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Doi:10.1016/s1473-3099(11)70035-4

Articles
Selective digestive tract decontamination and selective
oropharyngeal decontamination and antibiotic resistance
in patients in intensive-care units: an open-label, clustered
group-randomised, crossover study

Anne Marie G A de Smet, Jan A J W Kluytmans, Hetty E M Blok, Ellen M Mascini, Robin F J Benus, Alexandra T Bernards, Ed J Kuijper, Maurine A Leverstein-van Hall, Arjan R Jansz, Bartelt M de Jongh, Gerard J van Asselt, Ine H M E Frenay, Steven F T Thijsen, Simon N M Conijn, Jan A Kaan, Jan P Arends, Patrick D J Sturm, Martin C J Bootsma, Marc J M Bonten Summary
Background Previously, we assessed selective digestive tract decontamination (SDD) and selective oropharyngeal
Published Online
decontamination (SOD) on survival and prevention of bacteraemia in patients in intensive-care units. In this analysis, DOI:10.1016/S1473-
we aimed to assess eff ectiveness of these interventions for prevention of respiratory tract colonisation and bacteraemia 3099(11)70035-4
with highly resistant microorganisms acquired in intensive-care units.
See Online/Comment
DOI:10.1016/S1473-
Methods We did an open-label, clustered group-randomised, crossover study in 13 intensive-care units in the 3099(11)70067-6
Netherlands between May, 2004, and July, 2006. Participants admitted to intensive-care units with an expected Division of Perioperative
and Emergency Care
duration of mechanical ventilation of more than 48 h or an expected stay of more than 72 h received SOD (topical
(A M G A de Smet MD),
tobramycin, colistin, and amphotericin B in the oropharynx), SDD (SOD antibiotics in the oropharynx and stomach Department of Medical
plus 4 days’ intravenous cefotaxime), or standard care. The computer-randomised order of study regimens was applied Microbiology (H E M Blok MSc,
by an independent clinical pharmacist who was masked to intensive-care-unit identity. We calculated crude odds M A Leverstein-van Hall MD,
ratios (95% CI) for rates of bacteraemia or respiratory tract colonisation with highly resistant microorganisms in
Prof M J M Bonten MD), and
patients who stayed in intensive-care units for more than 3 days (ie, acquired infection). This trial is registered at Julius Centre for Health Sciences
http://isrctn.org, number ISRCTN35176830.
and Primary Care (M J M Bonten),
University Medical Centre
Utrecht, Utrecht, Netherlands;

Findings Data were available for 5927 (>99%) of 5939 patients, of whom 5463 (92%) were in intensive-care units Department of Intensive Care,
for more than 3 days. 239 (13%) of 1837 patients in standard care acquired bacteraemia after 3 days, compared Onze Lieve Vrouwe Gasthuis,
with 158 (9%) of 1758 in SOD (odds ratio 0·66, 95% CI 0·53–0·82), and 124 (7%) of 1868 in SDD (0·48, 0·38–0·60). Amsterdam, Netherlands
Eight patients acquired bacteraemia with highly resistant microorganisms during SDD, compared
(A M G A de Smet); Department
of Medical Microbiology,
with 18 patients (with 19 episodes) during standard care (0·41, 0·18–0·94; rate reduction [RR] 59%, absolute risk Amphia Hospital, Breda,
reduction [ARR] 0·6%) and 20 during SOD (0·37, 0·16–0·85; RR 63%, ARR 0·7%). Of the patients staying in Netherlands
intensive-care units for more than 3 days, we obtained endotracheal aspirate cultures for 881 (49%) patients (Prof J A J W Kluytmans MD);
receiving standard care, 886 (50%) receiving SOD, and 828 (44%) receiving SDD. 128 (15%) patients acquired Department of Medical

Microbiology and Infectious
respiratory tract colonisation with highly resistant microorganisms during standard care, compared with 74 (8%) Diseases, Vrije Universiteit
during SDD (0·58, 0·43–0·78; RR 38%, ARR 5·5%) and 88 (10%) during SOD (0·65, 0·49–0·87; RR 32%, Medical Centre, Amsterdam
ARR 4·6%). Acquired respiratory tract colonisation with Gram-negative bacteria or cefotaxime-resistant and (J A J W Kluytmans); Laboratory
colistin-resistant pathogens was lowest during SDD.

