127 Selective Decontamination of the Digestive Tract
Infections acquired in the intensive care unit (ICU) often occur during the treatment of critically ill patients, increasing morbidity, mortality, and health care costs.1,2 Several studies have suggested that the use of prophylactic antibiotic regimens such as selective decontamination of the digestive tract (SDD)3–6 and selective oropharyngeal decontamination (SOD) can reduce the incidence of respiratory tract infections in ICU patients.5,7,8 The SDD approach9,10 is directed to the prevention of secondary colonization with gram-negative bacteria, Staphylococcus aureus, and yeasts through application of nonabsorbable antimicrobial agents in the oropharynx and gastrointestinal tract, preemptive treatment of possible infections due to commensal respiratory tract bacteria through systemic administration of cephalosporins during the patient’s first 4 days in the ICU, and maintenance of anaerobic intestinal flora through selective use of antibiotics (administered both topically and systemically) without antianaerobic activity.10
Background
Anaerobic bacteria grow well on the mucosa of the gut and actively line the epithelium.11 Disruption of this layer by antibiotics that destroy the anaerobic flora may create a portal of entry for pathogenic microorganisms.
Combinations of nonabsorbable antibiotics have been used to selectively decontaminate the digestive tract and reduce the load of pathogenic aerobic microorganisms while maintaining the anaerobic flora. This concept was first investigated in mice9 and later developed into an infection prevention strategy for neutropenic leukemia patients, which the investigators called selective decontamination of the digestive tract, or SDD.12,13
From Concept to Practice in the ICU
The earlier experience with SDD in leukemia patients suggested that some infections in ICU patients might have an endogenous source and could be prevented in the same way. After an observational microbiological study among trauma patients during 2 years, an infection classification was proposed (Table 127-1) that included definitions for colonization and the use of SDD for infection prevention in trauma patients in the ICU.10,14,15 These studies resulted in an SDD regimen consisting of application of nonabsorbable antimicrobial agents in the oropharynx and gastrointestinal tract to prevent acquired colonization with gram-negative bacteria, Staphylococcus aureus, and yeasts, in combination with 4 days of intravenous administration of a third-generation cephalosporin to (preemptively) treat incubating respiratory tract infections with gram-positive and gram-negative bacteria. Topical and systemic antibiotics were selected based on their antibacterial spectrum and absence of activity on the anaerobic intestinal flora.14,15
| Colonization resistance | The strong protective effect of the endogenous anaerobic fraction of the intestinal microflora in resisting colonization by aerobe microorganisms along the alimentary canal. When the anaerobic flora is suppressed, there is an enhanced risk of overgrowth by gram-negative bacteria. |
| PPM | Potentially pathogenic microorganisms |
| SDD | Selective decontamination of the digestive tract is the selective elimination of PPM from the oral and intestinal flora by topical nonabsorbable antibiotics. |
| SOD | Selective oropharyngeal decontamination is the selective elimination of PPM from the oral flora by topical nonabsorbable antibiotics. |
| Primary endogenous infections | Caused by PPM with which the oropharynx and/or digestive tract of the patient was colonized at admission. These PPM are part of the “normal” flora of the patient. |
| Secondary endogenous infections | Caused by PPM with which the oropharynx and/or digestive tract of the patient was not colonized at admission but acquired during ICU stay |
| Exogenous infections | Caused by PPM not present at admission and developing without preceding colonization |
| Colonization | Presence of the same species of PPM in an organ system for more than 3 days (≥2 positive cultures) without signs of infection |
Clinical Results
Earlier Studies
