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Antimicrobial Resistance Where Do We Stand? Hannah R Palmer, PharmD, BCPS Infectious Diseases Clinical Coordinator St. Luke’s Episcopal Hospital Houston,

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Presentation on theme: "Antimicrobial Resistance Where Do We Stand? Hannah R Palmer, PharmD, BCPS Infectious Diseases Clinical Coordinator St. Luke’s Episcopal Hospital Houston,"— Presentation transcript:

1 Antimicrobial Resistance Where Do We Stand? Hannah R Palmer, PharmD, BCPS Infectious Diseases Clinical Coordinator St. Luke’s Episcopal Hospital Houston, TX

2 I have no conflicts of interest in relation to this program Disclosures

3 Objectives  Become familiar with current challenges in infectious diseases pharmacotherapy  Become familiar with the changing trends in resistance rates to antimicrobials  Understand the goals of antimicrobial stewardship programs  Understand the role pharmacists can play in optimizing the use of antimicrobials


5 Significance of infectious diseases #1 cause of mortality worldwide –26% of worldwide mortality in 2003 $120 billion spent annually in the U.S. on infectious diseases medical care 3 rd most common reason for US hospital admissions

6 Mortality due to infectious diseases

7 Defining Antimicrobial Resistance Acquired ability of a pathogen to withstand an antibiotic that kills off its sensitive counterparts Arises from –Random mutations –Horizontal gene transfer –Exposure to antibiotics –Replication

8 “The struggle against antibiotic resistance is a war we will never win. The strength of trillions upon trillions of microorganisms, combined with the ancient force of evolution by constant, unrelenting variation, will inevitably overpower our drugs” - American Academy of Microbiology


10 Challenges Hospital –50 – 75% of patients who present to the ER receive antimicrobials Up to 99% of these may be inappropriate –St. Luke’s: 71% of patients admitted > 48hrs receive antibiotics (2008) Lack of new antibiotics in the pipeline Am J Med 2006;119:S53-61 JAMA 1997;278:875 Br Med J 1997:315:1211 Arch Intern Med 2003;163:601

11 Number of new antibiotics approved by the FDA Clin Infect Dis 2009; 48:1–12

12 Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumanii Pseudomonas aeruginosa Enterobacter spp. Clin Infect Dis 2009; 48:1–12

13 Challenges Community –75% of pts with ARTIs receive antibiotics Only 1/5 th may require therapy –Over 38 million prescriptions annually for ARTIs alone 12 million of these unnecessary Increasing resistance with most commonly prescribed antibiotics to most common pathogens Am J Med 2006;119:S53-61 JAMA 1997;278:875 Br Med J 1997:315:1211 Arch Intern Med 2003;163:601

14 Challenges

15 Grijalva cg, et al JAMA 2009;302(7):758 Antibiotic prescriptions during ARTI visits

16 Grijalva cg, et al JAMA 2009;302(7):758 Antibiotic Prescription Rates for Acute Respiratory Tract Infections in US Ambulatory Settings

17 Prescribing habits for acute otitis media among children: 1998 - 2004 Coco AS. BMC Pediatr. 2009 Jun 24;9:41 Broad spectrum Amoxicillin/clavulanate Macrolides Cephalosporins Quinolones

18 Changing Habits: Antibiotic Prescriptions during ARTI visits Grijalva cg, et al JAMA 2009;302(7):758 ↑ 620%! ↑ 540%!

19 Resistance to respiratory tract bacteria in respect to previous antibiotic prescribing BMJ 2010;340:2096

20 Streptococcus pneumoniae Resistance Rates of high-level penicillin resistance (MIC 2 mg/mL): 1986–2001 respiratory tract–infection seasons Karchmer AW. Clin Infect Dis 2004; 39:S142–50

21 Influence of penicillin resistance Karchmer AW. Clin Infect Dis 2004; 39:S142–50

22 Levofloxacin for CAP Remains Level I recommendation –Evidence from well-conducted, randomized controlled trials –Should be used with caution when Pseudomonas aeruginosa a concern ↑ hospital resistance (SLEH ICUs – 56% resistant) Resistance –S. pneumoniae Increases with PCN resistance –H. influenzae – remains rare –Atypical bacteria – rare Moxifloxacin resistance - lower? –In one study*, 13.3% levo R vs. 8.9% moxi Mandell LA et al. Clin Infect Dis 2007;44:S27 *Ho PL, et al. JAC. 2001;48:659

