Addressing Today s Challenging Bacterial Infections: Expert Views on Treatment Paradigms

Transcription

1 Addressing Today s Challenging Bacterial Infections: Expert Views on Treatment Paradigms Symposium Outcomes Report Merck Grant ID: AAN

2 Overview Activity Description: This symposium provided lively discussion and expert clinical analysis of the latest clinical data and therapeutic paradigms for treating two major types of refractory bacterial infections: Gram-negative pseudomonas and C. difficile infections. New clinical practice guidelines from IDSA/SHEA and clinical best practices for optimal treatment of these challenging clinical situations were discussed by experts in the infectious disease field, within the wider clinical context of responsible antimicrobial stewardship. Two complex patient infection cases (including a recorded patient testimonial from a C. difficile patient) were presented for expert panel discussion and audience questions. Symposium Date: October 3, 2018 at IDWeek 2018 Credit: 1.5 AMA PRA Category 1 Credits TM for physicians and 1.5 contact hours for pharmacists Sponsored by: the Academy for Continued Healthcare Learning (ACHL) Supported by: an educational grant from Merck & Company Intended Audience: ID specialists, gastroenterologists, hospitalists, internists, and other physicians, nurse practitioners, and physician assistants who care for patients at risk of serious infection.

3 Activity Marketing

4 Executive Summary Participation 380 Clinical Participants; 68 Certificates (exceeded 200 participant guarantee) Practicing Type 62% Physicians, 17% Pharmacists, 5% Nurses, 16% Other HCPs Participant Satisfaction Objectivity and balance was rated as good/excellent by 100% of learners Learning Objectives 98% of learners strongly agree or agree that all learning objectives were met, with an average rating 3.63/4.0 Faculty Drs. Lewis, Khanna, McKinnell and Muto were highly rated 3.81/4.0

5 Executive Summary (cont d) 70% indicated participation in the activity will impact their patient outcomes. Major increases (up to +1175%) in knowledge on appropriate use of empiric Gram-negative coverage antimicrobial therapies, including novel therapies, in multi-drug resistant pulmonary Gram-negative infections. Changes made from this activity will impact 1,161 to more than 1,851 Gram-negative VAP/HAP patients each month, and 529 to more than 2,370 CDI patients each month. Cost, lack of administrative support and reimbursement/insurance issues were reported as the most common barriers to implementing changes in practice. Significant knowledge improvement/comprehension of appropriate use of fidaxomicin in the treatment/management of recurrent C. difficile infections in the context of the 2017 IDSA/SHEA clinical practice guidelines. Learners comprehension of bezlotoxumab increased as well, despite not being included in the guidelines. A strong majority (89%) of participants position fecal microbiota transplantation (FMT) correctly as a treatment of last resort in patients with multiple severe/fulminant C. difficile infections, after all 2017 IDSA/SHEA guideline-recommended drug therapies have failed.

6 Participation Participants Certificates Participation by Specialty Participation by Clinician Type ID/Critical Care - Physicians ID Pharmacists Physician 16% 62% Other 21% 62% Pharmacist 5% Nurse Other HCP 17% 17%

7 Demographics Participation by Country Participation by Practice Setting USA Argentina Brazil Japan Mexico Thailand Other 22% 3% 4% 4% 45% Hospital or Clinic Pharmaceutical/Biotechnology Industry University/Professional School Private/Group Practice 3% 3% Government 7% Other 17% 40% 8% 14% There was significant international clinician participation on this CME activity. Other countries represented include: Austria, Canada, Ecuador, France, Germany, India, Israel, Italy, Netherlands, Peru, Qatar, Russia, Saudi Arabia, Singapore, South Korea, Spain, Taiwan, United Kingdom, and Zambia. 30%

