidazole 250 mg QID for 10 days (N = 172) 80 76 70 60 n/N = 37/41 39/40 29/38 30/31 50 Mild/ Moderate CDI P = .36 Severe CDI P = .02 *≥ 2 points = severe disease. 1 point for age > 60 yrs, temperature > 101°F, albumin < 2.5 mg/dL, WBC > 15,000 cells/mm3; 2 points for PMC at colonoscopy, ICU patient. †Cure: diarrhea resolution by Day 6 and negative C difficile toxin A assay at Days 6 and 10. Zar FA, et al. Clin Infect Dis. 2007;45:302-307. Slide credit: clinicaloptions.com Fidaxomicin vs Vancomycin for Treating CDI Double-blind phase III trial in which patients with CDI were randomized to receive fidaxomicin or vancomycin (N = 629) 100 88.2 85.8 92.1 89.8 P = .006 77.7 74.6 67.1 64.1 P = .006 Patient (%) 80 Vancomycin Fidaxomicin 60 40 P = .005 P = .004 25.3 24.0 15.4 13.3 20 0 mITT PP Initial Response* mITT PP Recurrence mITT PP Sustained Response† *Clinical cure: resolution of diarrhea with maintenance of resolution for duration of therapy plus no additional need for CDI treatment as of the second day after the end of therapy. †Global cure: resolution of diarrhea without recurrence. Louie. NEJM. 2011;364:422. Slide credit: clinicaloptions.com 2017 IDSA-SHEA Guidelines for Treatment of an Initial Episode CDI Severity Nonsevere* Severe Fulminant (severe, complicated)† Treatment Vancomycin 125 mg 4 times daily PO for 10 days Fidaxomicin 200 mg BID PO for 10 days Vancomycin 500 mg 4 times daily PO or by nasogastric tube or enema plus metronidazole 500 mg Q8H IV *If vancomycin or fidaxomicin are unavailable for a patient with nonsevere CDI only, metronidazole (500 mg 3 times daily PO for 10 days) may be considered. †May be characterized by hypotension or shock, ileus, or toxic megacolon. McDonald. Clin Infect Dis. 2018;66:e1. Slide credit: clinicaloptions.com Management of Recurrent Disease Recurrent CDI: A Self-Perpetuating Cycle Antibiotic therapy Disturbed colonic microflora “Dysbiosis” (loss of colonization resistance) C difficile exposure and colonization Antitoxin immunity Toxin A and toxin B Symptomless carriage Diarrhea and colitis Kelly. NEJM. 2008;359:1932. Kyne. Lancet. 2001;357:189. Almeida. J Gastroenterol. 2016;51:1. Antibiotic treatment Slide credit: clinicaloptions.com Recurrent CDI Common: ~ 25% of patients treated with metronidazole or vancomycin suffer a recurrence[1,2] Mechanisms of recurrence[3,4]: ‒ NOT primarily due to antimicrobial resistance ‒ Instead, antimicrobial therapy perpetuates dysbiosis Recurrent infection can be same strain as initial episode (relapse) or a new strain (reinfection)[3] 1. Cornely. Clin Infect Dis. 2012;55(suppl 2):S154. 2. Pepin. Clin Infect Dis. 2005;40:1591. 3. Kyne. Lancet. 2001;357:189-193. 4. Almeida. J Gastroenterol. 2016;51:1. Slide credit: clinicaloptions.com Prior CDI Recurrence and Recurrence Risk 80 Recurrence Rate (%) > 50% 60 ~ 40% 40 ~ 25%* 20 0 Initial Episode First Recurrence Second Recurrence *Whether treated with metronidazole or vancomycin. McFarland. JAMA. 1994;271:1913. Pepin. Clin Infect Dis. 2005;40:1591. McFarland. Am J Gastroenterol. 2002;97:1769. Slide credit: clinicaloptions.com Risk Factors for Recurrent CDI Previous episode of recurrent CDI Aged 65 yrs or older Additional antibiotic use (perpetuates dysbiosis) Impaired immune response to C difficile toxins Severe underlying disease ‒ ICU admission ‒ Immunocompromise ‒ Renal impairment Acid antisecretory medication? Prolonged hospitalization Bauer. Clin Microbiol Infect. 