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

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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

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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

Learning Objectives

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CDI in the United States, 2011

Epidemiology

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

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 1st recurrence 20-25%

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§ 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

Overview of C. difficile

Furuya-Kanamori L, et al. BMC Infect Dis 2015:15:516 Photo courtesy of Microbe Canvas

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Pathogenesis

Rao K, et al. J Hosp Med 2016;11:56

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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

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McDonald, et al. Clin Infect Dis 2018:1

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Risk Factors

Microbial dysbiosis § Antibiotics § Gastric acid suppressants § Antineoplastic agents Poor immune response § Older age § Severe underlying disease § 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 Bartlett JG. Clin Infect Dis. 2008;46(10):1489-92 McFarland LV, et al. J Infect Dis. Sep 1990;162(3):678-84

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Risk Factors: Antimicrobial Agents

§ Risk increases with cumulative antibiotic exposure § More common with antibiotics that disrupt the gut flora

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Commonly associated Occasionally associated Rarely associated Clindamycin Carbapenems Cephalosporins (3rd/4th gen.) Fluoroquinolones Penicillins Cephalosporins (1st/2nd gen.) Trimethoprim-sulfamethoxazole Macrolides Aminoglycosides Tetracyclines Daptomycin Vancomycin

Leffler DA, et al. N Engl J Med 2015;372:1539

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Overview of Prevention Approaches

Target modifiable risk factors Antimicrobial stewardship Identify CDI early and accurately Optimize diagnostics Prevent acquisition & transmission Infection control

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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

Antimicrobial Stewardship

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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

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National Veterans Affairs CDI prevention initiative decreases hospital-onset CDI

Antimicrobial Stewardship

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Evans ME, et al. Infect Control Hosp Epidemiol 2016;37:720

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National fluoroquinolone control policy reduces CDI in England

Antimicrobial Stewardship

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Dingle KE, et al. Lancet Infect Dis 2017;17:411

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§ Consider alternative etiology of diarrhea § Test only patients with high probability of CDI § Consider two-step testing method

Optimize Diagnostics

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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

Fang FC, et al. J Clin Microbiol 2017;55:670 McDonald, et al. Clin Infect Dis 2018:1 *Must combine with a toxin test

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§ Early detection & isolation § Contact precautions § Hand hygiene with soap and water § Environmental cleaning & disinfection

Infection Control

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APIC Guide to Preventing Clostridium difficile infections

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Overview of Current Therapies

Kill C. difficile Metronidazole Vancomycin Fidaxomicin Correct dysbiosis Fecal microbiota transplantation Modulate immune response Bezlotoxumab

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§ 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 MIC90 values

Metronidazole

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Bolton RP et al. Gut 1986;27:1169 McDonald, et al. Clin Infect Dis 2018:1

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§ 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 MIC90

Vancomycin

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Gonzalez M, et al. BMC Infect Dis 2010;10:363 McDonald, et al. Clin Infect Dis 2018:1

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Vancomycin more effective than metronidazole in severe CDI

Metronidazole vs. Vancomycin

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Zar FA, et al. Clin Infect Dis 2007;45:302

90% 76% 15% 98% 97% 14% 0% 20% 40% 60% 80% 100% Clinical Cure (Mild) Clinical Cure (Severe) Recurrence

Metronidazole Vancomycin

P=0.02

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Vancomycin more effective than metronidazole overall

Metronidazole vs. Vancomycin

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73% 23% 81% 21% 44% 5% 0% 20% 40% 60% 80% 100% Clinical Success Recurrence

Metronidazole Vancomycin Tolevemer

P=0.02

Johnson S, et al. Clin Infect Dis 2014;59:345

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§ 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

Fidaxomicin

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Chilton CH, et al. J Antimicrob Chemother 2015;70:2598

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Fidaxomicin superior to vancomycin at preventing recurrent CDI

Vancomycin vs. Fidaxomicin

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86% 26% 88% 14% 0% 20% 40% 60% 80% 100% Clinical Cure Recurrence

Vancomycin Fidaxomicin

P<0.001

Crook DW, et al. Clin Infect Dis 2012;55:S93

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Overall treatment costs similar with first-line fidaxomicin therapy compared to vancomycin

