Gulf Coast Multidisciplinary Pharmacotherapy Conference Kelly R. Reveles, PharmD, PhD, BCPS College of Pharmacy, The University of Texas at Austin School of Medicine, UT Health San Antonio Email: kdaniels46@utexas.edu 1 Learning Objectives Pharmacist Objectives Describe the clinical significance of C. difficile infection (CDI) in acute care facilities and the community Identify current effective strategies for prevention and treatment of CDI Discuss innovative pipeline therapies and strategies for the prevention and treatment of CDI Pharmacy Technician Objectives Discuss the pharmacy technician s role in CDI prevention & treatment Identify the most common CDI therapies used in clinical practice Describe CDI therapy preparation 2 3 1
4 5 Outcomes Epidemiology CDI in the United States, 2011 Annual cases, n 453,000 Healthcare-associated cases, n 293,300 In-hospital mortality (all-cause) 9% Mean hospital stay 13 days Aggregate costs $8 billion 1 st recurrence 20-25% Lessa FC, et al. NEJM 2015;372:825-34 Lucado J, et al. HCUP Statistical Brief 124 Kelly CP. Clin Microbiol Infect 2012;18:21-7 6 2
Overview of C. difficile Gram-positive, spore-forming anaerobe Gut colonization rates vary by age and exposures Transmitted via the fecal-oral route Found in the environment, food, & healthcare facilities Furuya-Kanamori L, et al. BMC Infect Dis 2015:15:516 Photo courtesy of Microbe Canvas 7 Pathogenesis Rao K, et al. J Hosp Med 2016;11:56 8 Clinical Presentation Clinical suspicion Frequent diarrhea ( 3 unformed stools per day) Fever (>102 F) Abdominal tenderness & distention Leukocytosis Risk factors, particularly recent antibiotics Colonoscopy or abdominal CT Pseudomembranous colitis Ileus or megacolon 9 McDonald, et al. Clin Infect Dis 2018:1 3
Microbial dysbiosis Antibiotics Gastric acid suppressants Antineoplastic agents Risk Factors Bauer MP, et al. Lancet. 2011;377(9759):63-73 Bignardi GE. J Hosp Infect. 1998;40(1):1-15 Barbut F, et al. Arch Intern Med. 1996;156(13):1449-54 Bartlett JG. Clin Infect Dis. 2008;46(10):1489-92 McFarland LV, et al. J Infect Dis. Sep 1990;162(3):678-84 Poor immune response Older age Severe underlying disease Immunosuppression Healthcare exposures Prolonged hospitalization Inadequate isolation Long-term care residence 10 Risk Factors: Antimicrobial Agents Risk increases with cumulative antibiotic exposure More common with antibiotics that disrupt the gut flora Commonly associated Occasionally associated Rarely associated Clindamycin Carbapenems Cephalosporins (3 rd /4 th gen.) Fluoroquinolones Penicillins Cephalosporins (1 st /2 nd gen.) Trimethoprim-sulfamethoxazole Macrolides Aminoglycosides Tetracyclines Daptomycin Vancomycin Leffler DA, et al. N Engl J Med 2015;372:1539 11 12 4
Overview of Prevention Approaches Target modifiable risk factors Antimicrobial stewardship Identify CDI early and accurately Optimize diagnostics Prevent acquisition & transmission Infection control 13 Antimicrobial Stewardship Scope of the problem 1 out of 2 inpatients will receive an antibiotic 269 million outpatient antibiotics prescribed in 2015 Inappropriate outpatient antibiotic use up to 50% Goals of stewardship Optimize selection, dose, and duration Improve patient outcomes Limit antimicrobial resistance Baggs J, et al. JAMA Intern Med 2016;176:1639 Hicks LA, et al. Clin Infect Dis 2015;60:1308 Fleming-Dutra KE, et al. JAMA 2016;315:1864 14 Antimicrobial Stewardship National Veterans Affairs CDI prevention initiative decreases hospital-onset CDI 15 Evans ME, et al. Infect Control Hosp Epidemiol 2016;37:720 5
Antimicrobial Stewardship National fluoroquinolone control policy reduces CDI in England Dingle KE, et al. Lancet Infect Dis 2017;17:411 16 Optimize Diagnostics Consider alternative etiology of diarrhea Test only patients with high probability of CDI Consider two-step testing method Test Detects Sensitivity Specificity Toxigenic culture C. diff cells or spores High Low * Nucleic acid amplification test Toxin genes High Moderate Glutamate dehydrogenase C. diff antigen High Low * Cytotoxicity assay Free toxins High High Enzyme immunoassay Free toxins Low Moderate *Must combine with a toxin test Fang FC, et al. J Clin Microbiol 2017;55:670 McDonald, et al. Clin Infect Dis 2018:1 17 Early detection & isolation Contact precautions Hand hygiene with soap and water Environmental cleaning & disinfection Infection Control 18 APIC Guide to Preventing Clostridium difficile infections 6
