a Departments of Internal Medicine and h Medical Microbiology, University Hospital Utrecht; b Departments of Internal Medicine and c Intensive Care, University Hospital Nijmegen; d Department of Intensive Care, Free University Hospital, Amsterdam; e Department of Internal Medicine, Diaconessenhuis, Utrecht; f Department of Internal Medicine, Academic Medical Center, Amsterdam; g Department of Medical Microbiology, University Hospital Maastricht; i Department of Medical Microbiology and Infectious Diseases, University Hospital Dijkzigt, Rotterdam; j Department of Surgery, University Hospital Groningen, Groningen, The Netherlands
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Abstract |
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Introduction |
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The method for preventing infections that has been studied most extensively is selective digestive decontamination (SDD), based on the concept of colonization resistance. This concept, according to which the intact, anaerobic, intestinal flora has a protective effect against secondary colonization with Gram-negative aerobic bacteria, was first described by Van der Waaij et al. in 1971.3 Elimination of the anaerobic flora leads to increased colonization and, hence, to an increased risk of infection with these facultatively aerobic bacteria, particularly in seriously ill patients. The purpose of SDD is to eliminate these Gram-negative bacteria and fungi from the digestive tract without harming the anaerobic flora. SDD was first applied with good results in patients with granulocytopenia.4 Later research in these patients revealed that the use of antibiotics that achieve systemic concentrations is more efficient than the topical use of antibiotics that eliminate only Gram-negative bacteria from the intestine. However, maintenance of colonization resistance by the use of specific antibiotics, as demonstrated in neutropenic mice, does not hold in humans. At therapeutic doses, there is no antibiotic that fails to affect colonization resistance in humans.5 Strictly speaking, therefore, selective intestinal decontamination does not exist.
SDD was first used in ICU patients in 1984.6 As used in the ICU, SDD classically consists of four aspects: (i) selective eradication of potentially pathogenic microorganisms (Gram-negative aerobic intestinal bacteria, Staphylococcus aureus and fungi) in the oral cavity by application of orabase containing non-absorbable antibiotics [e.g. polymyxin E, tobramycin and amphotericin B (PTA)] and decontamination of the rest of the gastrointestinal tract by local administration of the same antibiotics; (ii) systemic prophylaxis (e.g. by means of cefotaxime) for the respiratory infections that may occur during the first few days of mechanical ventilation and are caused by commensal respiratory flora such as Streptococcus pneumoniae, Haemophilus influenzae and S. aureus; (iii) regular cultures of throat swabs and faeces in order to monitor the effectiveness of SDD; and (iv) optimal hygiene in order to prevent cross-infection. In the PTA schedule, polymyxin E and tobramycin were chosen because they are non-absorbable and usually cover Gram-negative aerobic intestinal bacteria, S. aureus and Pseudomonas aeruginosa. Amphotericin B was added to the regimen to prevent overgrowth with fungi. Cefotaxime was added to PTA because it covers the commensal respiratory flora and does not affect anaerobic bacteria. The last component of SDD (optimal hygiene) is not described explicitly in any of the studies and is, therefore, an unknown variable in all of them.
Although it has been suggested7 that failure to apply the complete four-component model will reduce the effectiveness of SDD, there are no known published data to support this claim. There is one prospective study8 in which the PTAcefotaxime regimen was compared, under comparable circumstances, with another combination (ofloxacin and amphotericin B in combination with systemic ofloxacin) and here the combination with ofloxacin was more effective. There are no studies in which varying dosages of antimicrobial agents have been compared. It is, therefore, impossible, on the basis of the studies available, to determine the optimal combination or optimal concentrations of antimicrobial agents to be used for SDD.
In this review, we will summarize the available scientific information on the effectiveness of SDD in ICU patients.