for Medical Microbiology and
Immunology, Rijnstate
Hospital, Arnhem, Netherlands

Interpretation Widespread use of SDD and SOD in intensive-care units with low levels of antibiotic resistance is (E M Mascini MD); Department
justifi ed.
of Medical Microbiology,
University Medical Centre,
Groningen, Netherlands

Funding None.
(R F J Benus MD, J P Arends MD);
Department of Medical

Introduction
ant pathogens, which is the main drawback of such Microbiology, Leiden University
Medical Centre, Leiden,
Respiratory tract infections acquired in intensive-care interventions. SDD aims to prevent colonisation by Netherlands (A T Bernards MD,
units have been associated with high rates of morbidity Gram-negative bacteria, Staphylococcus aureus, and yeasts E J Kuijper MD); Laboratories for
and mortality and increased health-care costs, especially in patients in intensive care through application of non- Pathology and Medical
when they are caused by highly resistant microorganisms absorbable antimicrobial treatments in the oropharynx Microbiology, Catharina
Hospital, Eindhoven,
(table 1).1–3 Reductions in the rates of respiratory tract and gastrointestinal tract. This intervention also pre- Netherlands (A R Jansz MD);
infections have been achieved through prophylactic emptively treats possible infections with commensal Department of Medical
antibiotic regimens such as selective digestive tract respiratory tract bacteria through systemic administration Microbiology and Immunology,
decontamination (SDD)4,5 and selective oropharyngeal of cephalosporins during the fi rst 4 days in intensive- St Antonius Hospital,
Nieuwegein, Netherlands
decontamination (SOD).6,7 However, prophylactic use of care units, and maintains anaerobic intestinal fl ora (B M de Jongh MD);
anti biotics might increase selection for antibiotic-resist- through selective use of antibiotics (both topically and www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
Articles
Department of Medical
systemically).8,9 SOD is oropharyngeal decontamination individualised, randomised design would have led to Microbiology, Medical Centre
only, without any specifi c recommendations for systemic interference between treated and untreated patients. Haaglanden, The Hague,
Therefore, cluster randomisation was needed and all Netherlands (G J van Asselt MD);
Regional Laboratory for Medical
We previously reported primary and secondary clinical three study regimens (SDD, SOD, and standard care) Microbiology and Infectious
outcomes, including rates of survival, bacteraemia, were to be applied to all eligible patients during 6 months Diseases, Dordrecht–Gorinchem
antibiotic use, length of stay, and duration of mechanical with the order of regimens randomly assigned. The and Albert Schweitzer Hospital,
ventilation, from a multicentre study10 comparing SOD study periods were preceded by a wash-in and/or wash- Dordrecht, Netherlands
(I H M E Frenay MD);
and SDD with standard care. Both interventions were out month during which newly admitted patients were Department of Medical
associated with improved day-28 survival and reduced treated according to the centre-specifi c allocation Microbiology, Diakonessen
incidence of acquired bacteraemia in 13 Dutch intensive- treatment for the following period, but actual inclusion Hospital, Utrecht
care units with low rates of antibiotic resistance. In the started after the wash-in period (see supplementary (S F T Thijsen MD); Department
of Clinical Microbiology,
paper10 and a subsequent analysis11 we reported the eco- online appendix of de Smet and colleagues10). Patients Slotervaart Hospital,
logical eff ects of SDD and SOD on the overall intensive- admitted to intensive-care units with an expected Amsterdam (S N M Conijn);
care-unit population including short-staying patients who duration of mechanical ventilation of more than 48 h or Department of Medical
were not enrolled in the study. Compared with standard an expected stay of more than 72 h were eligible for Microbiology and Immunology,
Mesos Medical Centre, Utrecht
care, SDD and SOD were associated with decreased inclusion. Expected stay was assessed by doctors (J A Kaan MD); and Department
mortality and reduced need for systemic antibiotics.10 responsible for care of patients in each unit.10 of Medical Microbiology,
Moreover, SDD was also associated with a reduction in The study protocol was approved by institutional Radboud University, University
occurrence of candidaemia and bacteraemia with Gram- review boards at all participating hospitals. Because Medical Centre Nijmegen,
Nijmegen, Netherlands
negative microorganisms as compared with SOD.
