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

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Presentation on theme: "Presented by: LCDR Jeffrey S. Gildow, Pharm.D., M.S., EMT-B Infectious Diseases Pharmacist Provider Indian Health Service: Winnebago Service Unit Winnebago,"— Presentation transcript:

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:

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:, 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:

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: 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: 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: 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.


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