Antimicrobial Resistance Where Do We Stand?

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Antimicrobial ResistanceWhere Do We Stand?

• Hannah R Palmer, PharmD, BCPS
• Infectious Diseases Clinical Coordinator
• St. Lukes Episcopal Hospital
• Houston, TX

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

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• http//www.youtube.com/watch?vQKaTlqOQTnw

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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
• 3rd most common reason for US hospital admissions

www.nih.gov www.who.gov
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Mortality due to infectious diseases
www.cdc.gov
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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

www.cdc.gov
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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
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Challenges

• Hospital
• 50 75 of patients who present to the ER
  receive antimicrobials
• Up to 99 of these may be inappropriate
• St. Lukes 71 of patients admitted gt 48hrs
  receive antibiotics (2008)
• Lack of new antibiotics in the pipeline

Am J Med 2006119S53-61 JAMA 1997278875 Br Med
J 19973151211 Arch Intern Med 2003163601
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Number of new antibiotics approved by the FDA
Clin Infect Dis 2009 48112
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• Enterococcus faecium
• Staphylococcus aureus
• Klebsiella pneumoniae
• Acinetobacter baumanii
• Pseudomonas aeruginosa
• Enterobacter spp.

Clin Infect Dis 2009 48112
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Challenges

• Community
• 75 of pts with ARTIs receive antibiotics
• Only 1/5th 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 2006119S53-61 JAMA 1997278875 Br Med
J 19973151211 Arch Intern Med 2003163601
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Challenges
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Antibiotic prescriptions during ARTI visits
Grijalva cg, et al JAMA 2009302(7)758
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Antibiotic Prescription Rates for Acute
Respiratory Tract Infections in US Ambulatory
Settings
Grijalva cg, et al JAMA 2009302(7)758
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Prescribing habits for acute otitis media among
children 1998 - 2004
Broad spectrum Amoxicillin/clavulanate Macrolides
Cephalosporins Quinolones
Coco AS. BMC Pediatr. 2009 Jun 24941
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Changing Habits Antibiotic Prescriptions during
ARTI visits
? 620!
? 540!
Grijalva cg, et al JAMA 2009302(7)758
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Resistance to respiratory tract bacteria in
respect to previous antibiotic prescribing
BMJ 20103402096
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Streptococcus pneumoniae Resistance
Rates of high-level penicillin resistance (MIC 2
mg/mL) 19862001 respiratory tractinfection
seasons
Karchmer AW. Clin Infect Dis 2004 39S14250
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Influence of penicillin resistance
Karchmer AW. Clin Infect Dis 2004 39S14250
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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 200744S27 Ho
PL, et al. JAC. 200148659
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Levofloxacin use and outpatient E. coli UTI
resistance versus time
Johnson L, et al. Am J Med 2008121876
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Urinary isolates in the ED St. Lukes
  E.coli (n123) Enterococcus (n71) Klebsiella (n30) Pseudomonas (n17) Proteus (n16)
Ampicillin 80 (65) 11 (15) NA NA NA
Levofloxacin 47 (38) NA 6 (20) 13 (76) 5 (31)
Ciprofloxacin 47 (38) NA  6 (20) 13 (76) 7 (44)
Cotrimoxazole 46 (37) NA  5 (17) NA  8 (50)
Nitrofurantoin 12 (10) 9 (13) 23 (77) NA  16 (100)
Over half of these patients required follow up
with an intervention, switching the original
antibiotic prescribed
Covey R, et al. 2009, Unpublished data
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Correlation of levofloxacin resistance and
alternative agents among E. coli UTIs
Clin Infect Dis 2010 51(3)280285
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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
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Fosfomycin (Monurol)
Class Phosphonic acid inhibitor bactericidal
Activity Most aerobic Gram-positive, Gram-negative pathogens
Penetration Excellent into kidneys/bladder/urine Cmax urine gt 1000 mg/mL (gt128 mg/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 200934206-515 Monurol
(fosfomycin) Package Insert 2007. Forest
Pharmaceuticals, St. Louis, MO
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Fofsomycin versus Comparators
Comparative agent Study population Outcome
Amoxicillin Chemotherapy 1990aa 3619 single doses of fosfo and amox Eradication, recurrence, re-infection no difference persistence less in F group
Amox-clav Chemotherapy 1990 3624-26 single dose of fosfo, mult doses amox/clav No difference in efficacy nor side effects
Nitrofurantoin Infection 1990 18S94-S97 Pharm World Sci 1993 15257 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 3646-49 Infection 1990b 18S70-S76 Single dose fosfo vs. differing doses FQs No difference in efficacy higher rate of SEs in F group
TMP-SMX Infection 1990 18S70-S76 Single dose fosfo vs. differing doses/days No differences in efficacy diarrhea higher in F group
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St. Lukes ED isolates fosfomycin susceptibility
Pathogen (n) No. of pathogens susceptible
E. coli 24 100
Enterococcus spp. 9 78 (2 VRE INT)
Staphylococcus spp 4 100
Klebsiella pneumoniae 3 100
Proteus spp. 2 100
Streptococcus spp 2 100
Enterobacter cloaecae 1 100
Citrobacter koseri 1 100
Pseudomonas aeruginosa 1 100
Morganella spp. 1 0
Chabria et al. 2010, Unpublished data
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Whats new with the flu?
hwww.cdc.gov/flu/weekly/
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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

www.cdc.gov
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Antiviral ResistanceAdamantadines

• 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

www.cdc.gov J Inf Dis 2007 196 249-57
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Antiviral resistanceNeuraminidase 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

www.cdc.gov J Inf Dis 2007 196 249-57
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Clostridium-difficile associated diarrhea
NAP1/ribotype 027
Arch Surg 2007142624-631
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Clostridium-difficile associated disease
treatment timeline
New epidemic strain of C. dif described
(NAP1/027)
SHEA CDAD position paper published
Prospective, randomized trial metro vs. vanc
PO Vancomycin FDA approved for CDAD
New IDSA/SHEA guidelines
C.dif described
1935
1980
2010
1995
1983
2000
2007
First randomized, prospective, double-blinded,
placebo-controlled trial comparing vancomycin and
metronidazole
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C. difficile-associated diarrhea
A Comparison of Vancomycin and Metronidazole for
the Treatment of Clostridium difficile-Associated
Diarrhea, Stratified by Disease SeverityFred A.
Zar, Srinivasa R. Bakkanagari, K.M. L. S. T.
Moorthi, and Melinda B. DavisUniversity of
Illinois at Chicago, Chicago, and Saint Francis
Hospital, Evanston, Illinois
Severe CDAD gt 2 points Severe CDAD gt 2 points
1 point 2 points
Age gt 60 years ICU
Tmax gt 38.3C albumin lt 2.5 mg/dL WBC gt 15,000 cells/mm3 Endoscopic evidence of pseudomembraneous colitis
Clin Infec Dis 200745302-7
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Rate of cure by disease severity and treatment
.006
Clin Infec Dis 200745302-7
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Changing paradigm in C. difficile St. Lukes
specific data
144 Evaluable patients with 1st or 2nd episode
Pre-implementation
Mild-moderate disease 85 (59)
Severe Disease 59 (41)
metronidazole 77 (91)
vancomycin 8 (9)
metronidazole 51 (86)
vancomycin 8 (14)
82 Evaluable patients with 1st or 2nd episode of
C. diff Post-implementation
Mild-moderate disease 47 (57)
Severe Disease 35 (43)
metronidazole 30 (64)
vancomycin 17 (36)
metronidazole 7 (20)
vancomycin 28 (80)
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Antibiotic Use A balancing act
Avoid unnecessary Antimicrobial Use
Appropriate Adequate Initial Antimicrobial
Treatment
? mortality
? drug resistance
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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

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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. Lukes Center for Antimicrobial Stewardship
  and Epidemiology (CASE)

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What can we do?
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 Infor
mation Management Medical Staff Members from, but
not limited to Infectious Disease Internal
Medicine Emergency Medicine General
Surgery Cardiovascular Surgery Orthopedics Patholo
gy
CASE Team Infectious Disease Pharmacists Infectiou
s Disease Physician Pharmacy ID Fellow Dir.
Infection Control
CASE Research Collaborative St. Lukes UH College
of Pharmacy
CASE Medical Director
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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

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ASP opportunities

• 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

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How ASPs can alter prescribing habitsAntibiotics
for HAP
Hanzelka K, et al. Ann Pharmacother (submitted)
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Impact of an ASP on Sepsis
Pre Post p value
Adequacy of empiric antibiotics 68 85 lt 0.05
28-day mortality 32 24 NS
Chest 2006130787-93
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Impact on outcomes
Clin Infect Dis 200133289
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www.IDsociety.org
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Antimicrobial ResistanceWhere Do We Stand?

• Hannah R Palmer, PharmD, BCPS
• Infectious Diseases Clinical Coordinator
• St. Lukes Episcopal Hospital
• Houston, TX