Figure 55.1. The four components of the full protocol of SDD, and the type of infection controlled by each component.

PPM = potentially pathogenic microorganism; ICU = intensive care unit.

55.4 Efficacy of SDD

SDD has been assessed in 59 randomised controlled trials (RCTs) [7], and 8 meta-analyses of only RCTs [8-15] (Table 55.2).

Table 55.2. Efficacy of selective decontamination of the digestive tract assessed in eight meta-analyses of only randomized controlled trials.

CI = confidence interval; NR = not reported; OR = odds ratio; RCTs = randomized controlled trials.

55.4.1 Carrier State

SDD significantly reduced oropharyngeal carriage by 87% (OR 0.13, 95% CI 0.07-0.2), and rectal carriage by 85% (OR 0.15, 95% CI 0.07-0.31) due to Gram-negative PPMs [14]. Gram-positive carriage was also reduced, but not significantly [14]. Additionally, fungal carriage was significantly reduced by 68% (OR 0.32, 95% CI 0.19-0.53) [12].

55.4.2 Lower Airway Infection

All meta-analyses showed a reduction of lower respiratory tract infection. The most robust meta-analysis by the Italian Cochrane Collaboration showed that the full protocol of SDD significantly reduced lower airway infection by 65% (OR 0.35, 95% CI 0.29-0.41) [10]. Five patients needed to be treated with SDD to prevent one episode of lower airway infection. Moreover, lower airway infection due to Gram-negatives was reduced by 89% (OR 0.11, 95% CI (0.05-0.20) and that due to Gram-positives by 48% (OR 0.52 95% CI 0.34-0.78) [14].

55.4.3 Bloodstream Infection

A recent meta-analysis including 51 randomized controlled studies comprising of 8065 patients demonstrated a significant reduction in bloodstream infections of 27% (OR 0.73, 95% CI 0.59-0.90) compared to control patients [13]. In particular, bloodstream infections due to Gram-negative PPMs were significantly reduced (OR 0.39; 95 % CI 0.24-0.63).

55.4.4 Fungal Infection

A recent meta-analysis evaluated the impact of SDD on fungal infections and demonstrated a significant reduction of fungal infections by 70% (OR 0.30, 95% CI 0.17-0.53), and a non significant reduction of fungemia due to a small sample size (OR 0.89, 95% CI 0.16-4.95) [12].

55.4.5 Mortality

Three large studies of 527 [16], 934 [17] and 6000 [18] patients have shown a mortality reduction of 30% (RR 0.70, 95% CI 0.51-0.95), 40% (OR 0.60, 95% CI 0.42-0.82), and 16% (OR 0.835, 95%CI 0.720-0.968), respectively. All meta-analyses, producing a large sample size, have shown a significant reduction in mortality. The Italian Cochrane group showed a significant mortality reduction of 22% (OR 0.78, 95% CI 0.68-0.96); twenty-one patients should be treated to save one life [10]. Similarly, the only meta-analysis with the endpoint of mortality and including randomized studies in which the full SDD protocol was used showed a mortality reduction of 29% (OR 0.71, 95% CI 0.61-0.82) [15]. This effect achieved a 42% mortality reduction in studies where SDD eradicated the carrier state (OR 0.58, 95% CI 0.45-0.77). In summary, all large randomized studies and robust meta-analyses demonstrated a significant reduction in mortality when the full SDD protocol of parenteral and enteral antimicrobials was used.

55.5 Efficacy of SDD in Patients With Neurological Disorders

Two RCTs of SDD were undertaken in subjects with neurological disorders [19,20]. Korinek et al. assessed the effect of SDD (PTA protocol including a 4% vancomycin paste) on carriage and infection in 123 neurosurgical patients: 63 received SDD and 60 placebo [19]. SDD significantly reduced Gram-negative bacilli carriage and significantly reduced the number of infected patients (29 SDD vs. 49 control, p<0.001), infection episodes (36 SDD vs. 71 control, p<0.01), bronchopneumonia (15 SDD vs. 25 control, p<0.04), urinary tract infection (12 SDD vs. 24 control, p<0.01). The authors concluded that SDD was an effective technique in reducing infectious morbidity in comatose neurosurgical patients. Gosney et al. performed a prospective, randomized, placebo-controlled, double blind study in patients with acute stroke: 103 patients received SDD and 100 received placebo [20]. There were significantly less patients with pneumonia in SDD group compared with placebo (p=0.029).

There are 22 RCTs of SDD which reported data on patients with neurological disorders at study entry (Table 55.3). Apart from the two above mentioned studies [19,20], in the other 20 RCTs [16,18,21-38], mainly in trauma patients, the number of patients with neurological disorders on admission was specified; this percentage ranged from 1.4% to 94% of the study population. In those 22 studies, including a total of 7669 patients (3782 SDD, 3887 controls), there were 851 (22.5%) and 935 (24%) patients with neurological disorders in the SDD and control groups, respectively. Remarkably, a meta-analysis of these 22 RCTs including neurological/neurosurgery patients showed that SDD significantly reduced all important infectious endpoints, such as overall infection, lower airway infection, bloodstream infection, urinary tract infection, and mortality (Table 55.3).

Table 55.3 Summary of randomized controlled trials of SDD including patients with neurological disorders at study entry and meta-analysis of the impact of SDD on infections and mortality. Data are retrieved after reviewing 59 published randomized controlled trials of selective decontamination of the digestive tract. Patients with neurological disorders included head trauma, brain bleeding, patients with Glasgow coma scale <8, impaired consciousness, neurological disease.

* data were found in a separate publication (Hammond JMJ, Potgieter PD, Chest 1993;104:547-51) of a subgroup of only neurological patients included in the main publication [27]. Results of meta-analysis are presented as Odds Ratios with 95% confidence interval using the random effects model. Heterogeneity was assessed by the Cochran Q statistic and the I2 measure of inconsistency. No heterogeneity was found in all comparisons with the Cochran Q statistic; I2 values of 15.6% (overall infection) and 6.5% (UTIs) were found, indicating a non significant level of heterogeneity;

SDD = selective digestive decontamination; C = control; RCT = randomized controlled trial; OR = Odds ratio; LRTI = lower respiratory tract infection; SDD = selective digestive decontamination; C = control; RCT = randomized controlled trial; OR = Odds ratio; LRTI = lower respiratory tract infection; BSI = bloodstream infection; UTI = urinary tract infection.

Additionally, six out of those 22 RCTs included an important percentage (>70%) of patients with head trauma on admission [19,26,30,32,33,36]. Table 55.4 shows the meta-analysis of these 6 RCTs: both overall infections and lower respiratory tract infections were significantly reduced by SDD, whilst the reduction in mortality was not significant due to the small sample size.

Therefore, these results support the use of SDD in neurocritically ill patients, including those with head trauma and severe coma, as morbidity and mortality are reduced by the prophylactic manoeuvre of SDD.

Table 55.4. Meta-analysis of six randomized controlled trials of SDD including a high percentage of patients with head trauma. All RCTs including a percentage of patients with head trauma >70% of the enrolled patients were included in the analysis. Results are presented as Odds Ratios with 95% confidence interval using the random effects model. Heterogeneity was assessed by the Cochran Q statistic and the I² measure of inconsistency. No heterogeneity was found in all comparisons.

C = control; CI = confidence interval; LRTI = lower respiratory tract infection; OR = Odds Ratio; RCT = randomized controlled trial; SDD = selective digestive decontamination.

55.6 Safety of SDD

The 25 year research on SDD demonstrated that SDD does not increase the resistance problem, but rather reduces it [39]. Two of the 59 RCTs [33,40] report an increase in resistance. Interestingly, the endpoint was the number of resistant isolates rather than the number of patients with resistant isolates in these two RCTs. Three RCTs evaluated the impact of SDD on the number of patients who carried antibiotic resistant aerobic Gram-negative bacilli (AGNB) [17,18,41]. A Klebsiella pneumoniae producing extended spectrum beta-lactamase was endemic in a Parisian hospital [41]: carriage and infection rates were 19.6% and 9%, respectively. Once enteral antimicrobials were added to the parenteral there was significant reduction in both carriage and infection (19.6% versus 1%; 9% versus 0%). A Dutch RCT including about 1000 patients reports that carriage of AGNB resistant to imipenem, ceftazidime, ciprofloxacin, tobramycin and polymyxins occurred in 16% of patients receiving parenteral and enteral antimicrobials, compared to 26% of control patients receiving only parenteral antibiotics with a relative risk of 0.6 (95% confidence interval 0.5-0.8) [17]. The largest multi-centre RCT to date [18] includes 6000 patients, and the proportion of patients with aerobic Gram-negative bacilli in rectal swabs that were not susceptible to the marker antibiotics was lower with SDD than with standard care or selective oropharyngeal decontamination (SOD), a modified SDD protocol without the gut component. For example, carriage of multi-resistant P. aeruginosa was 0.4% in SDD versus 0.8% in SOD and 1.3 in the group receiving standard care (p<0.05).

There are four long-term studies (≥2 years) evaluating the impact of polymyxin/tobramycin on resistance amongst AGNB [42-45]. The resistance data of the long-term studies confirm the RCT findings that rates of carriage and infection due to resistant AGNB in patients receiving enteral and parenteral antimicrobials are not increased but are actually lower compared with patients receiving solely parenteral antimicrobials. Most patients who require long term treatment on ICU have overgrowth of abnormal flora, defined as 10⁵ AGNB per ml of saliva and/or g of faeces. Gut overgrowth guarantees increased spontaneous mutation, leading to polyclonality and antimicrobial resistance [46]. As the parenteral antimicrobials generally fail to eradicate the abnormal carrier state in overgrowth concentrations, the enteral antimicrobials polymyxin/tobramycin aiming at converting the abnormal carrier state into normal carriage, are the essential component of SDD because they eradicate carriage and overgrowth of AGNB including resistant mutants, maintaining the usefulness of parenteral antimicrobials.

Vancomycin-resistant enterococci (VRE) and MRSA are intrinsically resistant to the parenteral and enteral antimicrobials of the SDD protocol. VRE carriage and infection were the primary endpoints of SDD RCTs in two American ICUs with endemic VRE [47,48]. There was no difference between test and control groups. There are seven RCTs conducted in ICUs where MRSA was endemic at the time of the trial [25,27,30,37,40,49,50], they report a trend towards higher MRSA carriage and infection rates in patients receiving SDD. The addition of enteral vancomycin to the classical SDD is required to control MRSA in ICUs with endemic MRSA [51]. Neither Staphylococcus aureus with intermediate sensitivity to vancomycin (VISA) nor VRE emerged in any of the six RCTs using enteral vancomycin [19,23,16,31,52,53]. Four studies using long term SDD with vancomycin (≥2 years) failed to report the emergence of VISA or VRE ([54-56], L. Silvestri, personal communication) (Table 55.5).

Table 55.5. Long-term studies (≥2 years) of enteral vancomycin on resistance amongst Staphylococcus aureus and enterococci: Staphylococcus aureus with intermediate sensitivity to vancomycin and vancomycin-resistant enterococci.

* L. Silvestri, personal communication

Surv = surveillance samples; Diagn = diagnostic samples; VISA = vancomycin-intermediate Staphylococcus aureus; VRE = vancomycin-resistant enterococci.

55.7 Conclusions

SDD has been assessed in 59 randomised controlled trials and 8 meta-analyses of only randomised controlled trials. SDD using parenteral and enteral antimicrobials consistently demonstrated a significant reduction in lower respiratory tract infection, bloodstream infection, fungal infection and mortality.

Twenty five years of clinical SDD research showed that SDD does not increase the resistance problem but rather reduces it. Two RCTs of SDD were undertaken in patients with neurological disorders, both neurosurgical patients and patients with acute stroke, and confirmed the previous results in mixed (e.g., medical/surgical) ICU population. Moreover, the majority of trauma RCTs of SDD comprised of different percentages of patients with head trauma or other neurological disorders, such as an impairment of consciousness. These studies showed a significant impact on infectious morbidity and mortality.

A meta-analysis of a subgroup of RCTs including a high percentage of neurological patients confirmed these results. For these reasons we advocate the use of SDD in critically ill neurological and neurosurgical patients.

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