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Oral, nasopharyngeal, and gut decontamination in the ICU 

Oral, nasopharyngeal, and gut decontamination in the ICU
Chapter:
Oral, nasopharyngeal, and gut decontamination in the ICU
Author(s):

Evelien Oostdijk

and Marc Bonten

DOI:
10.1093/med/9780199600830.003.0287
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date: 24 October 2020

Key points

  • Selective decontamination of digestive tract (SDD) aims to eradicate micro-organisms from the intestine, the stomach, and the oropharynx by non-absorbable antibiotics, which are combined with systemic antibiotic prophylaxis during the first days of ICU admission.

  • An alternative to SDD is selective oropharyngeal decontamination (SOpD) alone.

  • Both SDD and SOpD pursue decontamination of the oropharynx to prevent ventilator associated pneumonia.

  • Dutch studies show SDD and SOpD are associated with reduced ICU-mortality, ICU-acquired bacteraemia with Gram-negative bacteria, and systemic antibiotic use.

  • It is currently unknown to what extent these effects can be achieved in settings with different bacterial ecology.

The concept

In 1971 the concept of colonization resistance was proposed by van der Waaij et al. [1]‌, who suggested a beneficial effect of the anaerobic flora in resisting colonization by aerobic Gram-negative bacilli in the digestive tract in ICU patients. Many infections are caused by enteric bacilli, presumably from endogenous origin. Selective decontamination of the digestive tract (SDD) was developed to selectively eliminate the aerobic Gram-negative bacilli from the digestive tract, leaving the anaerobic flora unaffected. The first clinical studies with SDD were performed in granulocytopenic patients yielding favourable results [2]. In the early 1980s, Stoutenbeek and co-workers [3] adapted the principle for ICU patients. The full concept of SDD aims to eradicate micro-organisms from the intestine, the stomach, and the oropharynx by non-absorbable antibiotics, which are combined with systemic antibiotic prophylaxis during the first days of ICU admission. In the SDD regimen the combination of colistin and an aminoglycoside are generally used, both are effective against Gram-negative bacilli and Staphylococcus aureus, non-absorbable and do not affect the anaerobic intestinal flora. Amphotericin was added to prevent overgrowth with yeasts and systemic prophylaxis to prevent early infections. Since the introduction of this preventive strategy, more than 45 randomized studies and multiple observational studies in a variety of ICU populations have been performed [4]. However, there are large differences in the regimens of SDD that were studied, the endpoints used, and the designs applied.

Several meta-analyses of SDD studies have been published, with more or less comparable results. They generally conclude that SDD decreases the incidence of ventilator-associated pneumonia (VAP) caused by aerobic Gram-negative bacteria with relative risk reduction (RRRs) ranging from 0.40 to 0.78, although reported outcomes regarding prevention of VAP were related to the methodological quality of the individual studies [5]‌.

As an alternative to SDD, investigators have evaluated the effects of oropharyngeal decontamination alone [6,7]. In a prospective randomized placebo-controlled double-blind study, 87 patients received topical antimicrobial prophylaxis in the oropharynx and 139 patients received placebo. The aim of the study was to prevent VAP by modulation of oropharyngeal colonization, without influencing gastric and intestinal colonization and without systemic prophylaxis. Oropharyngeal colonization present on admission was eradicated in 75% of the patients (4% among control patients) and only 10% of study patients acquired oropharyngeal colonization, as compared to 61% of control patients. There were no significant differences in gastric and intestinal colonization. This regimen resulted in a RRR for VAP of 0.62 (95% CI 0.26–0.98) [6]‌.

Experience with SDD/SOpD in the Netherlands

Most detailed data on the effects of SDD and SOpD in ICU-patients come from two studies performed in Dutch ICUs [7,8] The ecological setting of these ICUs is characterized by low levels of antibiotic resistance: For instance, prevalence of meticillin-resistance among Staphylococcus aureus isolates was <1%, of vancomycin-resistance among enterococci was <1%, and of extended-spectrum betalactame production among Enterobacteriaceae was <5%.

