1 October 1992
Number 7
Volume 117
Annals of Internal Medicine Prevention of Infection in Critically 111 Patients by Selective Decontamination of the Digestive Tract Franklin R. Cockerill III, MD; Sharon R. Muller, RN; John P. Anhalt, PhD, MD; H. Michael Marsh, MBBS; Michael B. Farnell, MD; Peter Mucha, MD; Delmar J. Gillespie, MD; Duane M. Ilstrup, MS; Jeffrey J. Larson-Keller, BS; and Rodney L. Thompson, MD
• Objective: To determine whether selective decontamination of the digestive tract using oral and nonabsorbable antimicrobial agents and parenteral cefotaxime prevents infection in critically ill patients. • Design: Randomized, controlled trial without blinding. • Setting: Surgical trauma and medical intensive care units in a tertiary referral hospital. • Patients: One hundred fifty patients admitted to surgical trauma and medical intensive care units during a 3-year interval, whose condition suggested a prolonged stay (> 3 days). • Intervention: Patients were randomly allocated to an experimental group (n = 75) that received cefotaxime, 1 g intravenously every 8 hours for the first 3 days only, and oral, nonabsorbable antibiotics (gentamicin, polymyxin, and nystatin by oral paste and oral liquid) for the entire stay in the intensive care unit. Control patients (n = 75) received usual care. • Measurements: The number of infections, total hospital days, and deaths, as well as the number of days in intensive care unit, were recorded. • Results: Control patients experienced more infections (36 compared with 12, P = 0.04), including bacteremias (14 compared with 4, P = 0.05) and pulmonary infections (14 compared with 4, P= 0.03). Although total hospital days, days in intensive care, and the overall death rate all were lower in the treatment group, these differences were not statistically significant. Clinically important complications of selective decontamination of the digestive tract were not encountered. • Conclusions: Selective decontamination of the digestive tract decreases subsequent infection rates, especially by gram-negative bacilli, in selected patients during long-term stays in the intensive care unit.
JNosocomial infections cause considerable morbidity and mortality among patients requiring intensive care, and the associated costs represent a significant economic burden to the health care industry (1, 2). Reduction of nosocomial infection in the intensive care unit has been the goal of several recent clinical trials (3-10). These trials operated on the hypothesis that antimicrobial prophylaxis using oral and parenteral agents, which eliminate or decrease potentially pathogenic microorganisms but which do not affect colonization resistance by anaerobic flora of the digestive tract, should result in fewer nosocomial infections. This method has been referred to as selective decontamination of the digestive tract. Decontamination of the digestive tract to prevent infection has been tried previously with variable success in neutropenic patients using trimethoprim-sulfamethoxazole and quinolones given orally (11). Only recently has the same concept been applied to non-neutropenic, critically ill patients. In 1984, Stoutenbeek and associates (3) first reported the benefits of a novel oral and parenteral antimicrobial decontamination program in trauma patients requiring mechanical ventilation. Although historic controls were used and criteria for infection were imprecise, an impressive decrease in the infection rate was observed (81% among controls compared with 16% among treated patients). Nonabsorbable antimicrobials, including polymyxin E (2%), tobramycin (2%), and amphotericin B (2%) in a sticky paste, were applied to the oral mucosa. Polymyxin E (100 mg), tobramycin (80 mg), and amphotericin B (500 mg) were delivered as an oral suspension or by nasogastric tube if necessary. Initially, cefotaxime also was given intravenously until surveillance cultures showed that potentially pathogenic microorganisms had been eliminated (mean, 9 days). The authors provided no information on mortality and cost effectiveness, but, in a subsequent report (12), they noted no increase in drug-resistant
Annals of Internal Medicine. 1992;117:545-553. From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota. For current author addresses, see end of text.
