1. Antimicrobial Stewardship: Focus on IV to PO Antibiotics Michaelia Dunn, Pharm.D., BCPS Clinical Pharmacist, IUAH February 22 nd, 2012 mdunn4@iuhealth.org

2. Disclosure  Nothing to disclose

3. Objectives  Summarize key points from the 2007 SHEA/IDSA guidelines for antimicrobial stewardship  Discuss a general approach for de- escalation and streamlining antibiotics

4. Objectives  Differentiate between the inclusion and exclusion criteria for IV to PO conversions  Describe the potential impact on costs and clinical outcomes

5. “Antibiotics are the only medications that affect other people” -a really smart ID physician

6. 2007 SHEA/IDSA Guidelines Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.   Appropriate selection, dosing, ROUTE, and duration of antimicrobial therapy   Supported from:   American Academy of Pediatrics, American Society of Health-Systems Pharmacists, Infectious Diseases Society for Obstetrics and Gynecology, Pediatric Infectious Disease Society, Society for Hospital Medicine, Society of Infectious Disease Pharmacists

7. Primary Goal   Optimize clinical outcomes while minimizing unintended consequences, including toxicity, selection of pathogenic organisms (Clostridium difficile), and emergence of resistance   Supported by ASP here at IUAH Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

8. Secondary Goals   Reduce healthcare costs while not adversely impacting quality of care   Supported by ASP here at IUAH Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

9. Antimicrobial Stewardship Program (ASP)- IUAH   Multidisplinary team   Purpose:   Improve time to effective therapy, appropriate empiric treatment, duration of therapy, de-escalate therapy when appropriate, and ultimately improve patient care   Activities:   Development of protocols, pathways, criteria, guidelines   Data review and analysis over time   Direct educational efforts

10. Core Strategies for Antimicrobial Stewardship   1. Prospective audit with intervention and feedback   Results in reduction of inappropriate use of antimicrobials   Consultations - ID colleagues   Clinical pharmacists monitoring culture results and sensitivities Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

11. Core Strategies for Antimicrobial Stewardship   2. Formulary restriction and preauthorization   Current ID restrictions include:   Fidaxomicin (Dificid®)   Linezolid (Zyvox®)   Daptomycin (Cubicin®)   Micafungin (Mycamine®)   Voriconazole (Vfend®) Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

12. Core Strategies for Antimicrobial Stewardship   3. Education - Essential element   Provides a foundation of knowledge, influences prescribing behaviors, and increases acceptance of stewardship strategies   Education alone without active intervention is only marginally effective   Hospitalist presentations   Stress ulcer prophylaxis, asymptomatic bacteruria Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

13. Core Strategies for Antimicrobial Stewardship   4. Guidelines and clinical pathways   Evidence-based practice guidelines incorporating microbiology and resistance patterns   Clinical pathways have been explored, but not currently available at IUAH   Resident project- Criteria for use of specific antimicrobials as supported by ID and ASP Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

14. Core Strategies for Antimicrobial Stewardship   5. Antimicrobial Cycling   Insufficient data to support this as a means of preventing or reducing antimicrobial resistance over a prolonged time   Not utilized or supported by ASP here at IUAH Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

15. Core Strategies for Antimicrobial Stewardship   6. Antimicrobial order forms   Effective component and helps facilitate practice guidelines   Focused Management Order Sets   Pneumonia- Completed and currently available on PowerChart   Urinary Tract Infections- Currently underway and expected to be completed in the next couple months Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

16. Core Strategies for Antimicrobial Stewardship   7. Combination Therapy   Insufficient data to support this as a means of preventing or reducing antimicrobial resistance over a prolonged time   Does have a role in certain clinical context   Empiric therapy for critically ill patients at risk with multidrug-resistant organisms   ASP does not have a recommendation Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

17. Core Strategies for Antimicrobial Stewardship   8. Streamling or de-escalation of therapy   Can more effectively target the causative pathogen   Results in decreased antimicrobial exposure and substantial cost savings   ASP strongly recommends   Clinical pharmacists are encouraged to recommend based on cultures and sensitivities Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