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The studies |
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In addition to these variations on the original concept, the antimicrobial agents studied also show considerable diversity. The original SDD schedule (PTAcefotaxime) was investigated in seven studies. In other studies, cefotaxime was replaced by ceftriaxone,13 trimethoprim,24 ofloxacin8 or ceftazidime;25 tobramycin was sometimes replaced by norfloxacin24,26 or gentamicin;13,27 and amphotericin B was sometimes replaced by nystatin.27 There is the same diversity in antibiotic combinations in those studies in which only part of the SDD schedule was used.
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Pneumonia |
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The incidence of ventilator-associated pneumonia in the control groups varied from 5%27 to 85%.9 There are two important reasons for this large variation: (i) differences in the patient populations and (ii) differences in the way in which pneumonia was diagnosed. Failure to distinguish between colonization and infection of the respiratory tract may be an important source of diagnostic error. The diagnosis is usually reached on the basis of a combination of clinical, radiological and microbiological criteria. The specificity of this approach is known to be low, so that a proportion of the diagnoses of pneumonia will be falsepositives. For this reason, the use of bronchoscopic techniques with quantitative cultures is recommended,43 certainly for scientific studies. When such techniques are used, the incidence of pneumonia is 50% lower, on average, than on the basis of clinical, radiological and microbiological criteria alone.44,45 In studies in which pneumonia was diagnosed by means of bronchoscopy, the incidence of pneumonia was generally lower in the control groups, making it more difficult to demonstrate a positive effect of SDD.
In 21 of the 27 studies in which the incidence of ventilator-associated pneumonia was analysed, SDD significantly reduced the incidence of pneumonia. The calculated RRRs in these studies varied from 0.43 to 1. The reduction in the incidence of pneumonia seems to be independent of the choice of antimicrobial agents. The only two negative studies in which total decontamination and systemic prophylaxis were applied used the PTAcefotaxime schedule.
A significant reduction in the incidence of pneumonia was demonstrated in four of the nine studies in which only local (i.e. oropharyngeal and gastrointestinal) antimicrobial prophylaxis was used. The five negative studies were carried out in Spain,14 South Africa,15 Austria,10 France16 and the USA.19 An important cause of the absence of an effect seems to have been the endemicity of multi-resistant bacteria [methicillin-resistant S. aureus (MRSA) among others] in all of these ICUs.
A significant reduction in the incidence of pneumonia was also demonstrated in four of the five studies in which only oropharyngeal decontamination was investigated. In one of these studies, oropharyngeal decontamination had been combined with systemic prophylaxis. The only negative study20 had used only one antibiotic (gentamicin in combination with amphotericin B) for oropharyngeal decontamination. Although the colonization of the respiratory tract by Gram-negative microorganisms decreased significantly, there was no significant reduction in the incidence of pneumonia. In the only study in which the effect of intestinal decontamination (without oropharyngeal and systemic components) on the incidence of pneumonia was investigated,33 there was no demonstrable effect.
Six meta-analyses of SDD studies have been published3641 (Table II). With regard to the effect of SDD on the incidence of pneumonia, the results of all the meta-analyses are in agreement with those of most of the individual studies: SDD significantly reduces the number of cases of pneumonia.
It can be concluded that SDD in any form, with the exception of exclusive gastrointestinal tract decontamination, leads to a reduced incidence of pneumonia, provided that there is no endemic colonization with multi-resistant bacteria.
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Mortality |
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In conclusion, an effect of SDD on mortality has not been demonstrated. However, only major reductions in mortality could have been demonstrated with studies of this size. Larger studies are necessary in order to demonstrate smaller reductions (e.g. 20%). Significant reductions in ICU mortality were demonstrated in two meta-analyses39,40 when only studies in which the combination of local and systemic prophylaxis had been investigated were included. The reduction in mortality in these analyses was 20%40 and 40%39 when only studies with surgical patients were analysed.
The discrepancy between the reduction in the incidence of pneumonia and that in mortality calls into question the presumed association between this infection and a poorer prognosis. Although the results could be clouded by an excessively high incidence of pneumonia, recent studies also suggest that the additional mortality caused by the development of ventilator-associated pneumonia is low or even negligible.4648 Even when the diagnosis is made by means of the most specific method (bronchoscopy with quantitative cultures), no systemic inflammatory reaction can be demonstrated in most patients.46,49 The results of the SDD studies thus support the opinion that many patients with pneumonia do indeed die, but not because of pneumonia.
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Duration of mechanical ventilation and stay in the ICU |
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Use of antibiotics |
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The systemic administration of antibiotics was analysed in 19 studies, including 13 in which SDD resulted in a significant decrease in the incidence of pneumonia (Table III). There was little consistency in how the use of antibiotics was analysed in the various studies. Three studies calculated the average number of days for which patients were receiving antibiotics (excluding the systemic prophylaxis given as part of SDD), five the average number of days of antibiotic therapy per patient, and eight the percentage of patients on antibiotics. In two studies,16,22 the use of antibiotics was not further specified, and in one study35 the number of antibiotic episodes per patient was calculated. Significant reductions in the numbers of patients given systemic antibiotics were found in six studies.13,18,23,26,28,29 It should be pointed out, however, that the systemic prophylaxis given as part of the SDD in three of these studies13,26,28 was not taken into consideration in the analysis. In two studies12,27 the average number of days of antibiotic therapy per patient was lower in patients receiving SDD, but in one of these27 there was no significant reduction in the incidence of pneumonia. Finally, a reduction in the number of episodes of antibiotic treatment per patient was seen in one study.35 In conclusion, the use of SDD resulted in a reduction in the systemic administration of antibiotics in nine of 19 studies, but the systemic component of SDD was not taken into consideration in three of these nine and in one of the nine the reduction in antibiotic use was not accompanied by a reduction in the incidence of pneumonia.
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Cost-effectiveness |
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Although a significant cost reduction was shown in two studies,18,23 this effect was not confirmed in other studies. In three studies the costs were increased. Thus, based on the data available, it is not possible to conclude that SDD is cost-effective.
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Antibiotic resistance |
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What has been demonstrated is that SDD leads to an ecological shift in the microbial flora with an overgrowth of microorganisms that were already intrinsically resistant or had already acquired resistance to one of the agents used. This could result from the fact that all of the schedules studied also affect the colonization resistance.5 Thus, the PTA regimen selects for colonization and infections with Gram-positive bacteria such as Enterococcus faecalis and Staphylococcus epidermidis. It is generally assumed that these bacteria have low virulence, but they can lead to infections in seriously ill patients.5153 The greatest danger of SDD, on a worldwide scale, is the selection of MRSA. In an Austrian study,54 4.5 years of SDD, involving the use of ciprofloxacin, led to an increase in the number of MRSA from 17% to 81% and of ciprofloxacin-resistant S. aureus from 33% to 80%. In a Belgian study,8 the use of SDD (with PTA and cefotaxime or ofloxacin) was accompanied by an increased resistance of Gram-negative intestinal bacteria to tobramycin and ofloxacin, of P. aeruginosa to ofloxacin, and of S. aureus to methicillin. The number of infections caused by multi-resistant bacteria such as Acinetobacter spp. also seems to be increased by SDD.15
Studies carried out in France, Spain, South Africa and the USA, where colonization with multi-resistant pathogens is endemic in ICUs, have demonstrated the danger of SDD in these settings. The Dutch policy on antibiotics is restrictive and rational. Partly as a result of this and thanks to the active search for and isolation of patients with MRSA, the Dutch ICUs, together with those in the Scandinavian countries, are the only ones in which MRSA is not endemic.55
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Discussion |
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In this paper, the pros and cons of the routine use of SDD in ICUs have been discussed. In units in which there is no endemic colonization by multi-resistant microorganisms, SDD results in a decrease in the number of diagnosed cases of ventilator-associated pneumonia. However, it can be questioned whether the full SDD schedule is necessary for this. Several studies suggest that oropharyngeal decontamination is particularly important in preventing the pneumonias that develop after a number of days of mechanical ventilation. In patients in whom pneumonia develops in the first few days of mechanical ventilation, such as those with neurological trauma, even 1 day of systemic prophylaxis without local decontamination may be effective.56 In this case, antibiotic use should probably be regarded as early treatment rather than prophylaxis.
It is tempting to assume that a significant reduction in the incidence of pneumonia will be accompanied by decreases in the duration of mechanical ventilation and of the stay in the ICU, the use of antibiotics, costs and mortality. It has not been demonstrated, however, that these parameters are affected favourably. Individual studies have not demonstrated a decrease in mortality. The results of the various meta-analyses suggest that there may be an effect on mortality, but that large numbers of patients will have to be studied to demonstrate this in a statistically significant manner. The results of these SDD studies indicate an enormous discrepancy: the successful prevention of a feared infection seems to have hardly any effect on the secondary parameters. One can, therefore, question whether the diagnosis of pneumonia, even with the most specific techniques, is sufficiently accurate, whether the use of antibiotics in the ICU is determined by the number of infections demonstrated, and whether these infections, when treated appropriately, have any effect on the patient's prognosis.
At first glance, the results of the most recent metaanalyses seem to justify the use of SDD for preventing infection, but there are pitfalls in the interpretation of these data. The use of meta-analysis to provide answers to scientific questions, followed by the drawing of clinical conclusions, is highly controversial. Ideally, the results of a meta-analysis should be used to form a hypothesis and not to test one. As Borzak & Ridker have said,57 Firm recommendations for treatment should not be based on even the most promising meta-analysis in the absence of well-designed studies of sufficient size to justify the same conclusion. As indicated earlier, a significant reduction in mortality was demonstrated in only one small SDD study (101 patients). However, the reduction in mortality in this study 12 was no less than 52%, much more than that in other studies. This study originally included 151 patients, of whom 50 were later excluded for various reasons. On the basis of the intention-to-treat, the reduction in mortality was 30% (95% CI 1% to 60%; P > 0.05).
The result of a meta-analysis depends, among other things, on the quality of the studies included. Although SDD is one of the most frequently studied interventions in ICUs, the quantity of research is no guarantee of comparable quality. Every study in an ICU has to cope with the heterogeneity of the patient population and, as indicated before, individual studies often involved small numbers of patients and were usually not double-blind, and the SDD schedules investigated were rather variable. Moreover, five of the 33 studies in one of the meta-analyses40 had not (then) been published: the results of one study were based on a personal communication, three studies had been presented only in abstract form and one study was still in press. It is unwise to include studies in a meta-analysis that have not passed the peer-review process. One of these studies, published only in the form of an abstract,58 had a major effect on the results of the subgroup analysis in which a significant effect on mortality was demonstrated.
All of these reasons warrant a critical attitude towards the results of meta-analyses. Statements such as only 23 patients need be treated in order to prevent one death7 or the magnitude of survival benefit from this method is impressive59 are not justified on the basis of the available data. Only a prospective, randomized, preferably double-blind study of sufficient size can determine whether SDD really reduces the mortality among ICU patients.
In the absence of clearly demonstrated advantages, it is necessary to take a critical look at the possible disadvantages of SDD. The use of antibiotics in any form, whether therapeutic or prophylactic, leads to selection of microorganisms that are resistant to the agents used and related agents. This is also true of SDD. For this reason, endemic colonization with multi-resistant bacteria is an absolute contraindication for the use of SDD. It is our opinion that, at present, the suggested advantages of SDD are outweighed by the potential disadvantages, especially in the long term. The routine use of SDD in ICU patients on mechanical ventilation is, therefore, not recommended.
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Acknowledgments |
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Notes |
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Consultants of the Dutch Working Party on Antibiotic Policy are listed in the Acknowledgements.
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References |
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50
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Received 20 December 1999; returned 3 February 2000; revised 21 March 2000; accepted 10 April 2000