Generic Name cefotaxime
Drug Brand Name Claforan
© 1992 American College of Physicians
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gram-negative bacilli during the treatment. Subsequently, several trials using similar decontamination protocols in patients in intensive care units have reported similar results (4, 5, 7-10). We did a randomized, controlled study to further evaluate the efficacy of selected oral antimicrobial agents and parenterally administered cefotaxime in the prevention of nosocomial infection in our medical, surgical, and trauma intensive care patients. As in many previous studies, we used cefotaxime because the reduction of potentially pathogenic microorganisms from the digestive tract using oral antimicrobial agents may require treatment for as much as 1 week (3). In contrast to previous studies, however, cefotaxime was limited to nine infusions during a 72-hour period. A potential problem with all these studies was poor discrimination between infection and colonization. In contrast, we developed strict criteria for nosocomial infections. Finally, we sought to determine whether this method of selective decontamination of the digestive tract caused the emergence of multiply resistant organisms or decreased mortality for patients receiving intensive care in our institution. Methods Patient Selection All patients admitted to the surgical-trauma and medical intensive care units were eligible for the study during a 3-year interval if their conditions suggested a prolonged stay (> 3 days). Patients were excluded if they had infection, received antibiotics for more than 24 hours before randomization, were younger than 18 years of age, were pregnant, or were allergic to treatment drugs. One hundred fifty patients were studied from 1986 through 1989. Seventy-five patients were randomized to the control group and 75 to the decontamination group. The average patient age was 65 years for the control group and 65.5 years for the decontamination group (range, 19 to 94 years and 26 to 95 years, respectively). Cases were categorized at the time of admission as surgical, trauma, trauma cases requiring operation, and medical. Blocking within stratification with randomization to the control or decontamination group was achieved using randomization tables at a remote site by a neutral observer in the pharmacy. After randomization to the decontamination group, a patient remained in that group even if decontamination was discontinued during the study. Severity-of-Illness Assessment Each patient was evaluated for severity of illness using five measures: chronic health points, Glasgow coma score, injury severity, trauma score, and Apache score. Study Protocol This study was approved and monitored by the Mayo Institutional Review Board. All patients-were informed, and signed consent was obtained. If the patient was too ill, consent was obtained from the closest living relative or spouse. The intensive care unit study period began at impanelling, within 1 to 6 days of admission to the intensive care unit (mean, 1 day for each group) and continued for 2 days after dismissal from the intensive care unit or until death in the unit. The follow-up period consisted of the remaining hospital stay. Patients in the experimental group received cefotaxime (1 g) intravenously every 8 hours for the first 3 days only (maximum, 9 doses) and oral nonabsorbable antibiotics for the entire stay in the intensive care unit. Nonabsorbable antibiotics in Orabase (Colgate-Hoyt, Canton, Massachusetts), as sticky 546
paste, were applied to the oral cavity with a gloved hand four times daily. This paste contained gentamicin (2%), polymyxin B (2%), and nystatin (1 x 105 U/g). Liquid nonabsorbable antibiotics were taken orally or by nasogastric tube four times daily in a suspension that provided 80 mg gentamicin, 100 mg polymyxin B, and 2 million units nystatin per 10-mL dose. The decontamination protocol was discontinued at the time of dismissal from the intensive care unit. Control patients did not receive prophylactic antimicrobics. Microbiology Surveillance cultures for aerobic microorganisms in the oropharynx and rectum were obtained from patients in the decontamination group on day 3 of study and were repeated every 3 days until no growth of potential pathogens was shown. Intubated patients had endotracheal cultures done, and all patients had urinary cultures done twice weekly while in the study. Specimens for culture were obtained from pertinent sources when infection was suspected, and these were processed by methods described by Washington (13). Oropharyngeal and rectal swabs and tracheobronchial aspirates were streaked using the four-quadrant streak method on sheep blood, eosin-methylene blue, and inhibitory mold agars. Swabs and tracheal aspirates were also placed in brain-heart infusion broth. Urine (0.01 mL) was streaked separately across entire blood, eosin-methylene blue, and inhibitory mold agars. All agars and brain-heart infusion broth were incubated at 35 °C in room air for 18 to 24 hours with the exception of inhibitory mold agar, which was incubated for 48 hours at 30 °C. The following potentially pathogenic microorganisms were identified: Staphylococcus, coagulase negative; S. aureus', enterococci; aerobic gram-negative bacilli; yeast and fungi; and /3-hemolytic Streptococci with grouping. Susceptibility testing was done on these isolates, except /3-hemolytic Streptococci, using an agar dilution technique (13). Resistance was defined as follows: S. aureus, oxacillin MIC > 2 j/g/mL; Enterococci, gentamicin MIC > 500 /ig/mL; Enterobacteriaceae, gentamicin MIC > 2 /Ltg/mL or resistance to two or more of any combination of third-generation cephalosporins, imipenem, or aztreonam; Pseudomonas species, gentamicin MIC > 2 /ig/mL or resistance to two or more anti-pseudomonas penicillins or other beta-lactam antimicrobials. Oropharyngeal and rectal surveillance cultures were not done for control patients. Previous experience at our institution in liver transplant patients showed little benefit from such cultures. Nearly all control patients had heavy growth of mixed flora. Identification of all potentially pathogenic microorganisms from such cultures was found to be prohibitively tedious and costly. Definitions of Infection and Colonization Categories of infection are shown in Appendix Table B. Pneumonia was defined by clinical and laboratory evidence of infection and localization to the lung. A new or progressive pulmonary infiltrate compatible with pneumonia with purulent secretions, isolation of a potential pathogen, and fever, leukocytosis, or both were required. Rales and deterioration of blood gases usually occurred. In two patients, the diagnosis of pneumonia was made only at autopsy. Tracheobronchitis was defined as the presence of increased purulent endotracheal secretions requiring frequent suctioning and the presence of a potential pathogen. If pathogens were isolated from endotracheal secretions but criteria for pneumonia or tracheobronchitis were not met, colonization was recorded. A 90% concurrence rate between two investigators (one blinded) was achieved in the diagnosis of pulmonary infection. Bacteremia was defined as greater than or equal to two positive peripheral blood cultures in a 24-hour period with the same isolate. One positive peripheral blood culture was accepted when signs of bacteremia (fever, leukocytosis, hypotension) were present and 1) only one blood culture was drawn, 2) an intravascular device tip also was positive for the same organism, or 3) if the patient was receiving antibiotics effective against the isolated organism. Single positive blood cultures rarely occurred.
