antimicrobial stewardship 2014 (1)

The Coming Storm:Antimicrobial Resistance and Selection

Objectives

• Describe the role of antibiotic use in the development of resistance

• Review toxicity of commonly used antibiotics

• Understand the prevalence and clinical impact of carbapenem resistant enterobacteriaceae

• State the prognosis antimicrobial resistant Staph aureus infections

Which of the following are indications to treat asymptomatic bacteriuria?Choose all that apply

A. Pyuria

B. Pregnancy

C. Preparation for transurethral resection of the prostate

D. Diabetes

0

0.5

1

1.5

2

2.5

3

3.5

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

New Systemic Antibacterial Agents Approved

Why has the antibiotic pipeline failed?

• All the easy ones have been discovered

• Antibiotics are not a good investment for drug companies

• FDA regulatory system is outdated

Society expects antibiotics to be cheap

• Cost of Trastuzumab for breast cancer = $54,000 per year

• Cost of Ipilimumab for melanoma = $240,000 for induction course

• Cost of ceftriaxone x 4 weeks for viridansstreptococcal endocarditis=$1600

Clinical Impact of Antimicrobial Resistance

• Resistance is rising

• Resistance increases mortality

• Decreasing antimicrobial use reduces resistance

Klebsiella pneumoniae resistant to carbapenemsNHSN Data

0

2

4

6

8

10

12

14

2000 2007 2010

Colistin Use JHU

0

200

400

600

800

1000

1200

1400

1600

1800

Colistin Courses

2009

2014

96

1600

JG Bartlett, Clin Infect Dis. (2011) 53 (suppl 1): S4-S7

Mortality of resistant (MRSA) vs.

susceptible (MSSA) S. aureus

• Mortality risk associated with MRSA

bacteremia, relative to MSSA bacteremia:

OR: 1.93; p < 0.001.1

• Mortality of MRSA infections was higher than

MSSA: relative risk [RR]: 1.7; 95% confidence

interval: 1.3–2.4).2

1. Clin. Infect. Dis.36(1),53–59 (2003).

2. Infect. Control Hosp. Epidemiol.28(3),273–279 (2007).

Mortality associated with carbapenem resistant

(CR) vs susceptible (CS) Klebsiella

pneumoniae (KP)

0

10

20

30

40

50

60

Overall Mortality Attributable Mortality

Pe

rce

nt o

f s

ub

jec

ts

CRKP

CSKP

Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106

OR 3.71 (1.97-7.01) OR 4.5 (2.16-9.35)

p<0.001

p<0.001

Mortality Associated with CRE

• Crude mortality 48%-61%

• Infection-related mortality = 33%-40%

Patel G, ICHE 29:1099-1106, 2008; Snitkin ES, Science Translational Medicine 4:1-9, 2012Munoz-Price LS ICHE 31:1074-7, 2010

Gram Negative Resistance Mechanisms

• Beta-lactamases-ESBL

• Multi-drug efflux pumps

• Porin changes-reduce permeability of outer membrane (imipenem)

Gram Negative Resistance Mechanisms

• Carbapenemases

– KPC-Klebsiella pneumonia carbapenemase

– NDM-New Dehli Beta-lactamase

– VIM-Verona-integron-encoded metallobetalactamase-found often in P. aeruginosa, occasionally in Enterobacteriaceae

– IMP-imipenemase

What’s the big deal about KPC?

• It confers resistance to all beta-lactams, and is frequently associated with resistance to other drug classes

• Many isolates are sensitive only to aminoglycosides, colistin, and tigecycline.

What’s the big deal about KPC?

• It is coded by blaKPC gene, which is plasmid mediated and can be transferred from one organism to another, facilitating rapid spread of resistance

Annual prevalence of imipenem

resistance in P. aeruginosa vs.

carbapenem use rate

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100

% I

mip

en

em

-resis

tan

t P. aeru

gin

osa

Carbapenem Use Rate

45 LTACHs, 2002-03 (59 LTACH years) Gould et al. ICHE 2006;27:923-5

r = 0.41, p = .004

(Pearson correlation coefficient)

P. aeruginosa susceptibilities before and after

implementation of antibiotic restrictions (CID 1997;25:230)

0

20

40

60

80

100

Ticar/clav Imipenem Aztreonam Ceftaz Cipro

Perc

en

t su

scep

tib

le

Before After

P<0.01 for all increases

Impact of Improving Antibiotic Use on

Rates of Resistant Enterobacteriaceae

Carling P et al. Infect Control Hosp Epidemiol. 2003;24(9):699-706.