2009;15:1067. McFarland. Am J Gastroenterol. 2002;97:1769. Hu. Gastroenterology. 2009;136:1206. Do. Clin Infect Dis. 1998;26:954. Slide credit: clinicaloptions.com 2017 IDSA-SHEA Guidelines for Treatment of Recurrent CDI Recurrent Episode If initial therapy was with metronidazole If initial therapy was with vancomycin Treatment Vancomycin 125 mg 4 times daily PO for 10 days Fidaxomicin 200 mg BID PO for 10 days or Prolonged taper and pulsed vancomycin if standard regimen used for initial therapy: 125 mg 4 times daily for 10-14 days, 2 times daily for 1 wk, QD for 1 wk, then every 2-3 days for 2-8 weeks Metronidazole not recommended McDonald. Clin Infect Dis. 2018;66:e1. Slide credit: clinicaloptions.com Fidaxomicin vs Vancomycin for a First CDI Recurrence Subgroup analysis of randomized phase III trials assessing treatment with fidaxomicin or vancomycin for patients with a first CDI recurrence (N = 128) Patients With No Recurrence (%) Time to Recurrence by Treatment Group 1.0 Fidaxomicin 20% (13/66) recurred 0.9 0.8 0.7 Vancomycin 36% (22/62) recurred 0.6 0.5 0 Cornely. Clin Infect Dis. 2012;55(suppl 2):154. 5 10 15 20 Days of Follow-up 25 30 Slide credit: clinicaloptions.com 2017 IDSA-SHEA Guidelines for Treatment of Multiple Recurrent CDIs Treatment for Second or Subsequent Recurrent Episode Vancomycin in a tapered or pulsed regimen Vancomycin 125 mg 4 times daily PO x 10 days followed by rifaximin 400 mg 3 times daily for 20 days Fidaxomicin 200 mg BID PO for 10 days Fecal microbial transplantation McDonald. Clin Infect Dis. 2018;66:e1. Slide credit: clinicaloptions.com Turning to Nature’s Cures for CDI: Nonantibiotic Approaches Antibiotic therapy Disturbed colonic microflora Restore colonization resistance C difficile exposure and colonization Toxin A and toxin B Symptomless carriage Kelly. NEJM. 2008;359:1932. Diarrhea and colitis Immunity: active vaccine or passive immunotherapy Slide credit: clinicaloptions.com Duodenal Infusion of Donor Feces for Recurrent CDI Randomized, open-label clinical trial comparing abbreviated vancomycin + bowel lavage + donor feces infusion vs standard vancomycin vs standard vancomycin + bowel lavage in adults with relapsed CDI (N = 43) Patients Without Relapse Microbiota Diversity Patients With No Relapse (%) P < .001 P = .008 P = .003 93.8 100 80 81.3 60 40 30.8 20 0 23.1 First Infusion Infusion of Vancomycin Vancomycin of Donor Donor Feces (n = 13) With Bowel Feces Overall Lavage (n = 16) (n = 16) (n = 13) van Nood. NEJM. 2013;368:407. Kelly. NEJM. 2013;368:474. Simpson’s Reciprocal Index P < .001 250 200 150 100 50 0 Donors Patients Before Infusion Patients After Infusion Slide credit: clinicaloptions.com FMT and Beyond Nonoral delivery: ‒ Naso-enteric infusion ‒ Luminal instillation at colonoscopy ‒ Enema Oral delivery: ‒ Encapsulated fecal preparations (frozen or lyophilized) ‒ Defined bacterial cultures ‒ Fecal spores preparations ‒ Nontoxigenic C difficile spores Youngster. JAMA. 2014;312:1772. Baktash. Front Microbiol. 