Let’s Really Implement Antimicrobial Stewardship

1. Let’s Really Implement Antimicrobial Stewardship Chris Gentry, Pharm.D., BCPS Clinical Coordinator and Clinical Specialist, Infectious Diseases Oklahoma City VA Medical Center

3. Unintended consequences • Pt seen for approval of piperacillin/tazobactam, linezolid, daptomycin. • 79 yo MALE w/ h/o CKD, CHF, DM originally transferred from outside hospital 12/31 with ARF, new onset A.fib, and right pleural effusion. • Hospital course complicated by development of HCAP, HIT, NSTEMI, solar keratosis with hemorrhage. • HCAP treated empirically with pip/tazo 1/12-1/22; no opportunity to de-escalate due to lack of microbial etiology necessitating broad-spectrum therapy

4. Unintended consequences • Transferred to MICU 1/29 for altered mental status, GPC bacteremia & presumed nosocomial pneumonia. • Pip/tazo and ciprofloxacin added to vancomycin. • Trach aspirate and BAL culture grew a pip/tazo-resistant Enterobacter cloacae. • Patient's GPC bacteremia was found to be vancomycin-resistant Enterococcus faecium. • Vancomycin changed to daptomycin & linezolid for Gram positive bacteremia & pneumonia. • Patient also has purulent UA with culture growing Candida albicans.

5. Unintended consequences • Recommended dc pip/tazo since E. cloacae was pip/tazo-resistant. Given good MIC of the E. cloacae to ciprofloxacin, treated with ciprofloxacin monotherapy, increasing dose to 400 mg IV q12hr. • Recommended treating VRE bacteremia with either linezolid or daptomycin, but not both. In this circumstance either was appropriate but linezolid has confirmed activity against this isolate. • Recommended starting fluconazole for Candida albicans in urine.

7. Effect of broad-spectrum antibiotics on microbial ecosystems Green = susceptible/nice Red = resistant/mean ABX

8. Effect of narrow-spectrum antibiotics on microbial ecosystems Light Green = susceptible/nice Dark Green = resistant/nice Red = resistant/mean ABX

9. Inactive pipeline

10. Lack of unique classes From: Extendingthecure.org, RW Johnson Foundation, 2007

11. Gram negative antibiotic pipeline

12. Gram negative antibiotic pipeline • Nada

13. Gram negative antibiotic pipeline • Nada • Nothing

14. Gram negative antibiotic pipeline • Nada • Nothing • Zilch

15. Gram negative antibiotic pipeline • Nada • Nothing • Zilch • Non-existent

16. Why Antimicrobial Stewardship ? • Resistant organisms lead to poorer outcomes in efficacy: • Vancomycin-resistant enterococci • Glycopeptide intermediate or resistant Staphylococcus aureus • Penicillin-resistant Streptococcus pneumoniae • Extended-spectrum beta-lactamase producing Klebsiellapneumoniaeand E. Coli • Multidrug-resistant Acinetobacter sp and Pseudomonas aeruginosa • Candidemia

17. Why Antimicrobial Stewardship ? • Resistant organisms lead to poorer outcomes in safety, leading to ↑ use of: • Aminoglycosides • Carbapenems • Colistin • Linezolid • Voriconazole • Amphotericin

18. Why Antimicrobial Stewardship ? • Resistant organisms lead to increased lengths of stay

19. Why Antimicrobial Stewardship ? • Resistant organisms lead to more broad-spectrum antibiotic use • Which, in turn, leads to more resistant organisms

20. Multi-drug resistant Gram negative infections • ESBL-producing Klebsiella sp. and E Coli • Acinetobacter sp. and Pseudomonas sp. • Cases being seen that are PAN-resistant • Necessitating the rapid increase in use of carbapenems, tigecycline, and colistin

21. ICU Gram negative bacilli bloodstream infections Wisplinghoff H, et al. Clin Infect Dis 2004;39:309-317

22. 2009 ICU Gram negative bacilli susceptibilities Bertrand, Dowzicky. ClinTher 2012;34:124-137

23. Extended-spectrum beta-lactamase (ESBL)

24. ESBL-producing K. pneumoniaeand E. ColiSusceptibility & Resistance Characteristics • Resistant to: • All penicillins • Questionable activity for piperacillin/tazobactam • First, second and third generation cephalosporins • Questionable activity for cefepime • Aztreonam • Fluoroquinolones • Susceptibility rates of ~25% • TMP-sulfamethoxazole • Aminoglycosides • Tobramycin and amikacin can be susceptible

25. ESBL-producing K. pneumoniaeand E. ColiSusceptibility & Resistance Characteristics • Susceptible to: • Carbapenems • Some level of concern for ertapenem • Tigecycline • Colistin

26. ESBL incidence • Klebsiella sp. ESBL rates increased from ~10% in 2003 to ~15% thru 2008. • E.coli ESBL rates increased from ~3% in 2003 to 7% thru 2008 • Proteus mirabilus ESBL rates have been ~4%. Castanheira M, et al. American Society for Microbiology General Meeting. May 2010. San Diego, CA

27. Klebsiellapneumoniaecarbapenemase (KPC)

28. KPCsSusceptibility & Resistance Characteristics • Resistant to: • Penicillins • Cephalosporins • Aztreonam • Carbapenems • Usually • Carbapenemase activity may not provide resistance if other mechanisms are not present • Fluoroquinolones • Usually