Impact of fluoroquinolone restriction

on rates of C. difficle infection

0

0.5

1

1.5

2

2.5

2005 2006

Month and Year

HO

-CD

AD

cases/1

,000 p

d

2007

Infect Control Hosp Epidemiol. 2009 Mar;30(3):264-72.

Targeted antibiotic consumption and

nosocomial C. difficile disease

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

Tertiary care hospital; Quebec, 2003-2006

What Can I Do?

• Ensure antimicrobial resistance is recognized

• Control nosocomial transmission of resistant pathogens

• Reduce overall use of antimicrobial agents

What Can I Do?


– Proper laboratory test protocols

– Identify patients at risk for colonization

• Control transmission of resistant pathogens


– Urinary tract

– Skin and soft tissue

– Respiratory tract

Resistance Definition

• Nonsusceptible to one of the 3 carbapenems-imipenem, meropenem, or doripenem by 2012 CLSI breakpoints

AND

• Resistant to all of the third generation cephalosporins tested-ceftriaxone, cefotaxime, ceftazidime

*Morganella morganii, Proteus spp and Providencia spp. Are intrinsically resistant to imipenem-look for resistance to another carbapenem

Resistance-A Simplified Approach

Agent S I R S I R

Doripenem < 1 2 > 4

Ertapenem < 2 4 > 8 < 0.5 1 > 2

Imipenem < 4 8 > 16 < 1 2 > 4

Meropenem < 4 8 > 16 < 1 2 > 4

Old BreakpointsCLSA M100 S19

Revised BreakpointsJanuary 2012CLSI M-100 S22

What Can I Do?


– Proper laboratory test protocols

– Identify patients at risk for colonization



– Urinary tract



KPC Klebsiella pneumoniaecolonization

0

5

10

15

20

25

30

35

ICUs LTACHs

KPC Prevalence

KPC Prevalence

Lin M Y et al. Clin Infect Dis. 2013;57:1246-1252

What Can I Do?




CRE-Florida SICU Outbreak

• Daily CHG baths

• Cohorting during shifts-RTs, nurses, nurse aids

• Monitoring of environmental cleaning-black light and culture

• Active surveillance cultures

Munoz-Price LS ICHE 31:1074-7, 2010

CDC Guidance-Core Measures

1. Hand Hygiene

2. Contact Precautions for all patients who are colonized or infected with CRE

3. HCW Education

4. Minimize use of devices, e.g. CVCs, endotracheal tubes, urinary catheters

CDC Guidance-Core Measures

5. Cohort patients and staff

6. Notification system for lab to promptly inform Infection Control of all CRE

7. Antimicrobial stewardship

8. Screen contacts of patients colonized or infected with CRE

Contact Precautions-Starting and Stopping

• Micro lab should inform Infection Control of all CRE

• Flag chart to identify patient for precautions on re-admission

• Colonization may persist for 6 months or longer

• If screening for persistent colonization is used to DC precautions, must screen > once

• CRE should not preclude transfer to another facility

Contact Precautions for Long Term Care

• Patients who are dependent on caregivers for ADLs should be nursed in precautions

• For long term care residents who are able to perform hand hygiene, are continent of stool, are independent in ADLs and without draining wounds contact precautions might be relaxed

Risk Factors for Mortality from CRE

• Age

• Mechanical ventilation

• Malignancy

• Heart disease

• ICU stay

But-removal of the primary focus of infection (incision and drainage or device removal) is independently

associated with survival

What Can I Do?



• Reduce overall use of antimicrobial agents– Is an antibiotic truly needed?

– Discontinue or narrow therapy when data return

– Minimize duration of therapy

Antibiotic Assumptions

• Antibiotics are well tolerated insurance against a bad outcome

• Treating longer is better

• My duty is to the patient in my care-if treating him with an antibiotic increases societal risk, that is secondary

Case presentation

• 28 year-old male with no past medical history admitted with fever and rash.

• On morning of admission: Red, bumpy, itchy rash on right arm, pt thought possibly due to bed bugs

• Rash progressed over course of the day to involve chest, back, other arm, neck, face.

• Also c/o fever, malaise, sore throat, blurry vision.