18. Core Strategies for Antimicrobial Stewardship   9. Dose optimization   Dose based on individual patient characteristics, causative organism, site of infection, pharmacokinetic and pharmacodynamic properties, renal function, sensitivities   Clinical pharmacists assisting in antimicrobial dosing   Extended infusion of beta-lactams (Pip/Tazo, Meropenem, Cefepime, Ceftazidime, Amp/Sulb) Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

19. Core Strategies for Antimicrobial Stewardship   10. Parenteral to Oral Conversion   Can decrease length of hospital stay and health care costs   ASP supports IV to PO conversion when appropriate   Clinical pharmacists are expected to collaborate with physicians to make recommendations Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

20. De-escalation and Streamlining Antimicrobials   Continuing broad spectrum antibiotics lead to selection of resistant pathogens   More targeted therapy, decreases broad spectrum antimicrobial exposure, and helps to contain cost   Discontinuation of empiric antimicrobial therapy based on negative cultures Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

21. General Approach for De-escalation and Streamlining   Recognize and avoid redundant antimicrobial combinations   Example- Pipercillin/Tazobactam PLUS metronidazole for Bacteroides fragilis (anaerobe) coverage Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

22.   Recognize and avoid redundant antimicrobial combinations   Choose an antimicrobial that has specific or more narrow organism coverage   Helpful with cultures and sensitivities General Approach for De-escalation and Streamlining Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

23.   Recognize and avoid redundant antimicrobial combinations   Choose an antimicrobial that has specific or more narrow organism coverage   Good-excellent bioavailability   Moxifloxacin, Doxycycline, Ciprofloxacin, Linezolid, Amoxicillin, Cephalexin, Voriconazole, Fluconazole, Clindamycin, Metronidazole, SMX/TMP General Approach for De-escalation and Streamlining Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

24.   Recognize and avoid redundant antimicrobial combinations   Choose an antimicrobial that has specific or more narrow organism coverage   Good-excellent bioavailability   Penetration to the site of action   Example- Moxifloxacin into respiratory tissue General Approach for De-escalation and Streamlining Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

25. Benefits of IV to PO  Take 3-5 minutes for group discussion

26. Benefits of IV to PO   Decrease risk or avoidance of adverse effects or potential complications   Infection   Thrombophlebitis   Thromboembolism   Excess fluid administration

27. Benefits of IV to PO   Decrease risk or avoidance of adverse effects or potential complications   Decrease risk or avoidance of medication errors   More complex preparation and delivery by pharmacy   More complex administration procedures

28. Benefits of IV to PO   Decrease risk or avoidance of adverse effects or potential complications   Decrease risk or avoidance of medication errors   Increase in patient comfort and mobility

29. Benefits of IV to PO   Decrease risk or avoidance of adverse effects or potential complications   Decrease risk or avoidance of medication errors   Increase in patient comfort and mobility   Decrease healthcare costs   Medication costs   Savings by elimination of Alaris pumps and IV sets

30. Benefits of IV to PO   Decrease risk or avoidance of adverse effects or potential complications   Decrease risk or avoidance of medication errors   Increase in patient comfort and mobility   Decrease healthcare costs   Significant decrease in hospital length of stay with no adverse effect on clinical outcomes Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

31. Inclusion Criteria  Take 3-5 minutes for group discussion

32. Inclusion Criteria   Functioning GI tract   Tolerating a PO diet, a clear liquid diet, tube feeds without high residuals, other PO meds

33. Inclusion Criteria   Functioning GI tract   Afebrile for 24 hours

34. Inclusion Criteria   Functioning GI tract   Afebrile for 24 hours   Improving trend in WBC

35. Inclusion Criteria   Functioning GI tract   Afebrile for 24 hours   Improving trend in WBC   Other clinical signs of improvement

36. Inclusion Criteria   Functioning GI tract   Afebrile for 24 hours   Improving trend in WBC   Other clinical signs of improvement   Received at least 24 hours of IV therapy when appropriate Halm EA, et al. What factors influence physicians' decisions to switch from intravenous to oral antibiotics for community-acquired pneumonia?. J Gen Intern Med. 2001;16(9):599-605.

