Tackling Multiple Drug Resistant Organisms

1. This presentation was presented at Apollo
International Forum on Infection Control (AIFIC’
2013), Chennai
The presentation is solely meant for Academic purpose

2. Tackling Multiple Drug
Resistant Organisms

3. 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……

4. Intensive Care…
….is a “downstream” speciality…
…we face the consequences of
many therapeutic misadventures!!!

5. 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
Assault of the Acronym
Burkholderia
VISA
VRSA…..

6. Considering where
Antibiotics come from…
(not from the friendly neighbourhood drug dealer!)

7. …& 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

8. …antibiotic resistance is Inevitable !
Penicillin Methicillin
Penicillin-resistant Methicillin-resistant
S. aureus S. aureus S. aureus
[1950s] [1970s] (MRSA)
Vancomycin
[1997] [1990s]
Vancomycin Vancomycin-
Vancomycin- intermediate- resistant
resistant resistant enterococci (VRE)
[2002] S. aureus
S. aureus
(VISA / GISA)

9. Selection of Resistance
Antibiotic
exposure
Resistant strains: rare Resistant strains:
No survival advantage dominant

10. Use Promotes Resistance
Urinary E. Coli Resistance vs. Antibiotic Use
Usage (DDD/1000/day)
% Resistance
Antibiotic use is a strong Correlate of Resistance
JAC; DOI: 10.1093/ jac /dkg488 (but not the only factor)

11. Antibiotics & Resistance
50 p <0.01 for all
45 comparisons
% Resistant Organisms
40
35
Evidence:
30 Inpatient
Resistant organisms are 25 Outpatient
more common amongst
inpatients 20
15
ICUs (with highest use) 10
have highest rates of 5
resistance 0
SA
Z
SE
E
CT
VR
MR
MR
e ud
Ps
Archibald et al; ICARE Widespread use of antibiotics leads to the
Clin Inf Dis 1997; 24: 211-15 selection of antibiotic resistant strains

12. Percent Resistance
0
10
20
30
40
50
60
19
89
19
90
19
91
19
92
19
93
19
94
19
95
Aureus
19
96
Resistant
19
97
Methicillin
19
98
19
99
20
00
Staphylococcus

13. Percent Resistance
0
2
4
6
8
10
12
14
19
89
19
90
19
91
19
92
19
93
19
94
19
Beta
95
19
96
19
97
19
98
19
Extended
Spectrum
99
20
Lactamase
(Klebsiella)
00
7x

14. Percent Resistance
0
5
10
15
20
25
30
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
Quinolne
Resistant
19
98
Aeroginosa
19
99
20
Pseudomonas
00
3x

15. 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

16. 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

17. 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

18. 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)
Ann Int Med 2001; 135: 484-92
Diag Micr ID 2000; 36: 145-52
CID 2000; 30: 466-72
Newer studies (? more effective Rx) show
CID 2002; 34: 922-9 no difference

19. MRSA: Attributable Mortality
Debated with VAP*
Odds of death 2x with MRSA bacteremia vs. MSSA
Meta-analysis:
31 cohort studies
3963 patients
2/3 MSSA vs. 1/3
MRSA
Clin Inf Dis 2003; 36:53–9
*Anes Clin N A 2004: 22 ; 405 - 35

20. Risk Factors for MDRO
Age / co-morbidity
Severity of illness
ICU admission
Demographic
Prior Antibiotic exposure
Antibiotic / Prior colonization
infection control
Exposure to colonized/ infected patient
Procedural Invasive Device use
CID 2001; 33: 939-46
Inf Cont Hosp Epi 2009; 30: 1180-5

21. Approach to Preventing MDRO
Factors Early goal-directed
Severity of illness…. Rx
Device use Avoid Devices
Minimise
Antibiotic use
device-associated
infection
Cannot justify an
“I’m not to blame” Rational & conservative
attitude antibiotic use

22. CDC: Strategies
Is our empirical
strategy correct?
Administrative Support
What is the value of a
restricted formulary? Education
Antibiotic Use
Active Surveillance Culture
Culture vs. rapid detection? Isolation Precautions
Practicality? Environmental issues
Decolonization
Mupirocin & SDD?

