Selective decontamination of the digestive tract

8 Selective decontamination of the digestive tract C H R I S T I A A N P. S T O U T E N B E E K H E N D R I C K K. F. VAN SAENE

The prevention of infection by suppression of the intestinal flora with topical antibiotics dates back to 1939, when Garlock and Seley used sulphanilamide to prevent postoperative infections in colorectal surgery (Garlock and Seley, 1939). Since then many different antimicrobial agents such as sulphonamides, streptomycin, neomycin, kanamycin and paromomycin have been tried for this purpose. Because of the gap in the antimicrobial spectrum and the development of resistance when only one oral drug was used, Poth (1960) advocated a combination of neomycin and phthalylsulphathiazole. Later the combination of neomycin and erythromycin was used to cover both the anaerobic and aerobic fractions more completely. Up to the present time this combination is still widely used in colorectal surgery (Figueras-Felip et al, 1984). Oral antibiotic programmes are also extensively used in neutropenic patients, to prevent endogenous infections of the blood stream, respiratory and urinary tracts and skin. The most commonly used oral regimen consists of gentamicin, vancomycin and nystatin (GVN) to suppress both the aerobic and anaerobic intestinal flora (i.e. total decontamination). However, the increased risk of overgrowth by both sensitive and resistant organisms with this regimen necessitated reverse isolation (Bodey and Rosenbaum, 1974; Klastersky et al, 1974). Van der Waaij et al (1971) showed in animals that the elimination of the anaerobic flora by these antibiotics was responsible for the observed overgrowth by aerobic micro-organisms. This observation, and the fact that anaerobes are not frequently involved in infections, have led to more selective regimens such as the F R A C O N regimen (consisting of framycetin/neomycin, colistin and nystatin) or the combination of polymyxin B, neomycin, nalidixic acid and amphotericin B. With these regimens good results were obtained, in that overgrowth by sensitive or resistant organisms was less frequent even without reverse isolation (Storring et al, 1977; Sleyfer et al, 1980; Guiot et al, 1981). Another approach is the use of co-trimoxazole, which when given as prophylaxis for Pneumocy,~tis carinii infections in children with acute lymphocytic leukaemia was found to selectively suppress Enterobacteriaceae in the intestinal flora, thereby reducing the frequency of bacterial infections (Hughes et al, 1977). However, resistance against co-trimoxazole rapidly develops and often the addition of another agent such as colistin is necessary Bailli~re's Clinical Anaesthesiology-Vol. 5, No. 1, June 1991 ISBN 0-7020-1524-5

141 Copyright 9 1991, by Bailli6re Tindall All rights of reproduction in any form reserved

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(Wilson and Guiney, 1982; Rozenberg-Arska et al, 1983). Besides, as a consequence of absorption of the high oral dose, co-trimoxazole has undesirable side-effects, in particular prolonged bone marrow depression. Other conditions in which oral antibiotic regimens have been used are prevention of necrotizing enterocolitis in small infants and neonates (Egan et al, 1976; Grylack and Scanlon, 1978) and prevention of colonization and infection of wounds in burn patients (Jarret et al, 1978). However, these indications have never found general acceptance. Since 1981 selective decontamination of the digestive tract (SDD) has been introduced in surgical intensive care patients requiring prolonged mechanical ventilation (Stoutenbeek et al, 1984). The specific bacteriological problems in intensive care required a different antibiotic regimen from those used in leukaemic patients. This indication for SDD, although still controversial, is gaining increasing acceptance in Europe. DEFINITION Selective decontamination of the digestive tract (SDD) is a technique to prevent endogenous infections by selective elimination of potentially pathogenic micro-organisms (PPM) from both the oral cavity and gastrointestinal tract using oral non-absorbable antibiotics. The indigenous, mostly anaerobic flora is preserved as much as possible. Rationale for SDD

The rationale for SDD is, firstly, that the pathogenesis of most infections is endogenous, i.e. the micro-organisms are first carried in throat and gut before infection of blood, lower airways, urinary tract and skin occurs; secondly, micro-organisms causing infections are practically always aerobic PPMs (Enterobacteriaceae, Pseudomonadaceae, Staphylococcus aureus and yeasts); the anaerobes, which outnumber the aerobes by a ratio of 100 000 : 1 or more, relatively seldom cause an infection and have important physiological functions (Chapter 1); thirdly, most parenteral agents fail to eradicate carriage of PPMs. SDD REGIMEN

SDD consists of three elements:

1. 2. 3.