SDD and SOD were regarded as common practice in However, neither publication reported the eff ects of the Netherlands and not harmful to patients, and SDD and SOD on bacteraemia and respiratory tract because only a unit-wide approach would allow reliable colonisation with highly resistant microorganisms or estimation of the true eff ect of the interventions, the bacteria resistant to the SOD and SDD antibiotics that institutional review boards waived, after review, the were acquired while patients were in intensive-care units. need for informed consent. We obtained permission to We aimed to assess such outcomes in this study.
use patient-specifi c medical data for analysis from amga.desmet@gmail.com
Methods
Study sites and patients

Randomisation and masking
Our group did a pragmatic, open-label, clustered group- A clinical pharmacist, who was not involved in care of randomised, controlled, crossover study in 13 intensive- patients at any of the participating units, did the care units between May, 2004, and July, 2006. The randomisation and was masked to intensive-care unit participating intensive-care units diff ered in size and identity. The order of the three study regimens provided teaching status, covering all levels of intensive care in to patients was randomly generated by computer the Netherlands. Because the interventions included software and allocated to the wards in consecutive ecological changes in the intensive-care units, an order of study start.
Quinolones Aminoglycosides
Carbapenems Co-trimoxazole Ceftazidime Piperacillin
Penicillins Glycopeptides Oxacillin
Meticillin
Enterobacteriaceae
Glucose non-fermenting Gram-negative rods
Gram-positive bacteria
Resistance to one antibacterial agent in category A, to two or more in category B, or to three or more in category C is required to defi ne the microorganism as highly resistant. ESBL=extended-spectrum β-lactamase. *During the study, determination of ESBL was not standardised and multiple diff erent methods were used in participating laboratories; therefore, resistance to any third-generation cephalosporins (eg, cefotaxime, ceftazidime, and ceftriaxone) was used as proxy for presence of ESBL in Escherichia coli, Klebsiella spp, and Proteus spp.
Table 1: Defi nitions of highly resistant microorganisms
www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
Articles
Procedures
non-fermenters, and Gram-positive bacteria. Resistance The SDD regimen was 4 days of intravenous cefotaxime to any third-generation cephalosporin (eg, cefotaxime,
and topical application of tobramycin, colistin, and ceftazidime, and ceftriaxone) was used as proxy for the
amphotericin B in the oropharynx and stomach. Use of presence of extended spectrum β-lactamase in
antibiotics that impair colonisation resistance, such as Escherichia coli, Klebsiella spp, and Proteus spp.
amoxicillin, penicillin, amoxicillin-clavulanic acid, and
carbapenems was discouraged during SDD. Surveillance Statistical analysis
cultures of endotracheal aspirates and oropharyngeal and
We calculated crude odds ratios (ORs) and 95% CI for rectal swabs were done on admission and then twice rates of acquisition of bacteraemia and respiratory tract every week. The SOD regimen was oropharyngeal colonisation in intensive care units between the three application of the same paste as used for SDD, with groups, as well as rate reductions, absolute risk surveillance cultures of endotracheal aspirates and reductions, and numbers needed to treat. We did a time-oropharyngeal swabs done on admission and twice every to-fi rst-event analysis Kaplan-Meier survival analysis week, without restrictions in doctors’ choices of systemic with follow-up until 40 days (or discharge from the antibiotic therapy. During standard care, participating intensive-care unit if this was before 40 days). We tested intensive-care units were free to follow their own diff erences between groups with the log-rank test guidelines and surveillance cultures were not done in all (signifi cance defi ned as p<0·05).
