MDRO Strategies
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Transcript of MDRO Strategies
This presentation was presented at Apollo International Forum on Infection Control (AIFIC’ 2013), Chennai
The presentation is solely meant for Academic purpose
Disclaimer: My Perspective
I have neither the
intellectual depth
nor
the luxury of the
remote academic view
that ID specialists or
clinical microbiologists
may have……
Intensive Care…
….is a “downstream” speciality…
…we face the consequences of
many therapeutic misadventures!!!
MDRO Definition “Micro-organisms (predominantly bacteria) that are resistant to one or more classes of anti-microbial agents
MRSA
VRE
ESBL Gram negatives “Pan-resistant” Acinetobacter KPC- Klebsiella pneumoniae
VIM-2 / NDM-1 Klebsiella pneumoniae Stenotrophomonas
Burkholderia VISA
VRSA…..
Assault of the Acronym
…& the “Power of Bacteria”… (Historical & Numerical = Genetic)
Age: Bacteria 3,500,000,000 years (2000x) = 1yr
Eukaryotes 1,800,000,000 years (1000x)
Multi-cellulars 580,000,000 years (300x)
Australopithecus 4,000,000 years (2x)
Homo erectus <2,000,000 years (1) = 5.2 hrs
Antibiotic use 60 years (0.00003x) = 55 secs
Numbers: “ The number of E. Coli in the gut of each human being far exceed the number of people that now live or have ever inhabited the earth” !!! - Gould SJ; Life’s Grandeur
S. aureus
Penicillin
[1950s]
Penicillin-resistantS. aureus
Methicillin
[1970s]
Methicillin-resistantS. aureus (MRSA)
Vancomycin-resistant
enterococci (VRE)
Vancomycin
[1990s][1997]
Vancomycinintermediate-
resistantS. aureus
(VISA / GISA)[2002]
Vancomycin-
resistant
S. aureus
S. aureus
Penicillin
[1950s]
Penicillin-resistantS. aureus
Methicillin
[1970s]
Methicillin-resistantS. aureus (MRSA)
Vancomycin-resistant
enterococci (VRE)
Vancomycin
[1990s][1997]
Vancomycinintermediate-
resistantS. aureus
(VISA / GISA)[2002]
Vancomycin-
resistant
S. aureus
…antibiotic resistance is Inevitable !
Selection of Resistance
Antibiotic
exposure
Resistant strains: rare
No survival advantage
Resistant strains:
dominant
Use Promotes Resistance
JAC; DOI: 10.1093/ jac /dkg488
% Resistance
Usa
ge
(DD
D/1
000/
day
)
Urinary E. Coli Resistance vs. Antibiotic Use
Antibiotic use is a strong Correlate of Resistance
(but not the only factor)
Antibiotics & Resistance
Widespread use of antibiotics leads to the selection of antibiotic resistant strains
Archibald et al; ICARE
Clin Inf Dis 1997; 24: 211-15
Evidence:
Resistant organisms are more common amongst inpatients
ICUs (with highest use) have highest rates of resistance 0
5101520253035404550
% R
esis
tan
t O
rgan
ism
s
MRSA
MRSE
Pseud C
TZVRE
Inpatient
Outpatient
p <0.01 for all comparisons
Methicillin Resistant Staphylococcus Aureus
0
10
20
30
40
50
60
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Perc
en
t R
esis
tan
ce
Extended Spectrum Beta Lactamase (Klebsiella)
0
2
4
6
8
10
12
14
19891990
19911992
19931994
19951996
19971998
19992000
Per
cent
Res
ista
nce
7x
Quinolne Resistant Pseudomonas Aeroginosa
0
5
10
15
20
25
30
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Perc
en
t R
esis
tan
ce
3x
ESBL in the Developing World
Site Location %ESBL
Klebsiella E. coli
AIIMS, New Delhi1 Tertiary Hospital 80% -
Mathai 10 Tertiary Hosps. - >60%
KGMC, Lucknow2 Neonatal ICU 86% 64%
SMF, Chennai Nosocomial: ICU 84% 82%
SMF, Chennai Comm. Acquired: ICU 53% 44%
China, Shanghai3 University Hospital 51% 24%
Latin America4 SENTRY, Pneumonia 44% 29%
1: Ind J Med Res 2002;115:153-7 2: J Med Microb 2003; 52: 421-5 3: Zhou Yi Xue Za Zhi 2002;82:1476-9 4: Diag Mic Inf Dis 2002; 44: 301-11
Developing World ICUs International Nosocomial Infection Control
Consortium (INICC)
8 Countries; 55 ICUs; 46 Hospitals
NNIS (USA) INICC
1992-2004 2002-5
MRSA 59% 84%
ESBL 19% 55%
Quin. res Pseudo. 29% 59%
VRE 29% 5%
Ann Int Med 2006; 145: 582-91
Does ‘ESBL’ kill?
Case control study from Israel (198 patients)
Multivariate analysis;
ESBL remains independently associated
with
Mortality OR 3.6 (1.4 - 9.5) p <0.008
Delayed Rx OR 25.1 (10.5 - 60.2) p <0.001
LOS OR 1.56 p <0.001
Cost OR 1.57 p <0.003
Antimicrob Agents Chemo 2006; 50: 1257-62
VRE Implications: Mortality
Vancomycin Resistance is:
An independent predictor of death in
EC bacteremia (OR: 2.1; 95% CI:1.14-3.88)
Associated with J all cause mortality
(52% vs. 27% in vanco sensitive)
An independent predictor of infection
related death (OR: 5.2; 95% CI: 1.4-20.0)
Newer studies (? more effective Rx) show
no difference
Ann Int Med 2001; 135: 484-92
Diag Micr ID 2000; 36: 145-52
CID 2000; 30: 466-72
CID 2002; 34: 922-9
MRSA: Attributable Mortality
Clin Inf Dis 2003; 36:53–9
*Anes Clin N A 2004: 22 ; 405 - 35
Meta-analysis:
31 cohort studies
3963 patients
2/3 MSSA vs. 1/3 MRSA
Debated with VAP*
Odds of death 2x with MRSA bacteremia vs. MSSA
Risk Factors for MDRO
Age / co-morbidity
Severity of illness
ICU admission
Prior Antibiotic exposure
Prior colonization
Exposure to colonized/ infected patient
Invasive Device use
Demographic
Antibiotic / infection control
Procedural
CID 2001; 33: 939-46
Inf Cont Hosp Epi 2009; 30: 1180-5
Factors
Severity of illness….
Device use
Antibiotic use
Approach to Preventing MDRO
Avoid Devices
Minimise
device-associated
infection
Rational & conservative
antibiotic use
Early goal-directed
Rx
Cannot justify an “I’m not to blame” attitude
CDC: Strategies
Administrative Support
Education
Antibiotic Use
Active Surveillance Culture
Isolation Precautions
Environmental issues
Decolonization
Administrative Support
Education
Antibiotic Use
Active Surveillance Culture
Isolation Precautions
Environmental issues
Decolonization
Is our empirical strategy correct?
What is the value of a restricted formulary?
Practicality?
Culture vs. rapid detection?
Mupirocin & SDD?
Assumptions for use of Empirical Antibiotics
Infection J (attributable) mortality
Antibiotic treatment K mortality
Early administration of correct antibiotic is better than delayed administration
Adverse effects < the benefits of treatment
Attributable Mortality
Nosocomial Attributable
Infection mortality
All Nosocomial Infection 20% (2.8-44)
Blood-stream 25% (4.4-47.3)
Vent. Assoc. Pneumonia 25% (7.8-42)
Urinary Tract None Chest 2001; 120:2059–93
Definition:
Mortality caused by an infection (in excess of mortality in a similarly ill patient without infection).
Is death attributable to NI?
NI
Treat Don’t Treat
Is there a difference?
Yes No
NI kills Patient dies of
critical illness
Unethical to evaluate in this way!
Is death attributable to NI?
Cohort of ICU Patients
NI No NI
Rx No (appropriate) Rx
Severity of illness is a confounder;
May be adjusted by case-control studies
or Multivariate (regression) analysis
Ideally Propensity modeled
Definition:
Difference in death rates between
infected & uninfected patients after adjusting
for confounders
Effect of Appropriate Choice
Luna et al;
Chest 1997; 111: 676-85.
0
10
20
30
40
50
60
70
80
90
100
No Rx Correct Rx Incorrect
Ho
spit
al M
ort
alit
y (%
)
Effect of Appropriate Timing
0
10
20
30
40
50
60
70
80
90
100
Early Late
None Correct Incorrect
Ho
spit
al M
ort
alit
y (%
)
Luna et al;
Chest 1997; 111: 676-85.
