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: [email protected].
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: [email protected].
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