C-ing DIFFiculties in treating recurrent C. difficile infections: the role of pulsed and tapered antibiotic therapy

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1 C-ing DIFFiculties in treating recurrent C. difficile infections: the role of pulsed and tapered antibiotic therapy Pharmacotherapy Rounds Friday, December 7 th, 2018 Jessica Yang, Pharm.D. Post Graduate Year 1 Pharmacy Practice Resident South Texas Veterans Health Care System The University of Texas at Austin UT Health San Antonio Objectives 1. Describe the basic pathophysiology of Clostridioides difficile infection (CDI) 2. Identify the different treatment approaches to treating recurrent CDI (rcdi) 3. Evaluate the literature supporting pulsed and tapered vancomycin and fidaxomicin dosing in recurrent CDI 4. Apply knowledge to a patient case 1 Y a n g

2 Introduction I. Significance a. Clostridioides difficile (formerly Clostridium difficile) is the most common cause of infectious diarrhea in the health care setting 1 b. In 2011, the Centers for Disease Control and Prevention (CDC) estimated that the incidence of CDI was 453,000 2 i cases/100,000 persons ii. 293,300 of these cases (64.7%) were considered to be healthcare-associated iii. Estimated 29,300 patients died within 30 days of diagnosis c. CDI is associated with significant morbidity and mortality i. CDI mortality is estimated at % 3 ii. Poor outcomes associated with recurrent CDI (rcdi), hospital readmissions, discharge to longterm care facilities, colectomies and outbreaks d. Up to 25-30% of patients with CDI will experience recurrence 1,4 i. Risk of recurrence increases with each successive recurrence ii. rcdi associated with 33% increased risk for death within 6 months after completion of initial treatment 4 II. Microbiology 5 a. C. difficile is a Gram-positive, spore-forming, obligate anaerobic bacterium b. Survives via spores outside of the colon (vegetative state) i. Resistant to many chemicals, oxygen and extreme temperatures ii. Highly transmissible via fecal-oral route by ingestion c. Typically found in water, soil, and healthcare environments 6 III. Pathophysiology (Figure 1) 1,5 7 a. Disruption of normal gut flora, usually due to antibiotics b. C. difficile exposure and colonization i. Gut microbiota offer protection against C. difficile colonization ii. C. difficile is resistant to many antibiotics, which kill gastrointestinal flora, leaving C. difficile to infect its host c. C. difficile can secrete toxins (i.e., toxin A and toxin B) i. Lead to destruction of intestinal epithelium and loss of barrier integrity ii. Increase of inflammatory mediators fluid secretion d. Spore formation and germination key to transmission and prolonged infection 2 Y a n g

3 Figure 1. CDI Pathophysiology 8 IV. Pathophysiology for recurrent infections 6,7 a. Antibiotics used to treat CDI continue to disrupt the normal microbiota b. Evidence to suggest that recurrence may be associated with decreased microbiome diversity 9 V. Risk factors for developing CDI and rcdi (Table 1) 1,6 Table 1. Risk Factors for CDI and rcdi 1,6 Risk Factors for CDI Risk Factors for rcdi Antibiotic use Any prior episode of CDI o Risk increases with number of antibiotics and longer Antibiotic use duration o Concomitant and/or post CDI treatment o Highest risk with clindamycin, fluoroquinolones, Older age second generation or higher cephalosporins, Prolonged or recent stay in health care facility carbapenems Proton-pump inhibitor use Gastric acid suppressants Infection with NAP1/BI/027 stain Older age (> 65 years) Inflammatory bowel disease Prior hospitalization, including duration of Absence of antitoxin A antibody response (defective hospitalization immune response) Long term care facility residency Gastrointestinal surgery or manipulation Inflammatory bowel disease Clinical Presentation and Diagnosis I. Clinical Presentation (Table 2) 1,6 a. Fever, abdominal pain, tenesmus, diarrhea b. Leukocytosis, increased serum creatinine c. Fulminant disease can result in hypotension, shock and the development of toxic megacolon or intestinal perforation 3 Y a n g

