1. Presented by: LCDR Jeffrey S. Gildow, Pharm.D., M.S., EMT-B Infectious Diseases Pharmacist Provider Indian Health Service: Winnebago Service Unit Winnebago, Nebraska

2. “I have no financial relationship with pharmaceutical companies, biomedical device manufacturers or distributors, or others whose products or services may be considered related to the subject matter of my presentation.”

3. 1. Classify key mechanisms of bacterial antimicrobial resistance 2. Distinguish current trends in antimicrobial resistance 3. Summarize the role of Antimicrobial Stewardship Programs

5. There’s a problem with resistance to antibiotics?  June 26, 1945 – “…the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bread out….In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organisms. I hope this evil can be averted.” Sir Alexander Fleming Ref.: New York Times, June 26, 1945: 21

7.  -lactams MacrolidesTetracyclinesQuinolonesGlycopeptide Enzymatic inactivation ++++ (gram- negative) +-- Decreased perm. + (gram- negative) ++ (gram- negative) + (gram- negative) ++ (gram- negative) Efflux+++++++-- Alteration of target site ++++++ (H. pylori)+++ Protection of target site -- +++-- +++, most common, ++ common, + less common, -- no used Table modified from: Opal and Medeiros, 2005 * Over production of dihydropteroate synthase (DHPS) by felP – sulfonamide resistance and by folA for trimethoprim resistance ** By pass ABX inhibition (thymine dependent): Thymidylate synthesis via salvage pathways – resistant to SMX/TMP

8.   -lactamases Bush-Jacoby-Medeiros Functional Classification scheme of  -lactamases (Penicillinases, Cephalosporinase, Extended-spectrum, Carbapenemases)  Erthromycin esterases – isolated from E. coli (hydrolyze the lactone ring, plasmid mediated)  Tetracycline-inactivating enzyme – tetX (Described in Bacteroides spp.) Ref: Opal and Medeiros, 2005

9.  Outer Membrane Permeability Porin protein (ex. OmpF) suppression – cephalosporin resistance P. aeruginosa resistance is partly attributed to the loss of a specific entry protein – D2 porin Alterations of proteins – resistance to quinolones in S. marcescens and P. aeruginosa  Inner Membrane Permeability Pseudomonas mutants have been found to be deficient in certain cytochromes Ref: Opal and Medeiros, 2005

10.   -lactams P. aeruginosa has multidrug efflux pumps that protect microbe from  -lactam agents  Macrolides Some strains of S. pneumoniae (mef – macrolide efflux), S. pyogenes, S. aureus (msr), and S. epidermidis have active efflux mechanisms for macrolide resistance Ref: Opal and Medeiros, 2005

11.  Tetracyclines Some strains of E. coli, Shigella, and other Enteric microbes (ex: tet A, and tet B)  Fluoroquinolones Active efflux detected in enteric bacteria and staph May be related to a multiple antibiotic resistance transporter (norA) or specific quinolone efflux pump (EmrAB, AcrAB) Ref: Opal and Medeiros, 2005

12.   -lactams Alteration of penicillin binding proteins (PBP) Either change in the amount or decrease in affinity  Macrolides/Licosamides/Streptogramins Primary mechanism of resistance for gram- positives and gram-negatives MLS B – determinant methylase enzymes methylate the ribosome Ref: Opal and Medeiros, 2005

13.  Tetracyclines H. pylori possess a mutation in 16S ribosomal RNA that limits binding  Fluoroquinolones Alterations in DNA gyrase in P. aeruginosa and Enterobacteriaceae  Glycopeptides Alteration of D-ala-D-ala (termini of peptiodoglycan precursors) Both inducible and constitutive in S. aureus and Enterococcus -- class A-G ( vanA, vanB, etc) Ref: Opal and Medeiros, 2005

14.  Tetracyclines Interferes with ability to bind to ribosome tetM gene generates protein that stabilizes ribosome during transfer activities in presence of tetracycline  Fluoroquinolones Newly recognized mechanism that protects DNA gyrase from binding to FQ Ref: Opal and Medeiros, 2005

16. There’s a problem with resistance to antibiotics?  ESKAPE (E. faecium, S. aureus, K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter sp.)  MRSA/VISA aka GISA/VRSA  VRE  Multidrug-resistant S. pneumoniae  XDR-TB – resistant to INH & RIF + FQ & at least 1 of 3 second line drugs (capreomycin, kanamycin, or amikacin)

17.  MRSA  hVISA MIC 2-4 mcg/mL Questionable use of Vancomycin in MIC ≥2 Winnebago has increasing numbers of hVISA (~35%)  VISA aka GISA MIC 8-16 mcg/mL (some consider 4-8 mcg/mL)  VRSA >16 mcg/mL (some suggest >32 mcg/mL) Ref: http://cooper.imb.uq.edu.au/community_background.html

18. There’s a problem with resistance to antibiotics?  Extended-spectrum  -lactamase- producing and carbapenemase- producing Enterobacteriaceae  NDM-1 Enterobacteriaceae  Clostridum difficile NAP1 strain (resistant to fluoroquinolones – noted to produce several-fold more toxin in vitro) Ref.: Warny et al., 2005.