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Table 1. Patient Characteristics Characteristics
Control Group
Sex, n Male Female Stratification, n Trauma Surgery Trauma and surgery Medical Severity of illness scores Chronic health points Patients, n Median (mean) SD (range) Glasgow coma score Patients, n Median (mean) SD (range) Injury severity Patients, n Median (mean) SD (range) Trauma score Patients, n Median (mean) SD (range) Apache score Patients, n Median (mean) SD (range) Time in ICU prior to study, d Median (mean) SD
P Value
Decontamination Group
49 26
49 26
11 36 15 13
11 36 15 13
75 0(0) 0(0)
75 0 (0.21) 0.98 (0.38 to 1.58)
75 15 (13.6) 3.1 (3 to 15)
75 15 (13.2) 3.6 (3 to 15)
25 22 (24.0) 11.2 (4 to 50)
26 24.5 (24.8) 9.3 (0 to 48)
> 0.2
29 14 (13.6) 2.4 (9 to 16)
26 15 (13.9) 3.3 (0 to 16)
> 0.2
75 18 (18.3) 6.8 (5 to 36)
75 19 (18.6) 7.2 (6 to 42)
> 0.2
1.4 (1.0) 1.2
0.196
1.1 (1.0) 0.9
* ICU = intensive care unit; SD = standard deviation.
Bacteriuria was defined as colonization of the urinary tract unless the presence of fever, flank pain, and leukocyte casts suggested pyelonephritis or, in patients without a urinary catheter, if dysuria and frequency with bacteriuria and pyuria suggested cystitis. Surgical wounds and other nosocomial infections were diagnosed using standard infection-control guidelines. Statistical Methods Each study group contained 75 patients, yielding at least an 80% chance of detecting a difference of 15% in infection rates (for example, 20% compared with 5%). All significance tests were two-sided with a type I error rate of 5%. Comparisons of the proportion of an event in one treatment group compared to the other were made using the chi-square test or the Fisher exact test when necessary. Ninety-five percent confidence intervals (CIs) were calculated for the major events of interest. Comparisons of ordinal variables, such as the number of infection episodes for one patient, were made using the Wilcoxon rank-sum test. Rank-sum tests were also used to analyze non-Gaussian continuous variables. Comparisons of means were made using the two-sample Student Mest. Results Patient characteristics in the control and treated groups were similar and are summarized in Table 1. Stratification based on case type, the number of anesthetics used in surgical cases (99 in controls compared with 90 in decontamination patients), and use of histamine 2 blocking agents (60 patients compared with 62 patients in the control and treatment groups, respectively) were similar in the two study groups. Severity of illness
did not differ significantly between the two groups based on five assessments: chronic health points, Glasgow coma score, injury severity, trauma score, and Apache score (see Table 1) (14, 15). Of patients having decontamination, potentially pathogenic microorganisms were eliminated from the oropharynx in 50 of 75 patients (67%) and from the rectum in 41 of 75 patients (55%). In 23 cases, decontamination was not achieved at either site, but most patients left the intensive care unit in 4 days or less. Of the 75 patients in the treatment group, 10 dropped out or were withdrawn from the decontamination protocol because of dislike of the Orabase antibiotics or diarrhea. All are included in the analysis for this group. Table 2 shows the duration of intensive care therapy for both groups; 27 of 75 controls (36%) and 26 of 75 decontamination patients (35%) remained in intensive care 4 days or less. Total hospital days, number of days in the intensive care unit, and number of follow-up days did not differ significantly. Risk for adverse events related to the use of intravascular devices, including arterial and central venous cannulae, was similar. The median duration of intubation of the respiratory tract was shorter (3 compared with 5 days, P = 0.022) in the decontamination group. Eighty-nine percent (67 of 75) of controls and 80% (60 of 75) of decontamination patients required intubation during the study period. Control patients were more likely than treated patients to have fever while in the intensive care unit
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Table 2. Results from the Intensive Care Study Period for Patients in the Control and Decontamination Groups Variable Intensive care unit study period, d Line days, d Intubation, d Fever, d Therapeutic antibiotics, d
Control Group
DecontamiP nation Group Value
12/7 (14.8)
10/6 (11.4)
23/12 (30.9) 10/5 (14.2) 3.5/2 9/5
19/12 (21.4) 7/3 (9.4) 2.1/0 4/2
0.02 0.005 0.001
* Data expressed as mean/median (SD).