37. Exclusion Criteria  Take 3-5 minutes for group discussion

38. Exclusion Criteria   NPO or scheduled for surgery

39. Exclusion Criteria   NPO or scheduled for surgery   Recent therapeutic failure on PO therapy

40. Exclusion Criteria   NPO or scheduled for surgery   Recent therapeutic failure on PO therapy   Malabsorption disorders   Short gut syndrome, severe N/V/D, inflammatory bowel disease, bowel obstruction, ileus, continuous NG suctioning, active GI bleed

41. Exclusion Criteria   NPO or scheduled for surgery   Recent therapeutic failure on PO therapy   Malabsorption disorders   Patient is hypotensive (SBP<100 or DBP<60)

42. Exclusion Criteria   NPO or scheduled for surgery   Recent therapeutic failure on PO therapy   Malabsorption disorders   Patient is hypotensive (SBP<100 or DBP<60)   Neutropenia that is not resolving

43. Exclusion Criteria   NPO or scheduled for surgery   Recent therapeutic failure on PO therapy   Malabsorption disorders   Patient is hypotensive (SBP<100 or DBP<60)   Neutropenia that is not resolving   Infections where adequate antibiotic concentrations are not easily achieved or PO antimicrobials are inappropriate   Meningitis, bacteremia, endocarditis, deep joint infections, bone infections, etc. Halm EA, et al. What factors influence physicians' decisions to switch from intravenous to oral antibiotics for community-acquired pneumonia?. J Gen Intern Med. 2001;16(9):599-605.

44. Impact on Costs and Clinical Outcomes Solomkin JS, et al. Results of a randomized trial comparing sequential intravenous/oral treatment with ciprofloxacin plus metronidazole to imipenem/cilastatin for intra-abdominal infections. The Intra-Abdominal Infection Study Group. Ann Surg. 1996;223(3):303-315. TrialPatientsOutcomesConclusion Randomized, double-blind, multicenter trial, ITT and valid populations 671 patients with complicated intra- abdominal infections, IV CIP/ MTZ or IV IMI vs. IV/PO CIP/MTZ (when PO feeding) Success rates (ITT): CIP/MTZ IV vs. CIP/MTZ IV/PO vs. IMI IV (82% vs. 84% vs. 82%) Success rates (valid): CIP/MTZ IV vs. CIP/MTZ IV/PO vs. IMI IV (84% vs. 86% vs. 81%) Conversion to oral therapy with CIP/MTZ appears as effective as continued IV therapy in patients able to tolerate oral feedings

45. Impact on Costs and Clinical Outcomes Przybylski KG, et al. A pharmacist-initiated program of intravenous to oral antibiotic conversion. Pharmacotherapy 1997; 17:271–276. TrialPatientsOutcomesConclusion Intervention of pharmacist-initiated IV to PO program, prospective, over 12 months 240 patients (200 converted) determined to have “mild to moderate” infections Decreased hospital LOS by 1.53 days (p<0.003) Drug acquisition cost savings: $15,149 Reduced LOS costs: $161,072 Intervention program was found to be cost- effective without compromising patient care

46. Impact on Costs and Clinical Outcomes TrialPatientsOutcomesConclusion Pharmacist intervention (PI), 3 study periods of 3 months each, prospective 250 CAP patients, 3 groups: IV beta-lactam + macrolide (no PI), IV beta-lactam + IV/PO macrolide (PI switch), IV to PO moxifloxacin (Automatic PI sequential) Clinical success on day 3 of therapy was improved in the PI sequential group Similar in all 3 groups on day 7 of therapy and at the end of therapy. Hospital LOS was similar (mean, 4.39 days). Antibiotic costs were significantly reduced ($110/ patient) in the PI sequential group. IV to PO was accomplished more quickly for the same agent Reduced cost without compromising efficacy Davis SL. Pharmacoeconomic Considerations Associated with the Use of Intravenous-to-Oral Moxifloxacin for Community- Acquired Pneumonia. CID 2005;41(Suppl 2): S136-S143.