units. There were no restrictions on the choice of systemic Patients who had the same species of highly resistant antibiotic therapy. By contrast with the protocols for microorganism isolated during the fi rst 3 days of stay endotracheal aspirate surveillance cultures, there were no and after the third day were not included as an event in diff erences between the three groups in terms of the analysis. The same rule was applied for patients indication for taking blood cultures. with cefotaxime-resistant and tobramycin-resistant In this analysis, we used all microbiological culture Gram-negative rods. All analyses were done with SPSS results from blood and endotracheal aspirate samples version 15.0.
obtained from patients in the study. We use the term This trial is registered at http://isrctn.org, number colonisation to mean bacterial growth in respiratory tract ISRCTN35176830.
samples. For patients with more than one endotracheal aspirate culture in 1 day, we interpreted the results as one Role of the funding source
culture. We regarded bacterial growth in endotracheal There was no funding source for this study. All authors aspirate samples obtained on the day of admission or the had full access to all the data in the study and had fi nal 2 days after as colonisation on admission. We regarded responsibility for the decision to submit for publication.
bacterial growth in samples obtained after the third day,
and with documented absence in previous cultures, as Results
acquired in the intensive-care unit. Microbiological 5939 patients were enrolled and data for 5927 patients
procedures were identical for respiratory tract samples were available for analysis (table 2). Baseline characteristics
that were obtained for clinical reasons (ie, as in standard diff
ered between treatment groups (webappendix).10 See Online for webappendix
care, but also potentially SOD and SDD) as for surveillance Patients in the SDD and SOD groups had higher acute In all three study periods, we obtained blood cultures on Standard care
SOD (n=1904)
SDD (n=2034)
clinical indication, as assessed by the treating doctors. For (n=1989)
patients with more than one blood culture in 1 day, results were pooled as results for one blood culture. We regarded bacterial growth in blood cultures obtained on the day of admission or the 2 days after as bacteraemia on admission. We defi ned growth from blood cultures collected after the third day or later, with documented absence in cultures during the fi rst 3 days, as bacteraemia acquired in the intensive-care unit. We excluded coagulase-negative Patients with ≥1 EAC in fi rst 3 days in ICU Susceptibility testing was done according to the national guidelines.12 Only the fi rst culture results with an acquired EAC-days per patient-day in fi rst 3 days in ICU microorganism were analysed; further positive culture results with the same microorganism were regarded as EAC-days per patient-day after day 3 in ICU Data are n (%) or n (patient-days), unless otherwise stated. SOD=selective oropharyngeal decontamination. We defi ned highly resistant microorganisms according SDD=selective digestive tract decontamination. EAC=endotracheal aspirate culture. ICU=intensive-care unit.
to the national guidelines (table 1),13 and established Table 2: Population of patients and microbiological sampling
three main groups: Enterobacteriaceae, Gram-negative www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
Articles
Standard care
Crude odds ratio (95% CI)
(n=1837)
(n=1758)
(n=1868)
Data are n (%), unless otherwise stated. SOD=selective oropharyngeal decontamination. SDD=selective digestive tract decontamination. ARR=absolute risk reduction. NNT=number needed to treat. HRMO=highly resistant microorganism. *One case of Saccharomyces cerevisiae in the standard-care group. †One patient in the control group had two episodes of bacteraemia with HRMOs (one episode on day 9 with Enterobacter cloacae and Escherichia coli and one on day 30 with Acinetobacter baumanii).
Table 3: Patients with bacteraemia and candidaemia acquired in intensive-care units
standard care, 0·13 in SOD, and 0·11 in SDD (table 2). Standard care SOD
Bacteraemia occurred in 305 patients in the fi rst 2 days (n=1837)
(n=1758)
(n=1868)
after admission to intensive-care units.
Bacteraemia
Bacteraemia acquired in an intensive-care unit was more common in standard care than it was in SDD or SOD, and was more common in SOD than SDD (table 3). Candidaemia acquired in an intensive-care unit was more common in standard care and SOD than it was in SDD (table 3). 47 episodes of acquired bacteraemia were caused by highly resistant micro organisms (tables 3 and 4). One patient had more than one episode (table 3). Development of bacteraemia acquired in intensive-care units caused by highly resistant microorganisms was 59% less frequent Respiratory tract colonisation
with SDD than with standard care and 63% less frequent for SDD than with SOD (tables 3 and 4).