Case presentation

• Past medical history: kidney stone

• Past surgical history: none

• Medications: none on admission; recent Cipro use for kidney stone

• Allergies: NKDA

• Family history: DM in mother and father

Clinical course

• Persistent high fever, tachycardia• Rapidly progressive rash (vesicles large bullae) and

generalized facial edema• Transferred to ICU on HD #3 due to concern for airway

compromise, intubated

• Derm evaluation: – Clinical findings c/w toxic epidermal necrolysis– SJS/TEN confirmed by shave biopsy

• Dx: SJS/TEN due to ciprofloxacin

Stewardship optimizes patient safety:

decreased patient-level resistance

Cipro Standard

Antibiotic

duration

3 days 10 days

LOS ICU 9 days 15 days

Antibiotic

resistance/

superinfection

14% 38%

Study terminated early because attending

physicians began to treat standard care group

with 3 days of therapy

Singh N et al. Am J Respir Crit Care Med. 2000;162:505-11.

CPIS Score-VAPhttp://www.surgicalcriticalcare.net/Resources/CPIS.php

PSI Score-outpatientshttp://pda.ahrq.gov/clinic/psi/psicalc.asp

Parameter CriteriaConfusion Disoriented to time/place/person or by other objective test

Uremia >20 mg/dL. Our normal range is 10-26 mg/dL so I think above normal is an appropriate cutoff. Also, not everyone includes this as it requires having completed labs.

Respiratory rate > 30 breaths/minute

Low Blood pressure < 90 mm Hg systolic or > 60 mm Hg diastolic

Age > 65 years

Curb 65 Score: One point per factor, score > 2 warrants hospitalization

Pneumonia Scoring Systems

Date of download: 9/23/2014Copyright © 2014 American Medical

Association. All rights reserved.

Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-

Associated Pneumonia in AdultsJAMA. 2003;290(19):2588-2598. doi:10.1001/jama.290.19.2588

Probability of survival is for the 60 days after ventilator-associated pneumonia onset as a function of the duration of antibiotic

administration.

Figure Legend:

Pulmonary Infection Recurrence

0

5

10

15

20

25

30

35

40

45

50

Non-fermenters MRSA Other bacteria

8 day

15 day

* NSNS





– But…treating a patient with an antibiotic increases that patient’s risk of resistance

Effect of antibiotic prescribing in primary care on

antimicrobial resistance in individual patients:

systematic review and meta-analysis

Costelloe C et al. BMJ.

2010;340:c2096.

What Can I Do?




– Urinary tract



Case 1

• 79 y/o man admitted for left foot gangrene

• Surgeons plan amputation

• PMHx chronic foley for urinary retention

• ROS negative

• Pre-op UA

– Dipstick + leukocyte esterase

– Microscopy > 50 WBC/hpf

How should the team respond to this UA?

A. Order urine culture and treat empirically with ciprofloxacin

B. Order urine culture and await results

C. Change the foley catheter

D. Watchful waiting

Case 2

• 81 y/o man admitted with fever, hypotension, confusion

• PMHx DM, HTN, dementia, prostatism with a chronic foley

• ROS unable to provide due to confusion

• Exam suprapubic tenderness, no flank tenderness

Case 2

• Lab WBC 14,000 12% bands 75% segs

• UA

– Positive Leukocyte esterase

– > 50 WBCs/hpf, 3+ bacteria

What empiric therapy would you select?

A. Vancomycin + pipracillin-tazobactam

B. Vancomycin + cefepime

C. Meropenem

D. Ciprofloxacin

Case 2

• Hospital course: treated with vancomycin + pipracillin-tazobactam, defervesces, appears pleasantly demented on day 2

• Blood and urine growing lactose fermenting gram negative rods

How should therapy be altered?

A. Continue current management-he is responding

B. Discontinue vancomycin-there is no evidence of gram positive infection

C. Discontine vanc + pip-tazo and substitute ceftriaxone

D. Discontinue vanc + pip-tazo and substitute oral ciprofloxacin

Case 2

• C & S shows E. coli, resistant to cipro and sensitive to the following agents. Which one would you choose?

A. Ampicillin

B. Ampicillin-sulbactam

C. Cefazolin

D. TMP-SMX

Case 2

• What is the recommended duration of therapy?

A. 3 days

B. 7 days

C. 10 days

D. 14 days

antimicrobial stewardship 2014 (1)

Healthcare

antimicrobial resistance

use of device

mortality of resistant

aureus mortality risk

mortality of mrsa infections

role of antibiotic use

susceptible mssa

relative risk rr