1. Selective decontamination of the
digestive tract:
implications for the critically ill patient
Kriton S. Filos, MD
Professor
Director Department of Anaesthesiology and
Intensive Care Medicine
University of Patras,
26500 Patras - GREECE
2. The problem:
Patients in intensive care units (ICUs), represent
8 to 15% of hospital admissions.
Richards MJ, et al: Crit Care Med. 1999; 27: 887
Nosocomial infection rates are 5 to 10 times
higher in ICUs than on general wards
Vincent JL et al.: JAMA 1995; 274: 639
3. Aquired infections in the ICU
Pneumonia (47%) and
Lower respiratory tract infections (18%)
Urinary tract infections (18%) and
Bloodstream infections (12%)
Vincent JL et al.: JAMA 1995; 274: 639
4. Infections in the ICU
Community acquired: Already present at
admission
Nosocomial: Incubating 48 h after the admission
to the ICU
Exogenous infections
caused by potentially pathogenic micro-
organisms (PPMs) that have multiplied outside
the body
~ 20% of ICU infections
The high standards of hygiene are able to
prevent them
5. Infections in the ICU (cont.)
Endogenous infections
caused by PPMs carried in the throat and
GI- tract
Primary endogenous
caused by PPMs carried in the throat or
GI-tract on admission to the ICU
> 50% of all infections occurring in the ICU
Secondary endogenous
caused by PPM that have colonized the throat
and GI tract during the ICU stay
~ 33% of ICU infections
during hospitalization the initially colonizing
microorganisms are usually replaced, mainly by Gram-
negative bacteria.
6. Ventilator-associated pneumonia (VAP)
Ventilator-associated pneumonia (VAP) typically
refers to nosocomial pneumonia developing more
than 48 hours following endotracheal intubation
and mechanical ventilation.
The risk for the emergence of VAP is highest
within the first week after intubation and has been
calculated as ~ 3%/day of ICU stay
Vincent JL et al.: JAMA 1995; 274: 639
7.
8. Risk factors for development of VAP: Factors related to
Population
Increased age
Cardiorespiratory disease
Chronic obstructive pulmonary disease
Adult respiratory distress syndrome
Coma
Neurosurgery
Head trauma, polytrauma
Burns
Organ system failure
Cook D: Int. Care Med 2000; 26: 31
9. Risk factors for development of VAP: Factors related to
Ventilator & Airway Management
Mechanical ventilation
Intracuff pressure < 20 cm H2O
Reintubation
24 hour circuit changes
Tracheostomy
Failed subglottic aspiration
Cook D: Int. Care Med 2000; 26: 31
10. Risk factors for development of VAP: Factors related to
General ICU Management
Enteral nutrition
Supine positioning
Aspiration
Histamine-2-receptor antagonists
Paralytic agents
Antibiotics
Transport out of the ICU
Cook D: Int. Care Med 2000; 26: 31
11. What is SDD ?
SDD was developed to treat or prevent
nosocomial infections, especially pneu- monias,
by
selectively eliminating aerobic Gram-
negative potentially pathogenic micro-
organisms and Candida species
without disturbing the anaerobic flora
Stoutenbeek CP et al: Int. Care Med 1984; 10:185-92
12. SDD – Regimen:
Route of Antimicrobial used
administration
(1) Nonabsorbable Polymyxin E / tobramycin /
local (topical) amphotericin B administered
antimicrobials throughout the ICU stay
(PTA regimen):
(a) Oropharyngeal A small volume of a 2% mixture of
cavity: polymyxin E, tobramycin, and
amphotericin B in a paste with
carboxymethylcellulose (Orobase)
is applied to the buccal mucosa
with a gloved finger 4 times daily.
Stoutenbeek CP: Int. Care Med 1992; 18 :15
13. SDD – Regimen (cont.):
Route of Antimicrobial used
administration
(b) GI- tract: 9 ml of a suspension of polymyxin
E 100 mg, tobramycin 80 mg, and
amphotericin B 500 mg is
administered via the gastric tube 4
times daily.
Purpose: The non-absorbable antibiotics of the PTA
regimen (Polymyxin E / tobramycin and amphotericin B)
are applied topically in the throat and gut to eradicate
and/or prevent carriage of aerobic Gram-negative
bacilli, methicillin-sensitive Staphylococcus aureus and
Candida.
Stoutenbeek CP: Int. Care Med 1992; 18 :15
14. SDD – Regimen (cont.):
Route of Antimicrobial used
administration
(2) Short-term Usually a third generation
systemic cephalosporin (cefotaxime, may be
antibiotic exchanged by a quinolone or by
prophylaxis trimethoprim) administered IV for
the first 4 days of the ICU stay
Purpose: to control the primary endogenous infections
that are caused by PPMs present in the patient’s flora on
admission and in general develop during the first week
of stay in the ICU
Stoutenbeek CP: Int. Care Med 1992; 18 :15
15. Essentials for the success of SDD
High standards of hygiene
are able to prevent exogenous infections
Bacteriological monitoring :
to control the effectiveness of the decontamination
procedure,
to adjust the antibiotic regimen in case of
colonization by resistant strains (e.g., MRSA), and
to recognize and prevent exogenous infections
Stoutenbeek CP: Int. Care Med 1992; 18 :15
18. Caution and criticism
The members of the 1st European consensus
conference on SDD:
“The available information at this time does not
permit an unequivocal recommendation for the
use of SDD in any particular population of
patients"
Loirat P et al: Int Care Med 1992; 18: 182-8
19. Criticism: 5 underlying principles of antimicrobial resistance
(1) Given sufficient time and drug use, antibiotic resistance
will emerge.
(2) Antibiotic resistance is progressive, evolving from low
levels through intermediate to high levels.
(3) Organisms that are resistant to one drug are likely to
become resistant to other antibiotics.
(4) Once resistance appears, it is likely to decline slowly, if at
all.
(5) The use of antibiotics by any one person affects others in
the extended and in the immediate environment.
These principles apply to all antibiotic administration,
including the use of SDD.
Levy SB: N.Engl.J.Med. 1998; 338: 1376-8
20. Risks factors leading to the emergence of potentially resistant
pathogens in patients who required mechanical ventilation for >48h
Trouillet et al. examined 135 consecutive episodes of
VAP in order to provide a comprehensive description of
microorganisms responsible for VAP
77 episodes (57%) were caused by potentially
antibiotic-resistant bacteria
MRSA,
Pseudomonas aeruginosa,
Acinetobacter baumannii, and
Stenotrophomonas maltophilia.
Trouillet JL et al: AJRCCM 1998; 157: 531-9
21. Risks factors leading to the emergence of potentially resistant
pathogens in patients who required mechanical ventilation for >48h
Logistic regression analysis
the duration of mechanical ventilation for > 7 days,
prior antibiotic use,
prior use of broad-spectrum antibiotics (third-
generation cephalosporins, fluoroquinolones, and/or
imipenem)
were associated with the development of VAP
due to antibiotic-resistant pathogens
Trouillet JL et al: AJRCCM 1998; 157: 531-9
22. Influence of SDD on the development of antimicrobial resistance
New resistance is rarely reported, but
Severe problems have been encountered in hospitals
with endemic resistant bacteria, especially with
MRSA,
Serratia and
Acinetobacter
Emergence of tobramycin resistance was reported
when the standard SDD protocol (cefotaxime plus topical
polymyxin E, tobramycin and amphotericin B) was used
Verwaest C. et al.: Crit Care Med. 1997; 25: 63-71
23. Influence of SDD on the development of antimicrobial resistance (2)
However, 17% of the patients studied were already
colonized on admission by Morganella morganii and
Serratia;
the latter is frequently resistant to tobramycin and
both are usually resistant to polymyxin E.
Various authors investigators reject the further use of
SDD, because they have observed increasing rates of
infections with resistant Gram-positive bacteria
Kollef MH: Crit Care 2000; 4: 327-32
Webb CH: J.Hosp.Infect. 2000; 46: 106-9
24. Other risk factors have also been associated with the emergence
of antibiotic-resistant infections in the ICU
The need for invasive devices such as
an endotracheal tube,
intravascular and
urinary catheters
have been shown to predispose to infection with
antibiotic-resistant and antibiotic-sensitive bacteria.
Richards MJ et al: Crit Care Med. 1999; 27: 887-92
Likewise, a prolonged duration of hospital stay
appears to predispose to infection with antibiotic-resistant
bacteria
Trouillet JL et al: AJRCCM 1998; 157: 531-9
26. The effect of SDD on pneumonia and pneumonia morbidity (2)
Author Trials Pneumonia rate Mortality rate
included OR (95% CI) OR (95% CI)
(n-patients
studied)
D’Amico R et al., 1998 33 trials
· topical + systemic antibiotic (5727 0.35 (0.29 – 0.41) 0.80 (0.69 – 0.93)
· topical only patients) 0.56 (0.46 – 0.68) 1.01 (0.84 – 1.22)
Nathens AB et al., 1999 11 trials
· overall (only surgical 0.19 (1.15 – 0.26) 0.70 (0.52 – 0.93)
· topical + systemic antibiotic patients) NA 0.60 (0.41 – 0.88)
· topical only NA 0.86 (0.51 – 1.45)
NNT = 23
27. Why only meta – analyses ?
Are there no good single RCTs
supporting SDD ?
28.
29. The effect of topical and IV antibiotic prophylaxis on infections
and morbidity
Methodology
546 surgical ICU patients enrolled and stratified according
to APACHE II score
Randomized into 2 groups
Group 1 (SDD):
IV ciprofloxacine (400 mg * 2), 4 days +
Mixture of topical gentamicin and polymyxin E to
nostrils, mouth, and stomach throughout the ICU
stay
Group 2 (Placebo): Placebo IV and topical
Krueger WA et al AJRCCM 2002; 166: 1029-37
30. The effect of topical and IV antibiotic prophylaxis on infections
and morbidity
Infections acquired in the ICU SDD vs. Control
Pneumonias:
6 vs. 29 ( P < 0.007)
Other lower resp. tract infections:
N=546
39 vs. 70 ( P < 0.007)
Bloodstream infections:
14 vs. 36 ( P < 0.007)
Urinary tract infections:
36 vs. 60 ( P < 0.042)
P < 0.001, RR 0.477,
95% CI [0.367 – 0.620]
Krueger WA et al AJRCCM 2002; 166: 1029-37
31. The effect of topical and IV antibiotic prophylaxis on infections
and morbidity
Multiorgan failure SDD vs. Control
Renal failure:
17 vs. 38 ( P < 0.018)
ARDS / ALI:
15 vs. 27 ( NS)
Circulation:
27 vs. 45 ( NS)
N=546
Liver:
26 vs. 29 ( NS)
Coagulation:
15 vs. 27 ( NS)
CNS:
P < 0.0051, RR 0.636, 3 vs. 5 ( NS)
95% CI [0.463 – 0.874]
Krueger WA et al AJRCCM 2002; 166: 1029-37
32. Multiple organ dysfunction syndrome (MODS)
MODS is the unwanted outcome of successful shock
resuscitation, while
Shock is inadequate organ perfusion even after
adequate fluid resuscitation presenting as
Persistent hypotension or
Need for vasoactive drugs
As a syndrome MODS is defined as altered organ
function in the setting of
Sepsis
Septic shock OR
SIRS
33. MODS : Prognostic factors and mortality
Number of failing organs
1 organ: 20 - 42 %
2 organ : 30 - 62 %
3 organ : 80 - 100 %
Vincent JL et JE,Int Care Med 22:1996 1996
Zimmerman al, CCM 24: 1633, 707,
35. The effect of topical and IV antibiotic prophylaxis on infections
and morbidity
Multiorgan failure SDD vs. Control
Renal failure:
17 vs. 38 ( P < 0.018)
ARDS / ALI:
15 vs. 27 ( NS)
Circulation:
N=546 27 vs. 45 ( NS)
Liver:
26 vs. 29 ( NS)
Coagulation:
15 vs. 27 ( NS)
P < 0.0051, RR 0.636,
95% CI [0.463 – 0.874] CNS:
3 vs. 5 ( NS)
Krueger WA et al AJRCCM 2002; 166: 1029-37
36. Survival in patients and controls according to severity of
illness on ICU admission: systemic + topical prophylaxis
NNT = 12
Krueger WA et al AJRCCM 2002; 166: 1029-37
37. The effect of topical and IV antibiotic prophylaxis on infections
and morbidity
Development of bacterial resistance
Surveillance cultures from
tracheobronchial,
oropharyngeal,
gastric secretions and
from rectal swabs
did not show any evidence for the selection of resistant
microorganisms in the patients receiving prophylaxis.
Krueger WA et al AJRCCM 2002; 166: 1029-37
38. The effect of topical and IV antibiotic prophylaxis on infections
and morbidity
Krueger WA et al AJRCCM 2002; 166: 1029-37
39. Effects of Selective Decontamimation of the
Digestive Tract on Mortality and Antibiotic
Resistance
De Jonghe E., Schultz M.J. Spanjaard L. et al.