In the first study two ICU-wards, within a single university hospital, were compared. In one unit all eligible patients (n = 466) received during a two-year period SDD and in the other unit none of the 468 admitted patients received SDD [8]‌. Eligibility was defined as an expected duration of intubation of at least 48 hours or an expected stay in ICU of at least 72 hours if not intubated. The second study was a multicentre cluster-randomized cross-over study in 13 ICUs in the Netherlands [7]. During study-periods of six months all eligible patients (same criteria as in [8]) in a single unit received SDD, SOpD or standard care (no SDD and no SOpD), and all three regimens were applied in random order in all participating ICUs. The SDD-regimen was identical in both studies and in both studies interventions were applied for all patients eligible. As SDD and SOpD pursue a change in the bacterial ecology within the unit, a study design in which all patients are exposed to the same procedures in time is the best to quantify effectiveness. If patients are individually randomized decontaminated patients may offer some protection against acquired colonization and subsequent infection in those receiving standard care, and vice versa, and this will underestimate true effectiveness.

Effects on patient outcome

In both studies the ‘classical’ SDD regimen (tobramycine, colistine and amphotericin B) was, compared to a control population (no SDD/SOpD), and SDD and SOpD were associated with reduced mortality. In the cluster-randomized study both SOpD and SDD were associated with a lower day-28 mortality. Compared to the control population, the RRR for day-28 mortality was 11% and 13% for SDD and SOpD, corresponding to an absolute mortality reduction on day-28 of 2.9% and 3.5% for SDD and SOpD [7]‌. In the single-centre study the RRR for ICU- and hospital-mortality was 35% and 22%, respectively [9].

The design of both studies had, undoubtedly, many advantages as compared to a study with randomization of individual patients, but had, inevitably, also some disadvantages. In a cluster-randomized design individual patients are not randomized, which may facilitate inclusion bias. In the cluster-randomized study patients included in the control population had—at the time of ICU-admission—on average a lower APACHE-II score, were less frequently mechanically ventilated and were more frequently admitted for surgical reasons. All these determinants are associated with a better prognosis. A random-effects logistic-regression model was used to adjust for these baseline differences, which may not adjust for all confounders. In the single-centre study SDD was applied in one ICU-ward only and the availability of beds determined in which ICU a new patient was admitted. Although baseline characteristics were comparable for both groups, residual confounding cannot be ruled out. Nevertheless, both studies provide convincing evidence that SDD and SOpD reduce ICU-mortality under the circumstances tested.

Effects on ventilator-associated pneumonia

Both SDD and SOpD pursue decontamination of the oropharynx to prevent VAP. In many studies the incidence of VAP, therefore, was the primary study endpoint, though this comes with major methodological problems. The most widely used combination of clinical, radiographic, and microbiological criteria are partly subjective and have suboptimal specificity, as other conditions, such as acute respiratory distress syndrome (ARDS), may have a similar clinical presentation. Bronchoalveolar lavage with quantitative microbiological cultures of obtained samples has a higher specificity, but this invasive approach is used infrequently for routine diagnostic purposes. The use of subjective criteria for endpoint determination in the absence of blinding may introduce considerable bias. Only few studies quantified the effects of decontamination on VAP incidence using both a double-blind placebo-controlled design and invasive diagnostics with quantitative culturing in all patients with a clinical suspicion of VAP. In one such study, in the Netherlands, the RRR of VAP was 55% when applying SOpD (p < 0.05) [6]‌. There are several meta-analyses in which SDD and SOpD are associated with statistically significant reductions in the incidence of VAP, but the before-mentioned methodological drawbacks apply to almost all individual studies included in these analyses.

Effects on ICU-acquired bacteraemia, antibiotic use and costs

In the Dutch multicentre study the RRR of ICU-acquired bacteraemia caused by enteric Gram-negative bacteria was, compared to standard care, 81% and 30% for SDD and SOpD, respectively [7]‌. The incidence difference between SDD and SOpD also reached statistical significance, and results from a post-hoc analysis suggest that this difference in effectiveness resulted from successful intestinal decontamination, that is pursued during SDD, but not during SOpD.