4 Severity Non-severe Severe Fulminant Abbreviations: Scr = serum creatinine; WBC = white blood cells Table 2. Severity of CDI 1 Presentation WBC < 15,000 cells/ml Scr < 1.5 mg/dl WBC > 15,000 cells/ml Scr > 1.5 mg/dl Hypotension, shock, ileus, megacolon II. Laboratory Tests (Table 3) 1,10 a. Performed on patients with unexplained and new-onset > 3 unformed stools in 24 hours i. Encouraged to not submit stool specimens on patients receiving laxatives b. Diagnosed via positive stool toxin test and/or the presence of the organism typically part of a multistep algorithm c. Guidelines recommend against testing stool from asymptomatic patients and repeated testing within 7 days during the same episode of diarrhea d. Recurrence of symptoms following CDI treatment should be assessed by repeat testing with toxin detection e. Test for cure not recommended Table 3. Available Tests for CDI Test Sensitivity Specificity Description Toxigenic culture High Low Must be combined with toxin test Growth and identification of C. difficile vegetative cells or spores Nucleic acid amplification tests High Low/moderate Detects C. difficile nucleic acid toxin genes Glutamate dehydrogenase immunoassays High Low Must be combined with toxin test Detects C. difficile common antigen Cell culture cytotoxicity High High Identifies free toxins directly in stool neutralization assay Toxin A and B enzyme immunoassays Low Moderate Identifies free toxins via polyclonal antibodies Adapted from McDonald LC et al. Infectious Disease Society of America (IDSA) Guideline Recommendations for Management of CDI I. Infection Prevention and Control 1 a. Patients with CDI should have a private room with dedicated toilet to decrease transmission b. Gloves and gowns should be worn by healthcare professionals c. Handwashing should be performed with soap and water d. Disposable patient equipment used when possible e. Clean with sporicidal disinfectant II. Pharmacological Treatment for First Episode CDI (Appendix A) 1 a. Discontinue therapy with precipitating antibiotic as soon as possible to decrease the risk for recurrence b. Oral vancomycin or fidaxomicin are recommended over metronidazole (Table 4) i. Since 2000, two trials have demonstrated that vancomycin is superior to metronidazole 11,12 ii. Fidaxomicin has been shown to be noninferior to vancomycin in treating first episode CDI 13,14 1. Fidaxomicin is associated with lower rates of recurrence iii. In one recent study, fidaxomicin had higher cure rates and lower recurrence rates compared to vancomycin for first episode CDI 15 c. Fidaxomicin not recommended for fulminant CDI 4 Y a n g

5 Table 4. IDSA Recommendations for the Treatment of First Episode CDI 1 Severity Recommendation Strength of Recommendation Non-severe or severe Fulminant VAN 125 mg 4 times daily PO for 10 days OR FDX 200 mg 2 times daily PO for 10 days VAN 500 mg 4 times daily PO or NG tube AND MET 500 mg 3 times daily IV Strong/high Strong/high Strong/high Strong/moderate Abbreviations: FDX = fidaxomycin; IV = intravenous; MET = metronidazole; NG = nasogastric; PO = by mouth; VAN = vancomycin Adapted from McDonald LC et al. Comments For non-severe infection only, if VAN or FDX are unavailable, can give MET 500 mg 3 times daily for 10 days (weak/high) If ileus, consider rectal VAN via enema (weak/low) III. Pharmacological Treatment for rcdi (Appendix A) 1 a. Selection is based on prior treatment and number of recurrences (Table 5) b. Pulsed and tapered antibiotics provide more favorable pharmacokinetics and spare antibiotic use c. Newer therapies may be better at preventing recurrences compared to vancomycin, but rates of rcdi i. Fidaxomicin Similar response to therapy compared to vancomycin but significantly reduced rates of second recurrence % vs 35.5% (95% CI 30.4% to 0.3%; P = 0.045) ii. Bezlotoxumab is a monoclonal antibody against C. difficile toxin B Reduced the rate of rcdi in patients receiving antibiotics for primary or rcdi compared to placebo 2. MODIFY I trial: 17% vs 28% (95% CI 15.9 to 4.3; P<0.001) 3. MODIFY II trail: 16% vs 26% (95% CI 15.5 to 4.3; P<0.001) iii. Fecal microbiota transplant (FMT) involves installing processed stool from a healthy donor FMT administration has been reported to resolve rcdi in 80%-93% of patients 2. Third party payment may be difficult to obtain Although rare, FMT can result in transmissible infections from the donor 1 d. Guideline recommendations are weak, as there is limited evidence for the optimal medication regimen Table 5. IDSA Recommendations for the Treatment of rcdi 1 Severity Recommendation Strength of Recommendation Weak/low First recurrence Second or subsequent VAN 125 mg 4 times daily PO for 10 days if MET was used for initial episode OR Prolonged tapered and pulsed VAN regimen if standard VAN was used for initial episode OR FDX 200 mg 2 times daily PO for 10 days if VAN was used for initial episode VAN in a tapered and pulsed regiment OR VAN 125 mg 4 times daily PO for 10 days, followed by rifaximin 400 mg 3 times daily for 20 days OR Strong/high Weak/moderate Weak/low Weak/low Comments Example of tapered and pulsed regimen: 125 mg 4 times daily for days, 2 times daily for a week, once daily for a week, and then every 2 to 3 days for 2 8 weeks FDX 200 mg 2 times daily PO for 10 days OR Weak/low FMT Strong/moderate Abbreviations: FDX = fidaxomycin; FMT = fecal microbiota transplant; MET = metronidazole; PO = by mouth; VAN = vancomycin Adapted from McDonald LC et al. 5 Y a n g

