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 antimicrobialresistance

• Prepare for the new regulatory standards forAntimicrobial Stewardship Programs (ASPs)

• Outline strategies employed by ASPs toimprove outcomes

• Identify opportunities to apply AntimicrobialStewardship concepts

Pharmacy Technician Objectives

• Identify ways in which antibiotics are misused

• Explain the implications of antimicrobialresistance

• Recognize the core elements of AntimicrobialStewardship Programs

Audience Poll

• A 19 YOM is brought to your ED after anaccident cleaning his homemade shotgun,resulting in a penetrating eye socket injurywith a metal pipe.

– How many would recommend antibiotics?

– Which antibiotics would you use? (Whatpathogens 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 whileworking 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 diagnosedAML

• Antibiotic exposure:– Cetriaxone, clindamycin x

14 days (shin injury)– Vancomycin (cellulitis)– Augmentin and

ciprofloxain (prophylaxis)

• Febrile neutropenia 16days after admission– Blood cultures grew an

Extended spectrum β-lactamase (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

https://www.cdc.gov/drugresistance/about.html

Going Back to a Pre-Antibiotic Era?

• Antibiotic resistance hasbeen called one of theworld’s most pressingpublic health concerns

• Antibiotic resistance isassociated with increasedlengths of hospital stay,increased costs, andincreased mortality

“30-50% of antimicrobial use is eitherunnecessary or inappropriate.”

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10%

15%

20%

25%

30%

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Most Common Reasons for Unnecessary Therapy

NoninfectiousSyndrome

Tx ofColonization orContamination

Duration of txLonger thanNecessary

RedundantAbx Coverage

Reimann HA, D’Ambola J. JAMA. 1968;205(7):537.Hecker MT, et al. Arch Intern Med. 2003;163:972-78.

N = 576 DOT

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 treathighly susceptible bacteria

• The wrong antibiotic is used to treat an infection

http://www.cdc.gov/getsmart/healthcare/evidence.html

Antibiotic Prescribing Trends in USHospitals, 2006 - 2012

2006-2012

Baggs J, et al. JAMA Intern Med. doi:10.1001/jamainternmed.2016.5651

Piperacillin/tazobactam – ResistantPseudomonas aeruginosa

http://gis.cdc.gov/grasp/PSA/MapView.html, Accessed Aug 2016.

National Action Plan for CombatingAntibiotic-Resistant Bacteria

• 5 Goals– Slow the emergence and spread of resistant bacteria

• Includes the implementation of antimicrobial stewardshipprograms

– Strengthen national surveillance efforts of resistantbacteria

– Advance development and use of rapid diagnostictests

– Accelerate research and development of newantibiotics, therapeutics, and vaccines

– Improve international collaborations regardingantimicrobial 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 useof antimicrobials, improves patient outcomes, reduces

microbial resistance, and decreases the spread ofinfections 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 programoutcomes

Appoint a single pharmacist leader responsible forworking 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 improveantibiotic use

Evaluate ongoing treatment need after an initialtreatment period• E.g. “Antibiotic timeout” after 48 hours

Monitor antibiotic prescribing and resistance patterns

Regularly report information on antibiotic use andresistance to doctors, nurses, and relevant staff

Educate clinicians about resistance and optimalprescribing

CMS §482.42(b): Antibiotic StewardshipProgram Organization and Policies

• Effective January 1, 2017

• Demonstrate coordination among all componentsof the hospital responsible for antibiotic use andfactors that lead to antimicrobial resistance

• Document the evidence-based use of antibioticsin all departments and services of the hospital

• Demonstrate improvements, including sustainedimprovements in proper antibiotic use

https://s3.amazonaws.com/public-inspection.federalregister.gov/2016-13925.pdf

TJC’s NewAntimicrobialStewardship Standard

Effective January 1, 2017

Download available at:

https://www.jointcommission.org/standards_information/prepublication_standards.aspx

Antimicrobial Stewardship Team

ASP

Physician

Pharmacist

InfectionControl

InfectiousDiseases

Pharmacy

Informatics

Microbiology

HospitalAdmin

ASP Activities

• Patient Centered– Prospective audit and review

– Formulary management

– Identify patients who maybenefit from ID consult

• Institutional– Antibiograms

– Clinical pathways

– Dose optimization

Impact of Interventions

ASP Interventions

Patient

Institution

NationalGlobal

Goal: Decrease or slowantimicrobial resistance

ASP Core Strategies

Core Strategies Advantages Disadvantages

Prospective audit with directintervention and feedback

• May reduce inappropriateantimicrobial use

• Educate to modify futureprescribing

• Allows prescribers tomaintain autonomy

• Difficulty identifyingpatients with inappropriatetherapy and communicatingwith prescribers

Formulary restriction andpreauthorization requirements

• May result in immediateand substantial reduction inantimicrobial use and costs

• May increase staffingrequirements

• May delay orderimplementation withpotential adverse patientoutcomes

• May increase use of andresistance to alternativeantimicrobial agents

• Perceived loss of prescriberautonomy

Dellit et al. Clin Infect Dis. 2007;44:159-77.Drew et al. Pharmacotherapy. 2009;29:593-607.

ASP Supplemental Strategies

Dellit et al. Clin Infect Dis. 2007;44:159-77.Drew et al. Pharmacotherapy. 2009;29:593-607.

Supplemental Elements Advantages Disadvantages

Education • May influence prescribingbehavior

• Marginally effective whenused without activeintervention

Evidence based guidelines andclinical pathways

• May improve antimicrobialuse and practice variations

• Poor adherence

Streamlining or de-escalationtherapy

• Reduces antimicrobialexposure, selection ofresistant pathogens, andhealth care costs

• Prescriber reluctance to de-escalate when cultures arenegative and clinicalimprovement observed

Dose optimization • Tailors therapy to patientcharacteristics, pathogen,and PK/PD of antimicrobial

• Nursing concerns regardingincompatibilities andadministration

IV to PO conversion • May decrease length ofhospital stay and costs

• May reduce complicationsassociated with IV access

• Difficulty identifying patientsin whom conversion isappropriate

PATIENT CASEImplementing Antimicrobial Stewardship

Healthcare-Associated Pneumonia

• 49 YOF with history of severe COPD is admittedfrom a skilled nursing facility for respiratorydistress and acute disorientation (per family)

– Increased cough with sputum production over thepast 24h

– No fevers or chills

• Diagnosis: Acute hypoxic respiratory failure dueto 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, intermittentexpiratory 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 andpiperacillin/tazobactam

Antimicrobial Timeout

• As soon as possible, or within 48 hours:

1. Does the patient have an infection that willrespond 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 treatthe infection (de-escalate)?

4. How long should the patient receive theantibiotic(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 positivesMRSAMSSAS. pneumoniaE. faecalisE. faecium

52416

3019

85%93%

100%87%89%

98%98%

100%97%

100%

98%100%100%100%100%

Gram negativesE. coliKlebsiella spp.Pseudomonas spp.Acinetobacter spp.

1616230228

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%

Pardo J, et al. Ann Pharmacother. 2014; 48(1):33-40.

TTP = Time to Positivity

Impact of Prior Antibiotics onCultures

Positive by 48 hours Positive by 72 hours

OffAntibiotics

OnAntibiotics

P-valueOff

AntibioticsOn

AntibioticsP-value

Gram positives(n = 232)

183 / 186(98%)

44 / 46(96%)

0.258183 / 186

(98%)46 / 46(100%)

>0.99

Gram negatives(n = 161)

137 / 139(99%)

20 / 22(91%)

0.09138 / 139

(99%)21 / 22(95%)

0.255

Anaerobes(n = 23)

15 / 19(79%)

2 / 4(50%)

0.27018 / 19(95%)

3 / 4(75%)

0.324

All episodes(n = 416)

335 / 344(97%)

66 / 72(92%)

0.03339 / 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 resultsand 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

Hospital mortality 10 (25%) 15 (30.6%) 0.642

Clinical PulmonaryInfection Score, median

4 4 0.523

Signs/symptomsAbnormal tempAbnormal WBCSputum purulence

15 (48.4%)20 (69%)

24 (66.7%)

21 (61.8%)23 (65.7%)34 (80.9%)

0.3241.00

0.196

SuperinfectionBacteremiaRespiratory infectionMDR Superinfection

9 (22.5%)1 (2.5%)4 (10%)3 (7.5%)

18 (42.9%)3 (7.1%)

12 (28.6%)15 (35.7%)

0.0080.6160.0360.003

Raman K, et al. Crit Care Med. 2013; 41(7): 1656-63.

Comparison of 8 vs. 15 Days 60-Day VAP Mortality

How Long to Treat?

• Antibiotic duration for VAP– Primary outcome: death, 28

days after VAP onset

• Prospective, randomizeddouble-blind, clinical trial– 51 French ICUs

– May 1999 to June 2002

– Adults meeting clinicalcriteria for VAP

Chastre J, et al. JAMA. 2003; 290(19):2588-2598.

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. pneumoniaeantigen negative

• Blood cultures x 2 sets: nogrowth

Now What?

• MRSA nares has > 99%negative predictive value– Discontinue vancomycin

• Do we need Pseudomonalcoverage?– Consider de-escalating

piperacillin/tazobactam

– IV to PO if possible

• Duration: 7 days

DO YOU REALLY NEED DEDICATEDSTEWARDSHIP 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 helpcontain 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.

ASP Duties

• ID Physician, 0.5 FTE

• ID Pharmacist, 0.8 FTE

• Data Analyst, 0.05 FTE

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. thetrauma center)

UMMC ASP Program

Standiford HC, et al., Infect Control Hosp Epidemiol. 2012, 33(4):338-45.

Disbanded in 2008

Use resources to increase thenumber of ID physicians

Before, During and After UMMCASP

Antimicrobial Costs by Quarter, FY 98 – FY 10

Post-ASP Conclusions

• Despite unchanged quality markers,antimicrobial costs continued to increase (by41.2%) in the 2 years after the ASP ended

“…suggesting that more and more costly antibioticswere 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

Dedicated ASP Model

• 312 beds

• Average daily census: 230

• ID pharmacist rounds daily withthe ID team

• 2011 to 2012

Geographic ASP Model

• 137 beds

• Average daily census: 103

• 4 ward PharmDs round daily withtheir respective teams

• 2010 to 2011

• 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

Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.

Primary Endpoint

• Composite of compliance with the all of thefollowing:– 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 Departmentof Veterans Affairs (VA) National Formulary andVA Pharmacy Benefits Management group

Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.

Antimicrobial Stewardship Activities

Dedicated ASP Geographic ASP P-value

Discontinuation of therapywhen not bacterial

37/48 (77.1%) 11/33 (33.3%) 0.0002

Therapy modification based onlaboratory data

143/190 (75.2%) 51/100 (51%) < 0.0001

Therapy modification within 24hours of laboratory data

124/143 (86.7%) 37/51 (72.6%) 0.029

IV to PO conversion whenappropriate

97/120 (80.8%) 41/67 (61.2%) 0.0052

All of the above streamliningactivities

165/182 (90.7%) 47/95 (49.5%) < 0.0001

Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.

Conclusions

• An ASP with a dedicated pharmacist wasassociated with better adherence tostewardship activities

• There was a higher rate of adherence tostewardship activities even when ID wasconsulted

– Benefit of having both ID consult and an ASP withdedicated personnel

Bessesen MT, et al. Hosp Pharm. 2015; 50(6):477-483.

HOW CAN ONE PHARMACISTOVERSEE ALL ANTIMICROBIAL USE?

Using Clinical Pathways

• Concise summary ofnational guidelines

• Includes localsusceptibilityrecommendations

• Contains keyeducational points

• Goal is to capture 80%of patients with aparticular disease state

“…the strength of the Pack is the Wolf, andthe 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

• 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.

†Extrapolated savings based on cost data during intervention period

WE DON’T HAVE ANY INFECTIOUSDISEASE TRAINED SPECIALISTS

Stewardship Training Programs

Making a Difference in InfectiousDiseases (MAD-ID)

• Basic program

• Advanced program

• 19 contact hours (1.9 CEUs)each

• http://mad-id.org/antimicrobial-stewardship-programs/

Society of Infectious DiseasePharmacists (SIDP)

• Partnered with ProCE– info@proce.com

• Offers up to 43 contacthours (4.3 CEUs)

• http://www.sidp.org/Stewardship-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/Practice-

Resources/Antimicrobial-Stewardship

• CDC’s Get Smart Campaign– http://www.cdc.gov/getsmart/

– Checklist for Core Elements of Hospital AntibioticStewardship Programs

Summary

• Antibiotics are a communal but scarceresource

• Reducing unnecessary antibiotic use candecrease antibiotic resistance

• Starting in 2017, TJC and CMS will mandate allhospitals have ASPs

• Successful ASPs impact the patient, theinstitution, 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

cwalraven@salud.unm.edu