Optimising antibiotic treatment

in the current crisis

Stephan Harbarth

Geneva Univ Hospitals and WHO

Collaborating Center, Geneva (CH)

Disclosures

• Advisory board: Bayer, GSK, DNA electronics,

Novartis, Janssen

• Support for AMR research activities: B.Braun,

Pfizer, European Commission

Agenda

• Variation of hospital antibiotic use

• Antibiotic stewardship:

Old strategies and novel approaches

• Implement & evaluate local interventions

Hospital antibiotic use

varies between countries…

Vander Stichele et al. (2006).

J Antimicrob Chemother 58:159-67.

… between different hospitals within a

country…

Pakyz et al. (2008). Arch Intern Med 168:2254-60.

Data from 35 university teaching hospitals (USA)

… and between different units within the

same hospital

Kuster et al. (2008). J Antimicrob Chemother 62:837-42.

ICUs

General wards

University Hospital, Zurich

Most of this variation is explained by:

1) Differences in case-mix

2) Differences in infection rates

3) Adequacy of antibiotic use

• Up to 50% of antibiotic prescriptions in

hospitals are inappropriate

– „Overuse“

– „Misuse“

– „Underuse“Byl et al. (1999). Clin Infect Dis 29:60-6.

Sibgh et al. (2000). Am J Respir Crit Care Med 162:505-511

Lawton et al. (2000). Infect Control Hosp Epidemiol 21:256–9

Hecker et al. (2003). Arch Intern Med 163:972-8.

Vlahovic-Palcevski et al. (2007). Int J Clin Pharmacol Ther 45:169-74

Antibiotic

misuse

Insufficient knowledge

of the prescribing

physician

Low risk taking attitude

Insufficient information

e.g. availability

of lab resultsSuboptimal diagnostic

methods

Treatment duration

ill defined

Reasons for suboptimal antibiotic use

Antibiotic stewardship strategies

http://www.lettreauxhospitaliers.ameli.fr/Media/Newsletter/fiches/Depliant_Antibiotiques2006.pdf

Only treat bacterial infections

Do not treat colonization

Reevaluate the prescription after 72h

Stop the antibiotic treatment if not

necessary

Avoid unnecessary

antibiotic use

Choose the right drug

Avoid unnecessary combinations

Choose the right dosage and route

Use antibiotics in the

optimal way

Avoid invasive devices

Avoid cross-transmission

Vaccinate

Prevent infections

Adapted from the campaign for the prudent

use of antibiotics (CDC and APHP)

Only treat bacterial infections

Do not treat colonization

Reevaluate the prescription after 72h

Stop the antibiotic treatment if not

necessary

Choose the right drug

Avoid unnecessary combinations

Choose the right dosage and route

Avoid invasive devices

Avoid cross-transmission

Vaccinate

Antibiotic stewardship

➢ Education

➢ Audit and feedback

➢ Guidelines & clinical

pathways

➢ Formulary restriction

➢ Preauthorization

➢ Streamlining

➢ AB cycling/rotation

➢ Computerized decision

support

➢ Biomarkers & new

diagnostic tools

Dellit et al. (2007). Clin Infect Dis 44:159-77.

Adapted from the campaign for the prudent

use of antibiotics (CDC and APHP)

Indicator Africa Asia Europe North

America

Oceania South

America

Total N of participants 44 50 361 72 35 103

Country AMS Standards 10% 29% 58% 20% 50% 23%

Hospital AMS Standards 21% 62% 72% 45% 49% 51%

AMS Programme 14% 53% 66% 67% 47% 46%

Antimicrobial formulary 46% 84% 85% 78% 78% 63%

Antimicrobial guidelines 77% 84% 95% 78% 91% 73%

AMS ward rounds 54% 52% 70% 39% 61% 67%

Antimicrobial audits 77% 80% 82% 66% 82% 61%

Report antimicrobial usage 77% 80% 90% 76% 82% 59%

Restrict cephalosporins 0% 13% 56% 28% 45% 54%

e-prescribing (all areas) 2% 33% 13% 39% 7% 18%

Educate staff on AMS 92% 83% 90% 79% 74% 87%

Communicate with staff on AMS 100% 90% 93% 85% 78% 87%

Howard P et al. JAC 2015; 70: 1245-1255

Global survey on antimicrobial stewardship (2012)

What is the effect of antibiotic

stewardship on resistance?

