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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
Importance of appropriate empiric therapy
Effect of broad-spectrum therapy on resistance
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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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.
Importance of appropriate empiric therapy
Effect of broad-spectrum therapy on resistance
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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
Dellit et al. Clin Infect Dis 2007; 44:159–77
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
Dellit et al. Clin Infect Dis 2007; 44:159–77
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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.)
Dellit et al. Clin Infect Dis 2007; 44:159–77
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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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)
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
Dellit et al. Clin Infect Dis 2007; 44:159–77
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
SIDP – Antimicrobial Stewardship Certificate Program Optimizing Infectious Diseases Outcomes in Antimicrobial Stewardship Programs
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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
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