We did 19 404 microbiological cultures from endo- tracheal aspirates. When divided between the time of Other glucose non-fermenting Gram-negative organisms analysis, frequencies of microbiological cultures from endotracheal aspirates were lowest during standard care (table 2). Frequency of respiratory tract cultures was about 30% lower during standard care than it was in SOD We obtained endotracheal aspirate cultures on admission for 688 (35%) of 1989 patients in the standard-care group, 1044 (55%) of 1904 patients in the SOD group, and 1025 (50%) of 2034 in the SDD group (table 2). Distribution of species isolated was much the same between groups. Prevalence of highly resistant microorganisms at the time SOD=selective oropharyngeal decontamination. SDD=selective digestive tract decontamination.
of admission to intensive-care units was low, ranging from Table 4: Acquired highly-resistant microorganisms
2·4% during SDD to 3·9% during SOD, and did not diff er between study groups. Endotracheal aspirate cultures were obtained from 2595 (48%) of 5463 patients who physiology and chronic health evaluation (APACHE) II stayed in an intensive-care unit for more than 3 days: scores than did patients in standard care, and were more cultures were obtained for 881 (49%) of 1837 patients often mechanically ventilated and admitted to intensive- in standard care, 886 (50%) of 1758 in SOD, and care units for non-surgical reasons. Patients in the SDD 828 (44%) of 1868 in SDD.
group were older than were patients in the standard care After day 3 in the intensive-care unit, colonisation of all groups of Gram-negative bacteria that were acquired in 5463 (92%) of 5927 patients remained in an intensive- intensive-care units was highest in patients receiving care unit for more than 3 days (table 2). Blood cultures standard care. Acquisition rates of Acinetobacter spp and were obtained from 3421 (58%) of 5927 patients, at an Stenotrophomonas maltophilia (gathered as one group) average frequency per patient-day of 0·11 cultures in and of other glucose non-fermenting Gram-negative rods www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
Articles
Patients with length of stay >3 days and EACs
Crude odds ratio (95% CI)
Acinetobacter spp and Stenotrophomonas maltophilia Other glucose non-fermenting Gram-negative rods* Escherichia coli and Klebsiella spp Data are n (%), unless otherwise stated. EAC=endotracheal aspirate culture. SOD=selective oropharyngeal decontamination. SDD=selective digestive tract decontamination. ARR=absolute risk reduction. NNT=number needed to treat. HRMO=highly resistant microorganism. *Such as Pseudomonas aeruginosa. Haemophilus spp, Neisseria spp, and Pasteurella spp. ‡Vancomycin-resistant enterococci were not cultured. §Two patients in the SOD group and two patients in the SDD group acquired meticillin-resistant Staphylococcus aureus. Table 5: Patients with respiratory tract colonisation acquired in intensive-care units
(predominantly Pseudomonas aeruginosa) were much the and 30 (3%) of 1025 during SDD. We analysed the presence same in patients receiving both SDD and SOD. However, of cefotaxime resistance only for Enterobacteriaceae; the rate of acquired colonisation with Enterobacteriaceae prevalence at admission was nine (1%) during standard was lower with SDD than with SOD (table 5).
care, 20 (2%) during SOD, and 30 (3%) during SDD.
For Gram-positive bacteria, acquired colonisation with Colonisation with Gram-negative bacteria acquired in enterococci occurred more frequently in patients the intensive-care unit and resistant to tobramycin receiving SDD than standard care and SOD (table 5). occurred with much the same frequency and time to Acquired colonisation with yeasts and fungi was more acquisition during all three interventions (fi gure). common with SDD than with standard care (table 5).
