(Chest. 2003;123:464S-468S.)
© 2003
American College of Chest Physicians
Selective Digestive Decontamination Should Not Be Routinely Employed*
Marin H. Kollef, MD, FCCP
* From the Pulmonary and Critical Care Division, Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, MO.
Correspondence to: Marin H. Kollef, MD, FCCP, Pulmonary and Critical Care Division, Washington University School of Medicine, Campus Box 8052, 660 S. Euclid Ave, St. Louis, MO 63110; e-mail: kollefm{at}msnotes.wustl.edu
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Abstract
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There is a general consensus that antimicrobial resistance in the hospital setting has emerged as an important variable influencing patient outcome and resource utilization. Hospitals worldwide are faced with increasingly rapid emergence and spread of antibiotic-resistant bacteria. Both antibiotic-resistant Gram-negative bacilli and Gram-positive bacteria are reported as important causes of hospital-acquired infections. Few antimicrobial agents are available for effective treatment. Selective digestive decontamination (SDD) is a technique aimed at selectively eliminating aerobic Gram-negative bacilli and yeast from the mouth and stomach to reduce the occurrence of hospital-acquired infections, including ventilator-associated pneumonia. Unfortunately, the application of SDD has been associated with emergence of antibiotic-resistant bacterial strains, limiting its overall utility.
Key Words: bacteria • decontamination • hospital • outcomes • pneumonia • resistance
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Introduction
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The most important factor influencing the emergence of antibiotic-resistant bacterial infections has been the extensive use of antimicrobial agents both within hospitals as well as in the community setting. Levy1
formulated five underlying principles of antimicrobial resistance that highlight the importance of antibiotic use as a risk factor. First, given sufficient time and drug use, antibiotic resistance will emerge. Second, antibiotic resistance is progressive, evolving from low levels through intermediate to high levels. Third, organisms that are resistant to one drug are likely to become resistant to other antibiotics. Fourth, once resistance appears, it is likely to decline slowly, if at all. Fifth, the use of antibiotics by any one person affects others in the extended as well as the immediate environment. These principles apply to all antibiotic administration, including the use of selective digestive decontamination (SDD); therefore, the clinical benefits of SDD must be balanced against the potential for the greater emergence of antibiotic-resistant infections as a result of its use.
The practice of SDD can be defined in a number of different ways. For purposes of this review, the most common method of employing SDD will be considered, which is a topical paste administered into the aerodigestive tract in combination with a parenteral antibiotic having activity against Gram-negative bacteria. SDD is most often used in patients requiring intensive care, especially patients receiving mechanical ventilation. The goal of SDD is to prevent colonization of the aerodigestive tract with potentially pathogenic bacteria. The aspiration of contaminated secretions from the aerodigestive tract into the lower respiratory tract is the most common mechanism responsible for the development of ventilator-associated pneumonia (VAP)2
; however, antibiotic administration to patients requiring mechanical ventilation has also been shown to be an important risk factor for the acquisition of VAP due to antibiotic-resistant bacteria.3
Therefore, VAP associated with prior antibiotic administration could potentially be associated with worse clinical outcomes as a result of greater antimicrobial resistance.4
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Prevalence of Antimicrobial Resistance in the ICU
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ICUs, along with other specialty areas within hospitals (eg, organ transplant wards, oncology units), frequently have high levels of antimicrobial usage among patients maintained in close proximity. This type of environment may explain the high levels of antimicrobial resistance observed within such areas of the hospital. A multicenter European survey examined a total of 9,166 Gram-negative bacterial strains from 7,308 patients in ICUs from 118 hospitals.5
The most frequently isolated organisms were Enterobacteriaceae (59%), followed by Pseudomonas aeruginosa (24%), with the main sources being respiratory tract (42%), urine (26%), blood (14%), abdomen (11%), and skin and soft tissue (7%). Decreased antibiotic susceptibility was most common for P aeruginosa, Acinetobacter species, and Enterobacter species. Resistance to ceftazidime was > 70% in some countries for Acinetobacter species, while P aeruginosa had the highest overall incidence of resistance in all the surveyed countries (37% resistance to ciprofloxacin in Portugal, 24% resistance to imipenem in France).
Similar findings were demonstrated in the United States, where 33,869 nonduplicate Gram-negative isolates were examined from 396 ICUs from 45 states.6
Resistance to third-generation cephalosporins was found to be an emerging problem, with increasing resistance to ceftazidime between 1990 to 1993 for Klebsiella pneumoniae (3.6 to 14.4%, p < 0.01) and Enterobacter species (30.8 to 38.3%, p = 0.0004). Additionally, ceftazidime-resistant Gram-negative bacteria were also frequently resistant to aminoglycosides and ciprofloxacin. These data highlight the presence of important antibiotic resistance among clinically important bacterial species within ICUs in Europe and the United States.
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Risk Factors for Antibiotic Resistance
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A number of investigators have demonstrated a close association between the use of antibiotics and the emergence of antibiotic resistance both in Gram-negative and Gram-positive bacteria.7
8
9
10
11
The recent experience with antibiotic cycling or scheduled antibiotic class changes also demonstrates how rapidly antibiotic-resistant bacteria can emerge within the hospital setting as antibiotic use patterns change.12
13
14
Trouillet and coworkers15
examined 135 consecutive episodes of VAP, of which 77 episodes (57%) were caused by potentially antibiotic-resistant bacteria (methicillin-resistant Staphylococcus aureus, P aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia). According to logistic regression analysis, duration of mechanical ventilation for 
7 days, prior antibiotic use, and prior use of broad-spectrum antibiotics (third-generation cephalosporins, fluoroquinolones, and/or imipenem) were associated with the development of VAP due to antibiotic-resistant pathogens. This investigation confirmed the importance of previous antibiotic exposure as a risk factor for the development of nosocomial infections due to antibiotic-resistant bacteria.16
17
18
Additionally, the identification of specific risk factors for the occurrence of antibiotic-resistant infections, such as prior antimicrobial exposure, provides guidance for the development of potential interventions aimed at reducing these rates of infection and providing better antimicrobial treatment when they occur.19
20
In addition to prior antibiotic exposure, other risk factors have been associated with the emergence of antibiotic-resistant infections. Prolonged length of stay in the hospital appears to predispose to infection with antibiotic-resistant bacteria.15
This may be due, in part, to the greater likelihood of becoming colonized with such bacteria from either horizontal nosocomial transmission or endogenous emergence of resistance, the longer a patient remains in the hospital. Similarly, the presence of invasive devices such as endotracheal tubes, intravascular catheters, and urinary catheters also predisposes to infection with antibiotic-resistant as well as antibiotic-sensitive bacteria.21
Patients treated with SDD typically require intensive care; therefore, the above-noted risk factors predisposing to the emergence of antibiotic resistance should be applicable to patients receiving SDD. Unfortunately, large, long-term investigations of the use of SDD, examining its influence on antibiotic susceptibility patterns for clinically important microorganisms in the ICUs setting, have not been performed.
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Implications of Increasing Bacterial Antibiotic Resistance
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In general, infections with antibiotic-resistant bacteria are associated with greater hospital mortality and longer lengths of hospital stay.22
Colonization and infection with antibiotic-resistant bacteria increase the likelihood that patients will receive inadequate antimicrobial therapy (ie, antimicrobial therapy to which the identified causative microorganisms are resistant). Several investigations have demonstrated a strong association between the administration of inadequate antibiotic treatment and increased hospital mortality rates for patients with VAP.23
24
25
These studies independently demonstrated that patients receiving inadequate empiric antimicrobial treatment, initiated prior to obtaining the results of cultures from respiratory secretions, blood, and pleural fluid, had greater hospital mortality rates than patients receiving empiric antimicrobial regimens that provided full coverage of all identified bacterial pathogens. More important, it appears that, for patients initially receiving inadequate treatment, changing antimicrobial therapy based on the available culture results may not reduce the excess risk of hospital mortality associated with inadequate antibiotic treatment.24
Therefore, the timing of the administration of adequate antimicrobial therapy is an important determinant of outcome for patients with VAP.
