Antimicrobial Stewardship:
Response to a Global Crisis
Carla Walraven, PharmD, BCPS-AQ ID
University of New Mexico Hospital
Antimicrobial Stewardship Program
Pharmacist Objectives
• Explain the implications of antimicrobial
resistance
• Prepare for the new regulatory standards for
Antimicrobial Stewardship Programs (ASPs)
• Outline strategies employed by ASPs to
improve outcomes
• Identify opportunities to apply Antimicrobial
Stewardship concepts
Pharmacy Technician Objectives
• Identify ways in which antibiotics are misused
• Explain the implications of antimicrobial
resistance
• Recognize the core elements of Antimicrobial
Stewardship Programs
Audience Poll
• A 19 YOM is brought to your ED after an
accident cleaning his homemade shotgun,
resulting in a penetrating eye socket injury
with a metal pipe.
– How many would recommend antibiotics?
– Which antibiotics would you use? (What
pathogens are you concerned about?)
The Curious Case of Phineas Gage
(July 9, 1823 – May 21, 1860)
• In 1848, Phineas Gage was struck by a tamping iron while
working on the railroad
• He survived the accident, but was not the same afterwards
• Died at the age of 36, after a series of seizures
http://www.smithsonianmag.com/history/phineas-gage-neurosciences-most-famous-patient-11390067/?no-ist
Fast Forward to 2016…
• 61 YOM newly diagnosed
AML
• Antibiotic exposure:
– Cetriaxone, clindamycin x
14 days (shin injury)
– Vancomycin (cellulitis)
– Augmentin and
ciprofloxain (prophylaxis)
• Febrile neutropenia 16
days after admission
– Blood cultures grew an
Extended spectrum βlactamase (ESBL) E. coli
ESBL E. coli
MIC
Amikacin
16
Susceptible
Aztreonam
> 16
Resistant
Ciprofloxacin
>2
Resistant
Ceftriaxone
> 32
Resistant
Cefazolin
> 16
Resistant
Ertapenem
>1
Resistant
Gentamicin
>8
Resistant
Meropenem
4
Resistant
Ampicillin/sulbac
> 16/8
Resistant
Piperacillin/tazo
> 64/4
Resistant
Sulfameth/trimeth
> 2/38
Resistant
Going Back to a Pre-Antibiotic Era?
• Antibiotic resistance has
been called one of the
world’s most pressing
public health concerns
• Antibiotic resistance is
associated with increased
lengths of hospital stay,
increased costs, and
increased mortality
https://www.cdc.gov/drugresistance/about.html
“30-50% of antimicrobial use is either
unnecessary or inappropriate.”
Most Common Reasons for Unnecessary Therapy
% of Patients with Unnecessary
DOT
35%
N = 576 DOT
30%
25%
20%
15%
10%
5%
0%
Noninfectious
Tx of
Duration of tx
Syndrome
Colonization or Longer than
Contamination
Necessary
Reimann HA, D’Ambola J. JAMA. 1968;205(7):537.
Hecker MT, et al. Arch Intern Med. 2003;163:972-78.
Redundant
Abx Coverage
Antibiotic Misuse
Antibiotics are given when they are not needed
Antibiotics are continued longer than necessary
Antibiotics are given at the wrong dose
Broad spectrum antibiotics are used to treat
highly susceptible bacteria
• The wrong antibiotic is used to treat an infection
•
•
•
•
http://www.cdc.gov/getsmart/healthcare/evidence.html
Antibiotic Prescribing Trends in US
Hospitals, 2006 - 2012
2006-2012
Baggs J, et al. JAMA Intern Med. doi:10.1001/jamainternmed.2016.5651
Piperacillin/tazobactam – Resistant
Pseudomonas aeruginosa
http://gis.cdc.gov/grasp/PSA/MapView.html, Accessed Aug 2016.
National Action Plan for Combating
Antibiotic-Resistant Bacteria
• 5 Goals
– Slow the emergence and spread of resistant bacteria
• Includes the implementation of antimicrobial stewardship
programs
– Strengthen national surveillance efforts of resistant
bacteria
– Advance development and use of rapid diagnostic
tests
– Accelerate research and development of new
antibiotics, therapeutics, and vaccines
– Improve international collaborations regarding
antimicrobial use and misuse
https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf, Accessed Aug 2016.
