C. difficile and ASP Guidelines and Best Practices Belinda Ostrowsky, MD, MPH, FSHEA, FIDSA February 27 and 28, 2018
Disclosure I have no financial disclosures I have made a recent transition from Montefiore to take a position as a CDC, Medical Field Officer in NY (I will share our Montefiore ASP experience)
C. difficile Issues as Targets for ASP 1. Testing 2. Formulary issues 3. Treatment of C. difficile (new agents/guidelines) 4. Review of antibiotic/medication use (before & after C. difficile diagnosis) 5. ASP as part of the solution 6. Mention-- C. auris
CDC Antibiotic Threats Pathogen Est. Annual Cases Summary MDRO 2 million 23,000 Urgent (3) CRE 9,000 600 C. difficile 250,000 14,000 Severe (13) MDRO: Pseudomonas Acinetobacter Est. Annual Deaths 6,700 7,300 400 500 MRSA 80,000 11,000 VRE 20,000 1,300 Concerning (3) VRSA <5 <5 CDC. Antibiotic resistance threat in the US. 2013. Available at http://www.cdc.gov/drugresistance/threat-report-2013/ MDRO= multi-drug resistant organisms, CRE= Carbapenem Resistant Enterobacteriaceae, CDI= C. difficile, MRSA= methicillin resistant S. aureus, VRE= vancomycin resistant enterococcus, VRSA= vancomycin resistant S. aureus http://www.cdc.gov/drugresistance/biggest_threats.html
Faces of Resistance (C. difficile) My mom IDSA. Faces of Resistance. 2017 http://www.idsociety.org/templates/threecolumn.aspx?pageid=32212254747
Why ASP for C. difficile (CDI)? Rates of CDI remain high CDI is publically reported CDI transmission is likely multifactorial: Infection control, environment, inter-facility transfer Association with common antimicrobial use ASP offers strategies to prevention & control CDI: At several points in prescribing Complementary to other interventions Lessa et. Al. N Engl J Med 2015; 372:825-834 Elixauser et al, AHRQ at:http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.jsp Lesser et al. CID. 2012;55(S2):S65-70.
Number of Reports UK Experience CDI CDI Annual Lab Testing Interventions: Infection control + ASP Public Health England. Health Protection Report- Infection Report. 2015. 9 (21).
ASP for CDI Steps 1. Antibiotic damage Patient Status Normal flora Disruption of flora ASP Activities Formulary Abx before 2. CDI healthcare exposure C. difficile colonization 3. CDI toxin production 4. Toxin hyperproduction 5. Severe sepsis/shock C. difficile colitis Fulminant colitis Death from C. difficile Appropriate testing CDI treatment Abx/Meds after Adapted from:apic Guide to Prevention of C. difficile Infection. 2013,
Stewardship of CDI Testing Know what type of testing at your lab (don t use toxin alone) Colonization varies (can be high 16-50%+) Who you test: Don t test your patient for CDI if they had < 3 unformed stools in the past day. Don t test patients who received laxatives within the past 48 hours. Don t retest (especially multiple on same day). Don t test for cure. Timely Testing: delays affect the patient, surrounding patients and reporting..asm A Practical Guidance Document for the Laboratory Detection of Toxigenic Clostridium difficile 2010. http://www.asm.org/images/pdf/clinical/clostridiumdifficile9-21.pdf Hopkins One Minute Guide on C. difficile testing https://medicine-matters.blogs.hopkinsmedicine.org/2016/03/one-minute-guide-to-clostridium-difficile-testing/ 2017 IDSA/ SHEA CDI in adults & Children. CID. 2018; 1-48- online IDSA site.
Formulary Issues and CDI: The Case for a new drug--fidaxomicin: Enthusiasm over 1 st new CDI therapy in 25 years Questions: efficacy, incremental benefits, appropriate patients, costs ASP gathered stakeholders to review data and discuss place in therapy Formulated institutional CDI treatment algorithm Presented findings/algorithm to P & T for approval New guidelines- time to reassess Other Formulary discussions: Preferential drugs on formulary, restrictions (e.g. quinolones).
CDI Clinical Case You are treating a 50 y/o female with 4 episodes of watery diarrhea per day. She was recently admitted 3 months ago with C.difficile associated diarrhea, treated with oral metronidazole 500mg every 8h for 10 days with complete resolution. Now she has a BP of 120/70, P 75, R 16, O2 100%, Tmax 99F. She has no abdominal tenderness, normal bowel sounds and no distention. WBC count is 13 with 80% neutrophils. Cr is 0.7, Albumin is 4. Stool CDI test is positive. What is the best regimen for this patient? How do you guide your providers to the best management of this patient?