Although acquisition with tobramycin-resistant Entero- After day 3, we noted acquired colonisation with highly bacteriaceae was lowest during SDD, this reduced resistant microorganisms in 290 patients. Such colon- isation was most common during standard care with acquisition rate of tobramycin-resistant non-fermenting 128 (15%) patients, compared with 88 (10%) during SOD Gram-negative rods (table 6). Acquired colonisation and 74 (9%) during SDD (tables 4 and 5). Compared with with cefotaxime-resistant Enterobacteriaceae occurred standard care, SDD reduced the rate of acquired highly less frequently and later during SDD than it did in the resistant microorganisms by 38% and SOD by 32% other treatment groups (fi gure). SDD was associated (tables 4 and 5). Gram-negative bacteria accounted for 98% with a 62% reduction in acquisition rate of cefotaxime- of all such microorganisms (tables 4 and 5). Four patients resistant Enterobacteriaceae compared with SOD and acquired respiratory tract colonisation with meticillin- resistant Staphylococcus aureus in two centres; two patients Incidence of intensive-care-unit acquired respiratory were receiving SOD and two were receiving SDD. No tract colonisation with Gram-negative bacteria that were patients acquired vancomycin-resistant entero cocci intrinsically resistant to colistin (ie, Proteus spp and Serratia spp) was lower during SDD than it was in Tobramycin and colistin were used as topical antibiotics standard care and SOD, with rate reductions of 55% for in all patients during SOD (in oropharyngeal paste) and SDD compared with standard care and 48% for SDD SDD (in oropharyngeal paste and enteral suspension). compared with SOD (table 6). Diff erences between the Cefotaxime was given intravenously during the fi rst 4 days three interventions were not caused by clustering of to all patients receiving SDD. Gram-negative bacteria patients in a minority of the participating intensive-care resistant to either of these antibiotics were rarely found units (webappendix).
during the fi rst 3 days of admission to an intensive-care We also investigated the eff ects of less frequent unit. During standard care, 13 (2%) of 688 patients in an respiratory tract culture sampling during standard care intensive-care unit with one or more culture in the fi rst by comparing ORs for acquired colonisation with Entero-3 days after admission were colonised with a Gram- bacteriaceae, non-fermenter species, and Candida negative bacterium that was resistant to tobramycin at species for the units with comparable culture frequencies admission, compared with 42 (4%) of 1044 during SOD in all three study periods and the units with lower www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
Articles
Discussion
In intensive-care units with low rates of antibiotic resistance, the use of SDD was associated with a reduction in acquired bacteraemia and respiratory tract colonisation caused by highly resistant microorganisms compared with standard care. SOD reduced rates of acquired respiratory tract colonisation with highly resistant microorganisms compared with standard care, SDD vs standard care p=0·1421SOD vs standard care p=0·4974 but rates of bacteraemia from highly resistant microorganisms did not diff er. Daily use of topical tobramycin and colistin was not associated with higher acquisition rates of resistant Gram-negative bacteria. Intravenous administra tion of cefotaxime for 4 days as part of SDD, which is generally regarded as a risk factor Number at risk
for increasing resistance, was associated with a large reduction in the acquisition rate of cefotaxime-resistant Enterobacteriaceae in the respiratory tract compared with standard care and SOD.
Our study was the largest prospective assessment of topical antimicrobial prophylaxis in patients in intensive care, with an estimated overall inclusion rate of 89% in 13 Dutch centres from a cluster-randomised design (panel). Nevertheless, there were slight diff erences in the baseline characteristics between the study groups, suggesting that patients receiving SDD or SOD were more severely ill than were those receiving standard care.10 As a result, reductions in day-28 mortality were apparent only after adjustment for these baseline diff erences. In the present analysis of microbiological outcomes, no adjustments were made for these baseline characteristics and the reported diff erences in resistance between Number at risk
standard care and both intervention periods should, therefore, be considered as conservative estimates.
Surveillance of respiratory tract colonisation was done in all study groups, whereas surveillance of digestive tract Figure: Kaplan-Meier analysis of time to event of acquisition of tobramycin-resistant Gram-negative rods (A)
colonisation was done only in the SDD group. Therefore and cefotaxime-resistant Enterobacteriaceae (B)
comparison of colonisation of the digestive tract with SDD=selective digestive tract decontamination. SOD=selective oropharyngeal decontamination.
resistant microorganisms between the three groups was not possible. However, respiratory colonisation usually frequen cies during standard care. The average respiratory refl ects colonisation of the patient.