23 Levofloxacin use and outpatient E. coli UTI resistance versus time Johnson L, et al. Am J Med 2008;121:876

24 Urinary isolates in the ED – St. Luke’s E.coli (n=123) Enterococcus (n=71) Klebsiella (n=30) Pseudomonas (n=17) Proteus (n=16) Ampicillin80 (65%)11 (15%)NA Levofloxacin47 (38%)NA6 (20%)13 (76%)5 (31%) Ciprofloxacin47 (38%)NA 6 (20%)13 (76%)7 (44%) Cotrimoxazole46 (37%)NA 5 (17%)NA 8 (50%) Nitrofurantoin12 (10%)9 (13%)23 (77%)NA 16 (100%) Covey R, et al. 2009, Unpublished data Over half of these patients required follow up with an intervention, switching the original antibiotic prescribed

25 Clin Infect Dis 2010; 51(3):280–285 Correlation of levofloxacin resistance and alternative agents among E. coli UTIs

26 Fosfomycin: The Not-So-New, New Kid on the Block Phosphonic acid derivative FDA approved in 1996 for uncomplicated UTIs Only available as oral sachet in U.S. –Available in IV formulation in Europe Retains excellent activity against urinary pathogens (so far) even among MDR pathogens Use is increasing! Monurol (fosfomycin) Package Insert [2007]. Forest Pharmaceuticals, St. Louis, MO

27 Fosfomycin (Monurol) Class Phosphonic acid inhibitor; bactericidal Activity Most aerobic Gram-positive, Gram-negative pathogens Penetration Excellent into kidneys/bladder/urine C max urine > 1000  g/mL (>128  g/mL at 48hrs) Side effects GI – diarrhea (~10%), nausea (~5%) Availability Oral 3g sachet (US) Dose 3g sachet x 1 – uncomplicated UTIs 3g sachet qod x 3 doses – MDR urinary pathogens Cost $50/sachet Drug Interactions Metoclopramide (↓ fosfomycin concentrations) Int J Antimicrob Agents 2009;34:206-515 Monurol (fosfomycin) Package Insert [2007]. Forest Pharmaceuticals, St. Louis, MO

28 Fofsomycin versus Comparators Comparative agentStudy populationOutcome Amoxicillin Chemotherapy 1990aa; 36:19 single doses of fosfo and amox Eradication, recurrence, re- infection no difference; persistence less in F group Amox-clav Chemotherapy 1990; 36:24-26 single dose of fosfo, mult doses amox/clav No difference in efficacy nor side effects Nitrofurantoin Infection 1990; 18:S94-S97 Pharm World Sci 1993; 15:257 Clin Ther 1999; 21(11):1864-1872 Single dose fosfo vs. 7d nitro at multiple different (RCT) No differences in efficacy; higher relapse in nitro group Oflox/norflox Chemotherapy 1990; 36:46-49 Infection 1990b; 18:S70-S76 Single dose fosfo vs. differing doses FQs No difference in efficacy; higher rate of SEs in F group TMP-SMX Infection 1990; 18:S70-S76 Single dose fosfo vs. differing doses/days No differences in efficacy; diarrhea higher in F group

29 St. Luke’s ED isolates – fosfomycin susceptibility Pathogen (n)No. of pathogens% susceptible E. coli24100 Enterococcus spp.978 (2 VRE INT) Staphylococcus spp4100 Klebsiella pneumoniae3100 Proteus spp.2100 Streptococcus spp2100 Enterobacter cloaecae1100 Citrobacter koseri1100 Pseudomonas aeruginosa1100 Morganella spp.10 Chabria et al. 2010, Unpublished data

30 What’s new with the flu?

31 New CDC recommendations: Antivirals Confirmed or suspected influenza PLUS Severe, complicated, or progressive illness AND/OR Require hospitalization AND/OR Outpatients with underlying medical conditions AND/OR No known risk factors for severe illness if treatment can be initiated within 48 hours of illness onset AND/OR Based on clinical judgment

32 Antiviral Resistance Adamantadines Agents –Amantadine (Symmetrel, generic) –Rimantidine (Flumadine, generic) Resistance –Influenza B inherently resistant –Influenza A resistance 1995 – 0.8% 2004 – 12.3% 2005 – 96 % **No longer recommended** J Inf Dis 2007; 196: 249-57

33 Antiviral resistance Neuraminidase inhibitors Available agents –Oseltamivir (Tamiflu) – oral only –Zanamavir (Relenza) – inhaler only –Peramivir (Phase III studies) – IV Oseltamivir resistance –H274Y mutation seen in 2010 seasonal H1N1 and avian H5N1 viruses –Through June 2010, 300 oseltamivir-resistant novel H1N1 viruses detected worldwide Remain drugs of choice for Influenza J Inf Dis 2007; 196: 249-57

34 Clostridium-difficile associated diarrhea Arch Surg 2007;142:624-631 NAP1/ribotype 027

35 Clostridium-difficile associated disease treatment timeline 1935 C.dif described 1980 PO Vancomycin FDA approved for CDAD Prospective, randomized trial: metro vs. vanc New epidemic strain of C. dif described (NAP1/027) SHEA CDAD position paper published New IDSA/SHEA guidelines 2010 1995 2000 1983 2007 First randomized, prospective, double- blinded, placebo-controlled trial comparing vancomycin and metronidazole

36 A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile-Associated Diarrhea, Stratified by Disease Severity Fred A. Zar, Srinivasa R. Bakkanagari, K.M. L. S. T. Moorthi, and Melinda B. Davis University of Illinois at Chicago, Chicago, and Saint Francis Hospital, Evanston, Illinois Severe CDAD: > 2 points 1 point2 points Age > 60 yearsICU T max > 38.3°C albumin < 2.5 mg/dL WBC > 15,000 cells/mm 3 Endoscopic evidence of pseudomembraneous colitis C. difficile-associated diarrhea Clin Infec Dis 2007;45:302-7

37 .006 Clin Infec Dis 2007;45:302-7 Rate of cure by disease severity and treatment

38 Changing paradigm in C. difficile St. Luke’s – specific data 82 Evaluable patients with 1 st or 2 nd episode of C. diff – Post-implementation 144 Evaluable patients with 1 st or 2 nd episode – Pre-implementation metronidazole 77 (91%) vancomycin 8 (9%) metronidazole 51 (86%) vancomycin 8 (14%) Mild-moderate disease 85 (59%) Severe Disease 59 (41%) metronidazole 30 (64%) vancomycin 17 (36%) metronidazole 7 (20%) vancomycin 28 (80%) Mild-moderate disease 47 (57%) Severe Disease 35 (43%)

39 Appropriate & Adequate Initial Antimicrobial Treatment Avoid unnecessary Antimicrobial Use Antibiotic Use: A balancing act ↓ mortality ↓ drug resistance

40 Antimicrobial Stewardship Limit inappropriate use of antimicrobials Optimize selection, dose, route, and duration of antimicrobial therapy to maximize clinical cure or prevention of infection Limit emergence of resistance, adverse drug events, and cost

41 Antimicrobial Stewardship Programs (ASPs) Collaboration of a multi-disciplinary team –ID physician –Clinical pharmacist** –Clinical microbiologist –Information system specialist –Infection control professional/epidemiologist –Support from hospital administration St. Luke’s – Center for Antimicrobial Stewardship and Epidemiology (CASE)

42 Medical Executive Committee Quality of Care Committee Pharmacy, Nutrition, and Therapeutics Committee CASE Advisory Board CAS Medical Director Infectious Disease Pharmacists Infection Control Practitioner Clinical Microbiologist Nursing Information Management Medical Staff Members from, but not limited to: Infectious Disease Internal Medicine Emergency Medicine General Surgery Cardiovascular Surgery Orthopedics Pathology CASE Team Infectious Disease Pharmacists Infectious Disease Physician Pharmacy ID Fellow Dir. Infection Control CASE Research Collaborative St. Luke’s UH College of Pharmacy CASE Medical Director What can we do?

43 CASE initiatives Bug-drug mismatch lists –Bug-drug –Gram-positive Gram negative –Daptomycin-linezolid Sterile site list review Daptomycin policy Clostridium-difficile treatment policy Pharmacokinetic service/consults 24-hour pager

44 Medical Staff Education Prospective audit of antimicrobial use with feedback Antimicrobial Restrictions and Controls Antimicrobial Support Teams Pharmacokinetics/pharmacodynamics Therapeutic Substitutions Dose/drug optimization Automatic Stop Orders Antibiotic Order Forms Cost savings Interventional Pharmacists Reduction of Pharmaceutical Promotion? Rotational or Cyclic Antimicrobial Use? Promotion of Combination Therapy? Etc ASP opportunities

45 How ASPs can alter prescribing habits Antibiotics for HAP Hanzelka K, et al. Ann Pharmacother (submitted)

46 Impact of an ASP on Sepsis PrePostp value Adequacy of empiric antibiotics 68%85%< 0.05 28-day mortality32%24%NS Chest 2006;130:787-93

47 Impact on outcomes Clin Infect Dis 2001;33:289



50 Antimicrobial Resistance Where Do We Stand? Hannah R Palmer, PharmD, BCPS Infectious Diseases Clinical Coordinator St. Luke’s Episcopal Hospital Houston, TX

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