A. Place on contact isolation, treat this episode the same as her first episode of CDI (metronidazole) B. Place on contact isolation, start po vancomycin 125mg every 6 hours for first recurrence of CDI C. Start oral vancomycin 250mg every 6 hours D. Start oral vancomycin 125mg every 6 hours with oral metronidazole 500mg every 8 hours Answer: past would have been A, now guidelines say B (with some caveats)
Written C. difficile Policy For facilities with no current policy: Content areas to address CDI Treatment Formulary/Criteria for novel drugs Review of antibiotics/ meds before and after Stakeholders to develop and review Dissemination and implementation plan Measure of uptake/ compliance For facilities with current policy: Extending/consolidation policies (testing, isolation, environmental cleaning)
Let s step back and look at: Professional guidelines Literature Practical issues to help us formulate our CDI policy
Severe C. difficile Infection Increased odds ratio for morbidity/mortality: age >70 years leukocyte count >20,000 cells/ml albumin level <2.5 g/dl creatinine level >2 mg/dl small bowel obstruction or ileus CT showing colorectal inflammation IDSA/SHEA simplifies: WBC > 15, 000 cell/ ml Creatinine level > 1.5 mg/ dl Henrich. Emerg Infect Dis. 2009 March; 15(3): 415 422 2017 IDSA/ SHEA CDI in adults & Children. CID. 2018; 1-48- online IDSA site.
SHEA/ IDSA Guidelines Topics General: Assessment Strength rec Quality of evidence 2010 SHEA/ IDSA CDI Guidelines Adapted Canadian Task force: A-C I-III 2017 SHEA/ IDSA CDI Updated Guidelines GRADE System: Strong- Weak (S-W) High- Very low (HG- VL) Additions N/A Pediatrics ASP 2 recs (A-II) 3 recs (S/M, best practice) 2010 SHEA/ IDSA CDI in adults. ICHE 2010. 31 (5): 431-455. 2017 IDSA/ SHEA CDI in adults & Children. CID. 2018; 1-48- online IDSA site.
Treatment (adult) 2010 SHEA/ IDSA CDI Guidelines 2017 SHEA/ IDSA CDI Updated Guidelines Initial, non- severe Initial, severe Initial, fulminant 1 st recurrence 2 nd + recurrence Metronidazole 500mg oral (A-I) Vancomycin 125mg oral (B-I) Vancomycin 500 mg oral & PR (CIII) Same, based on severity (A-II) Vancomycin taper (B-III) No metronidazole (neurotoxicity) (B-II) 2010 SHEA/ IDSA CDI in adults. ICHE 2010. 31 (5): 431-455. 2017 IDSA/ SHEA CDI in adults & Children. CID. 2018; 1-48- online IDSA site. Vancomycin 125 oral (S/HG) Fidaxomicin 200mg oral (S/HG) Metronidazole 500mg oral (W/HG)- if unavailable Vancomycin 125 oral (S/HG) Fidaxomicin 200mg oral (S/HG) Vancomycin 500 mg oral (S/M) & metronidazole (S/M) & PR (W/L) Vancomycin (W/L), vancomycin taper (W/L) OR Fidaxomicin (W/M) Vancomycin taper or pulsed (W/L) Vancomycin then rifaxamin (W/L) Fidaxomicin (W/L) Fecal transplant (S/M)
Additional v Treatment Issues 2010 SHEA/ IDSA CDI Guidelines 2017 SHEA/ IDSA CDI Updated Guidelines Fidaxomicin Predates In many regimens IVIG Not addressed No rec Probiotics Not recommended (C- III) Insufficient Evidence /No rec PPI Not addressed Insufficient Evidence /No rec Prolonged prophylaxis No rec (C-III) Insufficient Evidence /No rec 2010 SHEA/ IDSA CDI in adults. ICHE 2010. 31 (5): 431-455. 2017 IDSA/ SHEA CDI in adults & Children. CID. 2018; 1-48- online IDSA site.
Vancomycin Oral for CDI AHRQ. Early Diagnosis, Prevention, and Treatment of Clostridium difficile: Update. 2016. /http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-andreports/?pageaction=displayproduct&productid=2208
Vancomycin ASP Considerations Making oral Vancomycin solution from IV solution Pharmacy to compound Stability/ storage Optimizing dosing: Encouraging 125 mg for most cases (except fulminant)
Fidaxomicin RCT FIDAXOMICIN Recurrence/Initia l Cure VANCOMYCIN Recurrence/Init ial Cure RR (CI) Louie 39/253 (15%) 67/265 (25%) 0.61 (0.43, 0.87) (2011) Corneley 28/221 (13%) 60/223 (27%) 0.47 (0.31,0.71) (2012) Total 67/474 (14%) 127/488 (265) 0.55 (0.42, 0.71) FDA approved based on 2 RCTs Excluded: life threatening CDI, > 1 CDI in 3 month, IBD Similar efficacy in hyperendemic strains Implications: Who would benefit most with relative high cost? Candidate for ASP Corneley, et al. Lancet Infect Dis 2012;12:281-9. Louie, et al. N Engl J Med 2011;364:422-31.