47. Impact on Costs and Clinical Outcomes Li JZ, et al. Effect of linezolid versus vancomycin on length of hospital stay in patients with complicated skin and soft tissue infections caused by known or suspected methicillin-resistant staphylococci: results from a randomized clinical trial. Surg Infect (Larchmt) 2003; 4:57–70. TrialPatientsOutcomesConclusion Randomized, ITT 230 complicated skin and soft tissue infection patients, IV Vancomycin vs. PO Linezolid Median LOS was five days shorter for the linezolid group than the vanco group (9 vs. 14 days, p = 0.052) Linezolid can reduce LOS for patients with complicated SSTI from suspected or confirmed MRSA

48. Impact on Costs and Clinical Outcomes TrialPatientsOutcomesConclusion Prospective, multicenter, randomized, open-label, parallel-group study 636 CAP patients, Cefuroxime IV BID or TID for 48 to 72 h followed by oral cefuroxime for 7 days, Clinical response rates were equivalent for TID and BID groups (cure/ improvement, 79% and 84%, respectively) and at follow-up (maintained cure, 87% and 82%, respectively) Effective and well- tolerated as rapid switch therapy and has the potential to reduce overall health care costs and improve patient satisfaction Van den Brande P, Vondra V, Vogel F, et al. Sequential therapy with cefuroxime followed by cefuroxime axetil in community-acquired pneumonia. Chest. Aug 1997;112(2):406-415

49. Impact on Costs and Clinical Outcomes   Other studies demonstrating decrease costs and hospital LOS while not affecting patient outcomes   Ramirez JA, et al. Early switch from intravenous to oral antibiotics and early hospital discharge: a prospective observational study of 200 consecutive patients with community- acquired pneumonia. Arch Intern Med. 1999;159(20):2449-2454.   Ramirez JA. Managing antiinfective therapy of community-acquired pneumonia in the hospital setting: focus on switch therapy. Pharmacotherapy. 2001;21(7 Pt 2):79S-82S.   Gollin G, et al. Oral antibiotics in the management of perforated appendicitis in children. Am Surg. 2002;68(12):1072-1074.   Starakis I, et al. Results of a prospective, randomized, double blind comparison of the efficacy and the safety of sequential ciprofloxacin (intravenous/oral) + metronidazole (intravenous/ oral) with ceftriaxone (intravenous)+metronidazole (intravenous/oral) for the treatment of intra-abdominal infections. Int J Antimicrob Agents. 2003;21(1):49-57.   Tomera KM, et al. Ertapenem versus ceftriaxone followed by appropriate oral therapy for treatment of complicated urinary tract infections in adults: results of a prospective, randomized, double-blind multicenter study. Antimicrob Agents Chemother. 2002;46(9):2895-900.

50. Impact on Costs and Clinical Outcomes   Hamilton-Miller J. Cefixime for switch therapy. Chemotherapy. 1998;44 (Suppl 1):24-27.   Fernandez P, et al. Community acquired pneumonia: from intravenous to oral cephalosporin sequential therapy]. Rev Med Chil. 2000;128(3):267- 272.   Parola D, et al. Efficacy and safety of clarithromycin in the treatment of community-acquired pneumonia. Recenti Prog Med. 2000;91(1):12-15.   Martinez MJ, et al. Clinical and economic impact of a pharmacist- intervention to promote sequential intravenous to oral clindamycin conversion. Pharm World Sci. 2000;22(2):53-58.   Finch R, et al. Randomized controlled trial of sequential IV and oral moxifloxacin compared with sequential IV and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment. Antimicrob Agents Chemother. 2002;46(6):1746-54.

51. Summary   Vast amount of studies that evaluate costs and clinical outcomes of IV to PO   Many of studies evaluated hospital LOS and clinical success rates   Potential impact for pharmacist interventions

52. Conclusions   2007 IDSA guidelines recommend several core strategies for antimicrobial stewardship, including IV to PO conversions   Patients should be carefully assessed for appropriate inclusion and exclusion criteria to be converted to oral regimens   IV to PO conversions have several benefits beyond costs

53. Conclusions   Several studies show IV to PO conversions decrease drug and hospitalization costs, decrease hospital LOS, and do not adversely affect clinical outcomes

54. Questions?

55. Antimicrobial Stewardship: Focus on IV to PO Antibiotics Michaelia Dunn, Pharm.D., BCPS Clinical Pharmacist, IUAH February 22 nd, 2012 mdunn4@iuhealth.org