29. KPCsSusceptibility & Resistance Characteristics • Susceptible to: • Tigecycline • Colistin • Aminoglycosides

30. MDR P. aeruginosa, Acinetobacter sp., and other non-fermenters

31. MDR P. aeruginosa, Acinetobacter sp., and other non-fermenters • Susceptible to: • Colistin • Use with an anti-pseudomonalcarbapenem or rifampin may produce synergistic killing and reduce emergence of colistin resistance • Amikacin • Acinetobacter sp. may be susceptible to: • Ampicillin-sulbactam • Minocycline • Tigecycline

32. Colistin and Tigecycline

33. ColistinBack to the Future • Polymixin E • look at your triple antibiotic ointment tube • 2.5-5 mg/kg/day, divided into 2 or 3 doses • Revived due to ICU outbreaks of multidrug resistant P. aeruginosa and Acinetobacter sp. infections • Should use in combination with carbapenem or rifampin to minimize emergence of colistin resistance • Nephrotoxicity in ~20-30% • Neurotoxicity (NMB) in ~10%

34. Tigecycline • New class: Glycylcycline • similar to tetracyclines without similar resistance • Very unique – good AND bad - microbiologic profile • Gram negative bacilli EXCEPT for: • Pseudomonas aeruginosa • Proteus mirabilus • Providencia sp. • Serratiamarcescens • Gram positive cocci INCLUDING: • MRSA • VRE • MDRStreptococcus pneumoniae • Anaerobic activity

35. Tigecycline • 100 mg IV load, then 50 mg IV q12h • Very low serum concentrations • Limits role in serious infections (along with being bacteristatic) • Reasonable volume of distribution • Primarily biliary excreted • Limits role in UTI’s • High rate of nausea (20-30%) and vomiting (10%) • Limited primarily to first couple of days

37. IDSA/SHEA Guidelines: Executive Summary 1. Core members of a multidisciplinary antimicrobial stewardship team include an infectious diseases physician and a clinical pharmacist with infectious diseases training (A-II) who should be compensated for their time (A-III), with the inclusion of..... Because antimicrobial stewardship, an important component of patient safety, is considered to be a medical staff function, the program is usually directed by an infectious diseases physician or codirected by an infectious diseases physician and a clinical pharmacist with infectious diseases training (A-III).

38. IDSA/SHEA Guidelines: Executive Summary 2. Collaboration between the antimicrobial stewardship team and the hospital infection control and pharmacy and therapeutics committees or their equivalents is essential (A-III). 4. The infectious diseases physician and the head of pharmacy, as appropriate, should negotiate with hospital administration to obtain adequate authority, compensation, and expected outcomes for the program (A-III).

39. Antimicrobial Stewardship Program: Personnel ID MD Epi ID PharmD ASP IT ICP Micro

40. Pharmacist level of impact ID-TRAINED Resistance & Case-specific expertise GENERAL CLINICAL Clinical practice guidelines STAFF Education IV to PO Renal dosing

41. Stewardship Strategies – Restriction enforcement model • Prospective audit • Maintains prescriber autonomy • Avoids potential delays in timely therapy • Recommendations may be optional • By drug, by culture, by disease state • Preauthorization • Use of “experts” at outset of therapy • May delay initiation of therapy • 24/7/365 • unless exceptions for after-hours are in place (ie, first dose sent)

42. Stewardship Strategies, cont’d. • Education • Not very effective when used alone • IV to PO • Traditionally big bang-for-the-buck intervention, but physicians are doing this better on their own. • Clinical practice guidelines • Development • Dissemination • Enforcement • Updating • Antimicrobial order forms • Good for initial empiric therapy, but then what?

43. Stewardship Strategies, cont’d. • De-escalation • Most effective with good quality, positive cultures • What about empiric therapy? • What if there are no culture data? • Dose optimization • Optimizes outcomes? • Doesn’t alter broad-spectrum activity • Antimicrobial cycling • Largely dismissed now, no real effect on resistance

44. Anti-infective spectrum funnel Gram positive Gram positive/ Gram negative Fungal Meropenem, Imipenem & Doripenem Piperacillin/tazobactam Cefepime & Ceftazidime Fluoroquinolones Ertapenem Ceftriaxone Amp/sulbactam Cefoxitin Cefazolin Ampicillin Daptomycin Linezolid Telavancin Quinopristin/ Dalfopristin Vancomycin Cefazolin Nafcillin Penicillin Amphotericin Voriconazole Posaconazole Echinocandins Itraconazole Fluconazole NONE

45. Types of interventions Trade one broad-spectrum regimen for another Narrow the spectrum based on culture and susceptibility results Patients doing well; change to po and/or discharge Patient cured; discontinue therapy

46. Antibiotic outcome timeline

47. Conclusions • MDR bacteria threaten our ability to treat outpatient infections with oral antibiotics and our ability to treat inpatient infections with intravenous antibiotics • Totality of evidence points only to increasing trends in the prevalence of MDR bacteria with current practices

48. Conclusions, cont’d • The antibiotics we are forced to use to treat MDR bacterial infections are: • limited in number • potentially less effective • generally less safe • generally more broad-spectrum (feeds vicious cycle) • The antibiotic pipeline looks dismal for the foreseeable future • Efforts need to focus on preventing infections and maximizing the durability of available treatment options with antimicrobial stewardship.