Intensive Care Med (1992) 18:459-463

IntensiveCare Medicine 9 Springer-Verlag 1992

The effect of selective decontamination of the digestive tract on gastrointestinal enterococcal colonization in ITU patients H. Humphreys 1, R. Winter 2 and A. Pick 1Departments of Microbiology and 2Anaesthesia, Bristol Royal Infirmary, Bristol, UK Received: 20 February 1992; accepted: 31 August 1992

Abstract. Objective: The effect of selective decontamination of the digestive tract (SDD) on Intensive Therapy Unit (ITU)-acquired enterococcal infection and colonization was studied. Changes in the predominant species isolated and resistance patterns to antimicrobial agents were also studied. Design: Three groups were investigated: historical control (HC), contemporaneous control (CC) and patients receiving SDD (topical polymyxin, amphoterecin B and tobramycin throughout ITU stay with intravenous ceftazidime for the first 3 days only). Setting: Adult general ITU with 7 beds. Patients: Patients with a nasogastric tube in situ and who were likely to remain in ITU for 48 h or longer were recruited. Results: Enterococcal infections occurred in 3 of 84 HC patients and 2 of 91 CC patients. There were no unit-acquired enterococcal infections in the SDD group. There were 140 episodes of enterococcal colonization occurring in 112 patients, with significantly more in the SDD and CC groups (/9 < 0.05. There were no significant differences in antibiotic sensitivities between the three groups. Enterococcus faecalis was the most frequently isolated species. Conclusion: SDD does not predispose to enterococcal infection but does encourage colonization in patients receiving the regimen and other patients in ITU at the same. There is a complex interaction of factors which influence faecal flora and the likelihood of patients becoming colonized or infected with enterococci.

Key words: Intensive care units - Streptococcus - Antibiotics - Antibiotic resistance

This study was supported by grants, from Bristol and Weston Health Authority and Glaxo Research (UK). RW was funded as a Research Fellow by Glaxo Research Limited (UK). The results of this study were presented in part at the 90th Annual Meeting of the American Society for Microbiology, Anaheim, California, May 1990

Enterococci are Gram-positive aerobic cocci, are mostly salt and bile tolerant, may group with Lancefield Group D antigen and are normal inhabitants of the human gastrointestinal tract. They include Enterococcus faecalis and Enterococcusfaecium, both recognised pathogens in the aetiology of nosocomial infection [1]. Approximately 2 - 7 % of clinically significant septicaemia is attributable to enterococci [2-4]. The increased recognition of these bacteria as serious nosocomial pathogens is in part due to the greater number of susceptible patients in high dependency and oncology/haematology units. A significant factor in this has been the use of broad-spectrum antimicrobial agents, especially the cephalosporins, w h i c h have good activity against Gram-negative bacilli but poor activity against enterococci and consequently encourage overgrowth sometimes resulting in superinfection [5]. Enterococci contribute to polymicrobial sepsis, especially following surgery. Although enterococcal septicaemia is less common than that due to Gram-negative bacilli, synergy with bowel anaerobes may be improtant in the development of intra-abdominal abscesses [6]. Part of the reason for their increasing importance is because enterococci are intrinsically resistant to many antimicrobial agents and have an impressive ability to acquire new resistant determinants [7]. Treatment is usually with ampicillin or, in systemic infection, a combination of a penicillin plus an aminoglycoside, such as gentamicin. 17.. faecium in less sensitive to the aminoglycosides than E. faecalis. High level penicillin (minimum inhibitory concentration, >200mg/1) and gentamicin (MIC, >1000mg/1) resistance amongst E. faecium isolates is now well described and this limits options for therapy [8, 9]. Spread of such isolates in highdependancy and other areas is associated with high Apache II scores and antibiotic treatment [1.0] and represents a problem for infection control [11, 12]. Significant factors in Intensive Therapy Unit (ITU)-acquired infection include, the severity of underlying disease in most patients, surgery, and the many diagnostic and therapeutic procedures required for patient management. Selective decontamination of the digestive

