Strategic in Preventing

Mi bi l Resistance
Microbial R it :
Antimicrobial Stewardship

DR Dr Latre Buntaran Sp
DR.Dr.Latre Sp.MK(K)
MK(K)
Clinical Microbiologist Consultant
Secretary General of PERDALIN ( INASIC )
Chairman of the Hospital Infection Control Compartment PERSI
Indonesia Coordinator of ANSORP Study
 Antibiotic Resistance
A worldwide problem1
Associated with increased morbidity,
morbidity
mortality, and hospital costs1
Occurs in both hospitals and the community2
Results
R l fromf ffactors such
h as antibiotic
ibi i misuse
i 1

Source:
1: R. A. Kulkarni et al. Indian J Surg. 2005: Volume 67(6): 308-315.
2 Ben-David D, Rubenstein E. Curr Opin Infect Dis 2002;15:151-156.
Pola kuman (5 Besar Mikroba tertinggi) di RS A
Januari - Juni 2014

1. Acinetobacter baumanii 23 %
2. Streptococcus viridans 18 %
3 Staphylococcus
3. St h l epidermidis
id idi 11 %
4. Klebsiella pneumoniae 10 %
5. Pseudomonas aeruginosa 10 %
Pola Mikroorganisme di ICU
J
Januari
i - Juni
J i 2014 (N : 60)
Sensitifitas Acinetobacter baumanii di ICU
Januari - Juni 2014
Persentase MDR Acinetobacter baumanii
Sensitifitas Klebsiella pneumoniae di ICU
J
Januarii - Juni
J i 2014
Persentase Klebsiella pneumoniae
ESBL & Non ESBL Producer

Klebsiella pneumoniae Non ESBL producer

Klebsiella pneumoniae ESBL producer

 Persentase Escherichia coli
ESBL & Non ESBL Producer

E h i hi coli
Escherichia li Non
N ESBL producer
d

Escherichia coli ESBL producer

Sensitifitas Pseudomonas aeruginosa di ICU
Januari - Juni 2014
Persentase MDR Pseudomonas aeruginosa
g
 MRSA & MSSA

67%

33%
Sensitifitas Staphylococcus epidermidis di ICU
Januari - Juni 2014
 MRSE & MSSE

60%

40%
Outcomes
O t Related
R l t d to
t MRSA
Surgical
g Site Infections

Cosgrove SE. Clin Infect Dis 2006; 42: S829.

Outcomes
O t for
f Patients
P ti t with
ith Emergence
E off
3rdGeneration Cephalosporinresistant
p p
Enterobacter species

Cosgrove SE. Clin Infect Dis 2006; 42: S829.

 Outcomes
O t off Infections
I f ti due
d tto
ESBL
S E.. co
coli & ESBL
S K.. p
pneumonia
eu o

Cosgrove SE. Clin Infect Dis 2006; 42: S829.

Mechanisms of Multiple Resistance
to Antibiotics
Chromosomal beta-lactamase.
Active Efflux pump.
Easily get mobile genetic elements harbouring,
resistance genes
genes, such as plasmid,
plasmid integrons and
transposons.
 Emerging Resistant Pathogens:
Health Care Facilities
Staphylococcus aureus : Oxacillin (multidrug
resistance including vancomycin)
vancomycin).
Enterococcus: Penicillins, aminoglycosides,
vancomycin, linezolid, dalfopristinquinupristin.
Enterobacteriaceae:
b i ESBL
S producers
d ((E. coli,
l K.
ppneumoniae, Enterobacter spp.).
pp )
Multidrug resistant: Pseudomonas aeruginosa,
Acinetobacter spp., and Stenotrophomas maltophilia.
 Potential Determinants
Pathogen and microbial ecology
Physicians
h i i prescribing
ibi practice
i
Population characteristics
Politics and healthcare policy
antimicrobial stewardship
 P
Prevention
ti and
d Control
C t l Measures
M