6 IV. Pharmacology of Pulsed and Tapered Antibiotics a. Alternative strategy to treating rcdi b. Basis and theory 23,24 i. Antibiotic-free period allows for recovery of gut microbiome and C. difficile spores to germinate ii. Pulsed antibiotic doses then kill newly germinated cells c. Pharmacokinetics i. In vitro gut models of vancomycin show promising effects on reducing antibiotic exposure while reducing C. difficile vegetative cells, spores and toxins See Appendix B for figures on C. difficile viable counts and vancomycin exposure 2. Still had deleterious effects on gut microbiota 3. rcdi seen after administration of vancomycin in some models ii. Lower levels of fidaxomicin after tapered dosing regimens have been shown to help recovery of gut flora in in vitro models Allowed persistence of fidaxomicin at inhibitory concentrations, prolonging suppression of C. difficile while facilitating microbiota recovery 2. No rcdi seen V. Guidelines list vancomycin pulsed and tapered dosing as an option for patients with rcdi; however, no specific regimen is recommended over another Clinical Question What place in therapy do pulsed/tapered antibiotics have in treating rcdi? I. Vancomycin Tapered and/or Pulsed Studies a. Four observational case series of pulsed and tapered vancomycin demonstrated % cure for rcdi (Appendix C) 23,24,27,28 b. Two randomized open-labeled trials compared vancomycin pulsed and tapered dosing to FMT 29,30 i. Vancomycin pulsed ± taper: % ii. FMT: 43.4%-65% iii. Results inconclusive Table 6. Studies of VAN Tapered and/or Pulsed vs FMT Study VAN VAN + FMT Results Cammarota, et al. 29 VAN-P: 125 mg 4 times daily x 10 days mg every 2-3 days x at least 3 weeks 125 mg 4 times daily 3 days + FMT by colonoscopy VAN-P: 5/19 (26%) had resolution of diarrhea 10 weeks after therapy Hota, et al. 30 VAN-TP: 125 mg 4 times daily x 14 days, 125 mg twice daily x 7 days, 125 mg daily x 7 days, 125 mg QoD x 7 days, 125 mg Q3D x 7 days 125 mg 4 times daily x 14 days + FMT by enema VAN + FMT: 13/20 (65%) VAN-TP: 7/12 (58.3%) had resolution of symptomatic lab-confirmed CDI within 120 days of intervention VAN + FMT: 7/16 (43.4%) Abbreviations: CDI = C. difficile infection; FMT = fecal microbiota transplant; Q3D = every third day; QoD = every other day; VAN = vancomycin; VAN-P = vancomycin; VAN-TP = vancomycin taper and pulse 6 Y a n g

