November 11, 2017

Samuel L. Aitken, PharmD, BCPS (AQ-ID)

Clinical Pharmacy Specialist, Infectious Diseases

slaitken@mdanderson.org

Antimicrobial stewardship in managing septic patients

MD Anderson

Conflict of interest statement

I have no conflicts of interest relevant to the content of this presentation

Advisory boards within the last 12 months

• The Medicines Company

• Zavante Therapeutics

• Achaogen

• Melinta

Current / pending research support

• Merck

• The Medicines Company

MD Anderson

Objectives

1. Identify when and why to de-escalate antibiotics in critically ill

patients

2. Discuss methods for incorporating antimicrobial stewardship

in the ICU

MD Anderson

The guideline-driven approach to antimicrobials

Selection

• …recommend empiric broad-spectrum therapy with one or more antimicrobials

(strong, moderate)

• …recommend against combination therapy for the routine treatment of

neutropenic sepsis/bacteremia (strong, moderate)

De-escalation

• …recommend that empiric antimicrobial therapy be narrowed once pathogen

identification and sensitivities are established and/or adequate clinical

improvement is noted (BPS)

• …recommend de-escalation…within the first few days in response to clinical

improvement…this applies to both targeted…and empiric combination therapy

(BPS)

• …recommend daily assessment for de-escalation (BPS)

Rhodes S, et al. Crit Care Med 2017;45(3):486-552

MD Anderson

Commonly used synonyms for de-escalation:

• Narrowing

• Streamlining

• Reducing

How I prefer to think of de-escalation:

• Targeting specific organisms

• Stopping unnecessary drug therapy

• One component of antimicrobial stewardship programs

De-escalation does not have a consistent definition

MD Anderson

Rationale for broad-spectrum

antimicrobial use

MD Anderson

Early initiation of appropriate antibiotics determines

mortality in septic patients

• Treatment directed at the likely pathogen and resistance pattern is essential

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

MD Anderson

Four primary pathogens account for half of

microbiologically-confirmed sepsis

Kumar A, et al. Chest 2009;136(5):1237-48

21.4

14.7

7.7 7.3

0

5

10

15

20

25

E. coli S. aureus K. pneumoniae P. aeruginosa

Pe

rce

nt o

f co

nfirm

ed

in

fectio

ns

• Primary pathogen identified in 71% of all cases of sepsis

MD Anderson

Just how common is antibiotic resistance in the ICU?

• Antibiotic resistance is not as common as we think at a national level

• Resistant organisms still must be considered in empiric therapy

Sader HS, et al. Diagnostic Microbiol Infect Dis 2014;78:443-8

MD Anderson

Like politics, all resistance is local

• Site-specific antibiograms are frequently different than national averages

• Local epidemiology is key to rational antimicrobial selection

Aitken SL. Unpublished data

MD Anderson

Why is antibiotic de-escalation and

discontinuation important?

MD Anderson

Definitive combination therapy with aminogylcosides for

bacteremia likely does more harm than good

• Nephrotoxicity 64% lower in monotherapy group (number needed to harm: 15)

• Similar results seen in pediatric patients

Paul M,, et al. BMJ 2004;328(7441):668Tamma PD, et al. JAMA Pediatr 2013;167(10):903-10

MD Anderson

Combination therapy is no better as definitive therapy

even for P. aeruginosa infections

• Other studies show no benefit of definitive combination therapy in P. aeruginosa

ventilator-associated pneumonia

• Role of combination empiric therapy is still being debated

Paul M, et al. Clin Infect Dis 2013;57(2):217-20Garnacho-Montero J, et al. Crit Care Med 2007;35(8):1888-95

MD Anderson

Vancomycin and piperacillin-tazobactam are

synergistically nephrotoxic

• Onset of nephrotoxicity is sooner than with vancomycin and other β-lactams

• Limited data in critically ill patients, but overall findings are similar

• Critically ill pediatric patients also see increased nephrotoxicity

Luther M, et al. Crit Care Med 2017;ePub ahead of print (Oct. 28)Holsen MR, et al. Pediatr Crit Care Med 2017;ePub ahead of print (Sep. 12)