Methodological Issues
CID 2007; 45: 329 - 37
Systematic review of 51 studies of “appropriate antibiotics” and mortality in bacteraemia
No distinction : Empirical vs. definitive
Only 16% (8) defined “appropriate” on the basis of in-vitro Cx + route + dose
Only 35% looked at attributable mortality
Only 21% (7) timed severity of illness measures; but 2 measured it at admission
33% (17) adjusted for septic shock
Only one study used Propensity scores
Lab confirmed
Suspect
infection
Avoiding Overuse: “De-escalation”
Initial Rx
Multiple drugs
wide-spectrum
De-escalate Rx
Chest 2002; 122:2183–2196.
Culture-based
de-escalation can
reduce resistance
Making De-escalation Possible De-escalation is seldom attempted
Recent study of VAP*
De-escalation only in 22% patients
Likely to occur if:
3-4 antibiotics were initially used
If adequate cover was initially provided
If major pathogen grew on culture
If culture method was more robust *Chest 2006; 129:1210–1218
Rational De-escalation?
Can we use sputum, BAL cytology & culture to make decisions?
Probability of VAP +ve -ve
BAL with bacteria >95% 25-50%
Sputum culture 95% 45%
BAL culture 72-95% 50%
No! JAMA. 2007;297:1583-93
Current Empirical Rx encourages overuse
Suspected VAP
Rx
VAP No VAP
Appropriate Inappropriate ?
Colonization by resistant bugs
& subsequent adverse outcome
65% 35%
No de-escalation
De-escalated
VAP: A Decision Analysis
A decision analysis based on available
data suggests:
Empirical Rx (using clinical diagnosis) :
66% mortality in the untreated patients
68% mortality in treated patients
Chest 1996; 110:1025-34
Reasons for unexpected death with Rx: Diagnostic certainty is low (0.23)
Uninfected pts colonize c resistant strains
Limitations: Old data; incomplete info
Cycling
Strategies to Reduce Resistance
Abx 2 Abx 3 Abx 1
Res
ista
nce
Abx 1
Presumes that a decline in resistance will occur with antibiotic cessation (ie, there is a ‘fitness cost’ to antibiotic resistance.)
Time
None of the evidence is “clean”
Mainly observational cohorts
Some studies are of a single scheduled change (not cycling)
Associated confounders:
Antibiotic restriction policies
Infection prevention strategies
Often evaulate nosocomial infection alone not colonisation rates
RCTs are needed
Cycling: The Evidence?
Gerding et al
AAC 1991; 35: 1284-90
Koleff et al
AJRCCM 1997; 156: 1040-8
Gruson et al
AJRCCM 2000; 162: 837-43
Raymond et al
CCM 2001; 29: 1101-8
Toltzis et al
Paediatrics 2002; 110: 707-11
Inefficacy of Cycling Restriction, Rotation, ?Rubbish…
Res
ista
nce
Abx 2 Abx 3 Abx 1 Abx 1
The rate of decline of resistance will depend on:
the cycling interval &
the fitness cost of antibiotic resistance
Proc Nat Ac Sci 1999; 96:1152-56
Mathematical Models
Model simulating hospital patients / NI
Bergstrom & Reluga:
Cycling and mixing are better than one drug
Non-optimal strategies of cycling or mixing degrade effect
Even in optimal conditions cycling is not much better than mixing
“Cycling is unlikely to reduce either the evolution or the spread of antibiotic resistance.” and “inappropriately optimized cycles may hinder resistance control”
Math Med & Biol 2005; 22: 187-208
PNAS 2004 ; 101: 13285–13290
Empirical Evidence
J Antimic Chemo 2006;
57: 1197–1204
44 month, single ICU evaluation of
4 strategies: Patient-specific antibiotic
Prioritized antibiotic (cycled)
Restricted antibiotic (cycled)
Maximal heterogeneity (mixed)
Antibiotic heterogeneity: Peterson Index
Homogeneity associated with
J Carbepenem Res. Acinetobacter : RR 15.5 (5.5–42.8)
J ESBL: RR 4.2 (1.9–9.3) and
J Enterococcus faecalis: RR 1.7 (1.1–2.9).
Preventive Strategies
Active Surveillance Cultures + Contact Precautions
Identify both colonized & infected patients early
Restrict spread by strict infection control processes
ASC + Precautions Best studied with MRSA; less with Gm Neg
ASC shows benefit in some; inconsistent
Mathematical modelling:
VRE: Culture (vs. none) K transmit ~40%
Culture + isolation K transmit 65%
MRSA: Routine cultures are ineffectual
ASC can reduce rates
Debated: When, how often, Which patients (all vs. at risk) Sites, Methods
Need RCT!
The RCT; You asked for it!
N E J Med 2011; 364: 1407-18
Cluster randomized study
10 intervention ICUs (surveillance Cx + barrier)
8 control ICUs (n= 5343 & 3705 respectively)
Surveillance cultures on all (reported to Rx grp)
MRSA+VRE colonization & infection unchanged
40.4+3.3 vs 35.6+3.7 / 1000 patient days (p 0.35)
Compliance with barrier precautions was suboptimal
The VA Initiative
2007 – 2010; 1.9 million admits ICU / non ICU 8.3 million patient days; “MRSA Bundle” initiated
Universal nasal surveill’nce: Chromgenic agar/ PCR
+ Contact precautions
K ICU MRSA ~62% (relative risk)
K Non-ICU MRSA 45%
“MRSA Bundle”
Universal nasal survl. Contact precautions Hand Hygiene “Infection control as everyone’s responsibility”
N E J Med 2011; 364: 1419-30
The Gist: STAR ICU vs. VA
While one can decry the deficiencies of observational cohorts; RCTs often underestimate benefits
The prime issue: methodology of surveillance
STAR: Routine Cx: Median positive ~ 5 days
VA: Chromgenic + PCR (“real time”)
Extrapolation to MDRO Gram negatives
Spot-tests for gram negative MDROs limited
Value of contact precautions is unsubstantiated
Decolonization:
I am not competent to discuss the merits of Mupirocin to prevent MRSA
But am tempted to introduce the concept of Selective Decontamination of the Digestive Tract (SDD)……
….interesting lessons!
The problem of
“Dutch” Ideas
Euthanasia
Legal drugs
Legal prostitution
“Going Dutch”
A function of living below sea level?
Methodology of SDD* *Selective Decontamination of the Digestive Tract
1. Oral application of antibiotic:
Tobra+ Amphotercin+ Polymixin
(Vancomycin added if MRSA is J)
2. NG administration
3. Systemic Antibiotics for 24-48 hr
CID 2006; 43: S70–4
1 & 2: “Selective”; anaerobes preserved
Reduce GI/ Oropharynx colonization
3: Prevents early colonization / VAP
Outcomes with SDD
D’amico
BMJ 1998; 316; 1275-85
Meta analysis
30 RCTs
5727 patients
Odds of VAP and death reduced;
VAP; OR 0.35 (0.29-0.41)
Death; OR 0.8 (0.69-0.93)
Death K from 30% to 24%
NNT to prevent one death = 16
Best effect in surgical ICU patients
Rx
Rx
So why not use SDD?
Resistance?
Fear of inducing bacterial resistance Not conclusively established
Resistance?
Will it work when rate of bacterial resistance is high in an ICU Has been used to combat outbreaks of resistant organisms; not in endemic high-resistance ICUs
AJRCCM 2001; 164: 382-88
AJRCCM 2001; 164: 338-9
AJRCCM 2002; 166: 1029-37
Intens Care Med 1999; 25: 1323-6
Rx
Rx
SDD in India?
Mathematical Modeling*
Maximum effect shown when: a. Colonization pr. with resistant bacteria is low
b. All patients at risk are given SDD
c. No external source of potential pathogens
Rx
Rx
* Bootsma et al
Intersci Conf Antimicrob Agents Chemother.
2003 Sep 14-17; 43:
abstract no. K-698.
None of the above can be met in our ICUs a. ESBL ~ 80%; MRSA ~50%; MDR
Pseudomonas~ 40%; MDR Acinetobacter
b. Not cost-effective to give SDD to everyone
c. Requires pre-emptive isolation (quarantine)
More Math Models!
The benefit of non-absorbable “antibiotic prophylaxis can only be substantial if patient-to-patient transmission has already been reduced to a subcritical level by barrier precautions”…..
“a firm theoretical argument against routine use of topical antimicrobial prophylaxis”
Tackling MDROs!
We are facing the consequences of decades of irresponsible use: So control processes will be expensive
Best option: ASC + Contact Precautions
Real-time surveillance need development
ICU Antibiotic use needs to be reduced
Prophylactic Abx only work after prevalence rates are reduced
Infection Control Processes remain supreme