Overview of Current Therapies Kill C. difficile Metronidazole Vancomycin Fidaxomicin Correct dysbiosis Fecal microbiota transplantation Modulate immune response Bezlotoxumab 19 Metronidazole Targets Gram-positive & Gram-negative anaerobes Recommended dose: 500mg PO TID x 10 days Alternative dose for complicated CDI: 500mg IV TID Well-absorbed systemically Stool concentrations might not reach MIC 90 values Bolton RP et al. Gut 1986;27:1169 McDonald, et al. Clin Infect Dis 2018:1 20 Vancomycin Targets Gram-positive aerobes & anaerobes Recommended dose: 125mg PO QID x 10 days Alternative for fulminant CDI: 500mg rectal QID Available as oral capsules or oral solutions Little to no systemic absorption Fecal concentrations 500-1000x MIC 90 Gonzalez M, et al. BMC Infect Dis 2010;10:363 McDonald, et al. Clin Infect Dis 2018:1 21 7
Metronidazole vs. Vancomycin Vancomycin more effective than metronidazole in severe CDI Metronidazole Vancomycin 100% 80% 60% 40% 90% 98% P=0.02 97% 76% 20% 15% 14% 0% Clinical Cure (Mild) Clinical Cure (Severe) Recurrence 22 Zar FA, et al. Clin Infect Dis 2007;45:302 Metronidazole vs. Vancomycin Vancomycin more effective than metronidazole overall Metronidazole Vancomycin Tolevemer 100% P=0.02 81% 80% 73% 60% 44% 40% 20% 0% Clinical Success Johnson S, et al. Clin Infect Dis 2014;59:345 23% 21% 5% Recurrence 23 Fidaxomicin Macrocyclic antibiotic targeting Gram-positive anaerobes Less disruption of the normal gut microbiota compared to vancomycin and metronidazole Recommended dose: 200mg PO BID x 10 days High fecal concentrations, with little systemic absorption Chilton CH, et al. J Antimicrob Chemother 2015;70:2598 24 8
Vancomycin vs. Fidaxomicin Fidaxomicin superior to vancomycin at preventing recurrent CDI Vancomycin Fidaxomicin 100% 80% 86% 88% 60% 40% 20% 26% P<0.001 14% 0% Clinical Cure Recurrence 25 Crook DW, et al. Clin Infect Dis 2012;55:S93 Vancomycin vs. Fidaxomicin Overall treatment costs similar with first-line fidaxomicin therapy compared to vancomycin $16,000 $15,000 $14,000 $13,000 $12,000 $11,000 $10,000 Vancomycin Overall Elderly Renal Impairment Reveles KR, et al. Pharmacotherapy 2017;37(12):1489-97 Fidaxomicin Cancer Concomitant Antibiotics 26 Vancomycin vs. Fidaxomicin Real-world fidaxomicin use protocol decreases hospital costs $600,000 $400,000 Vancomycin Fidaxomicin $454,800 $200,000 $0 $6,333 $62,112 Drug Acquisition Costs $196,200 Hospital Readmission Costs 27 Gallagher JC, et al. Antimicrob Agents Chemother 2015;59:7007 9
Fecal Microbiota Transplantation 28 Smits WK, et al. Nature Reviews 2016;2:1 Fecal Microbiota Transplantation Three-step sequence for administration Oral antibiotic Bowel preparation FMT administration Sokol H, et al. Digest Liv Dis 2016;48:242 29 Fecal Microbiota Transplantation Products & administration Local donor vs. stool bank Fresh vs. frozen preparations Upper vs. lower GI delivery FDA regulations FMT considered biological product and drug Investigational New Drug application required for use Enforcement discretion offered when used to treat CDI 30 Sokol H, et al. Digest Liv Dis 2016;48:242 10
Fecal Microbiota Transplantation Long-term outcomes & safety of FMT (n=611) Primary cure rate 91% Upper (82%) vs. lower GI (93%) delivery (p=0.015) Early recurrence rate 6% Upper (8%) vs. lower GI (6%) delivery (p=0.692) Most adverse events expected, short-lived, & self-limited Li YT, et al. Aliment Pharmacol Ther 2016;43:445 31 Bezlotoxumab Monoclonal antibody that provides passive immunity against C. difficile toxin B Indicated for prevention of recurrent CDI Must be used in combination with antibiotic therapy Single 10mg/kg IV infusion over 60 minutes Can be administered outpatient Wilcox MH, et al. NEJM 2017;376:305 32 Bezlotoxumab Bezlotoxumab plus standard of care reduces CDI recurrence 100% 80% 60% 40% 20% Bezlotoxumab Actoxumab-Bezlotoxumab Placebo 80% 80% 73% P<0.001 27% 17% 15% 0% Clinical Cure Recurrence 33 Wilcox MH, et al. NEJM 2017;376:305 11