Infection prevention / control

Identify cases
cases.
Clean hands.
Isolate and use barrier precautions.
precautions
Separate colonized/infected and noncolonized patients.
Cl
Clean andd control
t l off environmental
i t l or other
th potential
t ti l
sources.
Antimicrobial
A ti i bi l stewardship
t d hi
 Li it ti
Limitations off Infection
I f ti Control
C t l

Difficult with bacteria that colonize

gastrointestinal tract.
tract
Resource intensive.
Compliance often suboptimal.
 D fi iti
Definition

An ongoing effort by a health care institution to

optimize antimicrobial use among hospitalized patients
in order to :
Improve patient outcomes.
Ensure cost-effective therapy.
Reduce adverse sequelae of antimicrobial use
((includingg antimicrobial resistance).
)

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship. Clin Infect Dis 2007; 44: 15977.
 H
Hypothesis
th i

Antibiotic prescribing behaviors can be

changed.
changed
Antibiotic use is a primary cause of resistance.
A reduction in use will reduce or slow
resistance.
resistance
Appropriate use can improve outcomes and
costs.

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
G l off Antimicrobial
Goals A ti i bi l Stewardship
St d hi

Optimizing clinical outcomes while

minimizing unintended consequences of
antimicrobial use.
Reducing health care costs without adversely
impacting quality of care.
care

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
 T
Target
tOOutcomes
t

Reduction in total or targeted antimicrobial

use.
use
Increase in appropriate drug use.
Improvement in susceptibility profiles of
hospital pathogens.
pathogens
Improvement in clinical markers (such as
reduced
d d length
l h off stay).
)

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
 Comprehensive Evidence Based
St
Stewardship
d hi PProgram
11. Multidisciplinary antimicrobial stewardship team.
team
2. Collaboration between antimicrobial stewardship team,
hospital infection control, pharmacy & therapeutics
committees / their equivalents.
3. Support
pp & collaboration of hospital
p administration,, medical
staff leadership & local providers.
4. Hospital administrative support.
5. Health care information technology in the form of electronic
medical records.
6. Computerbased surveillance.
7. Microbiology laboratory.
8. Process measures and outcome measures.
IDSA/SHEA. Guidelines for developing an instutional program to enhance antimicrobial stewarship..
Clin Infect Dis 2007; 44: 15977.
 C
Core M
Members
b ffor A
Antimicrobial
ti i bi l
Stewardship
S ew ds p Teame
An infectious diseases physician.
p y
A clinical pharmacist with infectious diseases
training.
training
A clinical microbiologist.
An information system specialist.
An infection control professional
professional.
Hospital epidemiologist.
IDSA/SHEA. Guidelines for developing an instutional program to
enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
R l off IInfectious
Role f ti Di
Diseases Ph
Physicians
i i

As a supervisor.
To
T ensure :
Therapeutic guidelines.
Antimicrobial restriction policies.
Other measures
measures.
based on the best evidence & practice and not
putt patients
ti t att risk.
ik

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
Appropriateness
A i t off th
the E
Empirical
i i l Treatment
T t t
According to the Treating Physician

Byl B. Clin Infect Dis 1999; 29: 606.

 Proportion of
Infectious
disease bacteremic episodes
specialist appropriately treated
by infectious disease
Other
physicians specialist (circles) and
other physicians
(squares) over time.
The difference between the 2
curves is statistically
significant during the first 2
days.

Byl B. Clin Infect Dis 1999; 29: 606.

Appropriateness of the treatment given at the time when
bloodisolate gram stain &
antimicrobial susceptibility test results were available,
according to the treating physician.

Laboratory test Proportion (% of total) of P

results appropriate treatments by value
IDSs Other
physicians
Gram stain 249/258 (97) 94/106 (89) 0.008
Antimicrobial 265/265 (100) 84/87 (97) 0 015
0.015
susceptibility

Byl B. Clin Infect Dis 1999; 29: 606.

