Transcript Antimicrobial Resistance Where Do We Stand?

Antimicrobial Resistance
Where Do We Stand?
Hannah R Palmer, PharmD, BCPS
Infectious Diseases Clinical Coordinator
St. Luke’s Episcopal Hospital
Houston, TX
Disclosures
I have no conflicts of interest in relation to this program
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
http://www.youtube.com/watch?v=QKaTlqOQTnw
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
Mortality due to infectious diseases
www.cdc.gov
Defining Antimicrobial Resistance
• Acquired ability of a pathogen to withstand an
antibiotic that kills off its sensitive counterparts
• Arises from
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www.cdc.gov
Random mutations
Horizontal gene transfer
Exposure to antibiotics
Replication
“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
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
Number of new antibiotics approved
by the FDA
Clin Infect Dis 2009; 48:1–12
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Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumanii
Pseudomonas aeruginosa
Enterobacter spp.
Clin Infect Dis 2009; 48:1–12
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 2006;119:S53-61
JAMA 1997;278:875
Br Med J 1997:315:1211
Arch Intern Med 2003;163:601
Challenges
Antibiotic prescriptions during ARTI visits
Grijalva cg, et al JAMA 2009;302(7):758
Antibiotic Prescription Rates for Acute
Respiratory Tract Infections in US Ambulatory
Settings
Grijalva cg, et al JAMA 2009;302(7):758
Prescribing habits for acute otitis media among
children: 1998 - 2004
Broad spectrum
Amoxicillin/clavulanate
Macrolides
Cephalosporins
Quinolones
Coco AS. BMC Pediatr. 2009 Jun 24;9:41
Changing Habits: Antibiotic
Prescriptions during ARTI visits
1995-1996
2005-2006
70
60
↑ 620%!
50
40
↑ 540%!
30
20
10
Grijalva cg, et al JAMA 2009;302(7):758
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Resistance to respiratory tract bacteria in
respect to previous antibiotic prescribing
BMJ 2010;340:2096
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
Influence of penicillin resistance
Karchmer AW. Clin Infect Dis 2004; 39:S142–50
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
Levofloxacin use and outpatient E. coli UTI resistance
versus time
Johnson L, et al. Am J Med 2008;121:876
Urinary isolates in the ED – St. Luke’s
E.coli
(n=123)
Enterococcus
(n=71)
Klebsiella
(n=30)
Pseudomonas
(n=17)
Proteus
(n=16)
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
Correlation of levofloxacin resistance and
alternative agents among E. coli UTIs
Clin Infect Dis 2010; 51(3):280–285
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
Fosfomycin (Monurol)
Class
Phosphonic acid inhibitor; bactericidal
Activity
Most aerobic Gram-positive, Gram-negative pathogens
Penetration
Excellent into kidneys/bladder/urine
Cmax urine > 1000 mg/mL (>128 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 2009;34:206-515
Monurol (fosfomycin) Package Insert [2007]. Forest Pharmaceuticals, St. Louis, MO
Fofsomycin versus Comparators
Comparative agent
Study population
Outcome
Amoxicillin
single doses of fosfo and
amox
Eradication, recurrence, reinfection no difference;
persistence less in F group
single dose of fosfo, mult
doses amox/clav
No difference in efficacy
nor side effects
Single dose fosfo vs. 7d
nitro at multiple different
(RCT)
No differences in efficacy;
higher relapse in nitro
group
Single dose fosfo vs.
differing doses FQs
No difference in efficacy;
higher rate of SEs in F
group
Single dose fosfo vs.
differing doses/days
No differences in efficacy;
diarrhea higher in F group
Chemotherapy 1990aa; 36:19
Amox-clav
Chemotherapy 1990; 36:24-26
Nitrofurantoin
Infection 1990; 18:S94-S97
Pharm World Sci 1993; 15:257
Clin Ther 1999; 21(11):1864-1872
Oflox/norflox
Chemotherapy 1990; 36:46-49
Infection 1990b; 18:S70-S76
TMP-SMX
Infection 1990; 18:S70-S76
St. Luke’s 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
What’s new with the flu?
hwww.cdc.gov/flu/weekly/
New CDC recommendations: Antivirals
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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
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**
www.cdc.gov
J Inf Dis 2007; 196: 249-57
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
www.cdc.gov
J Inf Dis 2007; 196: 249-57
Clostridium-difficile associated diarrhea
NAP1/ribotype 027
Arch Surg 2007;142:624-631
Clostridium-difficile associated
disease treatment timeline
1935
1980
1983
1995
2000
2010
2007
First randomized, prospective, doubleblinded, placebo-controlled trial
comparing vancomycin and metronidazole
C. difficile-associated diarrhea
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 point
2 points
Age > 60 years
ICU
Tmax > 38.3°C
albumin < 2.5 mg/dL
WBC > 15,000 cells/mm3
Endoscopic evidence of
pseudomembraneous colitis
Clin Infec Dis 2007;45:302-7
Rate of cure by disease severity and treatment
.006
Clin Infec Dis 2007;45:302-7
Changing paradigm in C. difficile
St. Luke’s – specific data
144 Evaluable patients
with 1st or 2nd episode –
Pre-implementation
Mild-moderate disease
85 (59%)
metronidazole
77 (91%)
vancomycin
8 (9%)
Severe Disease
59 (41%)
metronidazole
51 (86%)
vancomycin
8 (14%)
82 Evaluable patients with
1st or 2nd episode of C. diff –
Post-implementation
Mild-moderate disease
47 (57%)
metronidazole
30 (64%)
vancomycin
17 (36%)
Severe Disease
35 (43%)
metronidazole
7 (20%)
vancomycin
28 (80%)
Antibiotic Use: A balancing act
Appropriate & Adequate Initial
Antimicrobial Treatment
↓ mortality
Avoid unnecessary
Antimicrobial Use
↓ drug resistance
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
Antimicrobial Stewardship
Programs (ASPs)
• Collaboration of a multi-disciplinary team
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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)
What can we do?
Quality of Care
Committee
Medical
Executive
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 Research
Collaborative
St. Luke’s
UH College of
Pharmacy
CASE
Medical
Director
CASE Team
Infectious Disease
Pharmacists
Infectious Disease
Physician
Pharmacy ID
Fellow
Dir. Infection
Control
CASE initiatives
• Bug-drug mismatch lists
– Bug-drug
– Gram-positive Gram negative
– Daptomycin-linezolid
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Sterile site list review
Daptomycin policy
Clostridium-difficile treatment policy
Pharmacokinetic service/consults
24-hour pager
ASP opportunities
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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
How ASPs can alter prescribing habits
Antibiotics for HAP
70
Pre
Post
60
50
40
30
20
10
0
Fluoroquinolone
Hanzelka K, et al. Ann Pharmacother (submitted)
Aminoglycoside
Zosyn+Cipro+Vanc
Impact of an ASP on Sepsis
Pre
Post
p value
Adequacy of empiric
antibiotics
68%
85%
< 0.05
28-day mortality
32%
24%
NS
Chest 2006;130:787-93
Impact on outcomes
Clin Infect Dis 2001;33:289
www.IDsociety.org
Antimicrobial Resistance
Where Do We Stand?
Hannah R Palmer, PharmD, BCPS
Infectious Diseases Clinical Coordinator
St. Luke’s Episcopal Hospital
Houston, TX