Update (9 Feb 2017)

Cochrane update (9 Feb 17)

• Evidence about effect of ABS interventions on:

Resistant Gram-negative bacteria (11 studies):

median -12.9%, IQR -35.3% to +25.2%

Resistant Gram-positive bacteria (9 studies):

median -19.3%, IQR -50.1% to +23.1%

Peter Davey and colleagues, Cochrane Review 2017 (update)

• Overall 9,056,241 patient-days and 159 IRR estimates

• The interventions included:

– formulary restriction (39)

– audit and feedback programme (32)

– education of personnel (21)

– guideline implementation (9)

– single antibiotic intervention (6)

– therapy duration intervention (4)

– antibiotic cycling (3)

– decision support system (4)

• In 27 ASPs was implemented together with infection control

measures (hand hygiene, enhanced ICM, patients and

environmental screening)

Systematic review

Lancet ID 2017; Courtesy: E. Tacconelli

Effectiveness of ABS:

Overall effect estimate

AMR pathogen Studies

included

Incidence

rate ratio

95%CI P value

ESBL-producing Gram

negatives 11 0,517 0,273 - 0,979 0.0428

Carbapenem-resistant

Gram negatives 19 0,486 0,345 - 0,683 <0.0001

C. difficile 11 0,68 0,527 - 0,876 0.0029

MRSA 17 0,627 0,448 - 0,877 0.0065

VRE 3 1,404 0,813 - 2,425 0.2233

FQ resistant

gram negatives 21 0,784 0,53 - 1,159 0.2224

Aminoglycosides resistant

gram negatives 16 0,821 0,563 - 1,195 0.3028

FQ resistant

gram positives 6 1,097 0,815 - 1,475 0.5416

Aminoglycosides resistant

gram positives 6 0,997 0,857 - 1,16 0.9701

Lancet ID 2017; Courtesy: E. Tacconelli

Strategic priorities to optimize antibiotic use

• Monitor and provide feedback on antibiotic utilisation

(quantity and quality) and occurrence of AMR

– Data & surveys

– Local data (hospital / ICU)

Numbers and percentages of susceptible and

resistant P. aeruginosa isolates from blood

cultures at public-sector sentinel sites, 2015.

Total number of isolates analyzed = 670.

• Monitor and provide feedback on antibiotic utilisation

and occurrence of AMR

• Optimize choice & duration of empiric antimicrobial

therapy

Strategic priorities to optimize antibiotic use

• Meta-analysis of 15 randomised trials

• No differences in clinical success for short

courses (≤7 days) vs extended courses (>7 days)

• Agents: β-lactams, quinolones, azithromycin

Optimal AB dosing:

82% 29% p= 0.001

ICU-free days:

20 d 17 d p= 0.14

Clinical cure:

70% 43% p= 0.037

Meropenem or Piptazo

continuous perfusion30 patients

Meropenem or Piptazo

intermittent perfusion30 patients

Continuous vs intermittent perfusion

of meropenem (multicenter RCT)

Dulhunty JM et al., Clin Infect Dis 2013; 56: 236-44

• Doripenem 500mg over 4 hours every 8 hours

vs.

• Imipenem 500-1000 mg over 30-60 minutes every 6-8 hours

• Phase III trial: 531 patients with VAP

• Clinical cure rates: 68.3% (Dori) vs 64.8% (Imi) –n=249; difference 3.5%; 95% CI, -9.1%-16.6%

Chastre J et al. Crit Care Med 2008;36:1089-1096

Does prolonged/continuous infusion impact on

resistance development in critically ill patients?

Courtesy: A. Brinks

Chastre J et al. Crit Care Med 2008;36:1089-1096

Does prolonged/continuous infusion impact on

resistance development in critically ill patients ?

Subset of Pseudomonas infected patients

Dori Imi

Baseline susceptibility 100% 76%

(28/28) (19/25)

Clinical cure rates 80% 43%

(16/20) (6/14)

Development of R 18% 50%

during therapy (5/28) (11/22)

Courtesy: A. Brinks

• Monitor and provide feedback on occurrence of AMR

• Optimize choice and duration of empiric antimicrobial

therapy

• Optimize perioperative antimicrobial prophylaxis

Strategic priorities to optimize antibiotic use

National Surgical Infection

Prevention Project

• Major surgery: 34’133 patients

• Adequacy:

– Choice of agent: 93%

– Timing: 56%

– Duration: 41%

Brathler DW et al. Arch Surg. 2005; 140: 174-182

Antibiotic resistance and extended prophylaxis in 2,641

cardiac surgery patients

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

Extended 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

From: From guidelines to practice: a pharmacist-driven prospective audit and feedback improvement model for

peri-operative antibiotic prophylaxis in 34 South African hospitalsJ Antimicrob Chemother. 2016;72(4):1227-1234. doi:10.1093/jac/dkw523

J Antimicrob Chemother | © The Author 2016. Published by Oxford University Press on behalf of the British Society for

Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

From: From guidelines to practice: a pharmacist-driven prospective audit and feedback improvement model for

peri-operative antibiotic prophylaxis in 34 South African hospitalsJ Antimicrob Chemother. 2016;72(4):1227-1234. doi:10.1093/jac/dkw523