In the Dutch multicentre study SDD and SOpD were associated with a 10% reduction in systemic antibiotic use, which included the routine use of cefotaxim during the first four days as part of SDD. As part of SDD it is recommended not to prescribe antibiotics with anti-anaerobic activity, which resulted in a decline in the intravenous use of clindamycin, piperacillin-tazobactam, and carbapenem antibiotics and in a relative increase of 85% in the use of cephalosporins [7]‌.

The results of this multicentre study were used to determine the cost-effectiveness of SDD and SOpD, in which costs for microbiology, antibiotics, and length of stay were compared to the benefits of life years gained, based on hospital mortality data. Both SOpD and SDD were associated with lower cost and were more effective than standard care. Even if the daily costs of the topical medication would increase tenfold (from €4 to €40 for SOpD and from €40 to €400 for SDD) SOpD would remain cost-saving. In such a scenario the costs of SDD would be €21,590 per life year gained.

Effects on antibiotic resistance

The benefits of SDD and SOpD should be carefully balanced against the potential disadvantages in the short-term, but also in the long-term. These include resistance against any of the antibiotics used and increased transmission of antibiotic-resistant bacteria in general because of the higher antibiotic pressure induced. In a systematic review and meta-analysis of 64 studies there was no evidence of a higher incidence of acquisition of resistance during SDD, as compared to control populations [4]‌. In the two Dutch studies SDD and SOpD were strongly associated with reduced incidences of infection and carriage with antibiotic-resistant bacteria (Table 287.1) [7,9]. As compared to SOpD, SDD offered better protection against ICU-acquired bacteraemia with antibiotic-resistant bacteria and against acquired carriage of the respiratory tract with Gram-negative bacteria intrinsically resistant to colistin and with acquired resistance for third-generation cephalosporins. The latter is quite remarkable, as the use of these antibiotics had increased with 85% during SDD.

Table 287.1 Overview of various endpoints obtained from Dutch randomized studies comparing SDD and/or SOpD to control

Endpoint

SDD versus control

SOpD versus control

SDD versus SOpD

Mortality

Day 28

RRR 13% [7]‌* (p < 0.05)

RRR 11% [7]‌* (p < 0.05)

Intensive Care mortality

  • RRR 15% [7]‌* (p < 0.05)

  • RRR 35% (95% CI 15%–51%) [9]‌

  • RRR 10% [7]‌* (p < 0.05)

  • RRR 33% (95% CI –5%–57%) [6]‌

Hospital mortality

  • RRR 9% [7]‌* (p < 0.05)

  • RRR 22% (95% CI 4%–37%) [9]‌

  • RRR 11% [7]‌* (p < 0.05)

  • RRR 22% (NS) [6]‌

One year survival

RRR 4% (NS)[4]

  • RRR 7% (NS)[4]

  • RRR –1% (NS) [6]‌

Infections

ICU-acquired bacteraemia

RRR 56% (95% CI 0.43–64%) [7]‌

RRR 32% (95% CI 14–47%) [7]‌

RRR 35% (95% CI 15–51%) [7]‌

Enterobacteriaceae

RRR 81% (95% CI 68–88%) [7]‌

RRR 30% (95% CI 2–50%) [7]‌

RRR 72% (95% CI 53–84%) [7]‌

GNF-GNR

RRR 57% (95% CI 33–74%) [7]‌

RRR 51% (95% CI 13–73%) [7]‌

RRR 12% (NS) [7]‌

Candida species

RRR 51% (NS) [7]‌

RRR 9% (NS) [7]‌

RRR 47% (NS) [7]‌

Enterococci

RRR 15% (NS) [7]‌

RRR 7% (NS) [7]‌

RRR 9% (NS) [7]‌

VAP

RRR 55% (95% CI 3–79%) [6]‌

Resistance

ICU-acquired bacteraemia with HRMO

RRR 59% (95% CI 6–82%) [17]