What is Antimicrobial Stewardship?
Coordinated program that promotes the appropriate use
of antimicrobials, improves patient outcomes, reduces
microbial resistance, and decreases the spread of
infections caused by multi-drug resistant organisms.
Barlam TF, et al. Clin Infect Dis. 2016; e1-e27.
http://www.apic.org/Professional-Practice/Practice-Resources/Antimicrobial-Stewardship
CDC’s Core Elements for ASPs
 Obtain leadership commitment
• Includes dedicating necessary human, financial and
information technology resources
 Appoint a single leader responsible for program
outcomes
 Appoint a single pharmacist leader responsible for
working to improve antibiotic use
 Obtain support from key stakeholder
•
•
•
•
Infection control and prevention
Information technology
Quality improvement
Clinicians
http://www.ahaphysicianforum.org/resources/appropriate-use/antimicrobial/content%20files%20pdf/CDC%20checklist.pdf
CDC’s Core Elements for ASPs
(cont.)
 Implement policies and interventions to improve
antibiotic use
 Evaluate ongoing treatment need after an initial
treatment period
• E.g. “Antibiotic timeout” after 48 hours
 Monitor antibiotic prescribing and resistance patterns
 Regularly report information on antibiotic use and
resistance to doctors, nurses, and relevant staff
 Educate clinicians about resistance and optimal
prescribing
CMS §482.42(b): Antibiotic Stewardship
Program Organization and Policies
• Effective January 1, 2017
• Demonstrate coordination among all components
of the hospital responsible for antibiotic use and
factors that lead to antimicrobial resistance
• Document the evidence-based use of antibiotics
in all departments and services of the hospital
• Demonstrate improvements, including sustained
improvements in proper antibiotic use
https://s3.amazonaws.com/public-inspection.federalregister.gov/2016-13925.pdf
TJC’s New
Antimicrobial
Stewardship Standard
Effective January 1, 2017
Download available at:
https://www.jointcommission.org
/standards_information/prepublic
ation_standards.aspx
Antimicrobial Stewardship Team
Hospital
Admin
Infection
Control
Microbiology
ASP
Physician
Pharmacist
Infectious
Diseases
Informatics
Pharmacy
ASP Interventions
ASP Activities
• Patient Centered
– Prospective audit and review
– Formulary management
– Identify patients who may
benefit from ID consult
Impact of Interventions
Goal: Decrease or slow
antimicrobial resistance
National
• Institutional
– Antibiograms
– Clinical pathways
– Dose optimization
Institution
Patient
Global
ASP Core Strategies
Core Strategies
Prospective audit with direct
intervention and feedback
Advantages
•
•
•
Formulary restriction and
preauthorization requirements
•
Disadvantages
May reduce inappropriate
antimicrobial use
Educate to modify future
prescribing
Allows prescribers to
maintain autonomy
•
Difficulty identifying
patients with inappropriate
therapy and communicating
with prescribers
May result in immediate
and substantial reduction in
antimicrobial use and costs
•
May increase staffing
requirements
May delay order
implementation with
potential adverse patient
outcomes
May increase use of and
resistance to alternative
antimicrobial agents
Perceived loss of prescriber
autonomy
•
•
•
Dellit et al. Clin Infect Dis. 2007;44:159-77.
Drew et al. Pharmacotherapy. 2009;29:593-607.
ASP Supplemental Strategies
Supplemental Elements
Advantages
Disadvantages
Education
•
May influence prescribing
behavior
•
Marginally effective when
used without active
intervention
Evidence based guidelines and
clinical pathways
•
May improve antimicrobial
use and practice variations
•
Poor adherence
Streamlining or de-escalation
therapy
•
Reduces antimicrobial
exposure, selection of
resistant pathogens, and
health care costs
•
Prescriber reluctance to deescalate when cultures are
negative and clinical
improvement observed
Dose optimization
•
Tailors therapy to patient
characteristics, pathogen,
and PK/PD of antimicrobial
•
Nursing concerns regarding
incompatibilities and
administration
IV to PO conversion
•
May decrease length of
hospital stay and costs
May reduce complications
associated with IV access
•
Difficulty identifying patients
in whom conversion is
appropriate
•
Dellit et al. Clin Infect Dis. 2007;44:159-77.