7 McFarland, et al. (2002) 24 McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol Jul;97(7): Objective To evaluate the success of vancomycin and metronidazole treatment strategies in a cohort of 163 patients with rcdi Methods Trial Design Retrospective case series Cases collected from placebo arm of two national, double blind placebo-controlled trials Participants & Setting Inclusion Age years Occurrence of active diarrhea before standard antibiotic treatment Positive C. difficile assay (culture or toxin) > 1 prior episode of CDI within 1 year Exclusion Active diarrhea due to cause other than C. difficile Immunosuppression within 3 months Negative C. difficile assay at time of enrollment Receiving current oral antifungal therapy Pregnancy Intervention Outcomes Statistical Methods Patients received either vancomycin (VAN) or metronidazole (MET) Study 1: dose and duration of antibiotic varied based on treating physician Study 2: low or high dose VAN or MET; if patients failed, subsequent treatment determined by treating physician VAN Low dose: < 1 g/day Medium dose: 1-2 g/day High dose: > 2 g/day Tapered Pulsed Other* MET Low dose: < 1 g/day Medium dose: 1.5 g/day High dose: 2 g/day Taper Pulse *consisted of VAN + rifampin and VAN + MET Stool samples assayed for C. difficile at enrollment, end of antibiotics, end of week 4, end of week 8 and anytime recurrence was suspected Cure (no recurrence) within 2 months after antibiotics Continuous variables: Student s t-test Nonparametric data: Wilcoxon rank sum test Nominal variables: chi-square or Fisher s exact test Two-tailed tests of significance at a level of p<0.05 Results Baseline Data N=163 cases o VAN only: 119 (73%) o MET: 38 (23.3%) o Other: 6 (3.7%) Age: years (mean 61.6 ± 18.5) Female: 127 (77.9%) Mean number of prior episodes: 3.2 ± 2.1 (range 1 14) 7 Y a n g

8 Mean total duration of rcdi: 20 days to 4 years (median 113 days) Outcomes Recurrences Treatment Recurrence (n=73) Cure (n=90) p-value VAN High dose: > 2 g/day 9 (42.9%) 12 (57.1%) 0.09 Medium dose: 1-2 g/day 10 (71.4%) 4 (28.6%) * Low dose: < 1 g/day 26 (54.2%) 22 (45.8%) 0.20 Taper 9 (31%) 20 (69%) 0.01 Pulse 1 (14.3%) 6 (85.7%) 0.02 Other 2 (33.3%) 4 (66.7%) 0.14 MET High dose: 2 g/day 0 2 (100%) 0.12 Medium dose: 1.5 g/day 2 (40%) 3 (60%) 0.24 Low dose: < 1 g/day 13 (44.8%) 16 (84.2%) 0.09 Taper 1 (100%) 0 -- Pulse 0 1 (100%) -- * Comparison group Statistically fewer recurrences in VAN tapered [9/29 (31%); P=0.01] and pulsed [1/7 (14.3%); P=0.02] regimens compared to medium dose regimen [10/14 (71.4%)] Mean days of taper 21.5 ± 10 o Recurrence 25.4 ± 13.3 vs cure 19.5 ± 8.0 Mean days of pulses o Recurrence 9 ± 0 vs cure 20.3 ± 11 Discussion Author s Conclusions Tapered or pulsed dosing regimens of VAN may result in significantly higher rcdi cure rates compared to traditional dosing Reviewer s Interpretation Strengths Limitations Compared to non-pulsed and non-tapered Small sample size VAN regimens Case series VAN dosing not standardized No information on prior CDI treatments Conclusions: Only study comparing VAN tapered and/or pulsed regimens to other VAN regimens Suggests that longer pulses may be needed to clear C. difficile and restore normal gut microbiota Suggests that tapered/pulsed vancomycin regimens are more effective than non-tapered/pulsed regimens at treating rcdi Abbreviations: NS = non-significant; MET = metronidazole; VAN = vancomycin 8 Y a n g