8 Learning Objectives Please rate the following objectives to indicate if you are better able to: Rating scale: 4=Strongly Agree; 1=Strongly Disagree Physician Learning Objectives Analysis of Respondents Pharmacy Learning Objectives Demonstrate an understanding of the molecular epidemiology of antibiotic resistance in bacterial pathogens. Summarize the salient features and critical differences between novel antibiotics for use against Gram-negative pathogens. Describe clinical strategies to optimize antimicrobial therapy to ensure effectiveness of antibiotics and reduce resistance. Outline patient and clinical factors that may predict C. difficile recurrence and implement effective tools/processes to identify at-risk patients. Compare and contrast evidence-based approaches for the management of first and second recurrences of C. difficile infection in diverse patient populations, and appropriate targeted therapeutic selections for each. Discuss newly released IDSA/SHEA clinical practice guidelines for C. difficile infection and how they compare with established practice patterns Demonstrate an understanding of appropriate antimicrobial stewardship in the context of increased resistance in high-risk bacterial pathogens. Summarize the pharmacokinetics and spectrums of activity of novel antibiotics for use against Gram-negative pathogens versus established therapies. Describe clinical strategies to implement current pharmacy best practices to ensure effectiveness of antibiotics and reduce resistance in Gram-negative pathogens. Outline patient and clinical factors that may predict C. difficile recurrence and implement effective tools/processes to identify at-risk patients. Compare and contrast evidence-based approaches for medication therapy management (MTM) of first and second recurrences of C. difficile infection. Discuss newly released IDSA/SHEA clinical practice guidelines for C. difficile infection and how they may affect existing antimicrobial stewardship protocols N=64 98% of learners strongly agree or agree that all learning objectives were met, with an average rating of 3.63/4.0.

9 Satisfaction Overall Evaluation Analysis of Respondents Rating scale: 4=Excellent; 1=Poor Quality of educational content 3.75 Usefulness of course handouts/educational material 3.57 Effectiveness of teaching method used 3.57 Appropriateness and effectiveness of active learning strategies (questions, cases, discussion, etc.) Importance of clinical topics (e.g. novel antimicrobials/antimicrobial stewardship protocols) All aspects of the activity were highly rated at 3.57 or higher. N=63 98% of learners would recommend this activity to a colleague.

10 Faculty Evaluation Please rate the faculty on the criteria listed: Rating scale: 4=Excellent; 1=Poor Ability to effectively convey the subject matter Ability to deliver an objective and balanced presentation Ability to present scientifically rigorous information Ability to adjust to the knowledge and experience level of the audience James Lewis II, PharmD, FIDSA Sahil Khanna, MBBS James McKinnell, MD Carlene Muto, MD, MS The faculty were rated good or excellent across all areas by 97% of learners, with an average rating of N=64

11 Objectivity & Balance Did you perceive any bias? 97% 3% 80% 70% 60% 50% 40% 30% 20% 10% 0% Rating of objectivity & balance 74% 26% Excellent Good Fair Poor Yes No N=60 Activity was perceived as objective, balanced and non-biased.

12 Outcomes Methodology Use of polling and paper-based post test to: 1) Map decision-making processes to patient cases through two lenses based on amount of background detail shared 2) Capture behavioral clinician insights at a single point in time 3) Measure learner knowledge and competence progression

13 Reviewing Treatment Behaviors Based on Case Detailing Empiric Gram-negative antibiotic coverage regimens Lucy is a 65-year-old female transferred to an academic medical center in Los Angeles from an outside hospital (OSH) for pneumonia. She has history of COPD, bronchiectasis, diastolic CHF, and recurrent pneumonia (prior pathogen history unknown). Lucy was treated 2 weeks ago in Mexico for pneumonia (prior antimicrobial therapy unknown) and was admitted to OSH 5 days ago w/ cough, sputum, and shortness of breath. At OSH, she was immediately intubated and received piperacillin-tazobactam gm IV q6hours. Now transferred to an academic medical center, Lucy continues to deteriorate (T: 101.2F; respiratory rate: 22; blood pressure: 104/62; heart rate: 125; oxygen concentration: 92%). She is also frail with slight temporal wasting, right lower lung rhonchi sounds, decreased muscle mass, and no skin rash; her positive end expiratory pressure (PEEP) is 8 cm H2O and 80% FiO2. She is currently on norepinephrine at 6 mcg/min; labs show WBC=13,000; glomerular filtration rate (GFR)>80, and liver function tests are within normal limits. Given what you currently know about this case, which of the following empiric antibiotic regimens would you use for Empiric Gram-negative Rod Coverage for Lucy? A. Continue Piperacillin-Tazobactam as currently dosed B. Carbapenem Monotherapy as Extended Infusion C. Combination regimen Carbapenem/Aminoglycoside D. Combination regimen Carbapenem/Fluoroquinolone E. Ceftazidime/Avibactam F. Ceftolazone/Tazobactam G. Other 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ARS (n=137) 29% 23% 23% 13% 7% 4% 1% A B C D E F G During the activity, this question was presented early in the clinical case to take a temperature check of the expert infectious-disease specialist attendees in terms of which empiric therapy they would choose given the information currently available. Given rapidly changing patterns of resistance among Gram-negative bacteria species, and the lack of susceptibility/pathogen information at this point in the case, there is no one correct answer to this question.

