By Trushil Shah, MD, MSc
Assistant Professor of Medicine, University of Texas Southwestern, Dallas
SYNOPSIS: The SuDDICU randomized controlled trial of Australian patients found that selective decontamination of the digestive tract (SDD) did not significantly decrease in-hospital mortality, although the confidence interval around the effect estimate includes a clinically important benefit. In a separate systematic review and meta-analysis that included 32 randomized trials and 24,389 participants, SDD was associated with reduced hospital mortality compared with standard care.
SOURCES: The SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group; Myburgh JA, Seppelt IM, Goodman F, et al. Effect of selective decontamination of the digestive tract on hospital mortality in critically ill patients receiving mechanical ventilation: A randomized clinical trial. JAMA 2022;328:1911-1921.
Hammond NE, Myburgh J, Seppelt I, et al. Association between selective decontamination of the digestive tract and in-hospital mortality in intensive care unit patients receiving mechanical ventilation: A systematic review and meta-analysis. JAMA 2022;328:1922-1934.
Selective decontamination of the digestive tract (SDD) has been studied for almost 40 years, with mixed results and unclear benefits. The SuDDICU trial was a cluster, crossover, randomized clinical trial of mechanically ventilated patients expected to remain on the ventilator > 48 hours from 19 intensive care units in Australia. Investigators also recruited all patients from participating intensive care units (ICUs) regardless of ventilation status for ecological assessment (i.e., changes in ICU microbiologic flora).
SDD involved a topical application every six hours of 0.5 g of oral paste (containing 10 mg of colistin, 10 mg of tobramycin, and 125,000 IU of nystatin) applied to the buccal mucosa and oropharynx, an administration every six hours of 10 mL of gastric suspension (containing 100 mg of colistin, 80 mg of tobramycin, and 2 × 106 IU of nystatin) to the upper gastrointestinal (GI) tract via a gastric or postpyloric tube, and a four-day course of an intravenous (IV) SDD-compliant antibiotic (e.g., a third-generation cephalosporin or ciprofloxacin), unless already treated with antibiotics, with activity against gram-negative bacteria during the first four days after enrollment.
SDD was implemented as an ICU-wide intervention, which enabled investigators to obtain a waiver of individual patient consent and allowed them to enroll all eligible patients. This trial was originally planned as an international trial in Australia, Canada, and the United Kingdom, but only data from Australia were published.
Between May 2017 and November 2021, 14,581 participants were recruited across 19 ICUs in Australia. Out of these, 5,982 participants (mean age 58.3 years; 36.8% women) were enrolled in the intervention study, and 8,599 participants were enrolled in the ecological assessment. By hospital discharge, 27% patients in the SDD group and 29.1% of patients in the standard care group died (mean difference, −1.7%; 95% confidence interval [CI], −4.8% to 1.3%; odds ratio [OR], 0.91; 95% CI, 0.82-1.02; P = 0.12).
In comparing SDD to standard of care, there was no significant difference in ICU mortality (mean difference, −1.4%; 95% CI, −3.5% to 0.7%), number of days alive and mechanical ventilation-free (mean difference, 2.09 days; 95% CI, −0.35 to 4.53 days), ICU admission (mean difference, 1.75 days; 95% CI, −0.62 to 4.12 days), and hospital admission (mean difference, 1.34 days; 95% CI, −0.89 to 3.58 days). There was a statistically significant reduction in the proportion of patients with antibiotic-resistant organisms cultured in the SDD group vs. the standard care group (23.1% vs. 34.6%, respectively; absolute difference, −11.0%; 95% CI, −14.7% to −7.3%) as well as the proportion with positive blood cultures (5.6% vs. 8.1%, respectively; absolute difference, −1.95%; 95% CI, −3.5% to −0.4%). In the ecological assessment, SDD was non-inferior to standard care for change in the proportion of new positive blood cultures and Clostridioides difficile infections, but not for the change in the proportion of positive cultures for antibiotic-resistant organisms.
The accompanying systematic review and meta-analysis in the same Journal of the American Medical Association issue included 32 randomized controlled clinical trials (RCTs) (including the SuDDICU trial) with 24,389 participants (median age 54 years; 33% female). RCTs and cluster RCTs that recruited ICU patients (75% of whom were mechanically ventilated) and compared SDD using antibacterial and/or antifungal agents to upper GI tract, stomach, and proximal small bowel with or without administration of systemic antibiotics to standard care/placebo were included.
There were 30 trials (24,034 participants) that contributed data to the primary outcome of mortality. Out of these, 10 trials (20,467 participants) reported in-hospital mortality, and 20 trials (3567 participants) reported mortality at ICU discharge. The pooled estimated risk ratio (RR) for mortality for SDD compared with standard care was 0.91 (95% credible interval [CrI], 0.82-0.99; I2 = 33.9%; moderate certainty), with a 99.3% posterior probability that SDD reduced hospital mortality.
The meta-analysis further notes the benefit of SDD was seen in trials that had an IV agent as part of SDD (RR, 0.84; 95% CrI, 0.74-0.94), but not in trials without an IV agent. In addition, SDD was associated with a reduced risk of ventilator-associated pneumonia (RR, 0.44; 95% CrI, 0.36-0.54) and ICU-acquired bacteremia (RR, 0.68; 95% CrI, 0.57-0.81).
COMMENTARY
Many ICU-acquired infections, including ventilator-associated pneumonia, often result from gram-negative bacteria, Staphylococcus aureus, and yeast, which frequently colonize the upper respiratory tract, oral mucosa, and upper GI tract. SDD decolonizes these mucosal surfaces of the culprit organisms by using non-absorbable antibiotics and antifungals as well as a short course of IV antibiotics targeting gram-negative organisms.1 SDD aims to decrease the incidence of ICU-acquired infections and thereby reduce mortality.1 However, the main concern for using an SDD strategy is the emergence of multidrug-resistant organisms and antibiotic resistance.2 The SuDDICU RCT was designed to answer these questions and assess the effect of SDD on unit ecology by recruiting a separate ecological assessment arm.
Multiple randomized controlled trials with individual patient randomization and cluster crossover design have shown mixed results of SDD on mortality. The SuDDICU study showed a trend toward lower in-hospital mortality, but this was not statistically significant. Secondary outcomes, like ICU mortality, duration of mechanical ventilation, duration of ICU, and hospital stay, also were not significantly different. However, the accompanying meta-analysis by Hammond et al showed a statistically significant reduction in mortality with SDD with a 99.3% posterior probability. This mortality benefit was more prominent in SDD studies where the intervention arm included IV antibiotics. In the meta-analysis, SDD also significantly reduced the risk of ventilator-associated pneumonia and ICU-acquired bacteremia.
In the SuDDICU study, patients undergoing SDD had lower risk of having positive blood cultures or antibiotic-resistant organisms, with no increased risk of C. difficile infections. Moreover, in the ecological assessment, SDD was non-inferior to standard of care for the development of new positive blood cultures and C. difficile infections but not for cultures of new antibiotic-resistant organisms. Also, SDD did not lead to any increase in adverse events. This suggests that SDD is a safe strategy for reducing ICU-acquired infections and may confer a mortality benefit.
The results of the SuDDICU RCT are encouraging and suggest a likely benefit of SDD in mechanically ventilated patients in ICUs in Australia. This study was planned as an international study with other countries involved, including Canada and the United Kingdom. Further data from these countries would help clarify the results. Most of the studies included in the meta-analysis were in ICUs with a low prevalence of multidrug-resistant organisms in Australia, New Zealand, and the Netherlands.2,3 A cluster randomized control trial of the use of SDD strategy in ICUs with moderate to high antibiotic resistance prevalence did not show benefit.4 This limits the generalizability of SDD in the United States, where antibiotic resistance prevalence is moderate to high in most ICUs.5 Also, most studies of SDD were performed in mechanically ventilated patients, and the utility of SDD outside of mechanically ventilated patients will need to be further studied.
REFERENCES
- Wittekamp BHJ, Oostdijk EAN, Cuthbertson BH, et al. Selective decontamination of the digestive tract (SDD) in critically ill patients: A narrative review. Intensive Care Med 2020;46:343-349.
- Bonten M. Selective decontamination of the digestive tract: An answer at last? JAMA 2022;Nov. 15. [Online ahead of print]. doi:10.1001/jama.2022.18623
- de Smet AM, Kluytmans JA, Cooper BS, et al. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med 2009;360:20-31.
- Wittekamp BH, Plantinga NL, Cooper BS, et al. Decontamination strategies and bloodstream infections with antibiotic-resistant microorganisms in ventilated patients: A randomized clinical trial. JAMA 2018;320:2087-2098.
- Kadri SS. Key takeaways from the U.S. CDC’s 2019 antibiotic resistance threats report for frontline providers. Crit Care Med 2020;48:939-945.