RRR –10% (95% CI–105–41%) [17]

RRR 62% (95% CI 15–83%) [17]

  • Acquired respiratory tract colonization

  • HRMO

RRR 42% (95% CI 22–57%) [17]

RRR 35% (95% CI 13–51%) [17]

RRR 11% (NS) [17]

Tobramycin resistant GNB

RRR –21% (NS) [17]

RRR –8% (NS) [17]

RRR –11 (NS) [17]

Cefotaxim resistant Enterobacteriaceae

RRR 74% (95% CI 39–88%) [17]

RRR 1% (NS) [17]

RRR 63% (95% CI 38–88%) [17]

Intrinsically colistin resistant GNB

RRR 59% (95% CI 43–71%) [17]

RRR 16% (NS) [17]

RRR 51% (95% CI 31–65%) [17]

Non-intrinsically colistin resistant GNB

RRR 31% (NS)

RRR –6% (NS)

RRR 35% (NS)

Acquired colonization with P. aeruginosa^

Ceftazidime resistant

RRR 83% (95% CI 23–96%) [9]‌

Ciprofloxacin resistant

RRR 92% (95% CI 39–99%) [9]‌

Imipenem resistant

RRR 94% (95% CI 51–99%) [9]‌

Tobramycin resistant

RRR -5% (NS) [9]‌

Acquired colonization with other GNB^

Ceftazidime resistant

RRR 19% (NS) [9]‌

Ciprofloxacin resistant

RRR 70% (95% CI 37–85%) [9]‌

Imipenem resistant

RRR 90% (95% CI 19–99%) [9]‌

Tobramycin resistant

RRR 56% (95% CI 26–73%) [9]‌

Polymyxin

RRR –57% (NS) [9]‌

* Corrected for present baseline differences using a random-effects logistic regression model.

^ Acquired colonization in sputum, throat, rectum, axilla, and wounds.

SDD, selective digestive tract decontamination; SOpD, selective oropharyngeal decontamination; RRR, relative risk reduction; 95% CI, 95% confidence interval; ICU, intensive care; VAP, ventilator-associated pneumonia; HRMO, highly resistant micro-organism; GNB, Gram-negative bacteria.

PC, personal communication; Effects of Decontamination of the Digestive and Oropharynx in ICU Patients on one-year survival, Oostdijk E.A.N. De S with A.M.G.A., Bonten M.J.M., On behalf of the Dutch SOD-SDD trialists group, accepted for publication.

Data from: Oostdijk EA et al., ‘Effects of Decontamination of the Digestive and Oropharynx in ICU Patients on one-year survival’, Journal of the American Medical Association, 2014, 312(14), pp. 1429–37; and various sources, see references.

The ecological effects of SDD and SOpD were determined through monthly one-day point prevalence surveillance of all patients present in any of the 16 participating ICUs [8]‌. The implementation of SDD/SOpD was immediately followed by a decline in the prevalence of antibiotic-resistant Gram-negative bacteria in the respiratory tract, but during the months that the interventions were used the prevalence of ceftazidim resistance increased (β‎ 0.09 (p < 0.05). After discontinuation of SDD/SOpD the prevalence returned to pre-intervention levels. Similar observations were made for intestinal carriage: a rapid decline in prevalence after implementation of SDD, and a rapid return to pre-intervention prevalence levels after discontinuation. Only for ceftazidim resistance prevalence levels remained elevated after SDD, as compared with pre-intervention. Stable and low prevalence levels of resistance during SDD were observed in longitudinal studies from Germany and Spain [10,11]. However, there are also reports of higher prevalence of carriage with Gram-positive bacteria during SDD, including MRSA, and of outbreaks with ESBL-producing Gram-negative bacteria.