tract culture frequencies were 0·30 per day during Another imbalance between the standard-care standard care, 0·31 during SOD, and 0·32 during SDD population and both intervention groups was the in centres with equal culture frequencies, and 0·18, culture frequency of respiratory tract samples. 0·30, and 0·30, respectively, in those with less frequent Respiratory tract samples were obtained twice every culture sampling during standard care. Compared with week during SDD and SOD, as per protocol, but this standard care, ORs for acquisition of Enterobacteriaceae was not included in the protocol for standard care. As a were 0·19 (95% CI 0·12–0·30) during SDD for the three result, culture frequency was 30% lower during centres with equal culture frequencies in all study standard care, which might have introduced a negative periods and 0·17 (0·12–0·24) for ten centres with lower detection bias for intensive-care-unit acquired culture frequencies during standard care, and 0·52 colonisation. Potentially, endo (0·36–0·75) and 0·64 (0·50–0·82), respectively, during done most frequently in the more severely ill patients SOD. For SDD compared with SOD, odds ratios were in standard care, which could have introduced a positive 0·36 (0·22–0·60) in those centres with equal culture selection bias. However, when we compared intensive-frequencies and 0·26 (0·18–0·39) in those with lower care units that had the same routine and frequencies of culture frequencies during standard care. ORs were also respiratory tract sampling for all three groups with much the same for the other groups of pathogens (data those units in which sampling occurred less frequently not shown).
for standard care, we noted equivalent ORs for www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
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Patients with length of stay >3 days and EACs
Crude odds ratio (95% CI)
Tobramycin resistance
Escherichia coli and Klebsiella spp Acinetobacter spp and Stenotrophomonas maltophilia Other glucose non-fermenting Gram-negative rods* Cefotaxime resistance
Colistin resistance
Proteus spp and Serratia spp Data are n (%) unless otherwise stated. EAC=endotracheal aspirate culture. SOD=selective oropharyngeal decontamination. SDD=selective digestive tract decontamination. ARR=absolute risk reduction. NNT=number needed to treat. *Such as Pseudomonas aeruginosa. Table 6: Respiratory tract colonisation with Gram-negative bacteria resistant to tobramycin, cefotaxime, or colistin acquired in intensive-care-units
acquisition of pathogens. Furthermore, microbiological However, we calculated these numbers needed to treat on procedures were identical for samples obtained for the basis of patients with a minimum length of stay in an clinical reasons or as part of surveillance, suggesting intensive-care unit of more than 3 days. In an intention-the eff ect of detection bias was small.
to-treat analysis, including the 8% of the patients with Baseline characteristics and culture frequencies did not less than 3 days’ stay (equally distributed over the three diff er between patients receiving SDD or SOD. Our data, study groups), the number needed to treat would be therefore, allow investigation of the eff ects of enteral higher. The attributable eff ects of such episodes on decontamination in combination with intravenous survival and length of stay will establish whether these administration of cefotaxime during the fi rst 4 days on fi gures justify a preference for SDD over SOD. In our acquisition of respiratory tract colonisation. SDD was study, with 1904 patients receiving SOD and 2034 receiving associated with a substantial reduction in acquired SDD, diff erences in bacteraemia rates did not produce respiratory tract colonisation with Enterobacteriaceae, signifi cant diff erences in outcomes.10but not with that of non-fermenting Gram-negative rods, By comparison with SOD, the number needed to treat such as Acinetobacter species, S maltophilia, and with SDD to prevent one episode of acquired respira -P aeruginosa. As most non-fermenting bacteria are tory col intrinsically resistant to cefotaxime, intestinal colonisation Enterobacteriaceae and 17 for intrinsically colistin- seems to be a relevant source for Enterobacteriaceae, but resistant Enterobacteriaceae. However, this benefi cial eff ect on the acquisition with cefotaxime-resistant As previously reported,10 clinical outcomes (eg, day-28 Enterobacteriaceae is, at least partly, balanced by higher mortality) were comparable between patients receiving acquisition rates of non-fermenting bacteria that are SDD and SOD, and therefore a preference for either intrinsically resistant to this antibiotic. Overall, rates of regimen was diffi cult to make. Another study14 showed