2018;9:1242. Slide credit: clinicaloptions.com Additional Investigational Strategies in Phase III Development Agent Ridinilazole SER-109 MoA Trial Nonabsorbable narrow-spectrum antibiotic with MoA still under investigation[1] Ri-CoDIFy 1 (NCT03595553) Ri-CoDIFy 2 (NCT03595566) Oral formulation of ~ 50 species of Firmicutes spores derived from healthy donor stool[2] ECOSPOR III (NCT03183128) Comparator Population Status Vancomycin Adults with CDI signs/symptoms warranting antimicrobial tx, stool presence of toxin A and/or B (target total N = 1360) Not yet recruiting Placebo Adults with qualifying episode of CDI (target N = 320) Recruiting -- Adults previously enrolled in SERES 012 study with CDI recurrence within 8 wks of receiving study drug (target N = 100) Recruiting ECOSPOR IV (NCT03183141; open-label extension of SERES 012 study) 1. Peng. Emerg Microfes Infect. 2018;7:15. 2. Khanna. J Infect Dis. 2016;214:173. Slide credit: clinicaloptions.com Prevention of Recurrence Bezlotoxumab for Prevention of CDI Recurrence Human monoclonal antibody that binds C difficile toxin B, preventing effects on host cells[1,2] ‒ IV systemic half-life ~ 19 days[1] FDA approved to reduce CDI recurrence in adults receiving antibacterial treatment for CDI and who are at high risk for recurrence[2] ‒ Not an antibacterial drug and not indicated for the treatment of CDI; must be used in conjunction with antibacterial drug treatment of CDI 1. Wilcox. NEJM. 2017;376:305. 2. Bezlotoxumab PI. Slide credit: clinicaloptions.com MODIFY I and II: CDI With Bezlotoxumab vs Actoxumab + Bezlotoxumab vs Placebo International, randomized, double-blind phase III trials Stratified by oral antibiotic, hospitalization status (inpatient vs outpatient) Bezlotoxumab 10 mg/kg* (n = 781) Adults with primary or recurrent CDI receiving SoC oral antibiotics for 10-14 days (N = 2559) Bezlotoxumab 10 mg/kg + Actoxumab 10 mg/kg* (n = 773) Placebo* (n = 773) Monitoring through Wk 12 with patients recording unformed bowel movements to Day 80-90 MODIFY I only: Actoxumab 10 mg/kg* (n = 232) Primary endpoint: proportion of patients in mITT with recurrent CDI during 12-wk follow-up *Single dose; infusions administered while receiving SoC antibiotics. Wilcox. NEJM. 2017;376:305. Slide credit: clinicaloptions.com CDI Recurrence Through Wk 12 (%)[1] MODIFY I and II: Bezlotoxumab Efficacy in Reducing CDI Recurrence in Subgroups With Baseline Risk Factors 45 40 35 30 29 28 27 15 25 22 17* 15* 15 15 153 178 405 390 10 5 0 Bezlotoxumab Bezlotoxumab + actoxumab Placebo 32 31 25 20 42 41 773 781 773 115 102 219 216 126 100 In post hoc analysis, for patients with no CDI risk factors, no difference between bezlotoxumab and placebo groups in CDI recurrence[2] *P < .001 vs placebo. Nonoverlapping 95% confidence intervals for all comparisons except the following: no risk factors and hypervirulent strain. All patients also received SoC antibiotics. Slide credit: clinicaloptions.com 1. Wilcox. NEJM. 2017;376:305. 2. Gerding. Clin Infect Dis. 2018;67:649. Key Take-home Points CDI is an increasingly prevalent nosocomial infection with a high burden of morbidity, mortality, economic cost Diagnosis should utilize clinical criteria and laboratory testing 2017 IDSA-SHEA treatment guideline recommendations ‒ Initial CDI: vancomycin or fidaxomicin for nonsevere or severe disease; combination of oral vancomycin and IV metronidazole for fulminant disease ‒ Recurrent CDI: standard vancomycin (if initial metronidazole); prolonged taper and pulsed-dose vancomycin or fidaxomicin (if initial vancomycin) ‒ Multiple recurrent CDI: taper and pulsed-dose vancomycin, standard vancomycin plus rifaximin, fidaxomicin, FMT Slide credit: clinicaloptions.com Thank you! clinicaloptions.com