K.S. Filos, MD PhD Selective Gut Decontamination

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K.S. Filos, MD PhD Selective Gut Decontamination

  1. 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. 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. 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. 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. 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. 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. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. SDD – does it work?
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. Risks factors leading to the emergence of potentially resistantpathogens 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
  20. 20. Risks factors leading to the emergence of potentially resistantpathogens 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
  21. 21. 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
  22. 22. 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
  23. 23. Other risk factors have also been associated with the emergenceof 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
  24. 24. So, does SDD work or not ?
  25. 25. 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
  26. 26. Why only meta – analyses ?Are there no good single RCTs supporting SDD ?
  27. 27. The effect of topical and IV antibiotic prophylaxis on infectionsand 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
  28. 28. The effect of topical and IV antibiotic prophylaxis on infectionsand 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
  29. 29. The effect of topical and IV antibiotic prophylaxis on infectionsand 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
  30. 30. 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
  31. 31. 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,
  32. 32. 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
  33. 33. The effect of topical and IV antibiotic prophylaxis on infectionsand 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
  34. 34. Survival in patients and controls according to severity ofillness on ICU admission: systemic + topical prophylaxis NNT = 12 Krueger WA et al AJRCCM 2002; 166: 1029-37
  35. 35. The effect of topical and IV antibiotic prophylaxis on infectionsand 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
  36. 36. The effect of topical and IV antibiotic prophylaxis on infectionsand morbidity Krueger WA et al AJRCCM 2002; 166: 1029-37
  37. 37. Effects of Selective Decontamimation of the Digestive Tract on Mortality and Antibiotic ResistanceDe Jonghe E., Schultz M.J. Spanjaard L. et al. Int Care Med. 28 (Suppl. 1), S12. 2002.
  38. 38. The effect of topical and IV antibiotic prophylaxis on mortalityand 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.
  39. 39. The effect of topical and IV antibiotic prophylaxis on mortalityand 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.
  40. 40. The effect of topical and IV antibiotic prophylaxis on mortalityand 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.
  41. 41. The effect of topical and IV antibiotic prophylaxis on mortalityand 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.
  42. 42. 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.
  43. 43. 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.
  44. 44. 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
  45. 45. 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.
  46. 46. Thank You

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