Most inadequate antimicrobial treatment of nosocomial infections appears to be due to infection with antibiotic-resistant Gram-negative and antibiotic-resistant Gram-positive bacteria.20
Although inadequate antibiotic therapy may explain, in part, the greater mortality rates associated with antibiotic-resistant bacterial infections, other factors may also contribute to this excess mortality. Gram-positive bacterial pathogens such as S aureus can express a number of virulence factors potentially contributing to the high rates of mortality associated with infection due to these pathogens.26
The presence of methicillin resistance in S aureus appears to further enhance its virulence and likelihood of infection-related mortality in infected patients27
; however, not all investigators have demonstrated greater mortality rates with infections due to methicillin-resistant S aureus compared to methicillin-sensitive S aureus.28
Some antibiotic-resistant Gram-negative bacteria are also associated with increased virulence factors as compared with antibiotic-susceptible pathogens.29
This may explain some of the excess attributable mortality observed in clinical studies examining infections due to antibiotic-resistant Gram-negative bacteria.4
Nosocomial bloodstream infections are among the most serious infections acquired by hospitalized patients. The coexistence of a pathogen population with an ever-increasing resistance to many antibiotics and a patient population characterized by increasingly complex clinical problems has contributed to an increase in bloodstream infections, particularly due to antibiotic-resistant Gram-positive bacteria.30
Antibiotic resistance appears to have contributed to increasing administration of inadequate antimicrobial therapy for nosocomial bloodstream infections, which is associated with greater hospital mortality rates.31
32
The problem of antibiotic-resistant bacteremia appears to be increasing both in the hospital setting as well as in the community.33
Given the current trend of greater severity of illness for hospitalized patients, it can be expected that infections due to antibiotic-resistant bacterial strains will be associated with greater morbidity and mortality, particularly when inadequate empiric antimicrobial therapy is administered.20
In addition to higher patient mortality rates, antibiotic-resistant bacterial infections are associated with prolonged hospitalization and increased health-care costs relative to antibiotic-sensitive bacterial infections.34
A study from Beth Israel Deaconess Medical Center examined 489 inpatients with positive clinical culture findings for P aeruginosa.35
The emergence of antibiotic resistance in infections due to P aeruginosa was independently associated with greater hospital mortality and longer lengths of hospital stay. These authors estimated that the emergence of antibiotic resistance increased hospital charges by $11,981. Other authors have also reported increased medical-care costs associated with antibiotic-resistant infections.36
The overall national costs of antimicrobial resistance in the United States have been estimated to be between $100 million and $30 billion annually for the control and treatment of infections caused by antibiotic-resistant bacteria.34
37
The increased costs of infection due to antibiotic-resistant bacteria have been attributed to prolonged hospitalizations and greater antibiotic costs.38
Additionally, the emergence of antibiotic resistance results in the need to develop new antimicrobial agents.39
40
The costs required for the development of new antimicrobial agents, including the necessary clinical research to demonstrate their effectiveness and safety, have also increased in the last decade, possibly explaining, in part, the relatively slow development of new antibiotics.41
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Recent Meta-analyses of SDD
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The main focus of SDD is to selectively eliminate aerobic Gram-negative bacilli and yeast from the aerodigestive tract using a combination of topical and parenteral antibiotics (Table 1
). A large number of clinical trials have examined the use of SDD in the ICU setting. Meta-analysis represents a method used to group randomized clinical trials in order to increase the power of their observations. Two large meta-analyses have been conducted that review the use of SDD. The first is a European analysis published in British Medical Journal.42
This review concluded that 15 years of clinical research suggests that antibiotic prophylaxis with a combination of topical and systemic antibiotics can reduce respiratory tract infections and overall mortality in critically ill patients42
; the authors stated that "this effect is significant and worthwhile, and it should be considered when practice guidelines are defined."
It is important to note that the European meta-analysis observed a reduction in mortality only when the use of topical and systemic antibiotic prophylaxis was compared with no use of prophylaxis (16 studies reviewed). There was no difference in mortality when topical and systemic antibiotic prophylaxis was compared with systemic antibiotic prophylaxis alone (7 studies) and when topical antibiotic prophylaxis was compared with no antibiotic prophylaxis (11 studies). These findings suggest that it is the administration of systemic antibiotic prophylaxis, and not the administration of topical antibiotic prophylaxis, that is responsible for the observed reduction in mortality. Another important element of this analysis is that the majority of patients evaluated who had a survival advantage were surgical and trauma patients (> 70%). Trauma and surgical patients have previously been shown to benefit from the use of systemic antibiotic prophylaxis, including reduced rates of nosocomial infection and improved hospital survival.43
44
The second meta-analysis was conducted by Nathens and Marshall45
in Canada. These investigators found that there was not a survival advantage of SDD in the 10 studies they reviewed with no more than 25% postoperative and trauma patients. A survival advantage was found in the 11 studies with > 75% postoperative and trauma patients. This meta-analysis also showed that the survival advantage was greatest in studies in which both topical and systemic antibiotic prophylaxis was used. The main conclusion of this investigation was as follows:
SDD notably reduces mortality in critically ill surgical patients, while critically ill medical patients derive no such benefit. These data suggest that the use of SDD should be limited to those populations in whom rates of nosocomial infection are high and in whom infection contributes notably to adverse outcomes.