New Treatment Recommendations! Initial Episode Suspected or confirmed CDI Non-severe Severe Fulminant Vancomycin PO or Fidaxomicin PO or (Metronidazole PO) Vancomycin PO or Fidaxomicin PO Vancomycin PO or Vanc PO/PR + Metro IV and surgery consult Severe = WBC 15 x 10 9 /L or SCr >1.5 mg/dl Fulminant = hypotension or shock, ileus, or megacolon McDonald, et al. Clin Infect Dis 2018:1 34 Clinical Practice Recommendations Recurrent CDI Initial metronidazole Initial vancomycin Initial fidaxomicin Suspected or confirmed recurrent CDI Vancomycin PO Vancomycin tapered or fidaxomicin PO Fidaxomicin PO 2+ recurrences McDonald, et al. Clin Infect Dis 2018:1 Vancomycin tapered or fidaxomicin ± fecal transplant 35 36 12
Overview of Pipeline Therapies Kill C. difficile Cadazolid Ridinilazole Correct or minimize dysbiosis 2 nd generation FMT Ecobiotics Ribaxamase Modulate immune response Vaccines 37 Cadazolid Strong inhibitor of C. difficile protein synthesis with limited impact on normal gut microbiota Non-inferior to vancomycin in Phase 2 trial 100% Cadazolid 250mg BID Vancomycin 125mg QID 80% 77% 68% 60% 50% 60% 40% 33% 20% 18% 0% Clinical Cure Recurrence Sustained Clinical Response Louie T, et al. Antimicrob Agents Chemother 2015;59:6266 38 Ridinilazole Non-absorbed, bactericidal oral antibiotic for C. difficile with limited effect on normal gut microbiota Phase 2 trial demonstrated superiority over vancomycin in sustained clinical response 100% Ridinilazole 200mg BID Vancomycin 125mg QID 80% 78% 70% 67% 60% 40% 35% 42% 20% 14% 0% Clinical Cure Recurrence Sustained Clinical Response Vickers RJ, et al. Lancet Infect Dis 2017;17:735 39 13
Second Generation FMT RBX2660 fecal microbiota suspension Commercially-prepared with enhanced donor screening Standardized microbial load 150mL administered via enema GI adverse effects common, but declined with time Phase 2B PUNCH CD Study Prevention of Recurrence 100% Dubberke R, et al. Clin Infect Dis 2018 (Epub) 80% 60% 40% 20% 0% 64% RBX2660 P=0.047 45% Placebo 40 Ecobiotics Rationally-designed combinations of microbe spores Does not require donor stool SER-109 in Phase 3 trial to reduce recurrent CDI Smits WK, et al. Nature Reviews 2016;2:1 41 Ribaxamase Recombinant beta-lactamase given with beta-lactam Degrades unmetabolized antibiotic in the colon Aims to reduce deleterious effects on the gut microbiota Phase 2 trial met primary endpoint of reducing CDI risk Ribaxamase + ceftriaxone: 71.4% relative risk reduction (p=0.045) in CDI recurrence vs. ceftriaxone + placebo 42 Ribaxamase (Synthetic Biologics) [Press Release, Aug 14, 2017] 14
Vaccines Inactivated toxoids A and B stimulate immune response to C. difficile toxins Clinical trials are targeting high-risk patients Product Antigen Clinical Trials ACAM-CDIFF (Sanofi Pasteur) Inactivated toxins A & B Phase 3 C. difficile vaccine (Pfizer) Inactivated toxins A & B Phase 3 VLA84 (Valneva) Toxin A & B recombinant protein Phase 2 Smits WK, et al. Nature Reviews 2016;2:1 43 Summary CDI continues to be a major public health problem A bundled approach to prevention should include stewardship, optimal diagnostics, and infection control CDI treatment strategies aim to kill C. difficile, correct microbial dysbiosis, and modulate the immune system 44 Summary Vancomycin should be used preferentially over metronidazole, especially in severe CDI Fidaxomicin might be cost-effective as first-line therapy FMT & bezlotoxumab can help prevent recurrent CDI when used with standard antibiotic therapy Pipeline antibiotics, microbiome therapies, and vaccines hold promise to reduce CDI risk and improve outcomes 45 15
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Gulf Coast Multidisciplinary Pharmacotherapy Conference Kelly R. Reveles, PharmD, PhD, BCPS College of Pharmacy, University of Texas at Austin School of Medicine, UT Health San Antonio Email: kdaniels46@utexas.edu 49 17