Probiotics Probiotic Type Studies Outcome lactobacillus vs. placebo S. boulardii vs. placebo Multiorganism probiotics vs. placebo 6 RCTs N=1251 6 RCTs N=1244 5 RCT N=3960 Prevent CDI: favors lactobacillus RR 0.27, 95% CI 0.15-0.49 Prevent CDI: not significant RR 0.77, 95% CI 0.38-1.54 Prevent CDI: favors multi-organism RR 0.50, 95%, CI 0.28-0.88 Preparations vary (pathogen, single vs. multiple) Data is mixed (series meta analysis) Implications: True effectiveness remains unclear Candidate for ASP Hempel, et al. JAMA 2012;307:1959-69. Johnston, et al. Ann Intern Med 2012;157:878-88. Allen, et al. Lancet 2013;382:1249-57. Pozzoni, et al. Am J Gastroenterol 2012;107:922-31.
Intravenous Immunoglobulins (IVIG) Use 1 st described in children with multiple CDI episodes Most small case series (1-20 patients) Varying: Ages (2-81 y/o) Dosing (150-400mg/kg, standard 30gm dose) Frequency (once- over weeks) and timing Outcomes: Cure rate 50-100% Recurrence 0-100% Implications: optimal regimen and when to give in disease course is not well established Candidate for ASP Leung, et al. J Pediatr 1991;118:633-7. Abougergi and Kwon. Dig Dis Sci 2011;56:19-26. AHRQ. Early Diagnosis, Prevention, and Treatment of Clostridium difficile: Update. 2016
Fecal Microbial Transplant (FMT) First reported in 1958 with pseudomembranous colitis Mainly case reports (recurrences) Meta-analysis 2013-300 patients- cure rates 85-90% RCT Netherlands: Outcome Vancomycin regimen, bowel lavage & donor feces via nasoduodenal tube 13/16 (2/3) A standard vancomycin regimen 4/13 A standard vancomycin regimen & bowel lavage 3/13 Implication: Likely effective- importance of microbiome yuck factor Kassam. Fecal microbiota transplantation Am J. gastro. 2013. 108;500-508. vannood. Duodenal infusion of donor.. NEJM. 2013; 368: 407-415. FDA backs down on fecal transplant rulehttp://www.medpagetoday.com/gastroenterology/generalgastroenterology/40628
repoopulating - The poop pill A variation on stool transplant--processed feces until only bacteria- encapsulated in 3 layer gelatin capsule Initial were smaller case series None had recurrences Advantages: covers more of GI tract, no invasive procedure, more comfortable / acceptable (9.6/10) Letter Editor- non responders- some standardized regimens Recent Non-inferiority, unblinded, randomized trial conducted in 3 academic centers, 116 patients- FMT vs. pills Non inferior to prevent CDI recurrence at 12 weeks Louie, ID Week abstract 89, Oct 3, 2013 and petrof Stool substitute repoopulating the gut. Microbiome. 2013;1:3-9. Stollman at al. Am J. gastroenterology. 2015; 110:600-601. Kao. JAMA. 2017;318(20):1985-1993. doi:10.1001/jama.2017.17077
Monoclonal Antibodies Two human monoclonal Ab bind & neutralize C. difficile toxins: Actoxumab Toxin A Bezlotoxumab Toxin B Recent NEJM: Randomized control trial, very complex methods Lower rates of recurrence among those receiving Bezlotoxumab w/ standard of care for 1 OR recurrent CDI NNT to prevent 1 episode of recurrence= 10 Actoxumab was not efficacious when given alone & provided no benefit when given concurrently with Bezlotoxumab Implications: Preliminary, more study needed; Candidate for ASP Wilcox MH et al. N Engl J Med 2017;376:305-317
Proton Pump Inhibitors (PPI) and CDI Data mixed 2 studies & editorial in May 2010: Less is more Respective cohort: 5 years, 1166 patients Recurrent CDI higher PPI (25.2 vs 18.5%) Many PPI no indications Pharmcoepidemiologic cohort: >100,000 discharges/5 yrs Dose relationship FDA warning- PPI & CDI Implications: Many no indication, associated with VAP, expense, after CDI Dx- stronger case Linsky, Arch Int Med 2010, Howell, Arch Int Med 2010; Katz, Arch Int Med 2010 FDA Drug Safety Communication. Available at: http://www.fda.gov/drugs/drugsafety/ucm290510.htm
Prophylaxis for CDI when on Systemic Antibiotics? Retrospective Study 203 patient w/ prior CDI & on antibiotics. Recurrence: Oral vancomycin (125 OR 250 mg po BID) 4.2 % 26.2% OR 0.12, CI (.04-.4), p < 0.001 Issues: small number & retrospective No vancomycin Considerations: Promotion of VRE, costs/ cost effectiveness (practical target patients/ populations) Pallin. CID. 2016: 63 (5): 651-653.