Interestingly, both of these analyses reported similar results. A common flaw of the two studies is a lack of a clear definition for SDD. SDD should be viewed as the use of antimicrobial agents to reduce oropharyngeal and GI colonization by pathogenic microorganisms, primarily Gram-negative bacilli and Candida species. Nathens and Marshall45
defined SDD as being made up of two components. The first component consists of topical, nonabsorbed antimicrobials including polymyxin E, tobramycin, and amphotericin B, a combination active against aerobic Gram-negative bacteria and fungi. The second component is IV cefotaxime sodium, or an equivalent parenteral antibiotic, generally administered for 4 days following the initiation of SDD. The European meta-analysis, however, demonstrated that there is considerable variation in how SDD is employed (topical antibiotics alone, topical and systemic antibiotics, variations in duration of antibiotic administration, variability in individual antimicrobials employed).
Additionally, an important element of the SDD strategy is to preserve the normal anaerobic flora within the intestinal lumen in order to prevent overgrowth with pathogenic organisms; unfortunately, this has not been demonstrated to occur. The available clinical data suggest that SDD alters the host’s bacterial flora, predisposing to the emergence of colonization and infection with antibiotic-resistant pathogens as demonstrated by the studies reviewed in the next section.
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SDD and Antibiotic Resistance
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In one of the largest trials of SDD, Gastinne and coworkers46
found that pneumonia due to staphylococci was more common among SDD-treated patients. The emergence of pneumonia due to Gram-positive bacteria in association with the use of SDD has also been reported by other investigators.47
Hammond and Potgieter48
found a statistically significant increase in the occurrence rate of infections caused by Acinetobacter species in the year after beginning a trial of SDD in their ICUs compared to the year preceding the trial (8.9% vs 5.2%, p = 0.05). Additionally, Acinetobacter species became the most common pathogen to colonize patients in their unit during this time period, although this occurrence could not be specifically linked to the use of SDD. Sanchez-Garcia and coworkers49
demonstrated reductions in the overall occurrence of nosocomial pneumonia with the use of SDD. However, the level of carriage of methicillin-resistant S aureus, coagulase-negative staphylococci, and enterococci was significantly higher in the SDD-treated patients. In a large study50
performed in Belgium, significantly more bacteremias due to Gram-positive bacteria were observed among SDD-treated patients. Increased antimicrobial resistance was also detected among the SDD-treated patients, including tobramycin-resistant Enterobacteriaceae, ofloxacin-resistant nonfermenters, ofloxacin-resistant Enterobacteriaceae, and methicillin-resistant S aureus. Finally, patient colonization with pathogenic bacteria, including Acinetobacter in areas like the skin and pharynx, which may not be decontaminated by SDD, casts doubt on the overall value of SDD as a useful clinical practice.51
As a result of its controversy, the use of SDD has not been commonplace in the United States. Similarly, clinical use of SDD has not gained a strong foothold in Europe, the continent where its clinical use has been most extensively investigated.52
In large part, it appears that fears over emerging antimicrobial resistance have limited the general use of SDD in Europe. A European consensus conference52
surveyed 279 ICUs physicians on their use of SDD; 18% used SDD to treat all patients receiving mechanical ventilation, 50% "never" employed SDD, and 32% used SDD for selected diagnoses and during epidemic outbreaks of infection. Interestingly, 92% of respondents surveyed 2 years earlier had not changed their practices. Cefotaxime or a second-generation cephalosporin were found to be the most common antibiotics employed (73%) for systemic administration, along with topical antibiotic prophylaxis. A concerning finding of this survey was the absence of any influence from rising antimicrobial resistance rates in Europe on clinical practices.5
Most respondents using SDD employed the same antibiotics during the years between the surveys and did not have epidemiologic data concerning predominant microbial pathogens and their antibiotic susceptibilities to help guide the use of SDD in their ICUs.
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Conclusion
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Antibiotic resistance has become a major concern for both community-acquired and nosocomial infections. The development and use of SDD has occurred during the recent explosion in infections due to antibiotic-resistant microorganisms. Unfortunately, the overall impact of SDD on the development of antibiotic resistance cannot be fully determined based on the existing medical literature. However, the use of SDD as well as other antibiotics should be carefully monitored as a potential stimulus for further antimicrobial resistance.1
53
Based on the available experience with SDD, and the likelihood that antimicrobial resistance will continue to be a major problem for the future, the routine or indiscriminate clinical use of SDD cannot be recommended at the present time. The development and application of new technologies, including novel antimicrobial agents and devices, hold the promise of achieving the goals of SDD without increasing antimicrobial resistance.54
55
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Footnotes
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Abbreviations: SDD = selective digestive decontamination; VAP = ventilator-associated pneumonia
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References
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TOP
Abstract
Introduction