Topical antibiotics: the long-term administration of topical antibiotics for oral and intestinal decontamination for as long as the patient is at high risk of infection. Systemic antibiotics: a short-term administration of systemic antibiotic prophylaxis in the first few days of SDD. Intensive bacteriological monitoring, to evaluate and adjust the SDD regimen when PPM are incompletely eliminated from all sites (see Chapter 1).

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Topical antibiotics Criteria for topical antibiotics The oral antimicrobial agents used for SDD should satisfy the following criteria.

1. Antibiotic spectrum. The antibiotic spectrum should cover all Enterobacteriaceae (including Serratia spp.), Pseudomonadaceae and Acinetobacter spp., but not the indigenous flora. The spectrum is generally based on the ratio between the maximum therapeutic serum level and the minimum inhibitory concentrations. However, when antibiotics are applied topically, the concentration is so high that only completely resistant strains are outside the spectrum. 2. Non-absorbable antimicrobials. The oral antibiotics should be nonabsorbable, to maintain high intraluminal antibiotic concentrations that are not gradually decreased by absorption; this is particularly important to prevent selection of resistant strains. Systemic effects of the oral antibiotics are unnecessary and unwanted except in the first few days of decontamination. 3. Bactericidal activity. The oral antibiotics should have low minimal bactericidal concentrations (MBC) for most PPM. Bacteriostatic agents are of no value, since there are no leucocytes present in the lumen of the oropharynx and intestinal canal to assist the action of antimicrobial agents. 4. Minimal inactivation. The oral antibiotics should not (or minimally) be inactivated by food or faecal compounds or be degraded by faecal enzymes. Van Saene et al (1985) investigated the complex interaction between microorganisms, faeces and antibiotics in vitro (Figure 1) and found that many antibiotics are inactivated by faeces. However, since the MBC for some strains such as Pseudomonas aeruginosa and Acinetobacter calcoaceticus increased more than those of other PPM, inactivation cannot fully explain this finding. Apparently some micro-organisms are more or less 'protected' by faeces. PTA regimen The most effective oral antibiotic regimen for SDD in intensive care patients, and the one that has been studied most extensively, consists of polymyxin E, tobramycin and amphotericin B (PTA) (van Saene et al, 1983; van Saene and Percival, 1991). The reasons for using this combination are discussed below.

Polymyxin E. Polymyxin E covers Pseudomonadaceae and Enterobacteriaceae except Proteus and Morganelta spp. (Sud and Feingold, 1970); it is not active against the indigenous flora (Hazenberg et al, 1983). Polymyxin E is not absorbed from the intestinal tract. The mode of action is disruption of

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the bacterial cell wall, making the cell wall permeable and causing cell death (Nord and Hoeprich, 1964). This mechanism is independent of enzymatic systems. Polymyxin E is an ideal antibiotic for SDD because it effectively binds and inactivates endotoxin, and also because acquired resistance is very rare (Sogaard, 1982). However, polymyxin E is inactivated by proteins, food and faecal compounds (Gotoff and Lepper, 1965; van Saene et al, 1985; Hazenberg et al, 1986) and should therefore be given in a large dose. Because of the gap in the spectrum and the faecal inactivation it should not be given as sole decontaminating agent. Polymyxin E may be substituted by polymyxin B.

Tobramycin. Tobramycin and polymyxin E have synergistic action against Pseudomonas, Acinetobacter and Serratia spp. Hazenberg et al (1985) showed that tobramycin in vitro has a selective action on the aerobic gram-negative PPM. These investigators introduced the selective decontamination factor (SD factor) to evaluate selectivity of antimicrobial agents. SD factor is defined as the ratio of the antibiotic concentrations giving 50% inhibition of obligate anaerobic bacteria and of Enterobacteriaceae. The SD factor for tobramycin varied between 13.5 and 1222, and for gentamicin between 1.94 and 15.5 (Hazenberg et al, 1985). These findings confirm animal experiments showing that tobramycin had little effect on the anaerobic flora (measured by the indirect parameters, [3-aspartylglycine and coecal weight) in doses that were still adequate to suppress completely the endogenous Enterobacteriaceae (van der Waaij et al, 1982). Another study, in volunteers, showed that the administration of tobramycin (300 mg per day orally) was effective in eliminating Enterobacteriaceae from the intestinal flora, without adverse effects on the anaerobic flora (Mulder et al, 1984). Tobramycin is not absorbed from the gut. However, in severe gastroenteritis or treatment with cytostatics (mucositis) absorption may take place (Rohrbaugh et al, 1984) and monitoring of serum levels may be necessary. The mode of action is bactericidal by inhibition of protein synthesis. Induction of resistance to aminoglycosides does not occur as frequently as with [3-1actam antibiotics. Compared with other aminoglycosides, tobramycin is least inactivated by faecal compounds and food (Figure 1).

