Selective decontamination of the digestive tract

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 a 2-year observational microbiologic study of trauma patients, an infection classification was proposed ( Table 110.1 ) that included definitions for colonization and the use of SDD for infection prevention in trauma patients in the ICU. ^{, ,} These studies resulted in the establishment of an SDD regimen consisting of the application of nonabsorbable antimicrobial agents in the oropharynx and gastrointestinal tract to prevent acquired colonization with gram-negative bacteria, S. 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 presumed absence of activity on the anaerobic intestinal flora. ^,

Earlier studies

The first study of SDD in ICU patients was performed in 63 trauma patients, using a historical control group of 59 trauma patients. Because of its design and use of a historical control group, this study not only triggered many critical comments and editorials but also led to additional studies in more heterogeneous ICU patient populations, with different combinations of absorbable and nonabsorbable antibiotics, with or without parenteral antibiotics. ^, 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.

SDD was also used early as a prophylactic strategy in major gastrointestinal surgery and showed a decreased rate of postoperative infections and anastomotic leakage. SDD has been reported to reduce gram-negative colonization and to decrease postoperative infection rates after esophagectomy. This study included a very limited patient group from a single center, and the surgical technique, perioperative care, and SDD protocols have changed over time.

Randomized ICU studies

A Dutch 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 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. ^, A subsequent multicenter, controlled, crossover study using cluster randomization and identical inclusion criteria that compared SDD with SOD was performed in the Netherlands. 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. ^, The results of this first Dutch multicenter trial (DMT-I) with almost 6000 patients showed that SDD and SOD groups were associated with a reduction in mortality at day 28 of 13% and 11% relative to controls, respectively, corresponding to an absolute reduction of 3.5% and 2.9%. There were several noteworthy limitations to this study; in particular, as with most SDD studies, it was not blinded, so all physicians were aware of the treatment patient participants would receive. 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, 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 with SOD and control patients.

A second Dutch open cluster, randomized, crossover, multicenter trial (DMT-II: 11,997 patients) compared 12 months of SDD with 12 months of SOD. Again, there was a baseline difference, with SDD patients being more severely ill. Mortality at day 28 was significantly higher in the SOD group (25.7% compared with 23.8%, respectively, with corresponding adjusted odds ratios (ORs) of 0.85 (95% confidence interval [CI] 0.77–0.93).

Various meta-analyses were published. In 2009 a Cochrane meta-analysis was published on the effects of topical antibiotics (with or without systemic antibiotics) and their effects on mortality and the incidence of respiratory tract infections (RTIs). This meta-analysis included 36 trials, with a total of 6914 patients (without DMT-I and DMT-II). They concluded that a combination of topical and systemic antibiotics as compared with controls resulted in 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).

Topical antibiotics alone as compared with controls or comparing topical plus systemic with systemic alone resulted in 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).

Another systemic review and meta-analysis published in 2014 compared SDD, SOD, and oropharyngeal chlorhexidine for the prevention of death and concluded that SDD had a favorable effect on mortality with a less certain effect of SOD. Both were superior to chlorhexidine, with a remark that chlorhexidine might be associated with increased mortality. In 2018 an individual patient data meta-analysis was published. It included all patients of six randomized controlled studies (including DMT-I and DMT-II) and found significantly lower hospital mortality during SDD and SOD as compared with control, with an OR of 0.82 (95% CI 0.72–0.93) and 0.84 (95% CI 0.73–0.97), respectively. In a head-to-head comparison, in-hospital mortality was lower during SDD than during SOD (adjusted odds ratio [aOR], 0.90; 95% CI, 0.82–0.97).

It has been a consistent critique that no large randomized controlled trials (RCTs) had been performed in countries with higher levels of antibiotic resistance. All Dutch trials were carried out in ICUs with low levels of antibiotic resistance. Wittekamp and colleagues performed a cluster randomized trial in a diversity of European countries in settings with moderate to high levels of antibiotic resistance. In 13 European, non-Dutch or Scandinavian ICUs, SDD, SOD, or a chlorhexidine mouthwash were used for 6-month periods. Only ICUs with an extended-spectrum beta-lactamase prevalence of at least 5% among Enterobacteriaceae-causing bloodstream infections were eligible. The order of interventions was randomized.

The difference with the trials performed in the Netherlands was the use of the chlorhexidine and omitting the standard systemic prophylaxis (4 days of intravenous [IV] cephalosporin) during SDD. Another difference with the Dutch randomized studies is that there were no protocol modifications for patients with tracheostomy, jejunostomy, or colostomy or for those with persistent respiratory tract colonization with yeasts or gram-negative bacteria. In total 8665 patients were included. No significant differences were found in the incidence of ICU-acquired bacteremias with multidrug-resistant, gram-negative bacteria and for mortality at day 28 between the three groups.

The “what, when, and why” of the different parts of the SDD regimen as it is used in the two Dutch randomized studies are shown in Table 110.2 .