Antimicrobial Stewardship – Stop the Fuel to the Fire

1. Antimicrobial Stewardship –Stop the Fuel to the Fire Deverick J. Anderson, MD, MPH Chair, Antimicrobial Stewardship and Evaluation Team, DUMC Clostridium difficile Prevention Conference Carolinas Center for Medical Excellence November 8, 2013

2. Outline • Background – the “Why?” • Components of Stewardship – the “What?” • Implementing Stewardship interventions – the “How?” • Proof is in the Pudding - the “Really?” • Take Home Points

3. Why Stewardship?

4. Why Do We Need Stewardship? • Increasing resistance • MRSA • VRE • Multidrug-resistant Gram negative bacteria • Patient Safety • Complex drugs • C. difficile • Cost savings

5. C. difficile: The Next Superbug

6. Antibiotic (Over)use and Bacterial Resistance Albrich et al. EID 2004;10:514.

7. Decrease Hospital Costs • Data for “overall” stewardship programs, but best evidence for antimicrobial restrictions • Studies of restrictive policies have show decreases in the use of the targeted antimicrobials, with annual antimicrobial cost savings of approximately $800,000 • Sometimes see concomitant increase in use of other agents • “Squeezing the balloon” Hayman. Am J Hosp Pharm 1985; 42:1343–7. Woodward et al. Am J Med 1987; 83:817–23. Coleman et al. Am J Med 1991; 90:439–44. Maswoswe et al. Am J Health SystPharm 1995; 52:1433–5. White et al. Clin Infect Dis 1997; 25:230–9.

8. Reasons for Stewardship Safety/ Improved Outcomes Resistance Cost

9. Reasons for Stewardship Resistance Safety Cost

10. Why Else? The STICK! • On-going discussions about stewardship metrics as part of • Public reporting • Hospital reimbursement (CMS? Pay for Performance?) • Likely to happen in some form or fashion soon • CMS Quality Assessment and Performance Improvement (QAPI) • TJC

11. What is Stewardship?

12. What is Antimicrobial Stewardship? • Decision support for prescribers of antimicrobials. • Multidisciplinary teams (MD, PharmD, RN/IP) • Educational, systems-based, 1:1, technology • Multi-level interventions • Active vs. Passive Dellit et al. ClinInf Dis. 2007;44(2):159-177.

13. Goals of Stewardship Primary: To appropriately use antibiotics Improve therapeutic choices (underuse) Reduce unnecessary use (overuse) Secondary: Decrease emergence of resistance Improve patient outcomes and patient safety Tertiary: Decrease costs for health system Satisfy regulatory requirements

14. Prospective audit with interaction and feedback Use Restriction Formulary Preauthorization Education De-escalation Guidelines and clinical pathways Order sets IV to PO conversion Dose optimization Bug-Drug mismatch Components of Stewardship Dellit et al. CID 2007; 2007; 44:159–77.

15. Framework for Stewardship BEFORE Rx AFTER Rx Audit with “real-time” feedback IV to PO Dose optimization Restriction Order Sets ACTIVE Antibiotic Rx MD Disposition PASSIVE Bug-DrugDe-escalationDurationTechnology Audit, reports Education Guidelines

16. What to do???

17. How Do We Perform Stewardship?

18. Planning is priceless. The plan itself is useless. - Gen. BinfordPeay US Army Gulf War Leader

19. How Stewardship? • Antibiotic use • Measure use • Interventions • General principles of good antibiotic use • Team components and approaches

20. Measure Use • Need to know baseline and time-trended consumption • Benchmarking • Exact method is unclear • Per unit? Per physician? Per hospital? • How to risk adjust? • Measurement • Daily defined dose (DDD) • Antibiotic days • Days of therapy (DOT) • Length of therapy (LOT)

21. Work Ongoing… • Group from VCU examined data from 70 hospitals that participate in UHC • 1 791 180 discharged adults, 63.7% received antibacterial drugs • Patients were assigned to 1 of 35 clinical service lines (CSL) based on their Medicare Severity Diagnosis Related Group. • Expected (E) use was determined by indirect standardization and compared with observed (O) use. Polk R et al. CID 2011; 53:1100.

22. Guidelines • Evidence-based practice guidelines • Hospital-specific • Multi-disciplinary • Typically passive, but can be more active by incorporating other interventions • Education • Restriction • Order sets • Implementation may be tedious and difficult • CPOE facilitates • Can target specific pathways or pitfalls • SEPSIS • Asymptomatic bacteriuria

23. Bug-Drug Match • Organism = X; • Resistant to Y and susceptible to Z • YET, patient receives Y • MRSA in blood, susceptible to vancomycin but treated with Ceftriaxone • Only happens every so often, right? • 30% of BSIs in ICU • 30-40% of infections due to MRSA Ibrahim et al. Chest 2000; 118:146-55.Kaye et al. CID 2008; 46:1568-77.

24. Audit with Feedback • To me, intervention with the most possibility • Dose • Monitoring for adverse events • Review for bug-drug match • De-escalation • Duration control • Unfortunately, most time intensive • Man-power vs. computer?

25. Audit with Feedback • Academic detailing • Randomized study with one-on-one education from a clinical specialist • Patient-specific review • 37% reduction in unnecessary use, reduced new starts • Randomized to “antimicrobial suggestions” by ID fellow and pharmacist • 2 fewer days of IV therapy, saved $400/patient • Prospective audit • 22% decrease in use of IV broad-spectrum agents • Decrease in rates of CDI and infection due to MDRO Solomon et al. Arch Intern Med 2001;161:1897-902.Fraser et al. Arch Intern Med 1997; 157:1689-94Carling et al. ICHE 2003;24:699-706.

26. Audit with Feedback • Intermittent audit (3 days a week) • Review abx for patients receiving multiple, prolonged, or high-cost agents • 69% of recommendations implemented • 19% reduction in antimicrobial expenditures for a savings of $177,000/year • Impact on future prescribing (education) hard to measure • Computer assistance • Automated decision support, approvals for restricted agents, and enhanced/facilitated communication • 12% decrease in antibiotic orders • $370,000 in projected savings • Many new computer systems offer many of these bells and whistles LaRocco et al. CID 2003;37:742-3.Agwu CID 2008; 15;47:747-53.

27. Embrace Principles of Good Antibiotic Use

28. Error is inevitable in a field premised on the art of balancing probabilities. - Sir William Osler

29. Work-up for Suspected Infected/Febrile Patient • Assess clinically: exam, history; select lab tests • Perform “Fever work-up” • Beware of colonization in sputum and urine • Always send 2 sets of blood cultures: both peripheral if possible • Empiric antibiotics should cover common pathogens associated with hospital-acquired infections: catheters, respiratory, urine, • S. aureus needs to be empirically covered

30. Empiric Treatment • Use your hospital antibiogram and unit-specific antibiograms • Send cultures at the beginning of therapy, before antibiotics when possible • It’s often ok to start out broad, as long as therapy is narrowed after cultures return • De-escalate • “Double coverage”

31. De-Escalation of Therapy • Concept: Start broad (EMPIRIC) and then narrow (TARGETED) • Helps solve conflict between providing appropriate empiric therapy and inappropriate over treatment • Clear connection between early, effective initial therapy and improved outcomes • Particularly among septic patients • Narrow treatment based on culture results • Respond to positive cultures • Respond to negative cultures (no MRSA, no PA, no infection) Dellit et al. CID 2007; 2007; 44:159–77.

32. De-Escalation of Therapy • Most studies involved VAP • Not always easy to pull off • 10-90% feasibility across hospitals • Recent study of 116 septic patients in an ICU demonstrated that de-escalation opportunities missed in >50% of patients, even when protocol in place • Patients who underwent de-escalation had fewer readmissions Morel et al. Crit Care Med 2010. 17; 14:225.

33. “Double Coverage” • Synergy, prevention of emergence of resistance, broad coverage • Enterococcal and PV Endocarditis • Probably reasonable in setting of sepsis, but remove one agent when organism/susceptibilities are known • GNR • Different antimicrobial classes • Pseudomonas aeruginosa: not a lot of data • +/- If 3rd generation cephalosporin used for Enterobacter, Citrobacter, Serratia

34. Double Coverage – With What? • Retrospective review of 760 patients admitted to ICU with severe sepsis/septic shock due to gram-negative BSI at Wash U • Patients who received appropriate therapy had better mortality • 52% v. 36% (p<0.001) • Patients who received double coverage were more likely to receive appropriate therapy • 78% v. 64% (p<0.001) • Renal toxicity higher among patients who received gent • 22% v. 14% (p=0.01) Micek et al. AAC 2010; 54:1742-8.

35. Double Coverage – At All? • Recent randomized open-labeled trial of 600 patients with severe sepsis or septic shock in 44 ICUs in Germany • Compare Meropenem alone (1g q8; n=298) vs. Meropenem+moxifloxacin (same + 400mg iv q24; n=302) • NOTE: patients with known or current history of MRSA or VRE were EXCLUDED • No major differences in degree of organ failure • No major differences in mortality and length of stay • More study-related “adverse events” in combination group (8.6% v. 3.8%, p=0.02), but not a difference in “serious” study-related adverse events. Brunkhorst et al. JAMA 2012;307:2390.

36. Asymptomatic Bacteriuria • Common: 5-20% of adults • Elderly, women • Bottom line: DON’T TREAT IT • Exceptions: • Prior to some urologic/surgical procedures • Pregnancy • Major cause of unnecessary antibiotic use • 30-50% treated unnecessarily Nicole et al. IDSA Guidelines. CID 2005.Cope et al. CID 2008

37. CAP >= 5 days HAP/VAP 7 days 14 d if NFGNB Meningitis 7-21 days CRBSI 1 – 6 weeks NV IE 2-6 weeks PV IE >= 6 weeks Intra-abd infection 4-7 days Pyelo 14 days UTI >= 3 days Length of Therapy Hayashi and Paterson. CID 2011;52:1132-40.

38. What About Technology? • Two different approaches • Better diagnostics • PCR • Other microbiological methods • Matrix-assisted laser desorption/inonization time of flight (MALDI TOF) mass spectrometry • Biomarkers to determine if/when use or stop antibiotics • Procalcitonin • CRP

39. Technology - Diagnostics • PCR • More and more possibilities • Point-of-care • Decreasing cost • Can lead to reduced antibiotic use and testing • Trial of rapid influenza PCR in Pediatric ED patients • Decreased use of CTX, urinalyses Sharma et al. Arch PediatrAdolesc Med 2002;156:41. Doan et al. Cochrane Database Syst Rev 2009:CD006452.Shiley et al. ICHE 2010; 31:1177

40. Technology - Diagnostics • PCR to rapidly determine MRSA v. MSSA in blood • S. aureusbacteremia = BAD disease • Strategy – combine results with pharmacist prospective audit and ID consult • Decreased vanco use, cost, and length of stay • But doesn’t ALWAYS translate into reduced use of antibiotics • 196 hospitalized patients with positive viral PCR (Flu A/B, parainfluenza, adenovirus, RSV) • 125 of 131 patients CONTINUED to receive antibiotic despite positive test • Majority had normal CXR • 8 (6%) developed CDI Bauer et al. CID 2010; 51: 1074.Shiley et al. ICHE 2010; 31:1177

41. Is Stewardship Effective?

42. Stewardship and Resistance • Before-after study at university-affiliated hospital • Targeted program • Specific antimicrobials • Cephalosporins, FQs, carbapenems, aztreonam • Long-term (7-years) trends reported • Big impact on resistant Enterobacteriaciae Carling et al ICHE 2003; 24:699–706.

43. Example/Exemplary Program Fishman N. Am J Med 2006; 119(6 Suppl 1):S53–S61

44. C. difficile-Specific • Stewardship programs lead to more “appropriate” antibiotic use • Less unnecessary exposure • More effective therapy • Decrease rates of C. difficile • Some programs include specific interventions to maximize doses • Correct over and under dosing • Allergy confirmation and correction Valiquette L et al. CID 2007; 45:S112–S121.

45. C. difficile-Specific • Biggest drivers of C. difficile • Clindamycin – 20-fold • Fluoroquinolones – 5.6-fold • Cephalosporins – 4.5-fold • Stewardship programs that limit these decrease incidence of C. difficile Deshpandeet al. JAC 2013;68:1951.

46. C. difficile-Specific • VAMC in Virginia • Required ID consultation for use of clindamycin • Rate of CDI decreased 4-fold • Of course, saw increase in other anti-anaerobic medications! • Decrease in fluoroquinolone use • Decrease NAP1 infection Climo et al. Ann Intern Med 1998. Riddle and Dubberke ID Clin NA. 2009.

47. Bottom Line • Antimicrobial stewardship is a key intervention to prevent C. difficile • Stewardship is hard, but can be done • Stewardship is rapidly evolving • Stay tuned!!