J Antimicrob Chemother | © The Author 2016. Published by Oxford University Press on behalf of the British Society for

Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Optimize antibiotic use (2)

• Decrease diagnostic uncertainty:

– Improve diagnostic tools

Decreasing diagnostic uncertainty

D0 D1 D3 D14D7

Adjustment phaseInitial empiric phase Final duration phase

Rapid molecular tests and

microbiologic culture results

Computerized decision

support systems

Biomarkers

Use of Procalcitonin to Shorten Antibiotic

Exposure in ICU Patients : The ProRata Trial

Bouadma et al. Lancet 2010

All patients VAP Intraabdominal

infection

UTI Positive blood

cultures

N

CAP

20 14

9.9

6.1

10.6

5.6

9.4

7.3

10.8

8.1

14.5

7.4

12.8

9.8

0

2

4

6

8

10

12

14

16

Dura

tion o

f tr

eatm

ent (d

ays)

314 307 101 79 66 75 18 24 53 55

PCT

Control

“It makes no sense to use

twenty-first century technology to

develop drugs targeted at specific

infections whose diagnosis is delayed

by nineteenth-century methods.”

Nathan C.

Nature 2004; 431:899-902

Time to initiating effective

therapy using PNA FISH

for enterococcal BSI

PNA FISH

Standard microbiologic reporting

Forrest GN et al. AAC 2008; 52: 3558-3563

Matrix assisted laser desorption ionisation

time-of-flight mass spectrometry

(MALDI-TOF MS)

• Compares mass spectral signals with a database of

spectra from reference standard spectra

• Very swift (<60 min.)

• Requires positive cultures, inocula>104 CFU/ml

• No reduction of time for antibiotic resistance testing

• Inaccurate identification of viridians Streptococcus spp.

(S. pneumonia, S. mitis) + polymicrobial infections

MALDI-TOF MS in Clinical Microbiology.

Patel R. Clin Infect Dis 2013; 57: 564-72.

Stewardship & Maldi-TOF MS….

Timeline comparison of pre-intervention (PI) and intervention (Int) study periods.

Adjusted therapy included de-escalation/escalation of antibiotic therapy, dosing/route

modifications, and/or discontinuation of unnecessary Gram-positive coverage.

Perez KK et al. J Infect 2014; 69: 216-25

…. improves patient outcomes

• Integrating rapid diagnostics with AMS improved time to

optimal antibiotic therapy (80.9 h pre- vs 23 hours in the

intervention period; P < .001)

• Mortality among patients during the intervention period

was lower (21% vs 8.9%; P = .01)

Perez KK et al. J Infect 2014; 69: 216-25

Comparison of time to organism identification,

availability of phenotypic antimicrobial

susceptibility results, and first appropriate

modification of antimicrobial therapy

Marketed molecular tests for BSI performed on whole blood

Assay/

Manufacturer

Amplification Anti-microbial

resistance

Work-

load/

Cost

Detectable

pathogens

Detection

limit

(CFU/ml)

Turn-

around

time (h)

SepsiTest

(Molzym,

Germany)

Broad range PCR +

sequencing

None High/High >300 different

pathogens

20-40 for S.

aureus

8-12

Vyoo (SIRS-Lab,

Germany)

Multiplex PCR + gel

electrophoresis

Mec, vanA, vanB,

vanC, blaSHV genes

High/High >40 different

pathogens

≥10 8

LightCycler

SeptiFast (Roche,

Germany)

Multiplex real-time

PCR

MRSA High/very

high

>25 pathogens 10-30 6

Plex-ID/ IRIDICA

(Abbot, USA)

Multiplex real-time

PCR + electrospray

ionization mass

spectrometry

MecA, vanA, vanB,

vanC, blaKPC genes

Low/High Multiple

pathogens

including virus,

semi-quantative

To be

determined

>1-3?

8-12

GeneXpert

(Cepheid, USA)

Multiplex real-time

PCR

TB rifampicine R Low/High Multiple

pathogens

NA 1-6 ??

BioSeeq (Smith

detection, USA)

Multiplex real-time

PCR

NA Low/NA NA NA NA

SeeGene (Korea) Multiplex real-time

PCR

vanA, VanB, mecA High/High >90 pathogens NA 3-4

Optimize antibiotic use (2)

• Decrease diagnostic uncertainty

• Implement formulary restrictions for important types of

antimicrobial use

Lafaurie et al. J Antimicrob Chemother. 2012 Apr;67(4):1010-5.

Reduction of fluoroquinolone use is associated with a decrease in

methicillin-resistant Staphylococcus aureus and fluoroquinolone-

resistant Pseudomonas aeruginosa isolation rates: a 10 year

study.