14 Changes in Treatment Decisions with Inclusion of Susceptibility Testing to Case Empiric Gram-negative antibiotic coverage regimens Lucy is a 65-year-old female transferred to an academic medical center in Los Angeles from an outside hospital (OSH) for pneumonia. She has history of COPD, bronchiectasis, diastolic CHF, and recurrent pneumonia (prior pathogen history unknown). Lucy was treated 2 weeks ago in Mexico for pneumonia (prior antimicrobial therapy unknown) and was admitted to OSH 5 days ago w/ cough, sputum, and shortness of breath. At OSH, she was immediately intubated and received piperacillin-tazobactam gm IV q6hours. Now transferred to an academic medical center, Lucy continues to deteriorate (T: 101.2F; respiratory rate: 22; blood pressure: 104/62; heart rate: 125; oxygen concentration: 92%). She is also frail with slight temporal wasting, right lower lung rhonchi sounds, decreased muscle mass, and no skin rash; her positive end expiratory pressure (PEEP) is 8 cm H2O and 80% FiO2. She is currently on norepinephrine at 6 mcg/min; labs show WBC=13,000; glomerular filtration rate (GFR)>80, and liver function tests are within normal limits. The academic hospital reports greater clinical burden of P. aeruginosa in its local MICU antibiogram versus carbapenem-resistant Enterobacteriaceae. Given the above case and relevant local antibiogram, which of the following empiric antibiotic regimen options would you consider using for Empiric Gram-negative Rod Coverage for Lucy until full susceptibility data are available? A. Continue Piperacillin-Tazobactam as currently dosed B. Combination regimen Carbapenem/Aminoglycoside C. Combination regimen Carbapenem/Fluoroquinolone D. Ceftazidime/Avibactam E. Ceftolozane/Tazobactam F. D or E, depending upon local susceptibility data 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 42% Post (n=57) 7% 2% 14% 35% A B C D E F This post-test question gave participants the opportunity to answer a more complete version of a similar question posed during polling: this time with all available clinical information and a complete local combination antibiogram, including rapidly evolving pathogen susceptibilities. Despite the new information, only 35% of participants chose the best answer, indicating continued knowledge gaps surrounding optimal Gram-negative treatment selection and related antimicrobial stewardship. Furthermore, 16% of participants selected one of the two possible partially correct agents in this case, which while demonstrating greater understanding of novel agents, indicates more training is needed surrounding appropriate interpretation of local combination antibiogram data and related treatment selection, which will vary in practice down to the patient-specific level----and may also change within days or weeks as pathogens develop additional resistance.

15 Antimicrobial Resistance Patterns in Carbapenem-resistant Pathogens Limited Profile Presentation Antibiotic regimens for 2 different carbapenem-resistant Pneumonia pathogens (Pseudomonas aeruginosa) w/ limited susceptibilities Which antibiotic regimens would you use for CR-Pseudomonas aeruginosa, only susceptible to Tobramycin or Amikacin on first testing? A. Tobramycin Monotherapy B. Amikacin Monotherapy C. Colistin Monotherapy D. Ceftazidime/Avibactam Monotherapy E. Ceftazidime/Avibactam Combination Therapy F. Ceftolozane/Tazobactam Monotherapy G. Ceftolozane/Tazobactam Combination Therapy H. Other This polling question was presented within the context of Lucy s case, and participants had not yet received all the latest evidence-based education to support the correct answer. While the correct answer was the most frequently chosen during polling, only 39% of the infectious-disease specialist audience chose the correct answer during the activity, indicating a strong need for continuing education regarding novel/rapidly evolving antimicrobial resistance patterns in carbapenem-resistant pathogens. Of note, pathogen resistance can develop very rapidly, including on a single patient receiving a single drug during a short time window (eg, 1 week or less), creating significant complexity. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ARS (n=139) 1% 2% 4% 2% 26% 17% 39% 9% A B C D E F G H

16 Antimicrobial Resistance Patterns in Carbapenem-resistant Pathogens - Full Case Detail Antibiotic regimens for carbapenem-resistant Pneumonias (Pseudomonas, Klebsiella) w/ limited susceptibilities Which antibiotic regimens would be the most effective under current susceptibilities for either a hospital-acquired pneumonia or ventilator-associated pneumonia (HAP/VAP) caused by carbapenem-resistant Klebsiella pneumonia, which is only susceptible to Tobramycin or Amikacin on first testing? A. Tobramycin monotherapy B. Amikacin monotherapy C. Colistin monotherapy D. Ceftazidime/avibactam Monotherapy E. Ceftazidime/avibactam Combination Therapy (eg, with tobramycin or amikacin) 100% 90% 80% 70% 60% 50% 40% Post (n=57) 81% In a more nuanced approach to selecting effective agents against carbapenemresistant pathogens, faculty requested a post-test question to evaluate resistance patterns of a second pathogen, CR-Klebsiella pneumonia, which has similar susceptibilities to CR-Pseudomonas aeruginosa discussed during the activity. While this pathogen occasionally requires similar therapy selection as the CR- Pseudomonas aeruginosa, some elements of the combination therapy regimen differ on a case-by-case basis, especially at the local antibiogram level. The role of this question was to illustrate how the spectrum of activity of Ceftazidime/avibactam differs significantly from Ceftolozane/Tazobactam s spectrum of activity----a key learning point during the activity. (The two therapies are not equivalent). 30% 20% 10% 0% 19% A B C D E

17 Polling Results Behavioral Insights at a Single Point in Time Management of severe CDI recurrences that do not meet FULMINANT criteria In patients with a Severe CDI recurrence that DOES NOT meet Fulminant criteria, which of the following are recommended under the 2017 IDSA/SHEA guidelines? A. VAN 500 mg PO/NG QID + MTZ 500 mg IV Q8 hours B. Tapered and pulsed VAN if standard regimen used for initial episode C. MTZ 500 mg PO TID for days D. FDX 200 mg BID X 10 days if VAN used for initial episode E. FMT F. B OR D 100% 90% 80% 70% 60% 50% 40% ARS (n=109) 67% This question had multiple possible correct answers and one BEST answer due to the structure of the 2017 IDSA/SHEA guidelines for the treatment of C. difficile infection. 89% of participants selected one of all possible correct answers during in-activity polling, while 67% chose the BEST answer, indicating strong existing knowledge base on optimal therapeutic selection for severe CDI recurrences under the current guidelines. 30% 20% 10% 0% 17% 7% 5% 4% A B C D E F

18 Polling Results Behavioral Insights at a Single Point in Time Management of multiple SEVERE CID recurrences under the 2017 IDSA/SHEA guidelines/use of FMT If Kathy s severe CDI (multiple episodes) were treated after the 3rd/4th recurrence today, which of the following is the BEST course of action under the 2017 IDSA/SHEA guideline recommendations? A. VAN 125 mg enterally QID for 10 days followed by rifaximin X 20 days B. VAN 125 mg enterally taper again C. FDX 200 mg given BID for 10 days D. Fecal Microbiota Transplantation (FMT) 100% 90% 80% 70% 60% 50% ARS (n=116) 83% Given the very strong correct answers received during in-activity polling even prior to presentation of FMT-specific educational content, it is clear that learners in infectious-disease practice are positioning use of FMT properly as a last-resort therapy for patients with multiple severe or fulminant recurrences after conventional drug therapies have failed. 40% 30% 20% 10% 0% 7% 9% 1% A B C D

19 Polling (Baseline) vs. Posttest Results Comparison of 2010 versus 2017 IDSA/SHEA guidelines for 1st occurrence of mild/moderate C. difficile infection. Kathy B, current age 74 (age at time of infection ~66-69/between ) experienced recurrent C. difficile infection following antibiotic treatment for recurrent (4X) diverticulitis. Upon the fourth recurrence of diverticulitis, for which she received ciprofloxacin, Kathy B was hospitalized; upon discharge, patient was notified by her attending physician that she also had mild/moderate C. difficile, for which she received PO metronidazole. Diverticulitis recurred (5th recurrence) shortly thereafter, requiring sigmoidectomy. 1 week post-surgery, Kathy B s C. difficile recurred as Severe episode, and she was re-hospitalized, given IV vancomycin, then switched to fidaxomicin days after antibiotic therapy stopped, C. difficile infection recurred; same disease cycle repeated 7 more times. Kathy B eventually received the investigational therapy SER-109 in a Phase I clinical trial which ended recurrences. If Kathy s initial occurrence of mild-moderate C. difficile were treated today, in 2018, what would be guideline-recommended for a patient with initial occurrence of Mild-Moderate CDI according to the 2017 IDSA/SHEA Guidelines? A. Enteral VAN 125 mg QID for 10 days B. Enteral FDX 200 mg BID for 10 days C. Enteral MTZ 500 mg QID for days D. FMT E. A or B 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ARS (n=134) Post (n=57) 88% 55% 32% 9% 6% 3% 5% 2% A B C D E This question was presented in the same format during in-activity polling and on the post-test. The structure of the 2017 IDSA/SHEA guidelines allows for multiple correct answers along with a single BEST answer, allowing for nuanced analysis of participant knowledge. When comparing in-activity polling data with post-test data, 93% of all answers were at least partially correct in-activity vs. 100% post for; while 55% of in-activity vs. 88% in post chose the best answer (ie, included ALL correct possible guideline-recommended therapies). This represents a 60% increase in perfect responses in a complex topic that can have multiple possible therapeutic options.

20 Polling (Baseline) vs. Posttest Results Comparison of 2010 versus 2017 IDSA/SHEA guidelines for 1st recurrence of SEVERE C. difficile infection. Pre (n=114) Post (n=58) If Kathy s 1st SEVERE C. difficile episode occurred TODAY in 2018, what would be the guidelinerecommended treatment for initial episode of SEVERE CDI under the 2017 IDSA/SHEA guidelines? A. Enteral MTZ 500 mg TID for days B. Enteral MTZ 500 TID+ enteral VAN 125 mg QID for days C. VAN 125 mg PO given QID for 10 days D. FDX 200 mg given BID for 10 days E. FMT F. C OR D Like the prior question, this question was presented in the same manner for both tests, allowing for the direct comparison of results. The structure of the 2017 IDSA/SHEA guidelines allow for multiple correct answers, and one BEST answer, which includes all possible correct therapeutic choices. Given the nuanced possible correct answers versus BEST answer, 75% of in-activity participants selected one of all possible correct answers vs. 94% post-test responses, while 55% of polling respondents selected the BEST answer, vs. 84% in post. When measuring percent increase of perfect responses, this represents a 53% increase in the application of the 2017 IDSA/SHEA guideline recommendations surrounding the treatment of SEVERE C. difficile infection. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 84% 55% 19% 14% 11% 4% 5% 1% 5% 2% A B C D E F

21 Post-test Result Knowledge Acquisition at a Single Point in Time Clinical trial data surrounding recurrence-prevention effectiveness of bezlotoxumab According to the MODIFY I and MODIFY II trials, by what percentage does bezlotoxumab reduce the recurrence of C. difficile infection at the end of 12 weeks versus placebo? A. 39% versus 18% for placebo in MODIFY I; 26% versus 17% for placebo in MODIFY II B. 28% versus 17% for placebo in MODIFY I; 26% versus 16% for placebo in MODIFY II C. 19% versus 12% for placebo in both MODIFY I and MODIFY II D. 19% versus 12% for placebo in MODIFY I, 21% versus 10% for placebo in MODIFY II Since bezlotoxumab is not included in the 2017 IDSA/SHEA guidelines due to the timing of its FDA approval, this question was only administered on the post-test. A small portion of activity content discussed optimal use of bezlotoxumab and related clinical research data, and 71% of post-test participants correctly identified C. difficile recurrence reduction data associated with two bezlotoxumab-related trials, indicating effective education on this clinical sub-topic. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Post (n=55) 71% 18% 4% 7% A B C D

22 Activity Impact Self-reported activity impact Yes No No change Increase competence 77% 0% 23% Improve performance 70% 0% 30% Improve patient outcomes 70% 0% 30% This activity was highly effective, with 70% of attendees indicating participation in this activity will improve their patients outcomes. N=61; see comments in appendix

23 Practice Change Change the management and/or treatment of my patients with Gram-negative VAP/HAP. Change the management and/or treatment of my patients with C. difficile infections/recurrent infections. Update clinical antimicrobial stewardship protocols, policies and/or procedures. 30% 31% 54% Other changes 2% This activity validated my current practice; no changes will be made 37% 0% 10% 20% 30% 40% 50% 60% 63% of learners will change their practice! N=54; multiple responses allowed

24 Patient Impact: Gram-negative Patients Number of patients with Gram-negative VAP/HAP seen per month: 0 9% 13% 15% >16 23% 40% Changes will impact 1,161 to more than 1,851 Gram-negative VAP/HAP patients each month. This assumes data in chart above is representative of all healthcare professionals in attendance (380), who indicated they would change their practice as a result of their participation in this activity (63%). N=53

25 Patient Impact: CDI Patients 0 Number of patients with C. difficile infection(s) seen per month: 2% >50 69% 10% 19% Changes will impact 529 to more than 2,370 C. difficile patients each month. This assumes data in chart above is representative of all healthcare professionals in attendance (380), who indicated they would change their practice as a result of their participation in this activity (63%). N=48

26 Barriers to Planned Change Lack of administrative support Lack of experience with challenging infections Lack of opportunity (patients w/ these infections) Lack of access to therapy donors (FMT) Lack of susceptibility testing resources Lack of time to assess/counsel patients Reimbursement/insurance issues Cost of novel therapies Patient compliance issues Other No barriers 2% 2% 2% 6% 6% 10% 17% 19% 19% 37% 44% 0% 10% 20% 30% 40% 50% Participants indicated cost (44%) as most common barrier to implementing changes in their practice, followed by lack of administrative support (19%) and reimbursement/insurance issues (19%). Of those who identified barriers, 45% will attempt to address the perceived barrier(s) in order to affect change. N=52; multiple responses allowed

27 Topics of Interest Gram-negative urinary tract infections 54% Fecal flora restoration/fecal microbiome transplant (FMT) 40% How to implement broad-based antimicrobial stewardship programs in hospitals/communities Identifying local antibiogram/clinical breakpoints in multi-drug resistant organisms Other 2% 48% 50% 0% 20% 40% 60% Gram-negative urinary tract infections was rated with highest interest for future education, with additional strong interest in antimicrobial stewardship protocols and identifying local antibiogram clinical breakpoints in multi-drug resistant organisms. N=50; multiple responses allowed

28 Activity Impact Self-reported increase in competence, performance and patient outcomes: Newer drugs New info on GO agents I have learned a lot more on the uses of the novel antimicrobials Was not aware of FDX Going to expand my combo antibiogram Especially with MDR GNR infections New info on GO agents Treatment of MDR gram negatives I now have more confidence on when novel antimicrobials are used Was assoc. so much less recurrence, also unaware of rifax chaser Especially with MDR GNR infections Better understanding of LDI guidelines Self-reported change in practice: Consider the expensive new antibiotics for VAP Understand full spectrum of susceptibility results Consider combo antibiograms Follow the 2017 IDSA C. diff treatment guidelines Insist on a more timely use of novel BL/BLI susceptibility testing Treatment of GNP pneumonia with combo tx New treatment for CDI No Metronidazole Will consider introducing combination antibiogram Vanco taper >42 days, Vanco rifaximin taper, consider FDX> vanco in recurrences 2 degree lower recurrence Follow antibiogram more closely Ask for expanded sensitivity testing for GNR Change the recommended dose of [ceftolozane/tazobactam] for HAP/VAP to 3 g IV g8h Expanding our current combo antibiogram Stewardship policies

29 Contact Information Richard Keenan VP, Education Development Academy for Continued Healthcare Learning (ACHL) E: P: ext. 215 C: