Optimizing Infectious Diseases Outcomes in Antimicrobial ...s3.proce.com/res/pdf/BachmeierHandout.pdfSIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases

SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs

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Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs

Harrison Bachmeier, PharmD, BCPSClinical Pharmacist Lee Memorial H ealth S ystem Fort Myers, FL

Disclosures

Dr. Bachmeier has NO financial disclosures


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Objectives

Discuss the impact of antimicrobial therapy and resistance on clinical outcomes

Review components of antimicrobial stewardship programs and opportunities to improve patient care

Recognize dosing strategizes to optimize antimicrobial pharmacodynamics

Describe the development of evidence-based guidelines to implement clinical pathways

Outline novel concepts of antibiotic heterogeneity to address gram negative resistance

Novel Drug Mechanism Targets are Lacking

Silver, L. L. Clin. Microbiol. Rev. 2011;24(1):71-109


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Critical Balance of Antibiotic Use

Importance of appropriate empiric therapy

Effect of broad-spectrum therapy on resistance

Mortality increases when initial therapy

is inappropriate

Resistance increases when broad-spectrum agents are overused

Resistance has a negative impact on

outcomes

Infection Prevention and

Antimicrobial Stewardship

Inadequate Treatment Leads to Poor Outcomes

100

80

60

40

20

0Bacteremia Community-acquired

BacteremiaS. aureus

BacteremiaVentilator-acquired

Pneumonia

p < 0.001

p < 0.05

p < 0.02p < 0.04

Pat

ient

Mor

talit

y, (%

)

Appropriate Initial Treatment

Inappropriate Initial Treatment

Impact of Empiric Antibiotic Treatment on Mortality

Chest. 2000; 118:146-55. Chest.2003; 123:1615-24. Eur J Clin Microbiol Infect Dis. 2006; 25:181-5, Intensive Care Med. 1996; 22:387-94


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Antibacterial Resistance is Increasing

Antimicrobial Resistance Among Staphylococcus aureus, enteroccoci and Pseudomonas aeruginosa in the United States

Antibiotic Resistance Leads to Poor Outcomes



Non-urinary tract isolates of ESBL Klebsiellaand E. coli vs non-ESBL infections

Length of stay

– 21 days vs. 11 days (p=0.006)Clinical success

– 48% vs. 86% (p=0.027)

Lee, et al. Inf Cont Hosp Epi 2006;27:1226-32

ESBL = extended spectrum beta-lactamase


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MRSA vs. MSSA bacteremia

– Clinical Failure• 59.6% vs. 33% (P<0.001)

– Length of Stay (infection-related)• 20.1 vs. 13.7 days (P<0.001)

– Mortality (infection-related)• 30.6% vs. 15.3% (P=0.001)

Lodise T. Diag Microbiol Inf Dis 2005;52.



Antibiotic Resistance Leads to Poor Outcomes

MRSA = methicillin resistant Staphylococcus aureus MSSA = methicillin susceptible Staphylococcus aureus

Guiding Antimicrobial Principles

For severe infections, start broad– If you get it wrong, you’re in trouble

Get it in the patient quickly

De-escalation of therapy is a necessity1,2

– The right drug is always the narrowest spectrum agent that produces a successful response and causes the fewest significant adverse effects and the least collateral damage

Treat for the most appropriate length of time, then stop

Each of these can be addressed through collaborative efforts

1. Am J Respir Crit Care Med. 2005;171:388-4162. Crit Care Med. 2013; 41:580–637


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Goals of Stewardship

Primary goals

– Improve clinical outcomes– Prevent adverse drug events– Limit the selection of pathogenic organisms– Reduce the incidence of antimicrobial resistance

Secondary goals

– Reduce healthcare related costs without adversely affecting outcomes

Dellit et al. Clin Infect Dis 2007; 44:159–77

Targeted Outcomes in Stewardship Programs

Patient specific

– Improved survival – Decrease length of hospital (and/or ICU) stay

Pharmacodynamic – Target dose attainment

Microbiologic – Increased drug/class susceptibility – Decreased clostridium difficile infections


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Antimicrobial Stewardship Team Members

Antimicrobial Stewardship Antimicrobial Stewardship Program DirectorsProgram Directors

•• ID Pharm.DID Pharm.D•• ID PhysicianID Physician

Hospital Administration Infectious

Diseases Dept.

Physicians;HospitalistsCritical Care

Chair, P&T Committee

Hospital Epidemiology & Infection Control

Medical Information

Systems

Microbiology Laboratory Clinical

Pharmacists


Comprehensive Antimicrobial Stewardship is Multifaceted

Active core strategies

– Prospective audit with intervention and feedback– Formulary restriction and preauthorization

Supplemental strategies

– Education– Guidelines and clinical pathways– Antimicrobial order forms– Antibiotic cycling – Dose optimization– De-escalating/streamlining therapy – Conversion from parenteral to oral therapy



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Pharmacist Role in Improving Antimicrobial Outcomes

Fishman et al. Clin Iinfect Dis 2001;33 :289-295Fishman. Am J Med 2006;119:S53

0102030405060708090

100

Appropriate Cure Failure

RR 2.8 (2.1-3.8) RR 1.7 (1.3-2.1)

RR 0.2 (0.1-0.4)

Pe

rce

nt,

%

Therapy

.

Clinical outcomes in a randomized controlled trial comparing the antimicrobial stewardship program to usual practice

Stewardship Program(n=96)Usual Practice(n=95)

The University of Kentucky Experience Multidisciplinary antimicrobial control program implemented in 1998

Initial focus on formulary management and restriction

– Cephalosporins – Vancomycin

Cephalosporins purchased and resistant Klebsiella spp.

Rates of MRSA isolates, %

Multidrug resistant P. aeruginosa, %

Antimicrobial drug expenditures, $

Projected

Actual

3rd Gen. cephalosporins

Cefepime

Martin CA et al. AJHP 2005;62(7):732-738


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Impact of Antimicrobial Stewardship on C. difficile Episodes

Valiquette L, et al. Clin Infect Dis. 2007; 45:S112–21

Improving Outcomes Through Thoughtful Dosing and Administration

Maximizing the benefit of a drug requires optimizing the pharmacodynamic properties of the drug

– Most benefit is in the sickest patients or those with risk factors for MDR organisms w/higher MIC values

Crucial considering our limited armamentarium

With the lack of new drugs for MDR organisms, being strategic with dosing and administration is more important than ever


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Optimal Pharmacodynamic Parameters Differ Among Antibiotics

24 x MIC16 x MIC4 x MIC1 x MIC ¼ x MICControl 0 2 4 6

10

8

6

4

2

0

Time, hr

Tobramycin

Lo

g10

CF

U m

l-1

0 2 4 6

10

8

6

4

2

0

Time, hr

Lo

g10

CF

U m

l-1

Ciprofloxacin

0 2 4 6 8

10

8

6

4

2

0

Time, hrL

og

10

CF

U m

l-1

Ticarcillin

Craig WA. Clin. Infect. Dis. 1998;26:1–12

Extended Infusions Optimize Beta-Lactam Pharmacodynamics

100

2 4 8 16 32 641

20

40

60

80

MIC, mg/L

3.375 g IV every 6 hoursgiven over 30 min

4.5 g IV every 6 hours

Probability of piperacillin-tazobactam target attainment of 50% fT>MIC

Pro

ba

bil

ity

of

Ta

rge

t Att

ain

me

nt,

%

given over 30 min

4.5 g IV every 8 hours given over 4 hours

Comparison of time above the MIC among various piperacillin doses

Visser LG et al. Clin Infect Dis 1993; 17:491-495Tam VH, et al. Clin Infect Dis 2008; 46:862–867


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Extended Infusion Dosing Strategies

Unnecessary to exceed MIC for a 24-hour interval in most cases

Target %fT > MIC for -Lactam antibiotics

– Penicillins – 50% fT > MIC– Cephalosporins – 60-70% fT > MIC– Carbapenems – 40% fT > MIC

Results of PK/PD experiments support extended-infusion dosing regimens for

-lactam antibioticsCraig WA et al. Clin Infect Dis 1998;26:1–10

Improved Survival Associated with Extended Infusion PTZ

Lodise TP et al. Clin Infect Dis 2007; 44:357-363


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The use of Clinical Guidelines to Improve Outcomes

IDSA Stewardship Guidelines Statements– Multidisciplinary development of evidence-based practice guidelines

incorporating local microbiology and resistance patterns can improve antimicrobial utilization (AI).

– Guideline implementation can be facilitated through provider education and feedback on antimicrobial use and patient outcomes (AIII).

Incorporate national guidelines when possible

An additional crucial step is to tailor the pathway based on microbiology, hospital formulary, etc.

Antimicrobial selection is only one component (diagnostics, etc.)


Get With the Guidelines

Multidisciplinary development of evidence-based practice guidelines incorporating local resistance patterns

Provides practitioners education and feedback

Pre-VAP Clinical Guideline

Post-VAP Clinical Guideline

Adequate initial therapy 48% 94%Duration of therapy 14.8 days 8.6 days

VAP recurrence 24% 8%

Ibrahim EH et al. Crit Care Med 2001 29;1109-15 VAP = ventilator associated pneumonia


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Additional Examples for Guideline Development

Community-acquired pneumonia1

– 20 hospitals randomized – Decreased LOS of 1.7 days

• 4.4 vs 6.1 days; p = 0.04– Fewer IV therapy days

• 4.6 vs 6.3 days; p = 0.01– No increase in complications or readmission

General ICU infections2

– 77% reduction in antimicrobial use– 30% reduction in overall cost of care– Decreased mortality

• 20% vs 5.6%; p = 0.02

1. Marrie et al. JAMA 2000;283:749-7552. Price et al. Crit Care Med. 1999;27(10):2118-2124

Moving From “Restriction” to “Facilitation”

Martin CA, Armitstead JA, Mynatt RP, and Hoven AD AJHP 2011; 68:109-10

– Programs with a heavy-handed restriction approach may inadvertently be doing a disservice to patients

– We should be focusing more on getting the right drug to the patient rather than merely restricting drugs

– The only dose of a drug proven to save lives is THE FIRST ONE


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Timeliness of Antibiotics Affects Survival in Sepsis

Delays in effective antimicrobial therapy increases mortality with each passing hour

Survival

within 1 hour within 6th hour

79.9% 42%

Kumar A, et al. Crit Care Med. 2006 ;34(6):1589-96

Mortality Risk and Time to Effective Antimicrobial Therapy

Time from Hypotension Onset, (hrs)Time from Hypotension Onset, (hrs)

Electronic Sepsis Bundle

Electronic order set– Can be initiated by any healthcare provider that recognizes

sepsis/septic shock

Automated notification to key personnel– Rapid response team– Hospital Operations Administrator

• (for bed transfer, nursing ratio, etc.)

– Materials management– Clinical Pharmacist ( PharmD on-call)

Septic Shock Carts– Deployed to key areas– Contains a ll supplies necessary for initial r esuscitation


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Initial Impact of Electronic Sepsis Bundle on Antimicrobial Timing

0

10

20

30

40

50

60

70

80

90

100

Antibiotics within 1 hour (3 hrs for ED)

Blood Cxs prior to antibiotics

Appropriate Antibiotics for

positive cultures

Before (n=46)

After (n=18)

% o

f p

ati

en

ts

0

1

2

3

4

5

6

7

8

Time to 1st Dose Antibiotics (Hours)

Before (n=46)

After (n=18)

Ho

urs

Local, unpublished data

Pharmacist Bedside Response in Initial Sepsis

Flynn J et al, Ann Pharmacotherapy 2014; 48(9):1145-1151

Outcomes

PharmD Sepsis Response

(n=49) Control(n=59)

OR (95% CI)

Primary Outcome

Antibiotics administered within 1 hour, n (%) 41 (77.5) 11 (23.7) 22.4 (7.5-69)

Secondary Outcomes

MAP > 65 mmHg within 6 h 43 (87.7) 45 (76.3) 2.2 (0.7-7.7)

CVP > 8 mmHg within 6 h 26 (53.1) 19 (32.2) 2.4 (1.0-5.6)

Death 24 (48.9) 32 (54.2) 0.5 (0.2-1.2)


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Delayed Antifungal Therapy Leads to Increased Mortality

Garey, et al. Clin Inf Dis 2006:43(1):25-31

0

5

10

15

20

25

30

35

40

45

Culture Day Day 1 Day 2 Day > 3

Days to start of Fluconazole

Mo

rta

lity

(%

)

Timing of antifungal therapy and mortality in patients with candidemia

The Candida Score: A Risk Stratification Tool

Simple point-based bedside scoring tool

Points

– Multifocal Candida colonization (1)– Surgery on ICU admission (1)– TPN (1)– Severe sepsis (2)

Scores >2.5 have 7x higher likelihood of invasive Candidiasis

Leon, et al. Crit Care Med 2006;34(3):730-7


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Candida Isolates in UKMC ICU PatientsOrganism 1CCU 1CT 1MED 1TIC 2BUR 2NS 2PAC 2SIC 3BMC 4NCU 4NIC 4PIC TOTAL

Candida albicans 24 35 26 26 7 33 7 21 6 9 4 13 211

Candida guilliermondii 0 0 0 1 0 0 0 0 0 0 0 0 1

Candida krusei 0 1 0 1 0 3 0 2 3 0 0 1 11

Candida lipolytica 1 0 0 0 0 0 0 0 0 0 0 0 1Candida lusitania 0 0 0 0 0 0 0 0 0 1 0 2 3

Candida parapsilosis 2 2 4 3 1 0 1 1 0 1 0 0 15

Candida tropicalis 4 2 12 2 5 9 0 1 1 0 0 3 39

Candida glabrata 19 10 19 13 4 12 3 7 9 1 1 2 100

Grand Total 52 52 63 47 17 60 12 34 19 12 5 23 396Projected fluconazole susceptibility

C. albicans 179 175 98%

C. glabrata 87 60 69% Susceptibility based on surveillance data: Pfa ller, et al. JCM 07

C. parapsilosis 14 13 93%

C. tropicalis 35 32 90%

C. krusei 7 0 0.63

Overall 86%

UKHealthCare Suspected Candidiasis Guideline Pathway

Candida Score >2.5

Yes

(Start micafungin)

Cx (-), pt improves (cont.

micafungin)

Cx (-), no improvement

(DC micafungin)

Cx (+), Flu-S species (change

to flu)

Cx (+), Flu-R species (cont. micafungin)

No

(No antifungal therapy) Continue to evaluate

Cx = culturePt = patientDC = discontinueFlu = fluconazoleS = susceptible R = resistant


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Antimicrobial Cycling

Scheduled removal and substitution of a specific antimicrobial for a given time period to prevent or reverse the development of resistance

Aimed to minimize selective pressures

Difficult to fully implement due to concerns regarding allergies, adverse effects, guideline recommendations

Insufficient data to support routine use– Leads to resistance patterns cycling


Promoting Antibiotic Heterogeneity Throughout Healthcare Systems

Novel concept of antibiotic mixing throughout a cohort to limit antimicrobial selective pressures

– Measured by antibiotic heterogeneity index (AHI)– Goal of >0.85 (complete heterogeneity = 1)

Prospectively favor or restrict antibiotic classes based on recent use and changes in resistance

Takesue Y et al. J of Hosp Infect. 2010;75:28–32


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Strategic Antibiotic Heterogeneity Reduces Gram Negative Resistance

Pre-establishment period PAMS P value

Resistant P. aeruginosa 8.9% 3.8% <0.001

Multidrug-resistant P. aeruginosa and A. bamannii 1.7% 0.5% <0.001

Metallo-B-lactamase organisms 1.2% 0.3% <0.001

ESBL organisms 2.2% 2.4% NS

Antibiotic utilization density Antipseudomonial Resistance

Takesue Y et al. J of Hosp Infect. 2010;75:28–32

An Honest Assessment of Where Antimicrobial Stewardship Stands

Does a good job of promoting the idea that antimicrobial use matters to society (at least the inpatient society)

– Nobel causesDoes a poor job of talking about community antibiotic use

– Not to mention the use in agriculture

Beginning to address use at the level of individual patients (timing, selection, etc.)

We need to be thinking about ways to win wars, not individual battles


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Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs

Harrison Bachmeier, PharmD, BCPSClinical Pharmacist Lee Memorial H ealth S ystem Fort Myers, FL

Documents

Optimizing Infectious Diseases Outcomes in Antimicrobial ...s3.proce.com/res/pdf/BachmeierHandout.pdfSIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases