K.S. Filos, MD PhD Selective Gut Decontamination

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

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

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

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

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.

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

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


 Ventilator & Airway Management

 Mechanical ventilation

 Intracuff pressure < 20 cm H2O

 Reintubation

 24 hour circuit changes

 Tracheostomy

 Failed subglottic aspiration



 General ICU Management

 Enteral nutrition

 Supine positioning

 Aspiration

 Histamine-2-receptor antagonists
 Paralytic agents
 Antibiotics
 Transport out of the ICU


What is SDD ?

 SDD was developed to treat or prevent
nosocomial infections, especially pneumonias,
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

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

SDD – Regimen (cont.):

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.

SDD – Regimen (cont.):

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


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


The effect of SDD on pneumonia and pneumonia morbidity:
Meta-analyses of RCTs published
Author Trials Pneumonia rate Mortality rate
included OR (95% CI) OR (95% CI)
(n-patients
studied)
Vandenbroucke-Grauls et al., 6 trials 0.12 (0.08 – 0.19) 0.70 (0.45 – 1.09)
1991 (491 patients)

SDD Trialists, 1993 22 trials
• overall (4142 0.37 (0.31 – 0.43) 0.90 (0.79 – 1.04)
• topical + systemic antibiotic patients) 0.33 (0.27 – 0.40) 0.80 (0.67 – 0.97)
• topical only 0.43 (0.33 – 0.56) 1.07 (0.86 – 1.12)
Heyland et al., 1994 24 trials
overall (3312 0.46$ (0.39 – 0.56) 0.87 (0.79 – 0.97)
topical + systemic antibiotic patients) 0.48$ (0.39 – 0.60) 0.81 (0.71 – 0.95)
topical only 0.43$ (0.32 – 0.59) 1.00 (0.83 – 1.19)
Hurley JC, 1995 26 trials 0.35 (0.30 – 0.42) 0.86 (0.74 – 0.99)
(3768
patients)

$: Relative risk

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

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

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

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

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

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

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

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

Why only meta – analyses ?

Are there no good single RCTs

supporting SDD ?

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

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]


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]


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

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,

MODS : SOFA - score and mortality
1 2 3 4
Respiratory: PaO2 / FiO2 < 400 < 300 < 200 < 100
Hematologic: Platelets/ mm3 < 150 < 100 < 50 < 20
Liver: bilirubine (mg/dL) 1.2 - 1.9 2.0 - 5.9 6.0 - 11.9 > 12
Cardiovascular: MAP(mmHg) < 70 Dopamine< 5 Dopamine > 5 Dopamine > 15

or or or Epinephrine

Dobutamine Epinephrine0.1 > 0.1

any dose or Norepi. < 0.1 or Norepi. > 0.1

CNS: GCS 13 - 14 10 - 12 6-9 <6
Renal: creatinine(mg / dL) 1.2 - 1.9 2.0 - 3.4 3.5 - 4.9 > 5.0
or diuresis (ml/ die) - - or 200 - 500 or< 200

SOFA - score : 9 – 12 13 – 16 17 - 20 > 20

Mortality: 25% 50% 75% 100%

Vincent JL et al, Int Care Med 22: 707, 1996

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)

Survival in patients and controls according to severity of
illness on ICU admission: systemic + topical prophylaxis

NNT = 12


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.


and morbidity


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.

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.

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


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



 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.


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.

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.

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

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.

K.S. Filos, MD PhD Selective Gut Decontamination

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