Amphotericin B. Amphotericin B is the most potent of antifungal drugs; it is added to prevent overgrowth by yeasts. Amphotericin B is not absorbed. It is readily inactivated by faeces (Bodey, 1969; van Saene et al, 1985) and should therefore be given in a large dose.

Alternative topical antibiotic regimens Most SDD regimens in intensive care used polymyxin B or E, although the dosage in some regimens was too low. The major variations are found in the choice of the second antibiotic. Instead of tobramycin, other antibiotics including gentamicin, neomycin, norfloxacin, ciprofloxacin or aztreonam

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have been used. Since tobramycin and amphotericin B are not available for oral use in the USA, gentamicin and nystatin have been used instead (Wiesner et al, 1988; Cockerill et al, 1990; Flaherty et al, 1990). Nystatin is less potent than amphotericin B, and to achieve successful yeast decontamination a 60-ml suspension (106 IU) is required. Often this high dose is associated with gastrointestinal side-effects. Comparison of the different regimens is difficult, since detailed data about the efficacy of the gastrointestinal decontamination, in particular with difficult pathogens such as Pseudomonas aeruginosa, Acinetobacter spp. or Staphylococcus aureus, are often lacking. Polymyxin E, neomycin and nalidixic acid. Brun Buisson et al (1989) used a regimen which has been used in leukaemic patients, consisting of 200 mg polymyxin E, 4 g neomycin and 4 g nalidixic acid per day. They were able to prevent gastrointestinal colonization by multiresistant Enterobacteriaceae but not by Pseudomonadaceae and staphylococci. This might be explained by faecal inactivation of polymyxin E when given in a relatively low dose, whereas neomycin and nalidixic acid are also strongly inactivated and have no effect on Pseudomonas spp. (van Saene et al, 1986). Polymyxin E and gentamicin. Clinical experience with the combination of gentamicin and polymyxin E in leukaemic patients shows that intestinal colonization with Pseudomonas and Klebsiella-Enterobacter spp. frequently occurred despite good in vitro sensitivity for gentamicin (Bodey and Rosenbaum, 1974; Klastersky et al, 1974). In the studies using gentamicin in intensive care patients, the eradication of potentially pathogenic microorganisms has not been sufficiently evaluated for this combination to be recommended as an effective decontamination regimen. Based on the spectrum and the in vitro inactivation data, the combination of polymyxin E and gentamicin might be less successful in the abolition of carriage of P. aeruginosa, Acinetobacter spp. or S. aureus. Quinolones. Most gram-negative pathogens are covered by quinolones, although Pseudomonas and Acinetobacter spp. may quickly become resistant. Quinolones possess some activity against S. aureus, but haemolytic streptococci are insensitive. The quinolones are readily absorbed from the gut and as a consequence the intraluminal concentrations in the colon will be very low. The mode of action is bactericidal by gyrase inhibition. Some inactivation by food and faeces does occur (van Saene et al, 1986); however, inactivation by aluminium-containing antacids is clinically more important (Jaehde et al, 1987). Ciprofloxacin has been used alone as an SDD agent in leukaemic patients with good results (Dekker et al, 1987). Two studies in intensive care patients used a low dose of norfloxacin in combination with polymyxin E with satisfactory results (Aerdts et al, 1990; Ulrich et al, 1990). Although the number of patients in these studies is too small to draw conclusions, elimination of Pseudornonas might be a problem.

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Mode of administration of the PTA regimen The gastrointestinal tract is decontaminated by a 10-ml suspension of polymyxin E (100mg), tobramycin (80 mg) and amphotericin B (500 mg), which is administered orally or through the gastric tube four times daily. Gastric suction is discontinued for 1 hour following administration. In the presence of paralytic ileus the topical antimicrobials prevent colonic flora from spreading into the small intestines and stomach. However, the colon can only be effectively decontaminated when the bowel function is normal. Intestinal decontamination generally takes 6-10 days due to absence of peristalsis. However, secondary colonization of the gastrointestinal tract with new pathogens can be almost completely prevented. Decontamination of the oropharynx is of utmost importance, especially in mechanically ventilated patients (Stoutenbeek et al, 1987a). A sticky paste (Orabase), containing 2% each of polymyxin E, tobramycin and amphotericin B, is applied to the buccal mucosa four times daily. Within 2 days after starting SDD the oropharynx should be free of PPM. The paste is essential to guarantee a long period of contact between the antibiotics and the PPM. An aqueous solution of antibiotics was found to have little effect (unpublished observations), probably because it was too quickly diluted. Unertl et al (1987) administered the oral antibiotic solution partly in the oral cavity and partly through the nasogastric tube. However, this study shows that oropharyngeal colonization by PPM occurred in 32% of patients. Disinfecting agents like chlorhexidine or povidone-iodine are found not to be very effective in preventing oropharyngeal colonization (Spijkervet et al, 1989). In two studies in which povidone-iodine 2% solution was used for oral decontamination, the effect of this procedure was not evaluated (Brun Buisson et al, 1989; Godard et al, 1990).