9 Soriano, et al. (2014) 31 Soriano MM, Danziger LH, Gerding DN, et al. Novel fidaxomicin treatment regimens for patients with multiple Clostridium difficile infection recurrences that are refractory to standard therapies. Open Forum Infect Dis. 2014;1(2):ofu069-ofu069. doi: /ofid/ofu069. Objective To describe the effects of using a fidaxomicin chaser regimen and fidaxomicin taper regimen in patients with multiple rcdi Methods Trial Design Participants & Setting Intervention Outcomes Statistical Methods Retrospective observational case series Setting/Location: Chicago Inclusion: Multiple rcdi (> 2 CDI episodes) with > 1 episode confirmed by stool assay for C. difficile Vancomycin taper (VAN-T) followed by a fidaxomicin chaser (FDX-Chaser) VAN-T or standard fidaxomicin (FDX) followed by a FDX taper (FDX-T) VAN-T + FDX-Chaser VAN-T or FDX + FDX-T VAN 125 mg four times daily x 10 days, 125 mg VAN-T or FDX 200 mg twice daily x 10 days twice daily x 6 days, 125 mg daily x 7 days, 125 mg QoD x 14 days FDX 200 mg twice daily x 10 days, 200 mg daily x 7 days, 200 mg every other day for 7-26 days FDX 200 mg twice daily x 10 days as chaser for a total duration of days Mean symptom-free interval (SFI) Recurrence defined as the reappearance of diarrheal stools with or without laboratory diagnostic testing Comparison of SFIs between fidaxomicin regimens and other regimens: Mann-Whitney U test Demographic data: Student s t-test Results Baseline Data Baseline Characteristic VAN-T + FDX Chaser (n=8) VAN-T or FDX-T + FDX-T (n=12) Mean age 66.9 ± 19 years 63.7 ± 16 years Female 6 (75%) 7 (58%) Mean number of CDI episodes no. (range) 5 (3-10) 5 (3-11) Outcomes Outcomes VAN-T + FDX Chaser (n=8) Most effective prior antibiotic treatment regimen* Mean SFI post treatment 278 (649) 56.5 (48) days (IQR) Recurrence no. (%) 3 (38) 25 (30) * Comparison group p = compared with non-fdx chaser SFI 9 Y a n g

10 Outcomes VAN-T or FDX + FDX-T (n=12) Most effective prior antibiotic treatment regimen* Mean SFI post treatment 257 (280) 56.5 (48) days (IQR) Recurrence no. (%) 2 (17) 25 (30) * Comparison group p = compared with non-fdx-t SFI Appendix D for additional information on patient demographics and prior treatment regimens The two patients who developed rcdi after the fidaxomicin taper had received additional oral antibiotics for other infections One patient receiving FDX-T had worsening CDI symptoms and did not complete treatment Discussion Author s Conclusions Fidaxomicin taper strategy for patients with multiple rcdi refractory to commonly used salvage therapies may be effective in breaking the cycle of recurrence. Reviewer s Interpretation Strengths Limitations Provides baseline support for the use of Observational cases FDX as a taper Small sample size Not all episodes confirmed by stool assay Patients given VAN-T or FDX prior to taper Conclusions: Fidaxomicin taper was able to control subsequent CDI recurrences in patients who have failed multiple therapies for rcdi, including prolonged vancomycin tapers Abbreviations: CDI = C. difficile infection; FDX = fidaxomicin; FDX-T = fidaxomicin taper; IQR = interquartile range; no. = number; QoD = every other day; rcdi = recurrent C. difficile infection; SFI = symptom free interval; VAN-T = vancomycin taper Guery, et al. (2018) 32 Guery B, Menichetti F, Anttila VJ, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomized, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018;18(3): doi: /S (17)30751-X. Objective To assess the clinical outcomes of extended-pulsed fidaxomicin (FDX-EP) compared with vancomycin Methods Trial Design Participants & Setting Phase 3b/4 randomized, controlled, parallel, superiority, open-label, multi-center trial Setting/Location: 86 hospitals in 21 European countries Dates: November 6, 2014 to May 5, 2016 Inclusion Hospitalized > 60 years old Clinically confirmed CDI (3+ diarrhea in 24 hrs before randomization + toxin A/B in stool within 48 hrs of randomization) Exclusion CDI therapy for more than 1 day in past 48 hrs > 2 previous CDI episodes within 3 months of enrollment Patients diagnosed with toxic megacolon or IBD Appendix E for complete list 10 Y a n g