460 t r a c t (SDD), i n c o r p o r a t i n g o r a l l y a d m i n i s t e r e d n o n - a b s o r b a b l e a n t i m i c r o b i a l agents, p a r e n t e r a l a n t i b i o t i c s a d m i n i s t e r e d initially a n d m i c r o b i o l o g i c a l screening, has b e e n a d v o c a t e d to reduce c o l o n i z a t i o n a n d i n f e c t i o n by p o t e n t i a l p a t h o g e n s [ 1 3 - 1 5 ] . However, this a p p r o a c h is controversial b e c a u s e o f the failure to d e m o n s t r a t e , in m o s t studies to date, a n i m p r o v e m e n t in overall mortality, cost o f the r e g i m e n a n d the p o t e n t i a l to select for resist a n c e [16]. S D D regimens u s u a l l y i n c l u d e a p a r e n t e r a l agent, most frequently a third generation cephalosporin, administered d u r i n g the first few days o n ITU. T h e c o m b i n a t i o n of an aminoglycoside administered topically and a c e p h a l o s p o r i n parenterally, has t h e p o t e n t i a l to select o u t enterococci a n d , p o s s i b l y increase i n f e c t i o n w i t h enterococci. We have s t u d i e d rectal e n t e r o c o c c a l c o l o n i z a t i o n a n d i n f e c t i o n rates in I T U p a t i e n t s d u r i n g the course o f a trial designed to assess the efficacy o f S D D in reducing I T U - a c q u i r e d infection. Here, we r e p o r t t h e effects o n u n i t - a c q u i r e d infections, rectal c o l o n i z a t i o n , species i s o l a t e d a n d a n t i m i c r o b i a l resistance,

Patients and methods

phology, a negative catalase reaction and aesculin hydrolysis. Lance field grouping was carried out by latex agglutination (Streptex, Wellcome) and the sole isolate or that present in heavy growth was identified to species level by the rapid API 20 Strep system (Bio-Merieux). Minimum inhibitory concentration (MICs) of ampicillin, gentamicin, netilmicin, tobramycin, ceftazidine, imipenem, vancomycin and teicoplanin were determined by multi-point inoculation on Diagnostic Sensitivity Test agar (DST, Oxoid) using a standard inoculum of 105-6cfu m1-1 from an overnight culture in nutrient broth [18]. Resuits were expressed in terms of the MIC9o, i.e. the MIC required to inhibit the growth of 90% of isolates. Betalactamse was detected using nicrocefin (Glaxo) dissolved in dimethyl sulphoxide. The endpoints of the study were infection and colonization with enterococci on one or more occasion. Infection was inferred when enterococci were isolated from a normally sterile site, e.g., blood, or from a non-sterile site with or without other pathogens when there were accompanying signs and symptoms of infection. Colonization was defined as the isolation of enterococci from two successive rectal samples and ended when a subsequent sample became negative.

Statistical analysis Results were analysed with the Minitab Statistical Package using the Kruskall-Wallis test and, where this indicted significance, the MannWhitney U test to identify intergroup differences. The Chi-squared test was used to analyse incidence data and statistical significance was inferred when p was less than 0.05. The MIC90 is used for display purposes but all statistical analysis was carried out on raw MIC data.

Study design The study was carried out on an adult general ITU consisting of 7 beds where the main reasons for adrrdssion are: post-operative care, gastrointestinal surgery, major trauma and the requirement for assisted ventilation and organ support. Patients, all of whom had a nasogastric tube in situ, were recruited if they were likely to remain on the unit for 48 h or longer. This study was approved by the Bristol and Weston Health Authority Ethics Committee. Informed consent was obtained from the patient or a close relative. Three groups of patients were studied: historical control patients (HC group) that is those recruited during the initial six months following which patients recruited over a period of 17 months were randomised, using consecutively numbered envelopes, in to those who received SDD (SDD group) and contemporaneous control patients, i.e. patients in ITU at the same time as other patients receiving SDD but not receiving SDD themselves (CC group). Both control groups received antibiotics when indicated for prophylaxis and treatment of confirmed or presumed infection, according to unit policy. Patients were not included in the study if they were known to be allergic to any of the antibiotics used, were over 85 years of age or were pregnant. The SDD regimen consisted of two components: a water soluble gel preparation containing 20/0 polymyxin E, 2% tobramycin and 2% amphotericin B applied to the buccal mucosa six-hourly during ITU stay and polymyxin E 100mg, tobramycin 80mg and amphotericin B 500mg administered via a naso-gastric tube q. 6h. Inravenous ceftazidime, 50 mg/kg/day in 3 divided doses, was administered to SDD patients only during the first 3 days of ITU stay. SDD patients received additional antimicrobial agents for treatment of confirmed or presumed infection according to unit policy. Patients in the three groups were clinically assessed daily for evidence of infection as described elsewhere [17].

Microbiology Rectal swabs were taken within 6 h of admission and subsequently at thrice weekly intervals during the course of ITU stay and finally, 4 days after discharge to a general ward in surviving patients. These specimens were screened for the presence of potential pathogens, i.e. Staphylococcus aureusand aerobic Gram-negative bacilli [14, 17] and growth density was graded 1-5 by a semi-quantitative technique. Enterococci isolated from screening specimens were identified on the basis of growth on MacConkey bile salt-lactose agar, colonial mor-

Results T h e r e were 84 p a t i e n t s recruited in the H C g r o u p with 92 a n d 91 in the S D D a n d C C g r o u p s respectively. T h e effect o f S D D o n the incidence o f all I T U - a c q u i r e d i n f e c t i o n a n d o u t c o m e are discussed elsewhere [17]. P o l y m i c r o b i a l I T U - a c q u i r e d infections c a u s e d b y enterococci were diagn o s e d in 3 H C a n d 2 C C g r o u p p a t i e n t s respectively. (Table 1). Two H C infections were i n t r a c a v i t y (E. faecium in o n e case) t h e t h i r d being a b a c t e r a e m i a . There was o n e int r a c a v i t y a n d one b a c t e r a e m i c i n f e c t i o n each in the C C group. T h e r e were n o I T U - a c q u i r e d e n t e r o c o c c a l infections in t h e S D D group. A t o t a l o f 112 p a t i e n t s h a d 140 e p i s o d e s o f e n t e r o c o c cal c o l o n i z a t i o n in the rectum. S i g n i f i c a n t l y m o r e p a tients in b o t h the S D D a n d C C g r o u p s were c o l o n i z e d b y d a y 5 (p < 0.05, Fig. 1). This difference b e c a m e m o r e exa g g e r a t e d a f t e r d a y 7 b u t as t h e n u m b e r s r e m a i n i n g in I T U after this p e r i o d d i m i n i s h e d in all 3 groups, statistical analysis is n o t m e a n i n g f u l . T h e r e was n o c o r r e l a t i o n b e t w e e n t h e increase in e n t e r o c o c c a l c o l o n i z a t i o n a n d red u c e d c o l o n i z a t i o n with a e r o b i c G r a m - n e g a t i v e bacilli in t h e S D D group. M I C values expressed as the MIC90 for the 140 rectal isolates are s h o w n in Fig. 2. T h e MIC90 o f a m p i c i l l i n for all isolates was 32 mg/1 a n d b e t a - l a c t a m a s e p r o d u c t i o n was n o t detected in any isolate. G e n t a m i c i n was the m o s t active a m i n o g l y c o s i d e tested, with a n MICg0 o f 16 mg/1 c o m p a r e d with 64 rag/1 for n e t i l m i c i n a n d 128 mg/1 for t o b r a m y c i n . O n l y 6 isolates with a n M I C o f over 128 m g / l o f g e n t a m i c i n were recovered: four in the S D D a n d 2 in the C C group. A l m o s t all isolates were resistant to e e f t a z i d i m e a n d the MICgo o f i m i p e n e m was 32 mg/1. T h e MIC9o o f a m p i c i l l i n for H C isolates was 2 m g / 1 c o m p a r e d with 32 mg/1 for the o t h e r 2 g r o u p s b u t this difference is n o t statistically significant. Similarly, the dif-

461 Table 1. Details of unit-acquired infections

HC

Age/Sex

Diagnosis and Apache II score on admission

Site of Infection

Microbiology

Outcome

59/M

Post-thoracotomy for bleeding oesophageal varices 15 Pancreatitis 3 Perforated gastric ulcer 18

Intracavity (empyema)

E. faecalis

Died on ITU

Bacteraemia

E. faecalis

Intracavity (peritonitis)

E. faecium

Mesenteric infarct 8 Multiple trauma 8

Intracavity (peritonitis) Bacteraemia and line sepsis

E. faecalis

36/M 75/M

CC

50/F 30a/M

plus Coag - v e staphylocci Coliforms Discharged

plus Coag - v e staphylococci Died on ITU

plus mixed coliforms and yeasts Discharged

plus mixed coliforms

E. faecalis

Discharged

plus Coag - v e staphylococci

a Injury severity score, 27

ference in MICg0 of imipenem in the 3 groups was not significant (HC, 8 mg/l, CC and SDD, 64 mg/1 p > 0.05). There were no significant differences in MICs between isolates recovered from patients in ITU and patients when discharged back to the ward. Table 2 outlines the use of the most commonly prescribed parenteral antimicrobial agents in the three groups. There were significantly fewer days of antimicrobial use in the SDD group compared with the CC group (p < 0.05). The increased use of ceftazidime in the SDD group is explained by its incorporation as the parenteral component of the regimen, and the higher number of days of cefuroxime and metronidazole in the other two groups, reflects the unit antibiotic policy for the prophylaxis and treatment of surgical infection. Ampicillin and vancomycin (agents of choice to treat enterococcal infection) were prescribed equally frequently in all three groups. Identification of the 140 enterococcal isolates to species is outlined in Table 3. Eighty isolates were identified as E. faecalis, 56 as E. faecium, 9 as Enterococcus avium and 5 as Enterococcus durans. Of 63 isolates in the CC group 29 (46%) were identified as E. faecium but this

higher proportion than in the other two groups (28~ in SDD and 9~ in the HC) is not statistically significant. When isolates were grouped in to E. faecium and non-E. faecium isolates, again, there was no significant difference. Finally, a higher but not statistically significance number of ward isolates were E. faecium (24 of 52, 46o7o) compared with ITU isolates (32 of 98, 33%). Discussion

'Much of the increased incidence of enterococcal infection acquired in hospital, especially that in high-dependency areas such as ITU, has been attributed to the selective pressure of broad-spectrum antimicrobial agents, especially cephalosporins [10]. Selective decontamination of the digestive tract is designed to prevent infection due to aerobic Gram-negative bacilli whilst at the same time minimising disruption of the normal, predominantly anaerobic flora. Concern has been expressed about the increased risk of resistance amongst Gram-negative bacteria [19] and superinfection with Gram-positive organisms [20]. Colonization and infection by enterococci was monitored for throughout this study. We did not, however, use MI%0 (nag/t)

100-

15 8 >128

9080 CO

128 64

39

70-

50 o

30-

2010-

0.5 0.25

0

Day1

Day2

Da 5

Da 8

.

k

Day11

Day of ITU Stay

Fig. 1. Rectal enterococcal colonization in the three groups during ITU stay with the number of patients in ITU per group indicated. [] SDD, [] contemporaneous control, 9 historical control

AMPICLLLIN TO[3RAMYCIN CEFTAZIDIME VANCOMYCIN GENTAMICIN NETILMICIN IMIPENEM TEICOPLANIN

Fig. 2. Minimum inhibitory concentrations (MIC90) of antimicrobial agents for isolates. Historical control 9 contemporaneous control E~, and SDD []

462

Pseudomonas and other Gram-negative bacilli, and in

Table 2. Parenteral antimicrobial use (days) in the three groups HC

CC

SDD

p-value

Cefuroxime Metronidazole Ceftazidime Flucloxacillin Gentamicin Penicillin Azlocillin Erythromycin Ampicillin Ciprofloxacin Netilmicin Amphoterecin B Vancomycin Tobramycin

193 174 l1 71 60 44 35 10 47 12 12 0 12 0

263 191 72 76 72 58 49 46 27 36 27 34 7 7

12 98 301 42 26 23 28 41 21 27 6 0 0 11

< 0.001 a < 0.05 a < 0.001 a NS NS NS NS NS NS NS NS NS NS NS

Total use

713

1007

658

0 . 0 5 HC, Historical control; CC, Contemporaneus control, SDD, Selective digestive tract decontamination

a selective culture medium or attempt to collect and identify more than one species per rectal swab and therefore may indeed have underestimated colonization rates. Only five cases of ITU-acquired enterococcal infection were diagnosed, all polymicrobial sepsis. No patient in the SDD group developed an ITU-acquired enterococcal infection and the absence of any increased use of antienterococcal agents in this group suggests that this was not due to a failure of diagnosis. This finding is in line with that of Konrad and colleagues who diagnosed enterococcal pneumonia in nine control patients compared with two SDD patients [21]. Similarly, Hartenauer and colleagues in a prospective consecutive crossover study describe 4 cases of enterococcal pneumonia in control patients compared with one receiving SDD [22]. Selective digestive tract decontamination has been used to control an outbreak of multi-resistant Gram-negative bacilli but only one of 12 infections in the SDD group were caused by Gram-positive bacteria compared with three in the non-SDD group [23]. Therefore the findings from these studies taken in conjunction with those reported here do not suggest that patients receiving SDD are more prone to enterococcal infection. Furthermore, urinary tract or blood stream infections caused by Gram-positive organisms are less devastating than those caused by

general, are easier to treat [24]. The failure of increased colonization rates in the SDD and CC groups to lead to higher infection rates is not easily explained but may have been influenced by a number of complex factors. It is possible that the use of SDD in more patients over a longer period of time might cause a shift to Gram-positive infections, including enterococci, as has been seen with neutropenic patients [25]. It is, however, likely that alterations in the normal bowel flora, overgrowth with potential pathogens such as Gramnegative bacilli, the use and route of administration of antimicrobial agents and altered gut motility influence enterococci in the gastrointestinal tract through a complex series of inter-relationships. Reduced gut motility, which is a feature of many ITU patients, has been associated with increased transmission of resistant enterococci [10, 12] and this may have greater significance in those patients receiving SDD where the number of Gram-negative bacilli is reduced. The higher colonization rate in the SDD and CC groups (80~ and 70~ respectively) compared with the HC group by day 5 (3007o) contrasts the 97070 and 82% rates for SDD and control groups in the consecutive study reported by Konrad and colleagues [21]. Patients in ITU at the same time as other patients receiving SDD, although not receiving it themselves, may undergo changes in bowel flora different from historical control patients and enterococci may be transmitted from patients in one group to another. The difference in antimicrobial use, especially the use of cephalosporins, was more marked between SDD and the other two groups rather than between the SDD and CC groups only which suggests that transmission between patients in ITU was important. We did not detect a shift in the species isolated from E. faecalis to E. faecium either during the trial or when patients were discharged back to the ward. The absence of a significant increase in MICs for the antimicrobial agents tested is re-assuring. The high MIC90 of 32 rag/1 of ampicillin for many isolates recorded in this study suggests that this would not be the agent of choice for treatment and therefore either vacomycin (MIC90, 4 rag/l), teicoplanin (MIC90, 0.25 mg/1) or even perhaps penicillin/ampicillin plus the beta-lactamase inhibitor, sulbactam [10] would be more appropriate. Notwithstanding the potential role of SDD in the prevention of unit-acquired sepsis, we strongly endorse the view that traditional infection control measures remain of paramount importance in reducing ITU-acquired infection [26]. Clustering of patients and the isolation of enterococci from the hands of hospital personnel has been shown to be important in the transmission of infection due to gentamicin-resistant E. faecalis [10, 27]. Surveillance is an important component of infection control in the ITU and is recommended to detect colonizing aerobic microorganisms of the pharynx and stomach [28] as well as changes in resistance amongst Gram-negative bacilli. Acknowledgements. We are indebted to Prof D. C.E. Speller, Drs A.P. MacGowan and S.M. Willaatts and all the staff of the Departments of

463 Microbiology and ITU for their interest and support. We acknowledge the assistance of Mr S. Brown and the Department of Pharmacy for their help in the preparation of antibiotics. We are grateful to Dr D.S. Reeves and Mr H.A. Holt, Department of Microbiology, Southmead Hospital, Bristol for their assistance in some laboratory aspects of this work.

15.

16.

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Dr. H. Humphreys Department of Microbiology University Hospital Queen's Medical Centre Nottingham NG7 2UH UK

The effect of selective decontamination of the digestive tract on gastrointestinal enterococcal colonization in ITU patients.

The effect of selective decontamination of the digestive tract (SDD) on Intensive Therapy Unit (ITU)-acquired enterococcal infection and colonization ...
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