23. Patterns of Antibiotic use
in the ICU

24. 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

25. Attributable Mortality
Nosocomial Attributable
Infection mortality
Definition:
Mortality caused by an All Nosocomial Infection 20% (2.8-44)
infection (in excess of
mortality in a similarly ill Blood-stream 25% (4.4-47.3)
patient without infection).
Vent. Assoc. Pneumonia 25% (7.8-42)
Chest 2001; 120:2059–93 Urinary Tract None

26. 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!

27. Is death attributable to NI?
Cohort of ICU Patients
Definition:
Difference in death NI No NI
rates between
infected & uninfected
patients after adjusting Rx No (appropriate) Rx
for confounders
Severity of illness is a confounder;
May be adjusted by case-control studies
or Multivariate (regression) analysis
Ideally Propensity modeled

28. Effect of Appropriate Choice
100
90
Hospital Mortality (%)
80
70
60
50
40
30
20
10
0
Luna et al; No Rx Correct Rx Incorrect
Chest 1997; 111: 676-85.

29. Effect of Appropriate Timing
100
90
80
Hospital Mortality (%) 70
60
50
40
30
20
10
0
Luna et al; Early Late
Chest 1997; 111: 676-85. None Correct Incorrect

30. Methodological Issues
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
CID 2007; 45: 329 - 37 Only one study used Propensity scores

31. Avoiding Overuse: “De-escalation”
Suspect
infection Initial Rx
Multiple drugs
wide-spectrum Lab confirmed
De-escalate Rx
Culture-based
de-escalation can
reduce resistance
Chest 2002; 122:2183–2196.

32. 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
*Chest 2006; 129:1210–1218 If culture method was more robust

33. 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%
JAMA. 2007;297:1583-93 No!

34. Current Empirical Rx encourages
overuse
Suspected VAP
Rx
65% 35%
VAP No VAP
Appropriate Inappropriate ?
De-escalated No de-
escalation Colonization by resistant bugs
& subsequent adverse outcome

35. 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
Reasons for unexpected death with Rx:
Diagnostic certainty is low (0.23)
Uninfected pts colonize c resistant strains
Chest 1996; 110:1025-34 Limitations: Old data; incomplete info

36. Gorillamycin Supersporin Kingkongopenem
Restrict
Cycle
Heterogeneous
use (Mixing)
0 1 2 3 months

37. Strategies to Reduce
Resistance
Cycling
Abx 1 Abx 2 Abx 3 Abx 1
Resistance
Time
Presumes that a decline in resistance will occur
with antibiotic cessation (ie, there is a ‘fitness cost’
to antibiotic resistance.)

38. Cycling: The Evidence?
 None of the evidence is “clean”
 Mainly observational cohorts
Gerding et al  Some studies are of a single scheduled
AAC 1991; 35: 1284-90 change (not cycling)
Koleff et al
AJRCCM 1997; 156: 1040-8
 Associated confounders:
Gruson et al
 Antibiotic restriction policies
AJRCCM 2000; 162: 837-43  Infection prevention strategies
Raymond et al
CCM 2001; 29: 1101-8
 Often evaulate nosocomial infection
alone not colonisation rates
Toltzis et al
Paediatrics 2002; 110: 707-11  RCTs are needed

39. Inefficacy of Cycling
Restriction, Rotation, ?Rubbish…
Abx 1 Abx 2 Abx 3 Abx 1
Resistance
The rate of decline of resistance will depend on:
the cycling interval &
Proc Nat Ac Sci 1999; 96:1152-56 the fitness cost of antibiotic resistance

40. 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
Math Med & Biol 2005; 22: 187-208
resistance.” and “inappropriately
optimized cycles may hinder resistance
PNAS 2004 ; 101: 13285–13290
control”

41. Empirical Evidence
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 Antimic Chemo 2006;  J ESBL: RR 4.2 (1.9–9.3) and
57: 1197–1204  J Enterococcus faecalis: RR 1.7 (1.1–2.9).