11 Intervention Outcomes Statistical Methods VAN vs FDX-EP VAN FDX-EP VAN 125 mg 4 times daily on days 1-10 FDX 200 mg twice daily on days 1-5 FDX 200 mg QoD on days 7-25 Stratified by o Severity: leukocytes > 15x10 9 cells/l, or rise in SCr > 50% baseline, or albumin < 30 g/l o Presence or absence of cancer o Age: > 75 or < 75 years o Number of previous CDI episodes in 3 months before study entry Evaluated for cure on day 12 for VAN and day 12 and 27 for FDX Evaluated recurrence on days 40, 55, 90 (end of follow up) Primary outcome: sustained clinical cure of CDI 30 days after the end of treatment in a microbiotasparing strategy Secondary outcomes: o Sustained clinical cure of CDI on days 40, 55, 90 o Clinical response of CDI at day 12 and 2 days after end of treatment Day 12 or day 27 for VAN and FDX-EP o Rate of relapse at day 90 o Time to resolution of diarrhea from start of treatment o Recurrence of CDI at days 40, 55, 90 o Time to CDI recurrence after end of treatment for patients with clinical response o Disease free survival after day 10 for patients with clinical response o Incidence of mortality and severity of adverse events at day 90 o Health related quality of life up to day 55 (reported separately) o Readmission and length of hospital stay at day 90 Safety assessed from day 1-90 Recurrence: return of diarrhea that was greater than frequency recorded on day 10 for VAN or day 25 for FDX-EP + positive stool toxin + requiring further therapy Assuming clinical cure 70% VAN and 85% FDX-EP, 90% power, α patients in each arm Descriptive statistics for continuous and categorical variables Comparisons using Cochran-Mantel-Haenszel test, logistic regression, Kaplan-Meier method, Cox proportional hazards model, and paired t tests Adjusted p-values obtained using Hochberg procedure if primary endpoint differed significantly between treatment arms Primary and secondary endpoints analyzed using per-protocol and modified full analysis sets Safety analysis conducted in all patients receiving at least 1 dose of treatment Results Enrollment: 403 patients screened 364 patients randomized 362 patients received at least one dose 356 had confirmed CDI Modified full analysis (n=356) Per protocol analysis (n=249) Safety analysis (n=362) VAN FDX-EP Y a n g

12 Baseline Data Characteristic VAN (n=179) FDX-EP (n=177) Mean age y (IQR) 75 (67 82) 75 (69 83) Female 100 (56%) 107 (60%) Number of unformed bowel movements 6.4 (3.4) 6.8 (4.7) per day - mean (SD) CDI severity - severe 67 (37%) 63 (36%) No CDI occurrences in past 3 months 140 (78%) 141 (80%) One CDI occurrence in past 3 months 29 (16%) 26 (15%) Two CDI occurrences in past 3 months 10 (6%) 10 (6%) Presence of cancer 37 (21%) 38 (21%) Use of antibiotics 90 days prior 129 (72%) 128 (72%) Nursing home or long term care facility 10 (6%) 5 (3%) Outcomes Primary outcome clinical cure at 30 days after completion of treatment VAN (n=179) FDX-EP (n=177) OR (95% CI) p-value 106 (59%) 124 (70%) 1.62 ( ) Results were similar in per-protocol set: VAN 81/125 (66.4%) vs FDX-EP 106/124 (85.5%) o OR 2.99; 95% CI ; P=0.001 No statistical difference seen when stratifying for prior episodes In multivariate analysis adjusted for baseline stratification, patients with severe CDI were less likely to achieve clinical cure (OR 0.57; 95% CI ; P=0.019) Secondary outcomes Outcome Sustained clinical cure at Day 40 Day 55 Day 90 Clinical response 2 days after end of treatment Recurrence of CDI at Day 40 Day 55 Day 90 Time to resolution of diarrhea h (95% CI) VAN (n=179) 106 (59%) 99 (55%) 92 (51%) FDX-EP (n=177) 133 (75%) 124 (70%) 116 (66%) OR (95% CI) 2.10 ( ) 1.91 ( ) 1.80 ( ) p-value (82%) 138 (78%) 0.81 ( ) (17%) 32 (18%) 34 (19%) 22 (10 30) 3 (2%) 7 (4%) 11 (6%) 34 (25 49) 0.09 ( ) 0.20 ( ) 0.29 ( ) < < Results were similar in per-protocol set No statistical difference seen when stratifying for prior episodes Time to recurrence of CDI after treatment completion longer in FDX-EP than VAN group (P<0.0001) The overall difference in disease-free survival after day 10 between two groups was significant (OR 0.26; 95% CI ; P=0.003), favoring FDX-EP o Hazard of CDI recurrence at any given time after day 10 for a VAN treated patient was about 3.8 times that of a FDX-EP treated patient Plasma concentrations of FDX were low and decreased with the change in dosing scheme Greater microbiota recovery in FDX-EP compared to VAN during treatment and follow up 12 Y a n g

13 Adverse Effects Outcome VAN (n=181) FDX-EP (n=181) Any treatment-emergent adverse event 128 (71%) 121 (67%) Any treatment-emergent adverse event related to study drug 9 (5%) 14 (8%) Any treatment emergent adverse event leading to discontinuation of study drug 5 (3%) 14 (8%) Adverse events that occurred in >5% of patients included anemia, cardiac failure, constipation, diarrhea, pyrexia, CDI, pneumonia, sepsis, urinary tract infection 65 (18%) deaths occurred during the study o VAN 36 (20%); FDX-EP 29 (16%) o Only one related to VAN (determined by investigator) - 73 year old died of sepsis and heart failure Discussion Author s Conclusions FDX-EP was superior to standard VAN for sustained cure of CDI The recurrence rates in the study are the lowest observed in a randomized clinical trial of antibiotic treatment in CDI Reviewer s Interpretation Strengths Limitations Multicenter, randomized clinical trial Unblinded Same overall fidaxomicin pill count Older patient population compared to traditional dosing High death rates Analyzed microbiota recovery and Limited number of CDI to 3 episodes pharmacokinetics of dosing regimen Included patients with first time CDI Did not compare to extended or tapered VAN Conclusions: FDX-EP was superior to VAN in sustaining clinical cure of CDI up to 90 days and had fewer recurrence rates in an older, hospitalized population Abbreviations: CDI = C. difficile infection; CI = confidence interval; FDX = fidaxomicin; FDX-EP = fidaxomicin extended pulsed; IBD = irritable bowel disease; IQR = interquartile range; OR = odds ratio; rcdi = recurrent C. difficile infection; Scr = serum creatinine; SD = standard deviation; y = year II. Future Directions a. NCT I Veterans Administration Cooperative Studies Program b. Vancomycin standard dosing versus fidaxomicin standard dosing versus vancomycin taper and pulse in patients with first episode CDI or rcdi Conclusions and Recommendations I. Patients with rcdi are at high risk for developing multiple recurrences a. Additional antibiotic use, particularly given close to the time of CDI treatment, increases risk for recurrence and relapse II. Results from the reviewed studies show tapered and pulsed dosing can be an efficacious for treating rcdi a. Vancomycin pulsed and/or tapered success rate: 61-81% b. Fidaxomicin pulsed and/or tapered success rate: 70-83% c. Data supports the hypothesis that regimens kill C. difficile while allowing gut microbiota recovery d. Pulsed and tapered dosing can be beneficial even after patients have failed several options III. Consider fidaxomicin extended-pulsed regimen for second recurrence CDI a. Particularly if the patient has failed treatments with vancomycin tapers b. Fidaxomicin is more effective than vancomycin in reducing recurrence IV. For vancomycin, recommend long duration of taper of at least 60 days with pulsed doses every 3 days a. Must consider patient s ability to remain adherent to regimen V. Future trials are needed to compare pulsed and tapered regimens against each other, with consistent dosing regimens 13 Y a n g

14 Appendix Appendix A. Medications Used for Treating CDI Medication Mechanism of Action Dose Dosage Adjustments Vancomycin (oral) 34 Metronidazole 35 Fidaxomicin 36 Bezlotoxumab 37 Abbreviations: IV = intravenous; PO = by mouth Inhibits cell wall synthesis by blocking glycopeptide polymerization Inhibits DNA synthesis by interacting with DNA, leading DNA degradation Inhibits protein synthesis by inhibiting RNA polymerase and RNA synthesis Monoclonal antibody that binds to C. difficile toxin B and neutralizes 125 to 500 mg PO 4 times daily 500 mg PO 3 times daily IV if fulminant 200 mg PO twice daily 10 mg/kg IV as a single dose None None None None Side Effects Abdominal pain, dysgeusia, nausea Headaches, nausea, vaginitis, metallic taste, neuropathy Nausea, abdominal pain, vomiting Cardiac failure exacerbation, infusion reaction, nausea 14 Y a n g