• Hôpital Saint-Louis, Paris (France)

• Interrupted time series

– monthly fluoroquinolone use MRSA &

fluoroquinolone-resistant P. aeruginosa isolates

• Three periods

– pre-intervention (January 2000–August 2005)

– intervention (September 2005–March 2006)

– post-intervention (March 2006–March 2010)

• Intervention

– audit & feedback, guidelines, indvidualized

consultations

Reduction of fluoroquinolone use is associated with a decrease in

methicillin-resistant Staphylococcus aureus and fluoroquinolone-

resistant Pseudomonas aeruginosa isolation rates: a 10 year

study.

FQ

useP

aeruginosa

MRSA

Lafaurie et al. J Antimicrob Chemother. 2012 Apr;67(4):1010-5.

Formulary restriction at

Mass Gen Hosp, Boston

(USA) :

“ Imipenem, tic/clav,

aztreonam, cefta, cipro,

pip/tazo require prior

approval by infectious

diseases “

The reality at the same

hospital ….

35-y old woman with

severe sepsis:

“ Ampicillin-sulb,

clindamycin, penicillin,

gentamicin, vancomycin

were infused

intravenously “

Gilbert et al.

Am J Med; 1998; 104: 17-27

Case report 28-2002 of the MGH,

NEJM Sept 12, 2002, p.831-37

Does restriction always work?

Optimize antibiotic use (2)

• Improve diagnostic tools

• Implement formulary restrictions for important types of

antimicrobial use

• Improve antimicrobial prescribing:

– Education (pre- and postgraduate)

– Administrative means

(antibiotic order forms)

– Practice guidelines

Impact of an educational program on antibiotic use in a tertiary care hospital in Thailand

Appropriate antibiotic use (in-patients, %)

Apisarnthanarak et al. Clin Infect Dis 2006; 42: 768

Impact of an educational program on antibiotic use in a tertiary care hospital in Thailand

Antibiotic resistance

Apisarnthanarak et al. Clin Infect Dis 2006; 42: 768

Optimize antibiotic use (2)

• Improve diagnostic tools

• Implement formulary restrictions for important types of

antimicrobial use

• Improve antimicrobial prescribing:

– Education (pre- and postgraduate)

– Administrative means

(antibiotic order forms)

– Practice guidelines

• Computer-assisted decision-support tools

Interventional trial (n = 2323)TREAT wards vs. controls

Appropriate therapy: protocol analysis

0%

20%

40%

60%

80%

100%

Control wards TREAT wards

OR = 3.4095%CI= 2-6

J Antimicrob Chemother. 2006; 58: 1238-45

J Antimicrob Chemother. 2007; 59: 1204-07

Agenda

• Variation in hospital antibiotic use

• Antibiotic stewardship:

Useful strategies

• Implement & evaluate interventions

Initiating the ABS Program

• Have a plan & project outline

• Know the resources required

• Adapt to your local situation & culture

– ID knowledge of physicians

– Microbiology support

• Develop the program (with key personnel)

• Set your goals (not only financial) and define

expected outcomes

Identify potential barriers…

Owens RC Jr, Schorr AF, Deschambeault AL.

Antimicrobial stewardship: shepherding precious resources.

Am J Health Syst Pharm 2009; 66: 12 Suppl 4: S15-22.

• Lack of leadership support

• Shortage of adequately trained ABS specialists

• Competition for funding with other programs

• Communicating with antagonizing colleagues

• Influence of marketing efforts

A Successful Antimicrobial Management Program

-- Netcare Group, South Africa --

• Implemented in 55 hospitals since 2010

• Adopted the IHI collaborative approach,

involving multidisciplinary teams

• Automated data collection for surveillance

• Established specific outcome measures

and deliverables (with ranking of hospitals)

• Workshops and teleconferences

• AB guidelines

• Audits & feedback

Local polynomial smoothed curves for the five

parameters targeted for improvement (weeks 1–104)

Antimicrobial stewardship education tools to assist health-care providers

CONCLUSIONS

Summary of ABS Measures

Middle

BHigh

CRessources

Measures

Low

A

Guidelines

Clinical algorithms

Antibiotic prophylaxis

AMR surveillance

AB committee

ABuse audits

Improved microbiologic support

Restriction & education

Streamlining program

Academic detailing

Early bug detection (PCR)

New diagnostic markers

Decision support systems

Antibiotic Stewardship Priorities

• Improve perioperative prophylaxis

• Promote short-course, high-dose AB therapy

• Promote local guidelines and training

• Decrease diagnostic uncertainty by any type of

diagnostic tools or decision support

• But: changing AB prescribing behavior is

complex and needs a multifaceted approach