Int Care Med. 28 (Suppl. 1), S12. 2002.
40. The effect of topical and IV antibiotic prophylaxis on mortality
and antibiotic resistance
Methodology
934 consequtive surgical and medical ICU patients
Expected duration of MV for > 48 h
Randomized into 2 groups
Group 1 (SDD):
IV cefotaxime, 4 days +
Mixture of topical tobramycin, polymyxin E and
amphotericin B to oropharynx and stomach
throughout the ICU stay
Group 2 (Placebo): Placebo IV and topical
De Jonghe E. et al.: Int Care Med. 28 (Suppl. 1), S12. 2002.
41. The effect of topical and IV antibiotic prophylaxis on mortality
and antibiotic resistance
Methodology – cont.
Weekly cultures from
rectum
oropharynx
axillary and
wound
Methicillin resistant S. aureus (MRSA)
Vancomycin resistant enterococci (VRE)
Tobramycin, polymyxin, ciprofloxacin and ceftazidime
resistant P. aeruginosa
Other Gram – negative bacteria
De Jonghe E. et al.: Int Care Med. 28 (Suppl. 1), S12. 2002.
42. The effect of topical and IV antibiotic prophylaxis on mortality
and antibiotic resistance
SDD Control Odds-ratio P-
(n = 468) (n=466) [95% C.I.] value
ICU-mortality (%) 14.8 22.9 0.6 [0.4 – 0.8] 0.002
Hospital-mortality (%) 24.2 31.2 0.7 [0.5 – 0.9] 0.02
ICU-LOS (days) 11.6 13.4 < 0.001
Tobramycin/P. aeruginosa 13 13 1.0 [0.5 – 2.3] NS
Tobramycin/other Gram neg. 20 47 0.4 [0.2 – 0.7] 0.001
Imipenem/ P. aeruginosa 1 16 0.1 [0.01 – 0.5] < 0.001
Imipenem/ other Gram neg. 1 10 0.1 [0.01 – 0.6] 0.01
Ciproflox./ P. aeruginosa 1 13 0.1 [0.01 – 0.6] 0.002
Ciproflox./ other Gram neg. 9 31 0.3 [0.1 – 0.6] 0.001
Vancomycin./ enterococcus 4 5 0.8 [0.2 – 3.1] NS
Methicillin./ S. aureus 0 0
De Jonghe E. et al.: Int Care Med. 28 (Suppl. 1), S12. 2002.
43. The effect of topical and IV antibiotic prophylaxis on mortality
and antibiotic resistance
In the setting with low prevalence of MRSA and VRE,
SDD significantly decreases ICU – mortality,
and furthermore, SDD decreases hospital mortality of
critically ill patients
Additionally, SDD decreases the LOS in the ICU.
Finally, SDD decreases colonization with (multi)-resistant
P. aeruginosa and other Gram- negative bacteria.
De Jonghe E. et al.: Int Care Med. 28 (Suppl. 1), S12. 2002.
44. SDD – does it work? Conclusions
SDD can cut the rate of VAP by one half on average
Two meta-analyses calculated a significant survival
benefit in patients receiving combined topical and
systemic prophylaxis
Nevertheless, SDD has not yet gained acceptance as a
routine treatment concept, mainly because of persisting doubts
about a true survival benefit as well as major concerns
about the risk of increasing resistance
Now, two recently published RCTs including 1480
patients could demonstrate lower mortality rates in patients
treated with SDD.
Krueger WA et al AJRCCM 2002; 166: 1029-37
de Jonge, E. et al Intensive Care Med. 28 (Suppl. 1), S12. 2002.
45. Conclusions (cont.)
SDD and resistance
In the setting with low prevalence of MRSA and
VRE, SDD significantly decreases ICU – mortality,
and furthermore, SDD decreases hospital mortality
of critically ill patients
Additionally, SDD decreases the LOS in the ICU
Finally, SDD decreases colonization with (multi)-
resistant P. aeruginosa and other Gram- negative
bacteria.
46. Conclusions (cont.)
Since equally effective alternative preventive
measures are not available at this time, SDD
should be seriously considered as a
concept, at least in surgical ICU patients, who are
mechanically ventilated for more than 48 h
47. What does the future hold?
Studies should clarify on three issues:
whether the intestinal component is necessary,
what the impact of the long-term use of SDD on
the overall bacterial ecology is and
if tailored regimens which cover Gram-positive
bacteria, might further add any clinical benefit in ICU
patients.