Systemic antibiotics The second component of SDD, short-term systemic antibiotic prophylaxis, is given for the following reasons: 1. 2. 3.

To eliminate carriage of community-acquired pathogens such as Streptococcus pneumoniae that are not covered by the topical antibiotic regimen. To cover the first few days of SDD in which the patient is not yet adequately decontaminated. To treat incubating or early infections with pathogens carried by the patient at the time SDD was started.

The spectrum of the systemic antibiotic therefore depends on the type of pathogens carried by the patient at the onset of SDD. Under normal conditions patients may carry only community-acquired pathogens. However, in patients with severe underlying disease, who have been hospitalized or have been treated with systemic antibiotics, carriage of hospital-acquired gram-negative pathogens readily occurs. Cefotaxime is a suitable antibiotic for most indications of blind systemic prophylaxis, since its

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spectrum covers both community-acquired as well as hospital-acquired PPM (excluding Pseudomonas and Acinetobacter spp.) and it has little effect on the indigenous flora (Pech6re, 1989); it has a broad therapeutic range with few adverse effects. Other antibiotics that are safe for the indigenous flora (e.g. parenteral cephalosporins, monobactams or quinolones) have either an incomplete cover of the Enterobacteriaceae (e. g. cephradine, cefuroxime) or of the gram-positive pathogens (e.g. ceftazidime, aztreonam). The spectrum of the new quinolones excludes S. pneurnoniae.

ANALYSIS OF AVAILABLE TRIALS IN INTENSIVE CARE Sixteen trials on SDD in intensive care have been reported so far," one of which in preliminary form only (Cockerill et al, 1990). The first 12 studies have been recently reviewed in great detail by Reidy and Ramsay (1990). Although these studies vary greatly in study design, patient selection and SDD regimen, a highly significant improvement in the overall rate of carriage and acquired infection has been found in all studies except one. However, in this study no oropharyngeal decontamination, no parenteral antimicrobial prophylaxis and a different SDD regimen were used (Brun Buisson et al, 1989).

Study design One of the criticisms of SDD trials is the lack of blinding (Condom 1990). Apart from the technical problems in conducting a properly placebo-blinded study, a randomized, placebo-controlled, double-blind study may not be the proper design to study the effect of SDD in intensive care, since the ecology of the ICU changes completely when half of the patients are treated with SDD. As a consequence the risk of acquisition and subsequent carriage in the concurrent control patients decreases significantly. This crossover effect has been demonstrated by Brun Buisson et al (1989), who showed a significant reduction in the risk of acquisition and intestinal carriage with multiresistant Enterobacteriaceae in the control group when half the patients were treated with SDD. A randomized trial might thus obscure treatment differences. To overcome this problem, some studies used consecutive groups or concurrent controls in two separate ICUs with crossover of the treatment after a period of time (Godard et al, 1990; Hartenauer et al, 1991).

Carriage/colonization/infection rate In the intensive care studies the most striking and consistent reduction has been found in the secondary bronchopulmonary infection rate in patients requiring prolonged mechanical ventilation. The effect on acquired wound or urinary tract infection rate or septicaemia rate is less consistent. The studies in liver transplantation and oesophageal resection included all

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postoperative infections. One observational cohort study in burned patients showed a relatively low incidence of wound infections (Manson et al, 1987). The effectiveness of an infection prevention regimen should not only be assessed by the infection rate. SDD reduces also the severity of acquired infections, the number of failing organs or the severity of organ failure as a consequence of infection and the duration of an infection, and as a consequence the amount of systemic antibiotics used is significantly reduced by SDD (Stoutenbeek et al, 1984b; Ledingham et al, 1988; Flaherty et al, 1990; Tetteroo et al, 1990). A careful analysis of the origin of the infections occurring during SDD is essential for further improvement of the infection prevention regimen. All infections fall into one of three categories: primary endogenous, secondary endogenous or exogenous infections. If exogenous infections are the major problem, specific hygienic measures should be reinforced, whereas primary endogenous infections can only be prevented by adequate systemic antibiotic prophylaxis, and secondary endogenous infections by improving the topical antibiotic regimen. Evaluation of cefotaxime prophylaxis can only be made in primarily non-infected patients. In most studies, however, primary endogenous infections could not be differentiated from infections existing on admission. Most patients were treated with systemic antibiotics as blinded therapy rather than as prophylaxis.