The first study with SDD in ICU patients was performed in 63 trauma patients, using a historical control group of 59 trauma patients.10 This study, because of its design and use of a historical control group, not only triggered many critical comments and editorials but also resulted in additional studies in more heterogeneous ICU patient populations, with different combinations of absorbable and nonabsorbable antibiotics, with or without parenteral antibiotics.3,16–18 The conflicting results of these clinical trials led to the conclusion that there was insufficient scientific evidence to recommend SDD as a routine infection control measure in ICU patients.19
Recent Studies
A single-center prospective, controlled, randomized, unblinded study in 2003 reported significantly lower ICU and hospital-mortality rates (35% and 22%, respectively), shorter length of stay, and a lower incidence of antibiotic resistance in patients with an expected duration of mechanical ventilation of ≥2 days and/or expected length of stay in the ICU of ≥3 days and receiving SDD.4,20 A subsequent multicenter controlled crossover study using cluster randomization and identical inclusion criteria was performed in the Netherlands that compared SDD with SOD. SOD was included because of the hypothesis that the main effect of SDD—a reduction in the incidence of ventilator-associated pneumonia (VAP)—could be achieved by oropharyngeal decontamination only, without intestinal decontamination and without the routine prophylactic use of systemic antibiotics during the first 4 days of ventilation.7,8 The results of this Dutch multicenter study with almost 6000 patients showed that compared to the control group, both SDD, SOD, and a control group were associated with an adjusted relative reduction of mortality at day 28 of 13% and 11%, respectively, corresponding with an absolute reduction of 3.5% and 2.9%.5 Of note, there were several limitations to this study, particularly the fact that the study was not blinded. Because of its unblinded nature, all physicians were aware of the treatment patient participants would receive, and because inclusion was based on several criteria, this created the possibility of selection bias. To minimize the occurrence of selection bias, patient eligibility and inclusion rates were monitored frequently and immediately followed by feedback to the participating investigators. Yet despite the use of these measures next to the objective inclusion criteria, in the end, there were baseline differences between the control and the two intervention groups. Patients in the intervention groups (SDD and SOD) were more frequently intubated, were less likely to be surgical patients, and had a higher baseline APACHE score. Further, SDD patients were older compared to SOD and control patients.5
A Cochrane meta-analysis was published in 2009 on the effects of topical antibiotics (with or without systemic antibiotics) and its effects on mortality and the incidence of respiratory tract infections (RTI).6 This meta-analysis included 36 trials with a total of 6914 patients (without the previously mentioned Dutch multicenter study for the reasons described). The authors concluded that:
This last conclusion contrasts the results of the Dutch multicenter trial which showed a significant reduction in mortality by using topical antibiotics in the oropharynx only.5
In Table 127-2 the “what, when, and why” of the different parts of the SDD regimen as it is used in the latest studies is listed.
TABLE 127-2 Selective Decontamination of the Digestive Tract Regimen
| What | When | Why |
|---|---|---|
| Baseline | ||
| Oropharyngeal application of 0.5 g of a paste containing polymyxin E, tobramycin, and amphotericin B, each in a 2% concentration* | 4 times daily until ICU discharge | Selective decontamination of the oropharynx |
| Administration of 10 mL of a suspension containing 100 mg polymyxin E, 80 mg tobramycin, and 500 mg amphotericin B via the nasogastric tube | 4 times daily until ICU discharge | Selective decontamination of the gut from stomach to rectum |
| Cefotaxime 1 g intravenously during the first 4 days of study (or other third-generation cephalosporins) | 4 times daily during the first 4 days | Preemptive treatment of primary endogenous infections |
| Avoidance of (systemic) antibiotics which might impair the colonization resistance (i.e., with antianaerobic activity) | During treatment with SDD, until ICU discharge | Avoidance of penicillins, carbapenems, etc. No addition of antibiotics for patients with colonization without clinical signs suggestive for infection |