15 Appendix B. Vancomycin Standard and Pulsed/Tapered Dosing in an In Vitro human gut model for CDI 24,38 Vancomycin given as a standard regimen in an in vitro gut model: vancomycin 125 mg four times daily x 7 days. C. difficile total viable counts (TVC) and spore counts (log10 cfu/ml), toxin levels (RU), and vancomycin concentrations (mg/l) are represented. Vancomycin given as a taper and pulse in an in vitro gut model: vancomycin 125 mg four times daily x 7 days, vancomycin 125 mg three times daily x 7 days, vancomycin 125 mg two times daily x 7 days, vancomycin 125 mg daily x 7 days, vancomycin 125 mg every other day for one week, vancomycin 125 mg every third day for one week. C. difficile total viable counts (TVC) and spore counts (log10 cfu/ml), toxin levels (RU), clindamycin and vancomycin concentrations (mg/l) are represented. The gray boxes indicate vancomycin administration. 15 Y a n g

16 Study & Design Appendix C. Observational Studies of VAN Tapered and/or Pulsed Regimens Number of prior VAN Regimen Duration, Cure recurrences VAN total Taper and Pulse: 125 mg 4 42 days, 22/22 (100%) times daily x 7 days, 125 mg 7,250 mg twice daily x 7 days, 125 mg daily x 7 days, 125 mg QoD x 7 days, 125 mg Q3D x 14 days Tedesco, et al. 23 Mean 3-4 (range 2-5) McFarland, et al. 24 Mean 3.2 ± 2.1 a (range 1-14) Bakken, et al. 27 Mean 4 (range 1-9) Sirbu, et al. 28 Mean 3.15 ± 1.3 (range 2-8) Low dose b : < 1 g/day Medium dose: 1-2 g/day High dose: > 2 g/day Taper Pulse Taper and Pulse: 125 mg 4 times daily x 14 days, 375 mg Q3D x 14 days, 250 mg Q3D x 14 days, 125 mg Q3D x 14 days Taper and Pulse: Taper to VAN daily dosing, QoD vs QoD + Q3D for at least 2 weeks Varied Low dose: 22/48 (45.8%) Medium dose: 4/14 (28.6%) High dose: 12/21 (57.1%) Taper: 20/29 (69%) Pulsed: 6/7 (85.7%) 56 days, 10,750 mg QoD: 60.3 ± 25.9 days QoD+Q3D: 86.3 ± 27.8 days 17/21 (81%) QoD: 22/36 (61.1%) QoD+Q3D: 52/64 (81.1%) Total: 74/100 (74%) Abbreviations: QoD = every other day; Q3D = every third day; VAN = vancomycin a. Includes those in the metronidazole arm of the study b. Dose, duration and type of regimen determined by treating physician Total: 77 ± 29.9 days 16 Y a n g

17 Appendix D. Demographic Characteristics and Outcomes of Patients Y a n g

18 Appendix E. Exclusion Criteria Patient took or required to be treated with prohibited medications. Prohibited medications that might have affected the evaluation of the study endpoints throughout the study (from informed consent to the EoS) were: o Prohibited concomitant medications or therapies: Non-study oral fidaxomicin Non-study vancomycin Metronidazole Oral bacitracin Fusidic acid Rifaximin Nitazoxanide a Tigecycline Antidiarrheal medications (except 2 doses permitted in the 24 hours prior to randomization) Prebiotics and probiotics. o Prohibited concomitant non-medication therapies: Fecal transplant o Allowed but not recommended medications: Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone were not recommended, but these medications were not prohibited. 2. Patient had received more than 1 day of dosing of any therapy for CDI within the last 48 hours. 3. Patient had experienced more than two previous episodes of CDI in the 3 months prior to study enrolment. 4. Patient was unable to swallow oral study medication. 5. Patient had a current diagnosis of toxic megacolon. 6. Patient was not willing to adhere to the provisions of treatment and observation specified in the protocol. 7. Patient had been randomized into this study previously, had taken any investigational drug within 28 days or five half-lives, whichever was longer, prior to enrolment or was currently participating in another clinical study which may have influenced the assessment of efficacy and/or safety endpoints of this study, in the opinion of the sponsor. 8. Patient had previously participated in a CDI vaccine study. 9. Patient had hypersensitivity to fidaxomicin, vancomycin or any of its components. 10. Any clinical condition which, in the opinion of the investigator, would not allow safe completion of this study. 11. Patient was at the time of the study diagnosed with IBD. 18 Y a n g

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