Mortality In four of the 13 studies a lower mortality was found in the SDD-treated group (Stoutenbeek et al, 1984a; Sydow et al, 1990; Ulrich et al, 1990; Hartenauer et al, 1991). However, two of these had a historical control, group. In two other studies (Kerver et al, 1988; McClelland et al, 1990) the infection-related mortality decreased, but not overall mortality. In some studies a difference in mortality has been found for subgroups of patients such as trauma patients or patients requiring more than 7 days of intensive care (Ledingham et al, 1988) or with more than 48 hours' stay in an ICU (Godard et al, 1990). However, the statistical power of most studies was not sufficient to find significant differences in outcome. The fact that the dramatic reduction in acquired infection rate is not accompanied by a significant reduction of mortality seems to challenge the widely accepted view that infection is the major cause of death in patients requiring prolonged intensive care. However, most of these studies included patients with severe underlying diseases and infections present on admission: e.g. in Kerver's study (Kerver, 1988) 23% of the control group and 39% of the SDD-treated patients were admitted to the ICU because of intra-abdominal sepsis. In these patients the prognosis is determined by the primary infection and the dnderlying disease rather than by the ICUacquired infections. In another study cerebral injury was the most common cause of death (Unertl et al, 1987). The effect of SDD on mortality can only be investigated in a properly designed multicentre trial in a homogeneous population of primarily noninfected patients, in whom ICU-acquired infections are a major cause of

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death. Polytrauma patients are an ideal study population, because they are previously healthy, the severity of the disease can be scored objectively, they are not infected upon admission and the microflora has not been influenced by prior antibiotic use or hospitalization, and sepsis and multiple organ failure are the main cause of late death. Analysis of the Injury Severity Score and outcome in a group of 167 multiple trauma patients treated with selective decontamination, showed that late mortality from multiple organ failure or sepsis could be completely prevented (Stoutenbeek et al, 1987c). Emergence of resistance With conventional antibiotic policies the major problem is supercarriage and superinfection with yeasts and resistant gram-negative pathogens. The gastrointestinal tract of patients is the major reservoir of multiple resistant pathogens in the hospital, from which other patients are contaminated (Selden et al, 1971; Flynn et al, 1987; Brun Buisson et al, 1989). Analysis of emergence of resistance should therefore always include cultures of the oropharynx and rectum. In these sites the circumstances for emergence of resistance are almost ideal during systemic antibiotic therapy or prophylaxis (Chapter 1). Elimination of these reservoirs by treating carriers with SDD decreases the risk of superinfection in these patients and prevents the transmission of these pathogens to other patients. All SDD studies showed a remarkable absence of superinfections, despite widespread use of cefotaxime. So far there is no indication that SDD increasesthe risk of selection of resistant pathogens during many years of uninterrupted use of the same regimen (Stoutenbeek et al, 1987b). Kerver et al compared the pattern of resistance among gram-negative bacilli in a four-year period before and after the introduction of SDD. They observed a significant decrease in gentamicin resistance in Pseudomonas and Acinetobacter strains after the institution of SDD. No increase in resistance to tobramycin or cefotaxime was found (Kerver, 1988). Further, SDD is proven to be highly effective in controlling outbreaks with multiply resistant Enterobacteriaceae in the ICU (Brun Buisson et al, 1989; Taylor and Oppenheim, 1991). During SDD, the circumstances for the emergence of resistance are unfavourable for two reasons. 1.

2.

Resistance to the combination of polymyxin E and tobramycin is rare. Although some pathogens are intrinsically resistant to polymyxin E (e.g. Proteus spp.), acquired resistance against polymyxin E has never been described. Resistance mediated by inducible bacterial enzymes to tobramycin is far less common than resistance to [3-1actams. The levels of the topical antibiotics in the lumen of the oropharynx and intestines exceed the minimal bactericidal concentrations (MBC) for most PPM by a factor of 100-1000; under these circumstances, selection of resistant strains is unlikely.

The isolation during SDD of methicillin-resistant coagulase-negative staphylococci, or streptococci resistant to aminoglycosides and cephalo-

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sporin, should not be considered as selection of resistance. The aim of SDD is to preserve the indigenous flora, which implies that only aerobic streptococci and coagulase-negative staphylococci should be isolated from cultures of throat, rectum or skin. These micro-organisms are commensals with a very low intrinsic pathogenicity and seldom require antibiotic treatment. If antibiotic therapy should be necessary, e.g. in patients with prosthetic material, the coagulase-negative staphylococci generally respond well to vancomycin and enterococci to ampicillin. In a study showing a 'selection of gram-positive cocci' the infection rate with gram-positive cocci in the SDD group of patients was even lower than in the control group (Konrad et al, 1989). P R E O P E R A T I V E SDD

Patients with severe underlying diseases, old age, prolonged hospitalization or prior antibiotic use are often abnormal carriers (Johanson et al, 1969; Valenti et al, 1978). Abnormal carriage includes (a) carriage of an abnormal type of PPM, with a high intrinsic pathogenicity or with an abnormal sensitivity pattern, e.g. a patient carrying a multiply resistant Enterobacter cloacae in the rectum; (b) carriage of a potentially pathogenic microorganism in an abnormally high concentration, e.g. a patient carrying Escherichia coli in a concentration of 108 colony-forming units per ml in the rectum; or (c) carriage in an abnormal site, e.g. a patient carrying E. coli in the stomach. The available data suggest that abnormal colonization increases the risk of postoperative infections in procedures with an otherwise low infection risk (Gatehouse et al, 1978; Nichols and Smith, 1975; Nichols et al, 1975; Muscroft et al, 1981). Obviously, systemic antibiotic prophylaxis is of no avail when the patient is carrying PPM that are resistant to this particular antibiotic or when the concentration is very high. Accidental spilling of minute amounts of highly contaminated intestinal contents during the operation may present an inoculum large enough to overcome the local defences, despite antibiotic prophylaxis. Attempts to cleanse the bowel mechanically by whole gut irrigation increase rather than decrease the aerobic bacterial counts (Weidema, 1982). Patients who are carriers may be treated preoperatively with SDD in addition to the perioperative systemic antibiotic prophylaxis. To identify abnormal carriage, surveillance cultures of throat and gut should be taken preoperatively from patients undergoing major surgery, and these cultures should be processed both qualitatively and (semi)quantitatively. There are no studies available as yet to support this hypothesis. Some surgical procedures have a high risk of postoperative infection despite adequate perioperative prophylaxis with systemic antibiotics, for example oesophageal resection or liver transplantation. Most of these infections are endogenous. A controlled trial in patients undergoing oesophageal resection showed that SDD, started 3 days preoperatively, effectively reduced the postoperative infection rate (Tetteroo et al, 1990).

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A pilot study on preoperative SDD in liver transplant recipients in the Mayo Clinic showed a remarkably low postoperative infection rate, compared with other centres (Wiesner et al, 1988). To identify the surgical procedures in which preoperative SDD might be beneficial, an analysis should be made of the postoperative infections that occur despite systemic antibiotic prophylaxis, with emphasis on the added morbidity, mortality and costs of these postoperative infections. In some operations such as bowel resection, the perioperative wound infection rate is about 8%. Only a few patients will require intensive care because of postoperative infection. However, the added morbidity and costs of treatment for these patients are substantial. Although an effective prevention regimen against infection might not significantly alter the postoperative infection rate, it might still be cost-effective. In Table 1 a tentative list of operative procedures in which SDD might be indicated is presented. Table 1. Indications for preoperative SDD.

Liver transplantation Pancreas (and kidney) transplantation Oesophagus/total gastric resection

Pharyngeal/laryngealoperations Tracheal segmentresection Cystectomyplus uretero-ileo-cntaneostomy Colon operations Abdominalaortic operations Irradiated patients Patients with abnormalcolonization

P E R O P E R A T I V E SDD

In patients undergoing emergency abdominal surgery for intra-abdominal sepsis, the optimal prevention seems to be peroperative total bowel irrigation and peroperative SDD, in addition to systemic antibiotic prophylaxis or treatment. With peroperative bowel irrigation in combination with SDD, it is possible to decontaminate the lower gastrointestinal tract effectively in a few hours; decontamination would otherwise take more than 10 days (unpublished observations). P E R I O P E R A T I V E ANTIBIOTIC PROPHYLAXIS

Figure 2 sets out an algorithm based on the considerations described below.

1. Perioperative systemic antibiotic prophylaxis (without SDD) is the standard type of antibiotic prophylaxis in patients with normal flora.

2.

Preoperative and postoperative SDD plus perioperative systemic antibiotic prophylaxis should be used in patients who are carriers of abnormal flora before the operation, or in high-risk surgical procedures.

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surgery?

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IY~s Yes

Pemperativebowelirrigation + peroperativeSDD+ perioperativesystemic antibioticprophylaxis

PreoperativeSDD+ [ perioperativesystemic antibioticprophylaxis

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Perioperativesystemic ! antibioticprophylaxis Figure 2. An algorithm of infection prevention9The essential determinants are (a) abnormal colonizationbefore the operation; (b) operative procedureswith high risk for infection despite systemic antibiotic prophylaxis; (c) emergency abdominal surgery.

3.

Peroperative and postoperative SD D plus systemic antibiotic treatment or prophylaxis may be used in patients undergoing emergency abdominal surgery, to reduce the decontamination time of the lower gastrointestinal tract.

4.

Postoperative SDD plus short-term systemic antibiotic prophylaxis should be used in patients with a high risk of infection during intensive care, e.g. polytrauma patients.

T H E GASTROINTESTINAL ORIGIN OF T H E SEPTIC STATE More than thirty years ago Fine et al pointed out that the intestinal flora plays an important role in shock (Fine et al, 1959; Woodruff et al, 1973). However, these studies received little attention at the time. Recently, the concept of the gut as a central organ during critical illness (Border et al, 1987; Wilmore, 1988) is being increasingly accepted. The abnormal carrier state may play an important role in critical ill patients in three different ways: 1.

Direct spread to neighbouring organs, e.g. pneumonia by aspiration of oral flora.

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Absorption of intestinal endotoxin. Translocation of viable bacteria through the mucosa.

The first mechanism is well established and has already been discussed extensively. Most of the evidence for the role of absorption of endotoxin and translocation is derived from animal experiments. To date, few clinical data exist to support this concept. In the following section the role of the abnormal carrier state is reviewed. The major factors determining translocation and absorption of endotoxin are (a) the type of micro-organisms; (b) the concentration of micro-organisms; (c) the site of carriage; and (d) the permeability of the gut mucosa. Absorption of intestinal endotoxin

The content of intestinal endotoxin in healthy individuals varies between 0.1 mg and 10 mg per gram of faeces, mean i mg/g (van Saene et al, 1989). After an intravenous dose as small as 0.1 g, symptoms of fever and thrombocytopenia develop. This implies that under normal conditions the gut mucosa must be an extremely efficient barrier against endotoxin entering the circulation. More than 90% of the intestinal endotoxin is derived from aerobic gramnegative PPM. The anaerobic gram-negative micro-organisms, which outnumber the aerobes by a factor of 100 000 to 1, produce less than 10% of the intestinal endotoxin (van Saene et al, 1989). The endotoxin of Bacteroides fragilis has considerably less biologic potency than that of aerobic gramnegative bacteria (Simon et al, 1985). The role of gut-derived endotoxin in the pathogenesis of the 'sepsis syndrome' and multiple organ failure in critically ill patients is difficult to confirm. Since most of the endotoxin is cleared by the Kupffer cells in the liver, the demonstration of endotoxin in the systemic circulation is a late symptom when the reticuloendothelial system is exhausted. Release of cytokines from the liver might be an earlier marker of portal endotoxaemia. Absorption of endotoxin should be distinguished from translocation of viable bacteria. Papa et al (1983) demonstrated absorption of radiolabelled endotoxin from the colon within 30 minutes after initiation of intestinal ischaemia in dogs. Up to 6 hours thereafter absorption of endotoxin, but no translocation of viable bacteria, was observed. Translocation

The role of translocation of intestinal PPM in humans has been controversial for a long time, since it is extremely difficult to confirm. Wells et al formulated an attractive hypothesis describing the route and the mechanism of translocation: motile phagocytes ingest intestinal bacteria, transport them to the extraintestinal site, fail to accomplish intracellular killing and then liberate the bacteria in the extracellular site (Wells et al, 1988b, 1989). Alexander et al studied the process of translocation with electronmicroscopic studies in thermally injured guinea-pigs and rats. They found that translocation of Candida albicans and E. coli occurred by direct penetration

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of enterocytes. Most of the micro-organisms in the lamina propria were phagocytized by macrophages and degraded in Peyer's patches, and few micro-organisms were found in the mesenteric lymph nodes (Alexander et al, 1990). The typical route of translocation is to the mesenteric lymph nodes. Positive blood cultures can only be found when the defence mechanisms are overwhelmed by the enteric micro-organisms. Probably the earliest marker of translocation is release of cytokines from Peyer's patches or the mesenteric lymph nodes in the lymphatic system. Micro-organisms with decreased intracellular killing in the motile phagocytes of the intestinal mucosa have the highest rate of translocation. Typical examples are the obligate enteric pathogens, e.g. Salmonella spp. The translocation rate for aerobic gram-negative PPM such as Klebsiella or Pseudomonas spp. is again higher than for the indigenous anaerobic bacteria (Steffen et al, 1988). The indigenous anaerobic flora not only has a very low potential for translocation but, moreover, this type of flora is thought to control carriage and translocation of aerobic PPM (Wells et al, 1988a), supporting the concept of 'colonization resistance' (van der Waaij et al, 1971). The concentration of PPM is also an important factor. Translocation to the mesenteric lymph nodes, liver and spleen in rats can be demonstrated when bacterial overgrowth is produced with oral penicillin treatment or by monoassociation of germ-free animals (Deitch et al, 1985; Wells et al, 1989). Translocation is also dependent on the site of carriage. Translocation is thought to occur more readily in the upper gastrointestinal tract than in the colon. In the small intestines there is an active absorptive process and carriage is uncommon. Another important factor determining translocation is the increased permeability of the intestinal mucosa as a result of major trauma (Rush et al, 1988), burns (Deitch et al, 1985; Ziegler et al, 1988), shock or endotoxin. Ischaemia of the intestinal mucosa, in particular postischaemic reperfusion injury, seems to be the common denominator (Grisham and Granger, 1989; Kvietys and Granger, 1989). In moderate ischaemia only aerobic PPM may translocate, whereas during severe ischaemia both aerobic and anaerobic bacteria may massively translocate (Wells et al, 1989). It has been demonstrated that a single injection of endotoxin increases the intestinal permeability in human volunteers (O'Dwyer et al, 1988). In particular in the presence of protein malnutrition small amounts of endotoxin enhance translocation (Deitch et al, 1987). Endotoxin may start a vicious circle of increased gut permeability, endotoxin absorption and a further increase of barrier loss until multiple organ failure ensues. Prevention of translocation and absorption of endotoxin by SDD SDD may be helpful in the prevention and treatment of translocation or absorption of endotoxin. Polymyxin antibiotics are known to bind to and neutralize endotoxin. In six healthy volunteers, treated with oral polymyxin E and tobramycin, E. coli was eradicated from the gut within 3 days resulting

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in a 3 log fall of faecal endotoxin levels, which implies a 99.9% reduction (van Saene et al, 1989). No endotoxin release as a result of bacterial cell lysis was observed. SDD eliminates the aerobic gram-negative PPM and yeasts which translocate most easily. Moreover, SDD prevents abnormal carriage in the upper gastrointestinal tract, where translocation and absorption of endotoxin occur probably more easily than in the colon. The preservation of the indigenous anaerobic flora by using antibiotics with a selective aerobic antibiotic spectrum might also play a role in the prevention of translocation of gram-negative PPM. However, in mice and rats treated with PTA and parenteral cefotaxime an increased translocation of enterococci to the mesenteric lymph nodes has been found compared to PTA alone or untreated controls (Speekenbrink et al, 1987; Jackson et al, 1990). So far no clinical studies have been published showing that SDD actually prevents multiple organ failure or the sepsis syndrome by preventing absorption of endotoxin or prevention of translocation.

INDICATIONS FOR SDD

Based on the results of the available studies a tentative list of indications for SDD includes: 1. 2. 3. 4. 5.

Prolonged mechanical ventilation (expected duration more than 2 days). Preoperatively in high-risk operations or in high-risk patients (Table 1). Burns. Treatment of severe infections. Outbreaks of multiply resistant micro-organisms.

SUMMARY

Selective decontamination of the digestive tract (SDD) is a technique to prevent endogenous infections by selective elimination of pathogens from the oral and intestinal flora with topical non-absorbed antibiotics. It is crucial that the oropharynx and the gastrointestinal tract are both decontaminated. The effect of SDD is determined by the choice of topical antibiotics, since only few antibiotics are suitable for decontamination. SDD is proven to be effective in preventing acquisition, subsequent carriage and infection in critically ill patients. Pathogens carried by the patient are not only responsible for infections but may also have a role in the pathogenesis of sepsis syndrome and multiple organ failure, probably by translocation through the intestinal mucosa. However, SDD needs time to become effective; the oropharynx can be quickly decontaminated, but the gastrointestinal tract takes much longer. In the meantime the patient may be infected by the pathogens he or she is carrying; the patient should therefore be protected by a systemic antibiotic

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against these endogenous pathogens. The infection risk is determined on the one hand by the host defence and on the other hand by abnormal carriage. Systemic antibiotic prophylaxis becomes less important if SDD is started before the patient is at risk of infection. In clinical practice it is often possible to start SDD preoperatively in high-risk operations and in selected high-risk patients. To identify patients at risk, surveillance cultures of the oropharynx and rectum should be taken before the operation, or SDD should be started 48 hours preoperatively when risk factors for abnormal colonization are present.

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