 R l off Cli
Role Clinical
i l Microbiologist
Mi bi l i t
Summary data on antimicrobial resistance rates

Current burden of antimicrobial resistance in the hospital

Antimicrobial Clinicians
Stewardship Team

Better selection of
Antimicrobial restriction
empirical therapy
IDSA/SHEA. Guidelines for developing an instutional program to
enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
35
 PPRA ( AMSP ):
Class on Antibiotics Policy

Classification of antibiotics
Cl
Class A : Not
N t restricted
t i t d
Class B : Not restricted, under
supervision
i i
Class C : Restricted
Implementation
Evaluation and surveillance
Auditing
 Classification of Antibiotics
Class A Class B Class C
Aminoglicoside Cephalosporine Vancomycine
Penicillin gen III Teicoplanin
C h l
Cephalosporini gen.I,II
I II Fl
Fluoroquinolone
i l Li
Linezolide
lid
Chloramphenicol gen III-IV Cefepime
Fucidic acid Sulperazone Cefpirome
Lincosamide Aztreonam Ceftazidime
Macrolide Pip-Tazo
Nitroimidazol Carbapenem
Fluoroquinolone Tigecycline
gen.I,II
Tetracyline
TMP-SMX
Fosfomicin
Polypeptide
Implementation of Antimicrobial
Policy in Hospital

Community Hospital
i f ti
infection i f ti
infection
Outpatient Class A Class A

Inpatient Mild
WARD Moderate Class B Class C
Severe

ICU Cl
Class B/C Cl
Class C
Treatment Option Against ESBL

Kuman/Specimen JUMLAH % sensitivitas

FOSFOMYCIN
Klebsiella pneumoniae Non ESBL producer 4 75%
Klebsiella pneumoniae ESBL producer 5 80%

Kuman/Specimen
p % sensitivitas
JUMLAH
FOSFOMYCIN
Escherichia coli Non ESBL producer 9 100%
Escherichia coli ESBL producer 9 100%
 C
Core St
Strategies
t i

1. Prospective audit, intervention & feedback

increasing appropriate use of antimicrobials.
antimicrobials
2. Formulary restriction and preauthorization
reducing antimicrobial use and cost
immediatelyy & significantly.
g y

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
1 P
1. Prospective
ti Audit,
A dit IIntervention
t ti & F
Feedback
db k

Setting
S i : Universityaffiliated
U i i ffili d teaching
hi hospital.
h i l
Intervention begin
g in 1991 A clinical
pharmacist with special training in infectious
diseases shares the responsibility for evaluating
each patient & making recommendations with an
infectious diseases physician who serves as team
leader.

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

1 P
1. Prospective
ti Audit,
A dit IIntervention
t ti & F
Feedback
db k

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

 Rates of nosocomial
Clostridium difficile
before and resistant
Enterobacteriaceae
infections before &
after implementation
after of the antibiotic
management
program

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

2 F
2. Formulary
l Restriction
R t i ti & Preauthorization
P th i ti
Setting : 500bed,
500 bed university
universityaffiliated
affiliated community
hospital.
Design
D i : a bbefore
f after
ft comparativeti 2year
2 ti l
trial.
Interventions :
A new antibiotic guideline excluded the use of
cephalosporins except for pediatric infection, single
dose surgical prophylaxis, acute bacterial meningitis,
spontaneous bacterial peritonitis, and outpatient
gonococcal infection.
infection
All other cephalosporin use required prior approval by
the infectious disease section.
section
Rahal JJ, et al. JAMA 1998; 280: 12337.
Change in Number and Incidence of Patient Related
Ceftazidime Resistant Klebsiella from 1995 to 1996
following Cephalosporin Restriction in 1996

Rahal JJ, et al. JAMA 1998; 280: 12337.

2 F
2. Formulary
l Restriction
R t i ti & Preauthorization
P th i ti

Setting : Hospitalized patients who developed

d a ea.
diarrhea.
Design :
Concurrent surveillance for identification of new
nosocomial cases.
Retrospective case
casecontrol
control analysis
analysis.
Hospital formulatory control of antibiotic use.