| Cultures of endotracheal* aspirates, oropharyngeal* and rectal swabs | On admission and surveillance cultures twice weekly | Determination of colonization pattern at admission and during treatment, including monitoring of effectiveness of SDD Detection of infection |
| Oropharyngeal care* | 4 times daily using sterile water or chlorhexidine† mouthwash, preceding application of oropharyngeal paste; includes brushing of teeth twice daily Clean visually contaminated oropharyngeal cavity with swab moistened with 1.5% hydrogen peroxide |
Cleansing of mouth and teeth Removing residue of paste Preparing mouth for (next) application of paste |
| Use of normal hygiene guidelines* | Always | Preventing transmission of pathogens in the patient Prevention of (exogenous) cross-contamination and infections from and to other patients Control of outbreak |
| Modifications for Patients with: | ||
| Tracheostomy* | 0.5 g of paste applied around the tracheostomy 4 times daily | Selective decontamination of the oropharynx |
| Duodenal tube or jejunostomy | Divide the 10 mL of suspension into 5 mL suspension via the gastric tube and 5 mL via the duodenal tube or jejunostomy | Selective decontamination of the gut from stomach to rectum |
| Colostoma or ileostoma | SDD suppositories (containing 100 mg polymyxin E, 40 mg tobramycin, and 500 mg amphotericin B) twice daily in the distal part of the gut | Selective decontamination of the gut from stomach to rectum |
| Documented cephalosporin allergy | Cefotaxime can be replaced by ciprofloxacin (twice daily 400 mg). | Avoidance of allergic reaction |
| Modifications for Patients with Persistent Respiratory Tract Colonization with Yeasts or Gram-Negative Bacteria | ||
| If a surveillance culture (>48 h after admission culture) of the throat yields yeasts and/or gram-negative bacteria* | Increase application of oropharyngeal paste to 8 times daily until 2 surveillance cultures are negative. | Decolonization |
| If a sputum surveillance (>48 h after admission culture) culture yields yeasts* | Nebulize 5 mL (5 mg) amphotericin B 4 times daily until 2 sputum cultures are negative. | Decolonization |
| If a sputum surveillance culture (>48 h after admission culture) yields gram-negative bacteria* | Nebulize 5 mL (80 mg) polymyxin E 4 times daily until 2 sputum cultures are negative. | Decolonization |
* The SOD regimen from de Smet AM, Kluytmans JA, Cooper BS et al. Decontamination of the digestive tract and oropharynx in intensive care patients. N Engl J Med 2009;360:20-31.
† Chlorhexidine was not used in the Dutch SDD-SOD trial. (N Engl J Med 2009;360:20-31).
Microbiological Effects of Selective Decontamination
Decontaminating Effect
There are few recent studies which describe the results of the decontaminating effect of SDD. The Dutch multicenter trial showed that the proportions of SDD patients colonized with gram-negative bacteria isolated from rectal swabs decreased from 56% at day 3 to 25% at day 8 and 15% at day 14. Oropharyngeal colonization rates with gram-negative bacteria decreased from 18% at day 2, to 4% at day 8 among SDD patients. The same trial showed a comparable decrease in oropharyngeal colonization rates with gram-negative bacteria in SOD patients from 20% at day 2 to 7% at day 8.5 These results were comparable to those reported in other studies.10,21,22
The positive effects of SDD (and SOD) on respiratory tract colonization and infection have been described extensively.4,6–8 The Dutch multicenter trial showed significantly lower incidences of ICU-acquired bacteremia during SOD and SDD for S. aureus, glucose-nonfermenting gram-negative rods (mainly Pseudomonas aeruginosa), and Enterobacteriaceae, as compared to controls. Patients receiving SDD had lower incidences of ICU-acquired bacteremia with Enterobacteriaceae than those receiving SOD. The incidence of ICU-acquired candidemia was lower in the SDD group compared to either SOD or control groups.5
Emergence and Selection of Antibiotic Resistance in Gram-Negative and Gram-Positive Microorganisms during Selective Decontamination
Enhanced selection of antibiotic-resistant microorganisms has been considered an important threat of SDD and SOD.23 Consistent use of surveillance cultures as part of SDD and SOD protocols makes it possible to assess the efficacy of enteral decontamination as well as detect emergence of antibiotic-resistant pathogens early.
Gram-Negative Microorganisms
Several studies showed an overall decrease of antibiotic-resistant gram-negative microorganisms in patients receiving SDD, including a significant beneficial effect on colonization with resistant gram-negative bacteria such as P. aeruginosa resistant to ceftazidime, imipenem, and ciprofloxacin and other aerobic gram negatives resistant to imipenem, ciprofloxacin, and tobramycin.4,18 Patients receiving SDD during the Dutch multicenter trial had lower incidences of ICU-acquired candidemia, bacteremia with Enterobacteriaceae, and bacteremia with highly resistant microorganisms (HRMO; according to Dutch guidelines24) than those receiving SOD.25 The incidence of candidemia and bacteremia caused by HRMO were low in this study, so whether this difference will translate into a difference in clinical outcome between both interventions depends on the overall incidence of candidemia and bacteremia caused by HRMO, the appropriateness of empirical antimicrobial therapy in such patients, and the attributable effects of such events on outcome and length of stay. These findings do not support the concern that use of topical antibiotics, with or without systemic prophylaxis with third-generation cephalosporins, increases prevalence levels of antibiotic resistance in gram-negative bacteria. Further studies are needed to distinguish the effects of the individual components of SDD.
Gram-Positive Microorganisms
Methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) are highly prevalent in ICUs in many countries, unlike the Netherlands where the last two major studies have been carried out. It is generally considered that the use of topical antibiotics for SDD or SOD is contraindicated in such settings, as such regimens may increase colonization and infection rates with these bacteria. Yet, few data are available on the effects of SDD or SOD in settings with high levels of MRSA. In one study, a shift toward gram-positive organisms was detected after the introduction of SDD in trauma patients that included an outbreak and increased carriage rates with MRSA 2 years after the introduction of SDD.26,27 This was successfully addressed by implementation of control measures.26 To prevent infections with MRSA, some investigators add vancomycin to the SOD or SDD regimen.7,28 When applied topically, vancomycin will not be absorbed and will reach high concentrations in the intestinal tract. In a Spanish burn unit, SDD with topical vancomycin was associated with improved patient outcome and lower colonization rates with MRSA.28 A disadvantage of such an approach will be the selection of VRE in ICUs where both pathogens are prevalent.
The results of the Dutch study indicated that both SDD and SOD were associated with higher rates of acquired respiratory tract colonization but not with higher bacteremia rates caused by enterococci. In ICU patients, enterococci will colonize all body sites (especially the skin) and contaminate the inanimate environment. Enterococci have become among the most frequent causes of hospital-acquired infections worldwide, and the proportion of infections caused by ampicillin-resistant enterococci (ARE) has increased substantially in Western countries, including the Netherlands.29 In the United States, approximately 35% of all ICU-acquired bacteremias caused by enterococci are due to VRE. The clinical relevance of ARE and VRE infections is unclear.
Widespread use of topical vancomycin in units with high levels of MRSA will enhance the selective pressure for VRE. This should be carefully balanced against the benefits of SDD or SOD with vancomycin. In the United States, ICUs with high levels of MRSA frequently also have high endemic levels of VRE. In such settings, addition of oropharyngeal chlorhexidine oral washings and/or chlorhexidine body washings may help in controlling spread and bloodstream infections caused by VRE and MRSA.30,31 Chlorhexidine is a bacteriostatic and bactericidal chemical antiseptic with effects on both gram-positive and, to a lesser extent, gram-negative bacteria. Several studies and meta-analyses addressing the use of oropharyngeal chlorhexidine demonstrated a significant reduction in pneumonia, but so far none have shown a significant reduction in mortality. New studies combining several infection-prevention measures using topical antibiotics combined with topical application of agents such as chlorhexidine should be performed, preferably in surroundings with a high incidence of gram-positive multiresistant bacteria.
Ecological Effects
During the Dutch multicenter study, surveillance cultures from the respiratory and intestinal tract were obtained each month on a fixed day from all patients present in the ICU, regardless of whether they were included in the study.5 These 18 point-prevalence studies in 13 ICUs allowed an analysis of the effects of SDD and SOD on the bacterial ecology in these ICUs together. Effects of SDD (during periods of 6 months) and of SDD/SOD (combined during periods of 12 months) on intestinal and respiratory tract carriage with gram-negative bacteria were determined by comparing results from consecutive point-prevalence surveys using intervention to consecutive point-prevalence data in the pre- and postintervention periods.32 The average proportions of patients colonized with ceftazidime, tobramycin, or ciprofloxacin-resistant gram-negative bacteria in the intestinal tract decreased during the use of SDD in the ICU and increased again after discontinuation. During combined SDD/SOD, resistance levels in the respiratory tract were low (≤6%) for all three antibiotics but seemed to increase gradually, with a significant increase only for ceftazidime resistance (P <0.05). After discontinuation of SDD/SOD, the resistance levels increased to levels of 10% or higher. Obviously, both SDD and SOD have marked ecological effects, particularly in the intestinal and respiratory tract for SDD and in the respiratory tract for SOD. Df note, some of these patients were only briefly in the ICU and the incidence of resistance in other hospital wards was unknown. An increasing incidence of resistance in the participating hospitals might have influenced these results. Yet the observed increase of ceftazidime resistance during SDD/SOD is of concern. Nevertheless, the ecological effects (i.e., lowest resistance levels during interventions) corroborate the positive effects of SOD and SDD on antibiotic resistance in individual patients.4,25 Larger and longer longitudinal studies are needed to determine the long-term effects of SOD and SDD on antibiotic resistance, with special attention to the changes in antibiotic resistance among gram-negative bacteria.
Other Issues
Effectiveness of SDD in Specific Patient Groups
There is some evidence that SDD might not be equally effective in all patient groups. In one meta-analysis, increased efficacy of SDD was observed in surgical patients.17
In a post hoc subgroup analysis of the Dutch multicenter study, different effects of SDD and SOD were found for surgical and nonsurgical patients.25 Compared to control, SDD was equally effective in reducing 28-day mortality in surgical and nonsurgical patients, but with significant reductions in duration of mechanical ventilation, ICU stay, and hospital stay among surgical patients. On the other hand, SOD appeared to be even more effective in reducing mortality in nonsurgical patients but was not associated with reduction in day-28 mortality in surgical patients, nor in duration of mechanical ventilation or ICU or hospital stay. These findings suggest that surgical patients benefit from the addition of the enteric and/or systemic component of the SDD regimen. These results should be considered as hypothesis generating; further studies are needed to confirm such observations. If confirmed, they may help elucidate the mechanisms of the protective action of SDD and SOD in specific groups of ICU patients.
Hospital-Acquired Infections After Treatment with SOD and SDD
In the SDD study by De Jonge et al., the relative risk reduction in ICU mortality of 35% decreased to 22% at hospital discharge.4 Triggered by these findings, it was hypothesized that this reduction in survival benefit after ICU discharge might have been related to an increased incidence of hospital-acquired infections (HAI) in patients who had received SDD in the ICU. Nested within the multicenter SDD-SOD trial, the incidence of HAI was prospectively monitored during the first 14 days after ICU discharge in all patients transferred to regular wards in two university hospitals.33 Most HAI were respiratory tract infections, with similar incidence and similar duration of infection in all three posttreatment study groups. The incidence of bloodstream infections was also similar in the three posttreatment groups, but time until infection tended to be longer in the post-SOD and post-SDD groups compared to the postcontrol group. On the other hand, the incidence of surgical site infections (SSI) seemed to increase in the postintervention groups. The proportion of patients developing post-ICU HAI in the post-SOD and post-SDD periods combined tended to be higher than during the postcontrol period, though this did not reach statistical significance. Considering the low rates of HAI, the overall low mortality rates after ICU discharge, and the low prevalence of infections among those who succumbed after ICU discharge, the hypothesis that discontinuation of SDD and SOD post ICU increases the infection rate and thus affects clinical outcome could not be supported.33
Antibiotic Use
No formal cost/benefit evaluations of the use of SDD or SOD have been performed. De Jonge evaluated the total costs of antibiotics, topical and systemic, which were 11% lower in the SDD group compared to the control group. This was primarily due to the decrease in the use of antibiotics such as ciprofloxacin, ceftazidime, imipenem, and antifungal treatment.4 These results were confirmed by the multicenter study, with (compared to control) a decrease of 12% and 10% in the use of daily defined doses of systemic antibiotics in SDD and SOD, respectively.5
Adverse Events
Three patients are reported who suffered from accumulation of the buccally applied oral SDD/SOD oral paste to large clots which caused obstruction in the esophagus or jejunum. This complication can be prevented by regular and appropriate oral care.34
Key Points
Stoutenbeek CP, van Saene HKF, Miranda DR, Zandstra DF. The effect of selective decontamination of the digestive tract on colonization and infection rate in multiple trauma patients. Intensive Care Med. 1984;10:185-192.
First study on SDD in ICU patients. Good description and overview of theoretical background.
Liberati A, D’Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. The Cochrane Library 2009, Issue 4. Available at. http://www.thecochranelibrary.com.
de Jonge E, Schultz M, Spanjaard L, et al. Effects of selective decontamination of the digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet. 2003;362:1011-1016.
de Smet AM, Kluytmans JA, Cooper BS, et al. Decontamination of the digestive tract and oropharynx in intensive care patients. N Engl J Med. 2009;360:20-31.
Bergmans DC, Bonten MJ, Gaillard CA, et al. Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2001;164:382-388.
1 Vincent J-L. Nosocomial infections in adult intensive-care units. Lancet. 2003;361:2068-2077.
2 Vincent J-L, Rello J, Marshall J, Silva E, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323-2329.
3 D’Amico R, Pifferi S, Leonetti C, Torri V, Tinazzi A, Liberati A. Effectiveness of antibiotic prophylaxis in critically ill adult patients: systemic review of randomised controlled trials. BMJ. 1998;316:1275-1285.
4 de Jonge E, Schultz M, Spanjaard L, et al. Effects of selective decontamination of the digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet. 2003;362:1011-1016.
5 de Smet AM, Kluytmans JA, Cooper BS, et al. Decontamination of the digestive tract and oropharynx in intensive care patients. N Engl J Med. 2009;360:20-31.
6 Liberati A, D’Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. The Cochrane Library 2009, Issue 4. http://www.thecochranelibrary.com.
7 Pugin J, Auckenthaler R, Lew DP, Sutter PM. Oropharyngeal decontamination decreases incidence of ventilator-associated pneumonia: a randomized, placebo-controlled, double-blind clinical trial. JAMA. 1991;265:2704-2710.
8 Bergmans DC, Bonten MJ, Gaillard CA, et al. Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2001;164:382-388.
9 van der Waaij D, Berghuis-de Vries JM, Lekkerkerk-van der Wees JEC. Colonization resistance of the digestive tract in conventional and antibiotic-treated mice. J Hyg (Lond). 1971;69:405-411.
10 Stoutenbeek CP, van Saene HKF, Miranda DR, Zandstra DF. The effect of selective decontamination of the digestive tract on colonization and infection rate in multiple trauma patients. Intensive Care Med. 1984;10:185-192.
11 Savage DC. Interactions between host and its microbes. In: Clarke R, Bauchop T, editors. Microbial ecology of the gut. London: Academic Press; 1977:277-310.
12 Sleyfer DT, Mulder NH, Vries-Hospers HGde, Fidler V, Nieweg O, van der Waay D. Infection prevention in granulocytopenic patients by selective decontamination of the digestive tract. Eur J Cancer. 1980;16:859-869.
13 Guiot HF, van der Meer JW, van Furth R. Selective antimicrobial modulation of human microbial flora: infection prevention in patients with decreased host defense mechanisms by selective elimination of potentially pathogenic bacteria. J Infect Dis. 1981;143(5):644-654.
14 Saene van HKF, Stoutenbeek CP, Miranda DR, Zandstra DF. A novel approach to infection control in the intensive care unit. Proceedings of a symposium on prevention and control of infection in intensive care. Acta Belg Anaest. 1983;34:193-209.
15 Stoutenbeek CP. Infection prevention in intensive care, infection prevention in multiple trauma patients by selective decontamination of the digestive tract (SDD). Thesis, 1987, ISBN 90-9001736-4.
16 Verwaest C, Verhaegen J, Ferdinande P, et al. Randomized, controlled trial of selective digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med. 1997;25:63-71.