Vancomycin vs. Fidaxomicin

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$10,000 $11,000 $12,000 $13,000 $14,000 $15,000 $16,000 Overall Elderly Renal Impairment Cancer Concomitant Antibiotics

Vancomycin Fidaxomicin

Reveles KR, et al. Pharmacotherapy 2017;37(12):1489-97

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Real-world fidaxomicin use protocol decreases hospital costs

Vancomycin vs. Fidaxomicin

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$6,333 $454,800 $62,112 $196,200 $0 $200,000 $400,000 $600,000 Drug Acquisition Costs Hospital Readmission Costs

Vancomycin Fidaxomicin

Gallagher JC, et al. Antimicrob Agents Chemother 2015;59:7007

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Fecal Microbiota Transplantation

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Smits WK, et al. Nature Reviews 2016;2:1

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Three-step sequence for administration § Oral antibiotic § Bowel preparation § FMT administration

Fecal Microbiota Transplantation

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Sokol H, et al. Digest Liv Dis 2016;48:242

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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

Fecal Microbiota Transplantation

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Sokol H, et al. Digest Liv Dis 2016;48:242

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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

Fecal Microbiota Transplantation

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Li YT, et al. Aliment Pharmacol Ther 2016;43:445

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§ 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

Bezlotoxumab

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Wilcox MH, et al. NEJM 2017;376:305

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Bezlotoxumab plus standard of care reduces CDI recurrence

Bezlotoxumab

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80% 17% 73% 15% 80% 27% 0% 20% 40% 60% 80% 100% Clinical Cure Recurrence

Bezlotoxumab Actoxumab-Bezlotoxumab Placebo

P<0.001

Wilcox MH, et al. NEJM 2017;376:305

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New Treatment Recommendations!

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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

Initial Episode

Severe = WBC ≥15 x 109/L or SCr >1.5 mg/dL Fulminant = hypotension or shock, ileus, or megacolon McDonald, et al. Clin Infect Dis 2018:1

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Clinical Practice Recommendations

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Suspected or confirmed recurrent CDI Initial metronidazole Initial vancomycin Initial fidaxomicin Vancomycin PO Vancomycin tapered

• r fidaxomicin PO

Fidaxomicin PO

Recurrent CDI

2+ recurrences Vancomycin tapered or fidaxomicin ± fecal transplant

McDonald, et al. Clin Infect Dis 2018:1

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Overview of Pipeline Therapies

Kill C. difficile Cadazolid Ridinilazole Correct or minimize dysbiosis 2nd generation FMT Ecobiotics Ribaxamase Modulate immune response Vaccines

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§ Strong inhibitor of C. difficile protein synthesis with limited impact on normal gut microbiota § Non-inferior to vancomycin in Phase 2 trial

Cadazolid

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77% 18% 60% 68% 50% 33% 0% 20% 40% 60% 80% 100% Clinical Cure Recurrence Sustained Clinical Response

Cadazolid 250mg BID Vancomycin 125mg QID

Louie T, et al. Antimicrob Agents Chemother 2015;59:6266

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§ 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

Ridinilazole

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78% 14% 67% 70% 35% 42% 0% 20% 40% 60% 80% 100% Clinical Cure Recurrence Sustained Clinical Response

Ridinilazole 200mg BID Vancomycin 125mg QID

Vickers RJ, et al. Lancet Infect Dis 2017;17:735

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§ 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

Second Generation FMT

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Dubberke R, et al. Clin Infect Dis 2018 (Epub)

Phase 2B PUNCH CD Study

64% 45% 0% 20% 40% 60% 80% 100% RBX2660 Placebo Prevention of Recurrence

P=0.047

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§ Rationally-designed combinations of microbe spores

§ Does not require donor stool § SER-109 in Phase 3 trial to reduce recurrent CDI

Ecobiotics

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Smits WK, et al. Nature Reviews 2016;2:1

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§ 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

Ribaxamase

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Ribaxamase (Synthetic Biologics) [Press Release, Aug 14, 2017]

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§ Inactivated toxoids A and B stimulate immune response to C. difficile toxins § Clinical trials are targeting high-risk patients

Vaccines

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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

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§ 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

Summary

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§ 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

Summary

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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

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