19. Public Health Problem  CDI associated with ABX use  Can be spread via fomites *to other patients not on ABX  Antimicrobials are the only medication misuse affects multiple people Ref.: Internet site: http://www.fitsnews.com/2008/12/10/heres-our-surprised-face/, accessed 3/31/12

20. Public Health Problem  Decreasing development of new antimicrobials Slow development due to difficult regulatory environment compared w/ more profitable markets Predicted in 2004 w/ est. of IDSA’s Antibiotic Availability Task force & the “Bad Bugs, No Drugs” document CDC & European Medicines Agency noted that the last new class of drugs active against gram- negative bacilli was trimethoprim the1970’s Ref.: Spellburg, et al, 2008.; Tabot, et al, 2006; ECDC/EMEA report

22.  Slow development of microorganism resistance  Optimize medication selection, dose, and duration  Reduce adverse events  Lower rates of morbidity/mortality  Reduce hospital stay  Drive down spending/cost Septimus & Owens, 2001

23.  ID pharmacist participation: Higher rates of appropriate use Higher cure rates Lower incidence of treatment failures Improved clinical and economic outcomes Decreased mortality and decreased adverse events Septimus & Owens, 2001

24.  Core strategies: Prospective audit with direct intervention and feedback Formulary restriction and preauthorization requirements Rapp et al, accessed 4/5/12

25.  Supplemental Elements: Education Evidence-based guidelines and clinical pathways Antimicrobial cycling (not routinely recommended in IDSA/SHEA guidelines) Antimicrobial order forms Combination therapy (not routinely recommended in IDSA/SHEA guidelines) Rapp et al, accessed 4/5/12

26.  Supplemental Elements cont.: Streamlining or de-escalation of therapy Dose optimization Parenteral to oral conversion  Computer programs are available to help monitor  Antimicrobial conservation Shortening treatment length (CAP, UTI) Rapp et al, accessed 4/5/12; MacDougall & Polk, 2005

27. Questions? Ref: http://madmikesamerica.com/2011/04/world-health-organization-europe-losing-battle-with-superbugs/

28.  LT Laura Botkins, Pharmacy Resident  Dr. Susan Porter, Deputy COP  Dr. Ahmed Mohammed, Physician  Ms. Verna Spotted Wood, I.C. RN  Ms. Patty Collisen, Lab Director

29. Contact Information  LCDR Gildow Email: jeffrey.gildow@ihs.gov Phone: 402-878-2231 ext. 2040 Cellular: 402-719-4280

30. References 1. European Centre for Disease prevention and Control, European Medicines Agency. ECDC/EMEA Joint Technical Report: the bacterial challenge: time to react. Available at: http://www.ecdc.europa.eu/en/publications/Publications/Forms/ECDC_DispForm.aspx?ID=4 44. Accessed 5 Apr 2012. 2. MacDougal C and Polk R. Antimicrobial Stewardship Programs in Health Care Systems. Clinical Microbiology Review. 2005;18:638-656. 3. Opal S and Medeiros. Molecular mechanisms of antibiotic resistance in bacteria. Ch. 17 in Principals and Practice of Infectious Diseases. Vol 1. 6 th ed. Editors Mandel, Bennett, and Dolin. Elsevier, Philadelphia, 2005. 4. Penicillin finder assays its future. New York Times. 26 June 1945:21. 5. Rapp R, Kaye J, Canon S, Hermsen E, DePestel D. A Hospital Pharmacist’s Guide to Antimicrobial Stewardship Programs. Available at: http://www.ashpadvantage.com/docs/stewardship-white-paper.pdf. Accessed: 5 April 2012. 6. Spellburg G, Guidos R, Gilbert D, et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community fro the IDSA. Clin Infect Dis 2008; 46:155-64. 7. Septimus E and Owens R. Need and potential of antimicrobial stewardship in community hospitals. Clinical Infectious Diseases 2011;53(S1):S8-S14. 8. Talbot GH, Bradley J, Edwards JE Rj, Gilbert D, Scheld M, Barlett JG. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the IDSA. Clin Infect Dis 2006; 42:657-68. 9. Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in north America and Europe. Lancet 2005; 366:1079-84.