Colistin is an old antibiotic, increasingly used worldwide as a last resort agent to treat infections with multiple antibiotic-resistant Gram-negative bacteria. Little is known about the mechanisms of resistance to colistin, but long-term intravenous treatment is considered an important risk factor. In Dutch ICUs daily use of topical colistin, as in SDD and SOpD, was not associated with acquired carriage of colistin-resistant Enterobacteriaceae in the respiratory tract [12]. Observed rates of acquired carriage were 1.1, 0.7 and 0.8 per 1000 patient days at risk during SOpD, SDD and control, respectively. For rectal carriage (only measured during SDD) comparable rates were observed, but the risk increased (to 15.5 per 1000 patient days at risk) in patients colonized with tobramycin-resistant Enterobacteriaceae.

Eradication or suppression of carriage reduces colonization pressure, and as such SDD has been applied successfully as a control measure (together with other interventions) during outbreaks, for instance in France and the UK [13,14]. In the Dutch setting, eradication of intestinal carriage with Enterobacteriaceae during SDD was equally successful for strains that were susceptible or resistant to third-generation cephalosporins. Eradication, was less effective, if these bacteria were also resistant to tobramycin [15]. In Israel SDD (with gentamycin and polymyxin E) was tested in a double-blind placebo-controlled trial for its effectiveness in eradicating carriage with carbapenem-resistant Gram-negatives [16]. Among those that received SDD 61% had a negative rectal culture after 2 weeks, as compared to 16% in the placebo group (OR 0.13 (0.02-0.74)). All throat cultures were negative after one week in SDD patients, as compared to 14.2% in the placebo group. Nevertheless, after discontinuation of SDD, carriage rates rapidly increased again.

Adverse events

The oral paste used in SDD and SOpD may cause oesophageal obstruction if not dispelled carefully before application of the next dosage. Furthermore, sustained use of SDD may lead to some absorption of tobramycin from the intestinal tract. For instance, 83 of 100 patients had detectable tobramycin levels in blood (>0.050mg/L) [17], and 12 out of 19 patients that received both continuous venovenous haemofiltration and SDD had detectable tobramycin levels, in one patient being toxic (>3.0mg/L) [18].

The recent large studies performed in Dutch ICUs have provided strong evidence that, in that particular ecological setting, SDD and SOpD reduce ICU-mortality, ICU-acquired bacteraemia with Gram-negative bacteria, and systemic antibiotic use in a cost-effective manner. During a period of ten years there was no evidence that SDD or SOpD were associated with increased resistance in these ICUs. If any, both measures were associated with reductions in systemic antibiotic resistance. These counterintuitive observations might result from the overall lower usage of systemic antibiotics or from the fact that the topical antibiotics are still active against many resistant bacteria. Yet, all studies have used conventional culture techniques that may suffer from antibiotic carryover effects, and it is currently unknown to what the non-culturable flora is affected by SDD and SOpD. In Dutch ICUs SDD and SOpD appear equally effective on relevant clinical outcomes, such as survival and length of stay. SDD seems more protective against ICU-acquired bacteraemia and respiratory tract carriage with resistant Gram-negative bacteria, and SOpD seems to have a more attractive cost-effectiveness profile.

It is currently unknown to what extent these effects can be achieved in settings with different bacterial ecology. Although successful application has been reported from several, solitary, ICUs across Europe, more studies are needed. The potential threat of enhanced selection of pre-existing multiresistant pathogens is becoming more important, with the current emergence of carbapenem-resistant pathogens. Nevertheless, if similar effects would be achieved as in Dutch ICUs, these interventions could save 7,000 deaths per year in British ICUs, only. The use of SDD (or SOpD) as a measure to control outbreaks with multidrug resistant bacteria, that could not be controlled with classical infection control measures, should strongly be discouraged, until more data on its ecological safety and effectiveness have been obtained.

References

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18. Mol M, van Kan HJ, Schultz MJ, and de Jonge E. (2008). Systemic tobramycin concentrations during selective decontamination of the digestive tract in intensive care unit patients on continuous venovenous hemofiltration. Intensive Care Medicine, 34(5), 903–6.Find this resource: