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 approach^9,¹⁰ 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

The digestive tract has been considered an important source of infections in ICU patients. The intestinal flora is highly diverse and consists primarily of anaerobic bacteria. Intact anaerobic flora is, amongst others, considered an important defense mechanism against intestinal colonization with (potentially) pathogenic microorganisms. The commensal flora of the oropharynx consists of hundreds of bacterial species, including enterococci and anaerobic bacteria, which are replaced by gram-negative bacteria during the first week of hospitalization in the ICU. Gastric acidity usually prevents bacterial overgrowth in the stomach. Yet, in ICU patients, reduced acid production due to underlying diseases, usage of acid-modifying medication (stress ulcer prophylaxis), and intragastric administration of enteral nutrition (with a pH of 6) leads to a gastric environment that favors bacterial growth, especially of gram-negative bacteria.

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 mice ⁹ 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

TABLE 127-1 Definitions

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:

1 In trials comparing a combination of topical and systemic antibiotics to control, there was a significant reduction in both RTIs (16 studies, OR 0.28, 95% CI 0.20-0.38) and mortality (17 studies, OR 0.75, 95% CI 0.65-0.87).

2 In trials comparing topical antibiotics alone to control, or comparing topical plus systemic to systemic alone, there was a significant reduction in RTIs (17 studies, OR 0.44, 95% CI 0.31-0.63) but not in mortality (19 studies, OR 0.97, 95% CI 0.82-1.16).

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