Pear SM. Ann Intern Med 1994: 120: 272 7.

Number of Cases of Clostridium difficileAssociated
Diarrhea Detected Each Month Before and After
Clindamycin Restriction.

Clindamycin
restricted

Pear SM. Ann Intern Med 1994: 120: 272 7.

2 F
2. Formulary
l Restriction
R t i ti & Preauthorization
P th i ti

Setting : 772bed universityaffiliated tertiary

care medical center.
center
Design : quasiexperimental study to compare
the effectiveness of the antimicrobial
g
management team ((AMT)) & ID ((Division of
Infectious Disease) fellows.

Gross R. Clin Infect Dis 2001; 33: 28995.

Comparison of Antimicrobial Treatment
Managed by an AMT or ID Fellows

Gross R. Clin Infect Dis 2001; 33: 28995.

 Differences in Economic Outcomes among
180 Patients whose Antimicrobial Treatment was
Managed by an AMT or ID Fellows

Gross R. Clin Infect Dis 2001; 33: 28995.

 S
Supplemental
l t l Strategies
St t i
1. Education.
2.. Gu
Guidelines
de es & cclinical
ca pathway.
pa way.
3. Antimicrobial cycling & scheduled antimicrobial
switch.
4. Antimicrobial order forms.
5 Combination therapy.
5. therapy
6. Streamlining / deescalation of therapy.
7 Dose optimization
7. optimization.
8. Parenteral to oral conversion.
IDSA/SHEA. Guidelines for developing an instutional program to
enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 15977.
 1 Ed
1. Education
ti

Setting : 250bed public teaching hospital.

4 intervention
i t ti steps
t :
Period 1 baseline.
Period 2 initial intervention period.
Period 3 education phase.
phase
Period 4 active control period.

Bantar C Clin Infect Dis 2003; 37: 1806.

V i ti
Variations in
i Use
U off IV A
Antibiotics
tibi ti

Bantar C Clin Infect Dis 2003; 37: 1806.

 Variations
V i ti in
i The
Th Frequency
F off
Prescription of Different Antibiotics

Bantar C Clin Infect Dis 2003; 37: 1806.

 2 G
2. Guidelines
id li & Clinical
Cli i l Pathway
P th

Design : observational cohort study with

preguideline & postguideline data collection.
collection
Patients :
48 preguideline patients with 56 episodes of severe
HAP defined by National Nosocomial Infections
S
Surveillance
ill (NNIS).
(NNIS)
58 guideline treated (GUIDE) patients with 61
episodes of severe HAP.

Hoo GWS. Chest 2005; 128: 277887.

Ad
Adequacy off E
Empiric
i i AAntimicrobial
ti i bi l Coverage
C :
NNIS vs GUIDE Group

Hoo GWS. Chest 2005; 128: 277887.

Comparison
C i off Survival
S i l Group
G :
GUIDE vs NNIS Group

Hoo GWS. Chest 2005; 128: 277887.

 2 G
2. Guidelines
id li & Clinical
Cli i l Pathway
P th
A prospective beforeandafter study of a clinical
guideline for the management of VAP & broad
empirical therapy based on local microbiology with
culturedriven deescalation and a standard 7day
course of therapy.
Implementation of the protocol led to :
Increased initial administration of adequate
antimicrobial therapy (94% vs. 48%).
Decreased duration of therapy (8.6 vs. 14.8 days).
Decreased VAP recurrence ((8% vs. 24%). )
Ibrahim EH. Crit Care Med 2001; 29: 110915.
 33. Antimicrobial
A ti i bi l Cycling
C li &
Scheduled
Sc edu ed Antimicrobial
c ob Switch
Sw c
Settingg : universityaffiliated
y teachingg hospital.
p
Design : preintervention vs intervention :
Preintervention patients received ceftazidime for the
empiric treatment of suspected gramnegative bacteria
infections.
Intervention patients received ciprofloxacin for same
indication.

Kollef MH. Am J Respir Crit Care Med 1997; 156: 10408.

Cli i l Outcome
Clinical O t Measures
M

Statisticallyy insignificant
g
Kollef MH. Am J Respir Crit Care Med 1997; 156: 10408.
 4 Antimicrobial
4. A ti i bi l Order
O d Forms
F
Purpose : impact of a novel antibiotic prescription
system on antibiotic use.
Method : use of perioperative prophylactic order
forms with automatic discontinuation at 2 days.
y
Results :
A decrease in the mean duration of antimicrobial
prophylaxis (from 4.9 to 2.4 days).
A decrease in the percentage of patients receiving
perioperative prophylaxis for 12 days (from 85% to
44%).
)
Durbin WA. JAMA 1981; 246: 1796800.
 5 C
5. Combination
bi ti Therapy
Th
64 trials with 7586 patients were included
included.
Results :
No difference in all cause fatality and the rate of
development of resistance.
Clinical failure was more common with combination
treatment overall.
No
N advantage
d to combination
bi i therapy
h among patients
i
with Gram negative infections (1835 patients) or
Pseudomonas aeruginosa infections (426 patients)
patients).
Nephrotoxicity was significantly more common with
combination therapy.
therapy
Paul M. BMJ 2004; 328: 66881.
6 St
6. Streamlining
li i / De
D escalation
l ti off Therapy
Th

Patients : 625 patients.

Intervention : review combination antimicrobial
therapy by a pharmacist & an infectious diseases
physician.
physician
Results :
S
Streamlining
li i recommendations
d i in
i 54% off antimicrobial
i i bi l
courses over 7 months.
Projected
P j t d annuall savings
i off $107
$107,637.
637

Briceland LL, et al. Arch Intern Med 1988; 148: 201922.

 7 D
7. Dose O
Optimization
ti i ti

Design : prospective, openlabel controlled study.

Setting : community teaching hospital.
hospital
Patients : 98 hospitalized patients prescribed
piperacillin ta obactam
piperacillintazobactam.
Interventions :
47 patients received continuous infusion of piperacillin
tazobactam.
51 patients received intermittent infusion of piperacillin
tazobactam.

Grant ME. Pharmacotherapy 2002; 22: 47183.

 Comparison of PiperacillinTazobactam
by Continuous or Intermittent Infusion
Continuous Intermittent
infusion group infusion group
Cli i l success rates
Clinical 94% 82%

Microbiologic
Mi bi l i 89% 73%
success rates
Days to normalization 1.2 0.8 days 2.4 1.5 days
to fever
Costs $399.38 $523.49
407.22 526.85
Grant ME. Pharmacotherapy 2002; 22: 47183.
 8 P
8. Parenteral
t l tot Oral
O l Conversion
C i
Design : opencontrolled trial.
Patients : 541 ppatients with communityy acquired
q
lower respiratory tract infection divided into 3 groups
Groupp 1 received 375 mgg coamoxyclav
y per
p oral
3x/day for 7 days.
Groupp 2 received 1.2 ggram coamoxyclav
y per
p iv
3x/day for 3 days followed by 375 mg coamoxyclav per
oral 3x/day for 4 days.
Group 3 received 1 gram cefotaxime per iv 3x/day for
3 days followed by 500 mg cefuroxime per oral 2x/day.

Chan R. BMJ 1995; 310: 13602.

 Outcomes of 3 Groups CommunityAcquired
Lower Respiratory Tract Infection

Group 1 Group 2 Group 3

Duration of hospital stay 6 days 7 days 9 days

No discharged
g within 3 days
y 36 11 10

Ingredient cost per patient 7.8 32 51

Cure 40.9% 34.8% 38.6%

Death 9% 13% 11%

Chan R. BMJ 1995; 310: 13602.