17 Nathens AB, Marshall JC. Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence. Arch Surg. 1999;134:170-176.
18 Krueger WA, Lenhart FP, Neeser G, et al. Influence of combined intravenous and topical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortality in critically ill surgical patients: a prospective, stratified, randomized, double-blind, placebo-controlled clinical trial. Am J Respir Crit Care Med. 2002;166:1029-1037.
19 Bonten MJ, Kullberg BJ, van Dalen R, et al. Selective digestive decontamination in patients in intensive care. The Dutch Working Group on Antibiotic Policy. J Antimicrob Chemother. 2000;46(3):351-362.
20 Bonten MJ, Kluytmans J, de Smet AM, Bootsma M, Hoes A. Selective decontamination of digestive tract in intensive care. Lancet. 2003;362:2118-2119.
21 Kerver AJH, Rommes JH, Mevissen Verhage EAE, et al. Prevention of colonization and infection in critically ill patients: a prospective randomized study. Crit Care Med. 1988;16:1087-1093.
22 Hartenauer U, Thülig B, Diemer W, et al. Effect of selective flora suppression on colonization, infection, and mortality in critically ill patients: a one-year, prospective consecutive study. Crit Care Med. 1991;19:463-473.
23 Bonten MJ, Brun-Buisson C, Weinstein RA. Selective decontamination of the digestive tract: to stimulate or to stifle? Intensive Care Med. 2003;29:672-676.
24 Kluytmans-VandenBergh MF, Kluytmans JA, Voss A. Dutch guideline for preventing nosocomial transmission of highly-resistant micro-organisms. Infection. 2005;33:309-313.
25 de Smet AMGA. Selective decontamination of the oropharynx and the digestive tact in ICU patients. Thesis, 2009, ISBN 978-90-393-5213-17.
26 Lingnau W, Allerberger F. Control of an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) by hygienic measures in a general intensive care unit. Infection. 1994;Suppl. 2:S135-S139.
27 Lingnau W, Berger J, Javorsky F, Fille M, Allerberger F, Benzer H. Changing bacterial ecology during a five-year period of selective intestinal decontamination. J Hosp Infect. 1998;39:195-206.
28 de la Cal MA, Cerdá E, García-Hierro P, et al. Survival benefit in critically ill burned patients receiving selective decontamination of the digestive tract: a randomized, placebo-controlled, double-blind trial. Ann Surg. 2005;241:424-430.
29 Top J, Willems R, van der Velden S, Asbroek M, Bonten M. Emergence of clonal complex 17 Enterococcus faecium in The Netherlands. J Clin Microbiol. 2008;46(1):214-219.
30 Vernon MO, Hayden MK, Trick WE, Hayes RA, Blom DW, Weinstein RA, Chicago Antimicrobial Resistance Project (CARP). Chlorhexidine gluconate to cleanse patients in a medical intensive care unit: the effectiveness of source control to reduce the bioburden of vancomycin-resistant enterococci. Arch Intern Med. 2006;166:306-312.
31 Climo MW, Sepkowitz KA, Zuccotti G, et al. The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial. Crit Care Med. 2009;37(6):1858-1865.
32 Oostdijk EA, De Smet AM, Blok HE, Thieme Groen ES, van Asselt GJ, Benus RF, et al. Ecological effects of selective decontamination on resistant gram-negative bacterial colonization. Am J Respir Crit Care Med. 2010;181:452-457.
33 de Smet AM, Hopmans TE, Minderhoud AL, Blok HE, Gossink-Franssen A, Bernards AT, et al. Decontamination of the digestive tract and oropharynx: hospital acquired infections after discharge from the intensive care unit. Intensive Care Med. 2009;35:1609-1613.
34 Smit MJ, van der Spoel JI, de Smet AM, de Jonge E, Kuiper RA, van Lieshout EJ. Accumulation of oral antibiotics as an adverse effect of selective decontamination of the digestive tract: a series of three cases. Intensive Care Med. 2007;33:2025-2026.