(mean, 0.67 episodes compared with 0.39 episodes; P = 0.01), and fever lasted longer in controls than in decontamination patients (mean, 3.5 days compared with 2.1 days; P = 0.005). A significant decrease was noted in the number of days that parenteral antibiotics were administered when controls were compared with decontamination patients (mean, 9 days compared with 4 days; P < 0.0001) only when cefotaxime required by the protocol was excluded. We observed a statistically significant difference in the number of infection episodes between the two study groups (36 episodes among 19 patients in the control group compared with 12 episodes among 10 patients in the treatment group; P = 0.04) (Table 3). Of the infections in the decontamination group, two occurred several days after discontinuation of oral nonabsorbable antibiotics. The difference was especially noticeable for infections caused by gram-negative bacilli: 23 compared with 3 infection episodes (P < 0.002) and 10 compared with 0 bacteremias (P = 0.004) in the control group and the decontamination group, respectively. Few cases of pneumonia occurred in either group, but tracheobronchitis was practically limited to patients in the control group. More bacteremias occurred in the controls for each category of bacteremia, and half were related to intravascular devices. Surgical wounds were reported only for patients who had operations during the study period and for whom decontamination might be ex-
pected to affect the rate. The surgical wound infection rate in these critically ill patients was high, and, although the data were not statistically significant, most infections occurred in controls (7 of 75 controls compared with 1 of 75 treated patients). If wound infections resulting from surgery before the study period are included in the analysis (most occurred at the time of admission to the intensive care unit), this group includes 12 of 75 control and 3 of 75 decontamination patients. Urinary tract infection was not documented during the intensive care unit study although bacteriuria was. Other infections included one case of peritonitis in the control group and one case of peritonitis and one gangrenous gallbladder in the decontamination group. Colonization of the respiratory tract and urinary tract (bacteriuria) was more frequent in controls than in decontamination patients during the intensive care period (42 episodes compared with 27 episodes; P = 0.01). Twenty-two episodes of bacteriuria occurred among controls, and 13 episodes occurred among decontamination patients; however, this finding was not statistically significant (P = 0.10). Fewer gram-negative bacilli were isolated from nonsurveillance sources in decontamination patients (Table 4), including those associated with infection (Table 5). Decontamination had little effect on gram-positive cocci, probably because of the natural resistance of these organisms (especially coagulase-negative staphylococci and enterococci) to the decontamination antimicrobials used. Complications during the intensive care period and follow-up until hospital discharge are shown in Table 6. Antibiotic-resistant bacteria were sought from the oropharynx, rectum, urine, and tracheobronchial sources in decontaminated patients. The frequency of multiply resistant, gram-negative bacilli in our hospital is low, and this is true in the intensive care units as well. Resistance to gentamicin or to two or more third-generation cephalosporins (or other new beta-lactam antibiotics) was shown in gram-negative isolates from 9 of 75 control (11% of isolates) and in 5 of 75 decontamination patients (16% of isolates).
Table 3. Bacterial Infection and Colonization in the Control and Decontamination Study Groups Variable Episodes
Infections Gram-negative bacilli Bacteremia Gram-negative bacilli Candida Gram-positive cocci Pulmonary Pneumonia Tracheobronchitis Surgical wound infections^ Other Colonization
Control Group Patients (95% CI)
Decontamination Group Patients (95% CI) Episodes
n
n(%)
n
n(%)
36 23 14 10 2 4 14 4 10 7 1 42
19 (25.3) (16.0 to 36.7) 15 (20.0) (11.7 to 30.8) 11 (14.7) (7.6 to 24.7) 8 (10.7) (4.7 to 19.9) 2 (2.7) (0.3 to 9.3) 4 (5.3) (1.5 to 13.1) 12 (16.0) (8.6 to 26.3) 4 (5.3) (1.5 to 13.1) 8 (10.7) (4.7 to 19.9) 7 (13.7) (5.7 to 26.3) 1 (1.3) (0.0 to 7.2) 31 (56.0) (44.1 to 67.5)
12 3 4 0 1 3 4 3 1 1 2 27
10 (13.3) (6.6 to 23.2) 3 (4.0) (0.8 to 11.3) 4(5.3) (1.5 to 13.1) 0 (0 to 4.8) 1 (1.3) (0 to 7.2) 3 (4.0) (0.8 to 11.3) 4(5.3) (1.5 to 13.1) 3 (4.0) (0.8 to 11.3) 1 (1.3) (0.0 to 7.2) 1 (2.0) (0.1 to 10.5) 2 (2.7) (0.3 to 9.3) 15 (20.0) (11.7 to 30.8)
P Value*
> > > >
* P value for episodes by the Wilcoxon rank-sum test. t Fisher's exact test. t In 51 control and 51 decontamination patients.