Examples of CDI Policies Combine Best Practices: Reassess based on new guidelines CDI ASP & Treatment Policies
What Impact Could Reduced Antibiotic Use have on CDI? CDC Study: Mixed methods, data sources In 323 hospitals, >55% patients received antibiotic 37% prescribing could be improved Wide variety in prescribing Estimated 30% reduction in antibiotic use, could decease CDI by 26% CDC. MMWR. Mar 7, 14. 63(09);194-200.
Strategies to Review Antibiotic Prescribing Before CDI 1 Review common and high volume antibiotics Review antibiotics in CDI cases Systemic approach Identify antibiotic prescribing most associated with CDI Tailored ASP interventions 1 ERASE Cdiff Toolkit. AHRQ. 2013. Available at: http://www.ahrq.gov/professionals/quality-patient-safety/patient-safetyresources/resources/cdifftoolkit/index.html#
Review Medications After CDI Diagnosis Antibiotics (short/ long term): Are they still needed (appropriate)? Can they be narrowed or the course shortened? Other Drugs: Anti-motility agents Narcotic Laxatives Immunosuppression
35 Layering of ASP Activities Over Time 2008-2018 Antibiotic empiric regimen card Sepsis protocol Noon conferences & other education Education Antibiotic Directed Stepwise changes to restrictions Default duration of 7 days (approved by P&T) Antibiotic prescribing screens SENTRI-7/Antibiotic surveillance report Enhanced auditing Extended ID consultation Technology Decision & Other Support Laboratory Improved CDI testing MALDI-TOF + Stewardship intervention for positive blood cultures
ASP as Part of the Solution Steps 1. Antibiotic damage Patient Status Normal flora Interventions ASP Disruption of flora 2. CDI healthcare exposure C. difficile colonization 3. CDI toxin production C. difficile colitis 4. Toxin hyperproduction Fulminant colitis 5. Severe sepsis/shock Death from C. difficile Inf. Control & Cleaning Clinical ASP & Lab Critical care, GI, ID & Surgery Adapted from:apic Guide to Prevention of C. difficile Infection. 2013,
Collaboration Working Together in NYS on CDI* Dates 2008-2009 1 Facilities Collaborators Interventions Outcomes 35 NYS DOH +GNYHA/ UHF -IPC & Cleaning Bundles -Education Mean HO- CDI 2010-2012, 2,3 10 GNYHA/ UHF + AHRQ/ CDC + Montefiore 2015- on 80 GNYHA/ UHF + NYSCHSP + Montefiore -CDI directed ASP -Education -ASP Course -ASP survey -CDI Point Prevalence -CDI ASP Posters GYNHA/ UHF=Greater NY Hospital Association/ United Hospital Fund, NYSCHSP= NYS Council Health Systems Pharmacists, HO-CDI= Hospital onset CDI 1) Koll. J. Healthcare Quality. 2013: 36 (3): 35-45. 2) Ostrowsky. ICHE. 2014: suppl 3:S86-95. 3) AHRQ Toolkit Available at: http://www.ahrq.gov/professionals/quality-patient-safety/patient-safety-resources/resources/cdifftoolkit/index.html# * Addition NYSDOH collaborative LTCF and CDI CDI Targeted antibiotics AHRQ CDI Toolkit Facilities (n) 80 61 53 16
HO CDI Rate At first you don t succeed, try, try again 25.0 20.0 HO CDI Over Time, by Campus Campus A HO CDI Rate Campus B HO CDI Rate Campus C HO CDI Rate 15.0 10.0 5.0 ASP ASP Overall decline in Combine HO- CDI Rates (p-=0.025). 0.0 2010 2011 2012 2013 2014 2015 Year
CDI rates remain high Conclusions New CMS regulatory requirements ASP can help: Testing Formulary Treatment for CDI (role for novel agents) Antibiotic/medication exposures before & after CDI Simple tools can help direct ASP to CDI (show in workshop) It may take time to see results ASP interventions complement to other strategies
C. auris ( The other C. diff ) Why is this concerning? Resistant fungi Difficulty in laboratory diagnosis Outbreaks in healthcare facilities especially relating to environmental contamination & Infection prevention breaches Epi center if NY/ NJ https://www.cdc.gov/fungal/diseases/candidiasis/candida-auris-qanda.html
What are the C. auris ASP Issues? Antifungal review Transitions of care- sharing of information: Review of antimicrobial regimen Intended durations (not restarted on transfer) Status for isolation (related issues)