Drew et al. Pharmacotherapy. 2009;29:593-607.
Implementing Antimicrobial Stewardship
PATIENT CASE
Healthcare-Associated Pneumonia
• 49 YOF with history of severe COPD is admitted
from a skilled nursing facility for respiratory
distress and acute disorientation (per family)
– Increased cough with sputum production over the
past 24h
– No fevers or chills
• Diagnosis: Acute hypoxic respiratory failure due
to healthcare-associated pneumonia
(HCAP)/aspiration with sepsis
HCAP
Physical Exam
• General: Obese female,
respiratory distress,
alert/responsive
• ENT: no nasal discharge
• Respiratory: Bilateral rhonchi,
crackles in right upper &
middle lobes, intermittent
expiratory wheeze
Vitals & Labs
• T 37.6˚C, HR 123, BP
151/73, RR 21, O2 91%
• WBC 24.4
• Lactate 1.8
• No medication allergies
Patient is started empirically on vancomycin and
piperacillin/tazobactam
Antimicrobial Timeout
• As soon as possible, or within 48 hours:
1. Does the patient have an infection that will
respond to antibiotics?
2. If so, is the patient on the right antibiotic(s),
dose, and route of administration?
3. Can a more targeted antibiotic be used to treat
the infection (de-escalate)?
4. How long should the patient receive the
antibiotic(s)?
http://pqc-usa.org/timeout/
Incorporating Culture Results
True Bacteremias
N
TTP at 24 h
TTP at 48 h
TTP at 72 h
Gram positives
MRSA
MSSA
S. pneumonia
E. faecalis
E. faecium
52
41
6
30
19
85%
93%
100%
87%
89%
98%
98%
100%
97%
100%
98%
100%
100%
100%
100%
Gram negatives
E. coli
Klebsiella spp.
Pseudomonas spp.
Acinetobacter spp.
161
62
30
22
8
88%
97%
97%
82%
100%
98%
100%
100%
100%
100%
99%
100%
100%
100%
100%
Anaerobic
23
39%
74%
91%
All Contaminants
210
48%
85%
92%
TTP = Time to Positivity
Pardo J, et al. Ann Pharmacother. 2014; 48(1):33-40.
Impact of Prior Antibiotics on
Cultures
Positive by 48 hours
Positive by 72 hours
Off
Antibiotics
On
Antibiotics
P-value
Off
Antibiotics
On
Antibiotics
P-value
Gram positives
(n = 232)
183 / 186
(98%)
44 / 46
(96%)
0.258
183 / 186
(98%)
46 / 46
(100%)
>0.99
Gram negatives
(n = 161)
137 / 139
(99%)
20 / 22
(91%)
0.09
138 / 139
(99%)
21 / 22
(95%)
0.255
Anaerobes
(n = 23)
15 / 19
(79%)
2/4
(50%)
0.270
18 / 19
(95%)
3/4
(75%)
0.324
All episodes
(n = 416)
335 / 344
(97%)
66 / 72
(92%)
0.03
339 / 344
(99%)
70 / 72
(97%)
0.348
Pardo J, et al. Ann Pharmacother. 2014; 48(1):33-40.
Using Surveillance Cultures
• Association between MRSA nasal swab results
and the presence of MRSA pneumonia
– Nasal colonization is a risk factor for infection
– Results within a few hours
MRSA PCR assay
N = 435
Sensitivity
88%
Specificity
90.1%
Positive predictive value
35.4%
Negative predictive value
99.2%
Dangerfield B, et al. Antimicrob Agents Chemother. 2014; 58(2):859-64.
Utility of Negative Culture Results
• Early antibiotic discontinuation with negative cultures
Early Discontinuation
(n = 40)
Late Discontinuation
(n = 49)
P-value
10 (25%)
15 (30.6%)
0.642
4
4
0.523
Signs/symptoms
Abnormal temp
Abnormal WBC
Sputum purulence
15 (48.4%)
20 (69%)
24 (66.7%)
21 (61.8%)
23 (65.7%)
34 (80.9%)
0.324
1.00
0.196
Superinfection
Bacteremia
Respiratory infection
MDR Superinfection
9 (22.5%)
1 (2.5%)
4 (10%)
3 (7.5%)
18 (42.9%)
3 (7.1%)
12 (28.6%)
15 (35.7%)
0.008
0.616
0.036
0.003
Hospital mortality
Clinical Pulmonary
Infection Score, median
Raman K, et al. Crit Care Med. 2013; 41(7): 1656-63.
How Long to Treat?
Comparison of 8 vs. 15 Days
• Antibiotic duration for VAP
– Primary outcome: death, 28
days after VAP onset
• Prospective, randomized
double-blind, clinical trial
– 51 French ICUs
– May 1999 to June 2002
– Adults meeting clinical
criteria for VAP
Chastre J, et al. JAMA. 2003; 290(19):2588-2598.
60-Day VAP Mortality
Stewardship Recommendations
Clinical Status & Culture Results
• T 36.7 ˚C, RR 18, HR 98, BP
128/62, O2 95% on 3L NC
• WBC 18.7
• MRSA nares negative
• Urine S. pneumoniae
antigen negative
• Blood cultures x 2 sets: no
growth
Now What?
• MRSA nares has > 99%
negative predictive value
– Discontinue vancomycin
• Do we need Pseudomonal
coverage?
– Consider de-escalating
piperacillin/tazobactam
– IV to PO if possible
• Duration: 7 days
DO YOU REALLY NEED DEDICATED
STEWARDSHIP PERSONNEL?
Lessons Learned from one ASP
• University of Maryland Medical Center
(UMMC)
• 725 bed medical facility in Baltimore, MD
– 175 ICU beds
– Active cancer, transplant, and trauma centers
• Stewardship program started in 2001 to help
contain increasing drug costs
– Goal: To save 10-20% the cost of antibiotics over a
3-year period
Standiford HC, et al. Infect Control Hosp Epidemiol. 2012: 33(4):338-45.
UMMC ASP Program
ASP Duties
• ID Physician, 0.5 FTE
• ID Pharmacist, 0.8 FTE
• Data Analyst, 0.05 FTE
Disbanded in 2008
Use resources to increase the
number of ID physicians
Standiford HC, et al., Infect Control Hosp Epidemiol. 2012, 33(4):338-45.
Duties
- Identify ineffective or excessive
antibiotic coverage
- Ensure adherence to hospital
policies and guidelines
- Identify opportunities for IV to
PO conversions
- Suggest ID consult in complex
cases
- Review restricted antibiotics
- Review patients not serviced by
the ID physicians (e.g. the
trauma center)
Before, During and After UMMC
ASP
Antimicrobial Costs by Quarter, FY 98 – FY 10
Post-ASP Conclusions
• Despite unchanged quality markers,
antimicrobial costs continued to increase (by
41.2%) in the 2 years after the ASP ended
“…suggesting that more and more costly antibiotics
were being used without an increase in benefit.”
Average Cost Savings:
$500K per year
(2001 – 2008)
Average Cost Increase:
$1 million per year
(2009 – 2010)
Differing ASP Models
•
Evaluation of two Department of Veterans Affairs Hospitals
• Similar range of services available
• ID consultation available at all times
• Inpatient rehabilitation facilities
• Antimicrobial stewardship efforts at both with active ID
physician participation
Dedicated ASP Model
• 312 beds
• Average daily census: 230
• ID pharmacist rounds daily with
the ID team
• 2011 to 2012
Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.
Geographic ASP Model
• 137 beds
• Average daily census: 103
• 4 ward PharmDs round daily with
their respective teams
• 2010 to 2011
Primary Endpoint
• Composite of compliance with the all of the
following:
– Therapy modification within 24 hours of laboratory
data
– Discontinuation of therapy when determined to be
non-bacterial
– Intravenous to oral (IV to PO) conversion when
appropriate
• Policies and guidelines based on the Department
of Veterans Affairs (VA) National Formulary and
VA Pharmacy Benefits Management group
Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.
Antimicrobial Stewardship Activities
Dedicated ASP
Geographic ASP
P-value
37/48 (77.1%)
11/33 (33.3%)
0.0002
Therapy modification based on
laboratory data
143/190 (75.2%)
51/100 (51%)
< 0.0001
Therapy modification within 24
hours of laboratory data
124/143 (86.7%)
37/51 (72.6%)
0.029
IV to PO conversion when
appropriate
97/120 (80.8%)
41/67 (61.2%)
0.0052
All of the above streamlining
activities
165/182 (90.7%)
47/95 (49.5%)
< 0.0001
Discontinuation of therapy
when not bacterial
Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.
Conclusions
• An ASP with a dedicated pharmacist was
associated with better adherence to
stewardship activities
• There was a higher rate of adherence to
stewardship activities even when ID was
consulted
– Benefit of having both ID consult and an ASP with
dedicated personnel
Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.
HOW CAN ONE PHARMACIST
OVERSEE ALL ANTIMICROBIAL USE?
Using Clinical Pathways
• Concise summary of
national guidelines
• Includes local
susceptibility
recommendations
• Contains key
educational points
• Goal is to capture 80%
of patients with a
particular disease state
“…the strength of the Pack is the Wolf, and
the strength of the Wolf is the Pack.”
Mean ± SD Expenditure
Cost Savings†
Baseline
Intervention
Daily
Yearly
Ceftazidime
$115 ± $47
$80 ± $27
$35
$12,775
Imipenem
$299 ± $84
$232 ± $112
$67
$24,455
Levofloxacin
$497 ± $35
$448 ± $31
$49
$17,885
Piperacillin/tazo
$2,110 ± $134
$2,037 ± $11
$73
$26,645
Vancomycin
$1,221 ± $79
$1,008 ± $9
$213
$77,745
†Extrapolated
savings based on cost data during intervention period
• Grady Memorial Hospital in Atlanta, GA
• Prospective audit with intervention and feedback of non-ICU
patients
• Mortality, LOS, and re-admissions were similar for both periods
• Emergence of resistance decreased from 9.5% to 5% (P = 0.06)
DiazGranados CA, et al. Am J Health-Syst Pharm. 2011;68:1691-2.
WE DON’T HAVE ANY INFECTIOUS
DISEASE TRAINED SPECIALISTS
Stewardship Training Programs
Making a Difference in Infectious
Diseases (MAD-ID)
Society of Infectious Disease
Pharmacists (SIDP)
• Basic program
• Advanced program
• 19 contact hours (1.9 CEUs)
each
• http://madid.org/antimicrobialstewardship-programs/
• Partnered with ProCE
– [email protected]
• Offers up to 43 contact
hours (4.3 CEUs)
• http://www.sidp.org/Stewa
rdship-Program
Additional Resources
• STEWARDSHIP-EDUCATION.org
– Collaborative project between SHEA, IDSA, PIDS, NFID,
MAD-ID, SIDP, and ASHP
• APIC’s Stewardship Toolkit
– http://www.apic.org/Professional-Practice/PracticeResources/Antimicrobial-Stewardship
• CDC’s Get Smart Campaign
– http://www.cdc.gov/getsmart/
– Checklist for Core Elements of Hospital Antibiotic
Stewardship Programs
Summary
• Antibiotics are a communal but scarce
resource
• Reducing unnecessary antibiotic use can
decrease antibiotic resistance
• Starting in 2017, TJC and CMS will mandate all
hospitals have ASPs
• Successful ASPs impact the patient, the
institution, and hopefully beyond
Questions?
Contact Info:
Carla Walraven, PharmD, BCPS-AQ ID
University of New Mexico Hospital
2211 Lomas Blvd NE
Pharmacy Department, 4ACC North
Albuquerque, NM 87106
(505) 272-4669
[email protected]