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0.04 0.002 0.05 0.004 0.2t 0.2t 0.03 0.2t 0.02 0.06t 0.2 0.010
Table 4. Microorganisms Isolated from Colonization or Infection during the Intensive Care Unit Study* Microorganisms Control Group
Enterobacteriaceae Enterobacter cloacae Escherichia coli E. aerogenes Klebsiella oxytoca Serratia marcescens Morganella morganii Citrobacter diversus Proteus mirabilis K. pneumoniae Other Total Haemophilus influenzae Pseudomonas aeruginosa Xanthomonas maltophilia Pseudomonas species Total Staphylococcus (coagulase-negative) S. aureus Enterococcus faecalis Other streptococci Total Candida species Anaerobes Total isolates
Isolates Decontamination Group n
administration and monitoring is added to the decontamination program, the savings from decreasing infection should be substantial (16). More importantly, the goal of reducing morbidity, and possibly mortality, was achieved. Discussion
16 9 8 7 5 5 4 3 3 2 62
17
2 13 3 1 19
11 2 1 14
9 8 8 3 28
10 8 3 3 24
33
14 1 70
142
2 5 3 1 1 2 1 2
* Colonization includes bacteriuria and respiratory isolates and excludes oral and rectal cultures.
Surveillance cultures of oropharyngeal or rectal specimens were done only for decontamination patients; therefore, the frequency of colonization by gentamicinresistant enterococci could be determined for digestive tract sources only in that group. Six of 25 isolates in these patients were resistant to gentamicin. Two of these resistant enterococci caused bacteriuria, and one was isolated in mixed culture from a leg wound. Methicillin-resistant S. aureus was not encountered. Diarrhea occurred in both groups, but protracted diarrhea (frequent loose stools for > 3 days) was noted more often in decontamination patients. During the intensive care period, 14 of 75 controls and 8 of 75 decontamination patients died; during the total hospitalization period, 16 controls and 11 decontamination patients died. Six control and two decontamination patients died during infection or with infection as the cause. After dismissal from the intensive care unit during the in-hospital follow-up period, neither the infection rate (P > 0.2) nor frequency of colonization (P > 0.2) was significantly different for controls and the decontamination patients. No post-treatment benefit or rebound of infection was detected in decontamination patients. The calculated cost of antibiotics used in decontamination for our 75 patients in the intensive care unit was $15 937 (about $212 per patient). Although the cost for
Several European trials of selective decontamination of the digestive tract in intensive care patients have been conducted since the Stoutenbeek trial (Appendix Table A). All these trials, except that conducted in France by Brun-Buisson and colleagues (6), used a decontamination regimen similar to that used in the Stoutenbeek trial and showed a reduction in acquired infection. Mortality was decreased in decontaminated patients in all trials, although, in each, the change was not statistically significant. In contrast to those studies, Brun-Buisson and colleagues (6) reported a randomized, controlled trial in which neomycin, polymyxin E, and nalidixic acid failed to decrease infection. They were able to eradicate multiply resistant Enterobacteriaceae by colonizing medical intensive care patients. Unlike all other trials, patients did not receive oropharyngeal decontamination with Orabase or parenteral antimicrobials (cefotaxime). In our study of selective decontamination of the digestive tract, an attempt was made to select patients at the time of admission to the intensive care unit who were likely to remain for several days. These patients had the highest risk for infections because of the severity of their illness and the prolonged need for invasive monitoring and support, especially endotracheal intubation. Selective use of decontamination of the digestive tract, if effective, would avoid risk without benefit for short-term intensive care patients and would be unlikely to select resistant microorganisms. Our study, like previous studies, was not blinded. Nevertheless, we feel this factor had little impact on outcomes, especially because strict requirements for the diagnosis of infection were enforced. Although physicians caring for these patients may have been aware of
Table 5. Microorganisms Associated with Infections during the Intensive Care Study* Microorganisms Control Group
Enterobacteriaceae Pseudomonas aeruginosa Xanthomonas Haemophilus influenzae Staphylococci Streptococci Candida Anaerobes Total
32 4 1 1 10 5 8 61
Isolates Decontamination Group n 4 1
9 1 1 16
* Control patients had 1.7 and decontaminated patients had 1.33 organisms per infection episode.
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Table 6. Complications and Follow-up Variable Isolates, n Resistant microorganisms Gentamicin-resistant enterococci Relatively resistant gramnegative bacteriat Episodes of diarrhea, n Any Protracted Deaths, n During intensive care period Infection-related Total Duration of follow-up (mean/median), d Episodes of infection, n Episodes of colonization, n Total hospital stay (mean/ median ± SD), d
Control Group
Decontamination Group
6 of 25* 9
5
15 7
23 12
14 6 16
8 2 11
21/11
18/9
10 8 29/18 ± 31.4
11 24 27/16 ± 26.4
* Surveillance plus clinical isolates. t Clinical isolates for controls; surveillance plus clinical isolates for decontamination patients.