MD Anderson

C. difficile risk increases with cumulative antibiotic use

0

5

10

15

20

25

30

35

40

< 4 4 - 7 8 - 18 > 18

Perc

en

tage

of

patien

ts

Duration of antibiotic therapy

CDI Cases Non-CDI Controls

Stevens V, et al. Clin Infect Dis 2011;53(1):42

• Cumulative number of antibiotics used also increases CDI risk

MD Anderson

0

10

20

30

40

50

60

70

0 days 1 - 3 days 4 - 21 daysPerc

ent

with a

ntibio

tic e

xposure

Duration of prior imipenem exposure

Colonized Non-colonized

Prolonged carbapenem use leads to colonization with

carbapenem-resistant Gram negatives

• Majority of resistance occurred through non-transmissible mechanisms

Armand-Lefèvre, et al. Antimicrob Agents Chemother 2013;57(3):1488-95

MD Anderson

Infection with resistant organisms is a predictable

consequence of prolonged antibiotic use

Percent with prior receipt of antibiotics

MDR

P. aeruginosa

No MDR

P. aeruginosa

p-value

Carbapenem, > 3 days 27 13 0.002

Fluoroquinolone, > 4 days 27 13 0.001

Aminoglycoside, >5 days 32 16 <0.001

Cefepime, > 9 days 16 5 0.001

Pip-tazo, > 12 days 34 17 <0.001

MDR – multidrug resistant

• If antibiotics aren’t needed, stop them as soon as possible

• “Just in case” can have serious consequences down the road

Lodise TP, et al. Antimicrob Agents Chemother 2007;51(2):417-22Lodise TP, et al. Infect Control Hosp Epidemiol 2007;28(8):959-65

MD Anderson

But is antibiotic de-escalation actually safe in the ICU?

• All studies performed to this point have major bias

• The data on downstream development of resistance are terrible

Tabah A, et al. Clin Infect Dis 2016;62(8):1009-17

MD Anderson

How can stewardship be successfully

implemented in the ICU?

MD Anderson

The key to stewardship is a team-based approach

The patient!

Critical care

Infectious diseases

Antimicrobial stewardship

Clinical microbiology

Informatics

Infection control

MD Anderson

The MD Anderson approach to stewardship - ABX

Targeted antibiotics

Daptomycin

Linezolid

Meropenem

Tigecycline

Vancomycin

Ceftazidime-avibactam

Ceftolozane-tazobactam

Targeted services

Leukemia

Stem cell transplantation

Lymphoma / myeloma

All ID consultant services

Aitken SL, ICAAC 2015Tverdek FP, et al. J Antimicrob Stewardship 2017; in press

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A completely passive email reduces antibiotic use

Aitken SL, ICAAC 2015Tverdek FP, et al. J Antimicrob Stewardship 2017; in press

• No active enforcement or verification of responses

• Semi-regular compliance summaries provided at the departmental level

MD Anderson

Time for a time-out?

• Anyone on the team can do a checklist assessment

• Can easily be customized to meet your needs

Aitken SL, ECCMID 2016

MD Anderson

Antibiotic checklists are safe and effective

1.4

15.712.9

18.6

3.2

12.7

15.9

19.1

0

5

10

15

20

25

30

Admit to ICUwithin 7 days

Newdocumented

infection

Recurrent fever Restart ofantibiotic

Pe

rce

nt o

f e

ligib

le p

atie

nts

Checklist Historic controls

p = 0.50 p = 0.62 p = 0.57 p = 0.62

• Antibiotic discontinuation rate at day 3 increased from 56% to 73% with checklist

• Required active maintenance and “nudging” to force use

Aitken SL, ECCMID 2016

MD Anderson

• Broad-spectrum antibiotics frequently are not needed

• Prolonged use of any antibiotic can have serious downstream

consequences

• De-escalation may help prevent some of these bad outcomes

• Stewardship needs to be individualized to the patient and the hospital

Conclusions

MD Anderson

The MDACC Antimicrobial Stewardship Team

• Micah Bhatti

• Farnaz Foolad

• Pat McDaneld

• Frank Tverdek

• Victor Mulanovich

Acknowledgements

November 11, 2017

Samuel L. Aitken, PharmD, BCPS (AQ-ID)

Clinical Pharmacy Specialist, Infectious Diseases

slaitken@mdanderson.org

Antimicrobial stewardship in managing septic patients