Rational use of antimicrobials versus control

of infection transmission: where to focus our efforts on

gram-negative bacilli?

Prof. Stephan Harbarth

Geneva University Hospitals, Switzerland

Source: European Antimicrobial Resistance Surveillance System (EARSS), 2009

<1%

1– 5%

5–10%

10–25%

25–50%

>50%

No data/low number

Other countries

Third-generation cephalosporin-resistant Escherichia coli, blood and CSF, 2008

Country with:

Significant increase (2005-2008)

Significant decrease (2005-2008)

Klebsiella pneumoniae – 3rd Generation Cephalosporin Resistance in Europe - 2010

Euro Antimicrob Resist Surv Syst (EARSS) & anresis.ch

Reasons for ESBL epidemic

? Food chain

Antibiotic overuse Cross transmission

Human migration

Emerg Infect Dis 2013; 19: 1206-13

Geneva food study

• 91% (50/55) of raw chicken meat samples were ESBL-positive

• No ESBL-positive isolates from cooked samples

• Food-handler colonisation not high (6.5%)

• No antibiotic residuals found

Stewardson A et al. (2014). Infect Control Hosp Epidemiol

Poulet cru: Standard vs. produits BIO

P>0.99*

55 10 N = * Fisher’s exact test

Stewardson A et al. (2014). Infect Control Hosp Epidemiol

Identify carriers

Screening Isolation

Eliminate carriage

Decolonization

Control of MDR-GNB in human medicine

Stop transmission Hand hygiene

Reduce antibiotic use Restriction

Infection control interventions

Improve infection control

Surveillance of multi-R GNB

Passive: Clinical cultures

Active: Surveillance swabs

Optional: Genotyping

Prevalence of multiresistant pathogens

in repatriates to the Netherlands

211 (18.1%) carriers of MDR pathogens

MRSA

VRE

MDR

18,1 %

GNB

2.7 %

2.7 % 14.1 %

Kaiser et al. Clin Micro Infect 2004; 10: 972-79

Dautzenberg MJ et al. Successful control of a hospital-wide outbreak of OXA-48 producing Enterobacteriaceae in the Netherlands, 2009 to 2011. Euro Surveill. 2014;19(9):pii=20723.

Dautzenberg MJ et al. Successful control of a hospital-wide outbreak of OXA-48 producing Enterobacteriaceae in the Netherlands, 2009 to 2011. Euro Surveill. 2014;19(9):pii=20723.

Dautzenberg MJ et al. Successful control of a hospital-wide outbreak of OXA-48 producing Enterobacteriaceae in the Netherlands, 2009 to 2011. Euro Surveill. 2014;19(9):pii=20723.

Carbapenem-R Enterobacteriacae HUG, Dec 2009 - Dec 2013

Improve infection control

Surveillance

Promote and improve hand hygiene

Implementation tools:

Key tools

Guide to

Implementation of

the WHO Multimodal

Hand Hygiene

Improvement

Strategy

Template Action Plan

Alcohol-based handrub at point of

care

Access to safe, continuous water supply, soap and

towels

2. Training and Education

3. Observation and feedback

4. Reminders in the hospital

5. Hospital safety climate

+

+

+

+

• The 5 core

components of the

WHO Multimodal

Hand Hygiene

Improvement

Strategy

1. System change

130 countries committed to address HAI 93.5% world population coverage

Update:

March 2013 October 2005 – March 2013 © World Health Organization

Johnson et al. Med J Australia 2005

Use of alcohol hand rubs

ESBL bacteremia

Johnson et al. Med J Australia 2005

Surveillance

Promote and improve hand hygiene

Use cohorting and isolation

precautions (gowns, gloves, signs)

Improve infection control

Gloves and gowns block 90% of resistant bacteria

Organism

HCW

Room

Entries

Hand +

Before

(%)

Gown

and/or

Glove +

After %

Hands +

After

Removal

Effectiveness

of PPE

A. baumannii 202 1.5% 38.7% 4.5% 88%

P. aeruginosa 133 0% 8.2% 0.7% 90%

Morgan D, et al, Infect Control Hosp Epidemiol July 2010; 31: 716-21

Effect of Contact Isolation

0

200

400

600

1991 1992 1993 1994 1995 1996 1997 1998

Nb

re d

e s

ou

ch

es c

lin

iqu

es KBLSE

A. baumannii

Paris, GH Bichat - Claude Bernard

Courtesy: JC Lucet

Infection prevention measures used for KPC

outbreaks and reported effects

CDC recommendation

In acute care settings, implement contact precautions for all patients known to be colonized/infected with MDROs including ESBL-producing bacteria

This was a grade 1B recommendation: Strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale

Surveillance

Promote and improve hand hygiene

Use cohorting and isolation

precautions (gowns, gloves, signs)

Environmental control

Improve infection control

Environmental Contamination

MRSA/VRE vs. GNB

0%

5%

10%

15%

20%

25%

30%

35%

40%

Chem

ise d

e n

uit

Ste

cktu

ch

Couverture Lit

Urinal

Table

de n

uit

Sol

Lunettes

de W

CD

ouche

Poig

née d

e p

orte c

ham

bre

patient

Poig

née d

e p

orte s

alle

de b

ain

s

Bouto

ns respirate

ur

Bouto

ns in

fusom

at

Faute

uil

Arm

atu

re d

ouch

e

Arm

atu

re la

vabo

Blo

use

pers

onnel

Main

s p

atie

nt vois

in

Main

s p

ers

onnel

Main

s p

atie

nt

Périnée

MRSA / VRE

GNB

Lemmen S et al. J Hosp Infect 2004; 56: 191

Acinetobacter Outbreak

Index patient

Severe burn injuries, transfer from Bali (Oct 2002)

Multi-R Acinetobacter at admission

Outbreak

Spread to 2 patients

6 months later: 6 new cases

Closure of the burn unit

Environnement

Widespread contamination: 16/161 (10%) positive swabs

Patients Environnement

► Environmental cleaning & disinfection

► Complete replacement of all disposable material

Zanetti G et al. Infect Control Hosp Epidemiol 2007; 28: 723-25

Surveillance

Promote and improve hand hygiene

Use cohorting and isolation

precautions (gowns, gloves, signs)

Environmental control

Decolonization

Improve infection control

Huttner et al. (2013). J Antimicrob Chemother. 38

Randomized, controlled study*

Colistin sulfate (50mg 4x/d)

+ Neomycine sulfate

(250mg 4x/day)

PLACEBO 10

days

Nitrofurantoine (100mg 3x/d)

PLACEBO 5

days

* investigator initiated, financed by HUG (PRD 08-II-6) ** 70% vs 30%, 1-beta 0.8, alpha 0.05 (two-sided)

Sample size: 27 patients in each group**

39

bl= baseline; d6t= 6th day of treatment d1=1st day after end of treatment; d7=7th day after end of treatment d28=28th day after end of treatment

0.1

.2.3

.4.5

.6.7

.8.9

1

fra

ction

ES

BL

-E p

ositiv

e

bl d6t d1 d7 d28study visits

Evolution of rectal ESBL - E carriage

40

Antibiotic control and reduction of multi-

resistant GNB: What is the evidence?

High-quality studies with drug & bug data

Effect: Effect No effect

MDR Gram-negative

5 0

Clostridium difficile 2 0

Vancomycin-R enterococci

1 1

MRSA 0 0

Peter Davey and colleagues, Cochrane Review 2005

-6

-4

-2

0

2

4

6

-6 -4 -2 0 2 4 6

Change in Level (immediate effect)

Ch

an

ge

in

Slo

pe

(s

us

tain

ed

eff

ec

t)

Gerding: first

restriction of

gentamicin

Landman,

ceftazidime R

Klebsiella

Carling

Meyerde Champs

Leverstein van

Hall

Gerding: re-

introduction of

gentamicin

Gerding: second

restriction of

gentamicin

Landman,

cefotaxime R

Acinetobacter

High-quality studies for multi-R GNB

Davey P et al, Emerg Infect Dis 2006; 12: 211

Evidence suggesting that limiting the use of specific antibiotics will reduce the

prevalence of resistant GNB

Improve antibiotic use

Monitor and provide feedback on antibiotic use and occurrence of multi-R GNB

Pseudomonas aeruginosa multi-R (HUG)

0

10

20

30

40

50

60

HUG Operasi_us Oclsi_us USI+

No

mb

re d

e p

atie

nts

2009

2010

2011

2012

2013

0

100

200

300

400

500

600

7001995

1997

1999

2001

2003

2005

2007

20

09

2011

2013

No

mb

re d

e p

ati

en

ts

Incidence ESBL HUG, 1995 – 2013

E. coli Klebsiella spp Autres

Non-duplicate, resistant E. coli isolates

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

01

2000

6 2

000

11

2000

4 2

001

9 2

001

2 2

002

7 2

002

12

2002

5 2

003

10

2003

3 2

004

8 2

004

01

2005

6 2

005

11

2005

4 2

006

9 2

006

2 2

007

7 2

007

12

2007

Incid

en

ce p

er

100 p

ati

en

t d

ays

R_E.Coli_ciprofloxacine

R_E.Coli_cotrimoxazole

ESBL

Transfer function model for E. coli resistant to cefepime (ESBL)

Variable Lag

(months)

Parameter (SE) t-Statistic P-value

d - ceftriaxone HUG 0 0.0041 (0.0017) 2.4047 0.0195

d - ciprofloxacin HUG 1 0.0043 (0.0013) 3.2126 0.0022

5 0.0045 (0.0014) 3.2045 0.0022

d - cefepime HUG 3 0.0034 (0.0016) 2.1502 0.0358

d - piperacilline/tazobactam HUG 3 0.0099 (0.0042) 2.3073 0.0247

d - ciprofloxacin GE 4 0.0247 (0.0080) 3.0809 0.0032

Autoregressive term 1 -0.5877 (0.01084) -5.4236 0.0000

Transfer function model on ESBL incidence explains 51% of ESBL variation over time

Antibiogrammes, BGN BLSE-positifs

HUG (2012)

Improve antibiotic use

Monitor and provide feedback on occurrence and impact of AMR

Optimize choice and duration of empiric antimicrobial therapy

Empiric antibiotic treatment and intestinal

carriage of resistant GNB in NICU patients

De Man P. et al., Lancet 2000, 355 : 973

NICU A

NICU B

Ampicillin-cefotaxim

Penicillin-tobamycin Ampicillin-cefotaxim

Penicillin-tobamycin

Bacili resistant to regimen of unit,

Bacili sensitive to regimen of unit but

resistant to regimen of the other unit

Pen-Tobra better than Amoxi-Cefotaxim !

Survival Among 401 Patients with

Nosocomial Pneumonia Assigned to Short (8 d) or

Long (15 d) Antimicrobial Treatment P

rob

ab

ilit

y o

f S

urv

iva

l

0 10 20 30 40 50 60

Days after Bronchoscopy

0.0

0.2

0.4

0.6

0.8

1.0

15-day

8-day

Courtesy: J. Chastre, Paris JAMA 2003; 290: 2588-98

42.1%

62.3%

0

20

40

60

80%

“8-day”

(n=197)

“15-day”

(n=204)

Emergence of multiresistant pathogens for patients

who had pulmonary infection recurrence

P = 0.04

Courtesy: J. Chastre, Paris JAMA 2003; 290: 2588-98

Improve antibiotic use

Monitor and provide feedback on occurrence of AMR

Optimize choice and duration of empiric antimicrobial therapy

Optimize perioperative antimicrobial prophylaxis

Misuse of prophylactic antibiotics in a university hospital, China

Suping Hu et al. J Infect 2003; 46:161-63

0

5

10

15

20

25

30

35

40

45

50

Duration of perioperative prophylaxis

<7d

8-13d

>13d

%

80% of prophylactic antibiotics (191/239) were started after the end of the operation

Antibiotic resistance and extended prophylaxis in 2,641 cardiac surgery patients

Harbarth et al, Circulation 2000; 101: 2916-21

Long AB prophylaxis (>48 h; 43%) was associated with

acquired resistance (Gram-negative bacteria & VRE):

Adjusted OR : 1.7 [95% CI, 1.1-2.7]

- Conditional logistic regression, matched by type of agent and calendar time

- Adjusted for gender, age, transfer, ICU stay, comorbidities, ASA score, type of

surgery, other AB exposure

Improve antibiotic use (2)

Decrease diagnostic uncertainty:

Increase adherence to culture results

Improve diagnostic support

Pneumococcal pneumonia

Improve antibiotic use (2)

Decrease diagnostic uncertainty

Implement formulary restrictions for important types of antimicrobial use

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1 2 3 4 5 6 7 8 9 10 11

Months

Cas

es o

f cef

tazi

dim

e-re

sist

ant

K. p

neum

onia

e/1

000

patie

nt d

ays

Start of barrier

precautions and

ceftazidime restriction

(post-intervention – pre-intervention) P

in level Decrease by 38.6 cases/1000 patient days <0.001

in slope Decrease by 6.7 cases/1000 patient days <0.001

Meyer et al. Annals of Internal Medicine 1993; 119: 353-8

Improve antibiotic use (2)

Improve diagnostic tools

Implement formulary restrictions for important types of antimicrobial use

Improve antimicrobial prescribing:

Education (pre- and postgraduate)

Practice guidelines & clinical algorithms

Gottesman et al. (2009).

Clin Infect Dis 49:869–75.

Consumption of ciprofloxacin

Susceptibility of ciprofloxacin

(E. coli urinary cultures)

Correlation between fluoroquinolone use and resistance in Israel

Message for the Quinolone-Fans…

» L

Leave

the

Queen

Alone !

Cystitis therapy: Nitrofurantoin OR Fosfomycin

Treat UTI in 2012 with antibiotics of the 1960s!

Super-heros never die!!

Improve systems to recognize multi-R GNB and communicate clinical impact

Promote adherence to alcohol-based hand hygiene & basic infection control

Detect patients colonized with multi-resistant GNB (incl. carbapenemases)

Implement barrier precautions in high-risk situations and during outbreaks

Infection Control

Antibiotic Control

Improve perioperative prophylaxis

Promote short-course, high-dose AB therapy

Decrease diagnostic uncertainty by any type

of diagnostic tools or decision support

Promote local guidelines and drug committees

Reduce impact of marketing pressure

Thanks for your

attention!