their status, the infectious diagnoses they made were similar to those of the authors. Trials of selective decontamination of the digestive tract have used various definitions of infection, and some investigators applied more stringent criteria than others. In these trials, the differentiation between colonization and infection, especially of the respiratory and urinary tracts, is often imprecise (3-5). Unfortunately, these infections accounted for more than 50% of the total infections reported in studies on selective decontamination to date. In our study, criteria for pneumonia included a compatible new or progressive pulmonary infiltrate with purulent secretions, isolation of potential respiratory tract pathogens, and systemic evidence of infection. Although pneumonia developed in only 5% of our patients, intraobserver concordance was 90%. A diagnosis of tracheobronchitis required an increased quantity of purulent secretions that would be expected to compromise respiratory function and delay extubation. This factor prolonged the risk for nosocomial pneumonia and other complications and increased the length of stay in the intensive care unit. It is difficult to elicit symptoms and signs (costovertebral tenderness with pyelonephritis and urgency, frequency, and dysuria with cystitis) to support a diagnosis of urinary tract infection in critically ill patients. Bacteriuria with or without pyuria in the catheterized patient was considered sufficient to indicate colonization. In our study, respiratory tract infections accounted for 14 of 53 infections (26%), and no urinary tract infections were diagnosed. We noted a significant difference between total infections in the control and decontamination groups. Differences were noted for pulmonary infections, bacteremia, and gram-negative bloodstream infections and for colonization of the urinary and respiratory tracts. The decrease in bacteremias, especially gram-negative aerobic 550
bacilli, usually was not reported in previous trials of selective decontamination (3-6, 8-10). Total febrile days, number of febrile episodes, and total days of therapeutic antibiotics were decreased for decontamination patients, a result that correlates with the decreased incidence of infection compared with controls. Although total hospital days, days in intensive care, days with an intravenous line, days of follow-up, febrile days after intensive care, and overall death rate were lower in the decontamination group, these differences were not statistically significant. The follow-up period of our study after dismissal from the intensive care unit included the remainder of hospitalization for all patients. Previous decontamination patients no longer received this treatment and no difference was seen in total infections or in respiratory tract or urinary tract colonization. In our study, the role of resistance to colonization by maintenance of normal anaerobic bowel flora was not investigated, and no attempt was made by the investigators to influence the selection of therapeutic or prophylactic antibiotics other than the protocol study drugs. Suppression of potentially pathogenic microorganisms alone appeared sufficient to produce a decrease in infection. Decontaminated patients were often followed for many days without isolation of such organisms from a clinical site, and this was not the case in controls. We used cefotaxime in addition to oral nonabsorbable antimicrobials because results of previous studies suggested that cefotaxime augments decontamination of the digestive tract (3). Cefotaxime use was limited to 3 days, and no increase in early infections was seen in our mixed group of patients. Persistence of effective oral antibiotics in the oropharynx may be critically related to the sticky paste used for decontamination. The fact that Brun-Buisson and colleagues (6) did not find a decrease in infection with their decontamination program might be attributed to the absence of cefotaxime and Orabase antibiotics in their protocol. The emergence of resistant microorganisms is a potential risk whenever antibiotics are given. The proportion of patients in an intensive care unit having decontamination and the prevalence of resistant organisms are probably both important factors. In our study, the relatively small number of patients having decontamination at a time and the low frequency of resistant organisms may have minimized this risk. Published studies in which many or all intensive care patients had decontamination have shown, however, that resistance has never been a problem. A significant proportion of enterococci isolated from the digestive tract of decontaminated patients during our study were resistant to gentamicin; however, comparable bowel surveillance cultures were not done in controls. Few partially resistant gram-negative bacteria were isolated in either group. It would be useful to screen all decontaminated patients for resistant isolates periodically and at the conclusion of therapy. Isolation of carriers, cessation of decontamination, or treatment of resistant organisms could be considered. Although data were not statistically significant, diarrhea occurred more frequently in patients having bowel decontamination with oral agents. Stool cultures for
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enteric pathogens and assay for Clostridium difficile toxin were done and were negative in all patients with diarrhea. Other factors, such as enteral feeding, were present in most cases, and the mechanism of diarrhea in the decontaminated patients was unexplained. In some cases, diarrhea resulted in withdrawal from the program. Fewer deaths occurred among decontaminated patients. Although this result was not statistically significant, improved outcome with decontamination has been suggested in other studies as well. Because many factors contribute to the death of a critically ill patient in an intensive care unit, a larger study would probably be necessary to show the effect on mortality yielded by reducing infectious complications. Our results suggest that selective decontamination of our patients was cost saving; a more elaborate cost analysis is being done to confirm this finding. In our institution, selective decontamination of the digestive tract decreased infection, especially by gramnegative bacilli, in selected patients in the intensive care
unit. Carefully designed studies at other institutions are required to confirm this method of infection prophylaxis. Institutional variation in patient population, antimicrobic use, and microbial resistance patterns may obviate the usefulness of the selective decontamination method used in this study. The important finding of this and similar studies is that the gastrointestinal tract is a critical source of pathogenic microorganisms and that infections in the intensive care unit can be prevented by interventions at this site. Grant Support: In part by Hoechst-Roussel Pharmaceuticals, Inc. Requests for Reprints: Franklin R. Cockerill, III, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Current Author Addresses: Drs. Cockerill, Anhalt, Farnell, Mucha, Gillespie, and Thompson and Ms. Muller, Mr. Marsh, Mr. Ilstrup, and Mr. Larson-Keller: Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905.
Appendix Table A. Summary of Selective Decontamination of the Digestive Tract* Investigator (Reference) (Year)
Trial Design
Antimicrobial Agents Infection Control/ Treatment
Stoutenbeek et al. (3) (1984)
Historic controls
Ledingham et al. (4) (1988)
Historic controls
Kerver et al. (5) (1988)
Randomized, controlled trial
Ulrich et al. (9) (1989)
Randomized, controlled trial
Oral 2% Orabase: polymyxin E, tobramycin, amphotericin B four times daily. Suspension: polymyxin E, 100 mg; tobramycin, 80 mg; amphotericin B, 500 mg four times daily Systemic Intravenous cefotaxime, 40 mg/kg body weight per day (mean, 9 days) Oral 2% Orabase: polymyxin E, tobramycin, amphotericin B four times daily. Suspension: polymyxin E, 100 mg; tobramycin, 80 mg; amphotericin B, 500 mg four times daily Systemic Intravenous cefotaxime, 40 mg/kg body weight per day for 4 days Oral 2% Orabase: polymyxin E, tobramycin, amphotericin B four times daily. Suspension: polymyxin E, 200 mg; tobramycin, 80 mg; amphotericin B, 500 mg four times daily Systemic Intravenous cefotaxime 50 to 70 mg/kg for 5 to 7 days Oral 2% Orabase: norfloxacin, polymyxin E, amphotericin B. Suspension: norfloxacin, 50 mg; polymyxin E, 100 mg; amphotericin B, 500 mg four times daily Systemic Trimethoprim, 500 mg per day, variable duration
* ICU = intensive care unit; NR = not reported. t Statistically significant.
Mortality Overall Related to Infection Control/ Control/ Treatment Treatment
81/16t
NR
NR
24/10t
24/24
NR
81/39t
32/28.5
17/4f
44/6t
54/31
15/0
Continued
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Appendix Table A—Summary of Selective Decontamination of the Digestive Tract (Continued) Investigator (Reference) (Year)
Trial Design
Antimicrobial Agents
Infection
Control/ Treatment Brun-Buisson et al. (6) (1989)
McClelland et al. (7) (1990)
Hartenauer et al. (8) (1990)
Cockerill et al. (1990)
Flaherty et al. (10) (1990)
32/32 Oral Orabase: none Suspension: neomycin, 1 g; polymyxin, 50 mg; nalidixic acid, 1 g four times daily Other: endotracheal povidone-iodine irrigations three times daily Systemic None Historic controls Oral 83/33t 2% Orabase: polymyxin E, tobramycin, amphotericin B four times daily. Suspension: polymyxin E, 100 mg; tobramycin, 80 mg; amphotericin B, 500 mg four times daily Systemic Intravenous cefotaxime, 40 mg/kg body weight per day for 4 days Randomized, Oral Bronchopulmonary placebo2% Orabase: polymyxin E, tobramycin, ICU 1 45.6/10t controlled amphotericin B four times daily ICU 2 45/10t crossover trial Suspension: polymyxin E, 200 mg; Urinary ICU 1 16.4/10 tobramycin, 80 mg; amphotericin B, ICU 2 35/8.2 500 mg four times daily Septicemia Systemic ICU 1 6.6/6 Intravenous cefotaxime 50 to 70 mg/kg for 5 ICU 2 7.5/16.3 to 7 days Randomized, Oral 36/12t controlled trial Orabase: 2% gentamicin; 2% polymyxin B; 5 nystatin, 1 x 10 U/g Suspension: gentamicin, 80 mg; polymyxin B, 100 mg; nystatin, 2 x 106 U/10 mL Systemic Intravenous cefotaxime 1 g every 8 hours for 3 days Randomized pilot Oral 27/12$ study (selective Orabase: 2% gentamicin; 2% polymyxin B; 5 decontamination nystatin, 1 x 10 U/g compared with Suspension: gentamicin, 80 mg; polymyxin sucralfate) B, 100 mg; nystatin, 2 x 106 U/10 mL Systemic Intravenous cefazolin (variable doses all patients) Randomized, controlled trial
Mortality Overall Related to Infection Control/ Control/ Treatment Treatment 10/8.5
NR
42/40
73/42
47.5/38 42.5/30.6
NR NR
16/11
6/2
0/1
0/1
* ICU = intensive care unit; NR = not reported. t Statistically significant. $ Sucralfate treated.
Appendix Table B: Definitions of Infection Bacteremia Two or more peripheral blood specimens for culture obtained within 24 hours and yielding the same organism. One positive peripheral blood culture and signs of septicemia (fever, leukocytosis, hypotension) and patient receiving antibiotics, or a line tip also positive for same organism, or only one culture drawn Intravascular device-related One or more peripheral blood culture and > 15 colonies on semiquantitative culture of the device tip with the same microorganism Indeterminate No source determined after study Secondary An active infectious source with isolation of the same microorganism Pulmonary infection Pneumonia
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Clinical and laboratory evidence of infection in the lung with a compatible infiltrate, purulent secretions, and a pathogen isolated plus evidence of infection with fever and/or leukocytosis; autopsy showing pneumonitis Tracheobronchitis Purulent secretions of clearly increased volume and a pathogen isolated Urinary tract infection: Pyelonephritis Flank pain, fever, pyuria, bacteriuria Cystitis Dysuria, frequency, and bacteriuria in a noncatheterized patient Surgical wound infection Purulent drainage from incision spontaneously or on reopening Other infections Any nosocomial infection by standard infection-control guidelines (Continued)
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Colonization Pulmonary G r o w t h of a potential bacterial p a t h o g e n from e n d o t r a cheal s e c r e t i o n s o r from s p u t u m w i t h o u t criteria for infection Urinary G r o w t h of 10 4 o r m o r e m i c r o o r g a n i s m s from a c a t h e t e r ized s p e c i m e n w i t h o u t criteria for u r i n a r y tract infection References 1. Miranda DR, Van Saene HK, Stoutenbeek CP, Zandstra DF. Environment and costs in surgical intensive care unit: the implication of selective decontamination of the digestive tract (SDD). Acta Anaesthesiol Belg. 1983;34:223-32. 2. Miller PJ, Farr BM, Gwaltney JM J r . Economic benefits of an effective infection control program: case study and proposal. Rev Infect Dis. 1989;11:284-8. 3. Stoutenbeek CP, van Saene HK, Miranda DR, Zandstra DF. The effect of selective decontamination of the digestive tract on colonisation and infection rate in multiple trauma patients. Intensive Care Med. 1984;10:185-92. 4. Ledingham IM, Alcock SR, Eastaway AT, McDonald J C , McKay IC, Ramsay G. Triple regimen of selective decontamination of the digestive tract, systemic cefotaxime, and microbiological surveillance for prevention of acquired infection in intensive care. Lancet. 1988; 1:785-90. 5. Kerver AJ, Rommes J H , Mevissen-Verhage EA, et al. Prevention of colonization and infection in critically ill patients: a prospective randomized study. Crit Care Med. 1988;16:1087-93. 6. Brun-Buisson C, Legrand P, Rauss A, et al. Intestinal decontamination for control of nosocomial multiresistant gram-negative bacilli: study of an outbreak in an intensive care unit. Ann Intern Med. 1989;110:873-81.
7. McClelland P, Murray AE, Williams PS, et al. Reducing sepsis in severe combined acute renal and respiratory failure by selective decontamination of the digestive tract. Crit Care Med. 1990;18: 935-9. 8. Hartenauer U, Thiilig B, Lawin P, Fegeler W . Infection surveillance and selective decontamination of the digestive tract (SDD) in critically ill patients—results of a controlled study. Infection. 1990; 18(Suppl l):S22-30. 9. Ulrich C, Harinck-de Weerd J E , Bakker NC, Jacz K, Doornbos L, de Ridder VA. Selective decontamination of the digestive tract with norfloxacin in the prevention of ICU-acquired infections: a prospective randomized study. Intensive Care Med. 1989;15:424-31. 10. Flaherty J, Nathan C, Kabins SA, Weinstein RA. Pilot trial of selective decontamination for prevention of bacterial infection in an intensive care unit. J Infect Dis. 1990;162:1393-7. 11. Bow EJ, Rayner E, Louie TJ. Comparison of norfloxacin with cotrimoxazole for infection prophylaxis in acute leukemia: the trade-off for reduced gram-negative sepsis. Am J Med. 1988;84:847-54. 12. Stoutenbeek CP, van Saene HKF, Zandstra DF. The effect of oral non-absorbable antibiotics on the emergence of resistant bacteria in patients in an intensive care unit. J Antimicrob Chemother. 1987; 19:513-20. 13. Washington JA. Laboratory Procedures in Clinical Microbiology. 2d edition. New York: Springer-Verlag; 1985. 14. Champion HR, Sacco W J , Hannan DS, et al. Assessment of injury severity: the triage index. Crit Care Med. 1980;8:201-8. 15. Knaus WA, Draper EA, Wagner DP, Zimmerman J E . An evaluation of outcome from intensive care in major medical centers. Ann Intern Med. 1986;104:410-8. 16. Haley RW, Schaberg DR, Crossley KB, Von Allmen SD, McGowan JE J r . Extra charges and prolongation of stay attributable to nosocomial infections: a prospective interhospital comparison. Am J Med. 1981;70:51-8.
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