Pharmacist Objectives Describe the clinical significance of C. - PDF document

6/1/18 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

6/1/18 4 5 Epidemiology – CDI in the United States, 2011 Outcomes 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 6 Lucado J, et al. HCUP Statistical Brief 124 Kelly CP. Clin Microbiol Infect 2012;18:21-7 2

6/1/18 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 7 Furuya-Kanamori L, et al. BMC Infect Dis 2015:15:516 Photo courtesy of Microbe Canvas Pathogenesis – 8 Rao K, et al. J Hosp Med 2016;11:56 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

6/1/18 Risk Factors – Microbial dysbiosis Poor immune response § Antibiotics § Older age § Gastric acid suppressants § Severe underlying disease § Antineoplastic agents § Immunosuppression Healthcare exposures § Prolonged hospitalization § Inadequate isolation § Long-term care residence 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 10 Bartlett JG. Clin Infect Dis. 2008;46(10):1489-92 McFarland LV, et al. J Infect Dis. Sep 1990;162(3):678-84 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 Penicillins Aminoglycosides Carbapenems Cephalosporins (1 st /2 nd gen.) Tetracyclines Cephalosporins (3 rd /4 th gen.) Trimethoprim-sulfamethoxazole Daptomycin Fluoroquinolones Macrolides Vancomycin 11 Leffler DA, et al. N Engl J Med 2015;372:1539 12 4

6/1/18 Overview of Prevention Approaches – Target modifiable Identify CDI early Prevent acquisition risk factors and accurately & transmission Antimicrobial Optimize Infection control stewardship diagnostics 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 14 Hicks LA, et al. Clin Infect Dis 2015;60:1308 Fleming-Dutra KE, et al. JAMA 2016;315:1864 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

6/1/18 Antimicrobial Stewardship – National fluoroquinolone control policy reduces CDI in England 16 Dingle KE, et al. Lancet Infect Dis 2017;17:411 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 Low * Glutamate dehydrogenase C. diff antigen High Cytotoxicity assay Free toxins High High Enzyme immunoassay Free toxins Low Moderate *Must combine with a toxin test 17 Fang FC, et al. J Clin Microbiol 2017;55:670 McDonald, et al. Clin Infect Dis 2018:1 Infection Control – § Early detection & isolation § Contact precautions § Hand hygiene with soap and water § Environmental cleaning & disinfection 18 APIC Guide to Preventing Clostridium difficile infections 6

6/1/18 Overview of Current Therapies – Modulate immune Kill C. difficile Correct dysbiosis response Metronidazole Fecal microbiota Vancomycin Bezlotoxumab transplantation Fidaxomicin 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 20 Bolton RP et al. Gut 1986;27:1169 McDonald, et al. Clin Infect Dis 2018:1 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 21 Gonzalez M, et al. BMC Infect Dis 2010;10:363 McDonald, et al. Clin Infect Dis 2018:1 7

6/1/18 Metronidazole vs. Vancomycin – Vancomycin more effective than metronidazole in severe CDI Metronidazole Vancomycin 98% 97% 100% P=0.02 90% 76% 80% 60% 40% 15% 20% 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 P=0.02 100% 81% 80% 73% 60% 44% 40% 23% 21% 20% 5% 0% Clinical Success Recurrence 23 Johnson S, et al. Clin Infect Dis 2014;59:345 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 24 Chilton CH, et al. J Antimicrob Chemother 2015;70:2598 8

6/1/18 Vancomycin vs. Fidaxomicin – Fidaxomicin superior to vancomycin at preventing recurrent CDI Vancomycin Fidaxomicin 100% 88% 86% 80% 60% P<0.001 40% 26% 20% 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 Vancomycin Fidaxomicin $16,000 $15,000 $14,000 $13,000 $12,000 $11,000 $10,000 Overall Elderly Renal Cancer Concomitant Impairment Antibiotics Reveles KR, et al. Pharmacotherapy 2017;37(12):1489-97 26 Vancomycin vs. Fidaxomicin – Real-world fidaxomicin use protocol decreases hospital costs Vancomycin Fidaxomicin $600,000 $454,800 $400,000 $196,200 $200,000 $62,112 $6,333 $0 Drug Acquisition Costs Hospital Readmission Costs 27 Gallagher JC, et al. Antimicrob Agents Chemother 2015;59:7007 9

6/1/18 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 29 Sokol H, et al. Digest Liv Dis 2016;48:242 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

6/1/18 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 31 Li YT, et al. Aliment Pharmacol Ther 2016;43:445 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 32 Wilcox MH, et al. NEJM 2017;376:305 Bezlotoxumab – Bezlotoxumab plus standard of care reduces CDI recurrence Bezlotoxumab Actoxumab-Bezlotoxumab Placebo 100% 80% 80% 80% 73% 60% P<0.001 40% 27% 17% 15% 20% 0% Clinical Cure Recurrence 33 Wilcox MH, et al. NEJM 2017;376:305 11