42. Preventive Strategies
Active Surveillance Cultures + Contact Precautions
Identify both colonized & infected patients early
Restrict spread by strict infection control processes

43. 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,
Need RCT! Which patients (all vs. at risk)
Sites, Methods

44. The RCT; You asked for it!
Cluster randomized study
Compliance with 10 intervention ICUs (surveillance Cx + barrier)
barrier precautions 8 control ICUs (n= 5343 & 3705 respectively)
was suboptimal
Surveillance cultures on all (reported to Rx grp)
MRSA+VRE colonization & infection unchanged
N E J Med 2011; 364: 1407-18 40.4+3.3 vs 35.6+3.7 / 1000 patient days (p 0.35)

45. The VA Initiative
“MRSA Bundle” 2007 – 2010; 1.9 million admits ICU / non ICU
Universal nasal survl. 8.3 million patient days; “MRSA Bundle” initiated
Contact precautions Universal nasal surveill’nce:
Hand Hygiene Chromgenic agar/ PCR
“Infection control as
everyone’s + Contact precautions
responsibility” K ICU MRSA ~62% (relative risk)
N E J Med 2011; 364: 1419-30
K Non-ICU MRSA 45%

46. 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 Spot-tests for gram negative MDROs limited
MDRO Gram Value of contact precautions is unsubstantiated
negatives

47. Decolonization:
I am not competent to discuss the
merits of Mupirocin to prevent MRSA
The problem of
“Dutch” Ideas
But am tempted to introduce the
 Euthanasia
 Legal drugs
concept of Selective Decontamination
 Legal prostitution
of the Digestive Tract (SDD)……
 “Going Dutch”
A function of living below
….interesting lessons!
sea level?

48. 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
1 & 2: “Selective”; anaerobes preserved
Reduce GI/ Oropharynx colonization
CID 2006; 43: S70–4 3: Prevents early colonization / VAP

49. Outcomes with SDD
Rx Meta analysis
30 RCTs
5727 patients
Odds of VAP and death reduced;
Rx VAP; OR 0.35 (0.29-0.41)
Death; OR 0.8 (0.69-0.93)
Death K from 30% to 24%
D’amico NNT to prevent one death = 16
BMJ 1998; 316; 1275-85 Best effect in surgical ICU patients

50. So why not use SDD?
Rx
Resistance?
Fear of inducing bacterial resistance
Not conclusively established
Rx
Resistance?
Will it work when rate of bacterial
resistance is high in an ICU
AJRCCM 2001; 164: 382-88
AJRCCM 2001; 164: 338-9
Has been used to combat outbreaks of
AJRCCM 2002; 166: 1029-37 resistant organisms; not in endemic high-
Intens Care Med 1999; 25: 1323-6 resistance ICUs

51. SDD in India?
Rx
Mathematical Modeling*
Maximum effect shown when:
a. Colonization pr. with resistant bacteria is low
b. All patients at risk are given SDD
Rx c. No external source of potential pathogens
None of the above can be met in our ICUs
a. ESBL ~ 80%; MRSA ~50%; MDR
* Bootsma et al Pseudomonas~ 40%; MDR Acinetobacter
Intersci Conf Antimicrob Agents
Chemother. b. Not cost-effective to give SDD to everyone
2003 Sep 14-17; 43:
abstract no. K-698. c. Requires pre-emptive isolation (quarantine)

52. 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”

53. 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

54. “Antibiotics are a non-
renewable resource”….
Laxminarayan & Brown 2001
…..use them wisely!