 C
Computer
t B Based
d Surveillance
S ill
Setting : 12
12bed
bed shocktrauma
shock trauma respiratory ICU at acute
referral hospital and teaching center.
Patients : all patients admitted to the unit from July
1992 June 1995.
Intervention :
Using a computerized decisionsupport program linked
to computerbased
computer based patient records.
records
All patients was managed with use of the program.
If physicians
h i i didnt
did t order
d antiinfective
tii f ti recommended d d by
b
the program, he/she should explain their reasons.

Evans RS. N Engl J Med 1998; 338: 2328.

 I t
Intervention
ti
Computerized
C t program
t i d decisionsupport
d ii
Assist physicians in the use of antiinfective agents
& improve the quality of care.
Give epidemiologic
p g information,, along g with
detailed recommendations & warnings.
Recommends antiinfective regimens & courses of
therapy for particular patients.
Provide immediate feedback.
feedback

Evans RS. N Engl J Med 1998; 338: 2328.

Outcomes of Patients who Received Antiinfective
A t :P
Agents Preintervention
i t ti vs Intervention
I t ti Periods
P i d

Evans RS. N Engl J Med 1998; 338: 2328.

 Mi bi l
Microbiology Laboratorium
L b t i
Patients :
273 patients in the Rapid Antimicrobial Susceptibility Test.
300 patients in the Overnight Antimicrobial Susceptibility
Test.
Conclusions :
Significant cost saving for patients with sameday in vitro
susceptibility testing and bacterial identification.
identification
Rapid testing may be related to lower mortality rates in
patients with infection.
infection

Doern GV, et al. J Clin Microbiol 1994; 32: 175762.

Antimicrobial Prescribing Process &
A ti i bi l Stewardship
Antimicrobial St d hi Strategies.
St t i

MacDougall C & Polk RE. Clin Microbiol Rev 2005; 18(4): 638 56.
A ti i bi l Resistance
Antimicrobial R it Control
C t l Strategy
St t
Successful resistance prevention strategies
Eliminate antibiotics from animal feeds
Restricted hospital formulary
Unsuccessful resistance prevention strategies
Rotating formularies
CCU/ICU formularies
Restriction certain antibiotic classes
Reserving antibiotics for future use
Combination therapy to avoid resistance
Successful resistance control strategies
Effective infection control measure
Microbial surveillance to detect resistance problem early
Rapid implementation of infection control precaution
Restricted hospital formulary
 Antimicrobial Resistance:
Keyy Prevention Strategies
g
Susceptible Pathogen
Prevent Prevent
Transmission f
Infection

Antimicrobial Infection
Resistance
Effective
Optimize
O ti i Di
Diagnosisi
Use and Treatment
Antimicrobial Use CDC 2002
 12 Steps to Prevent Antimicrobial
Resistance: Hospitalized Adults
12 Contain your contagion Prevent
11 Isolate the pathogen Transmission
10 Stop treatment when cured
9 Know when to say nono to vanco
8 Treat infection, not colonization Use
7 Treat infection, not contamination Antimicrobials
6 Use
U local
l l data
d t Wisely
5 Practice antimicrobial control
4 Access the experts Diagnose and
3 Target the pathogen T
Treat Effectively
Eff i l
2 Get the catheters out Prevent
1 Vaccinate Infection

CDC 2002
 C
Conclusion
l i (I)
IImproving
i antimicrobial d hi is
ti i bi l stewardship
t i an
important first step.
A multidisciplinary team approach effective
antimicrobial stewardship.
Central to an effective program is a proactive strategy
incorporating
p gp prospective
p audit with direct
intervention and feedback to the provider and/or
preauthorization requirements
p q for antimicrobial use.
 C
Conclusion
l i (II)

A comprehensive evidencebased stewardship

pprogram
og a includes
c udes elements
e e e s chosen
c ose fromo among
a o g thee
following recommendations based on local
antimicrobial use and resistance p problems and on
available resources that may differ, depending on
the size of the institution or clinical setting.
g
Effective antimicrobial stewardship programs can be
self supporting and improve patient
financially selfsupporting
care.