acquired respiratory tract colonisation with highly that respiratory tract decolonisation was associated with a resistant microorganisms did not diff er signifi cantly 33% reduction in occurrence of bacteraemia with Gram- negative bacteria acquired in intensive-care units; Selection for antibiotic-resistance is an important intestinal tract decolonisation was associated with a 45% threat associated with SDD and SOD.15 The results of reduction in this study. This eff ect can explain why we our study suggest the opposite. SDD was associated reported large and signifi cant relative reductions in with a 48% reduction in the rate of bacteraemia with bacteraemia in both interventions. The clinical highly resistant microorganisms, and both interventions signifi cance of these fi ndings can best be expressed in yielded reductions in acquired respiratory tract numbers needed to treat. Compared with SOD, 43 patients colonisation with highly resistant microorganisms of would have to be treated with SDD to prevent one episode 32% for SOD and 38% for SDD. Moreover, compared of bacteraemia, 127 patients to prevent one episode of with standard care, SOD was not associated with higher candidaemia, and 145 patients to prevent one episode rates of acquired colonisation with tobramycin-resistant with bacteraemia with highly resistant microorganisms. or colistin-resistant Gram-negative bacteria and SDD www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
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The ecological eff ects of SOD and SDD need to be Panel: Research in context
established in more detailed and longer studies.
Results from the Extended Prevalence of Infection in Systematic review
Intensive Care (EPIC) II study confi rmed a strong We searched the PubMed database without language relation between infection rate and mortality, and 62% of restrictions for papers published up to Feb 15, 2011 with the participating patients had infections with Gram-negative search terms “ICU” AND “antibiotic resistance” AND “SOD” OR bacteria and 17% with Candida species; 71% of patients “selective oropharyngeal decontamination” AND “SDD” OR received antibiotics as prophylaxis or treatment.3 New “selective digestive decontamination”. Of 639 search results, approaches for control of infections and antimicrobial no studies compared eff ects of selective digestive resistance in intensive-care units are needed.
decontamination (SDD) with selective oropharyngeal The benefi ts of prophylactic antibiotic use need to be decontamination (SOD), or SOD with standard care with balanced against the inevitable risks of selection of regard to emergence of antibiotic resistance in patients in antibiotic-resistant bacteria. As such, widespread use of intensive-care units. One study5 compared the eff ects of SDD topical antimicrobial prophylaxis in patients in intensive- with standard care on incidence of antibiotic resistance, and care units has been the subject of debate for years. The had an equivalent study design to our analysis (unit-wide benefi cial eff ects of SDD and SOD on outcomes, together with the favourable results for infection and colonisation Interpretation
with antibiotic-resistant pathogens reported in this study, We report a novel study quantifying the eff ects of SDD, SOD, justify the extended use of these interventions in settings and standard care on occurrence of bacteraemia and with low rates of antibiotic resistance. However, the respiratory tract colonisation with highly resistant long-term eff ects on development of resistance, especially microorganisms acquired in intensive-care units. SDD was with presently reported increase in infections caused by associated with a 59% rate reduction of highly resistant extended-spectrum β-lactamase-producing bacteria and bacteraemia compared with standard care in this setting, and carba penamase-producing bacteria, should be carefully a 63% rate reduction compared with SOD. SOD was monitored. Our results warrant further studies in associated with a rate reduction in acquired respiratory tract settings with higher baseline rates of resistance than in colonisation with highly resistant microorganisms of 32% compared with standard care, and SDD was associated with a Contributors
38% reduction compared with standard care.
AMGAdS, JAJWK, and MJMB designed and managed the study. MCJB, EMM, ATB, EJK, MALvH, BMdJ, SFTT, and JAK critically reviewed the study design for intellectual content. AMGAdS, JAJWK, EMM, RFJB, ATB, EJK, MALvH, ARJ, BMdJ, GJvA, IHMEF, SFTT, was even associated with reduced acquisition rates of SC, JAK, JPA, and PDJS collected data. AMGAdS, JAJWK, MCJB, bacteria resistant to cefotaxime and colistin. These HEMB, and MJMB did the data analysis. AMGAdS, JAJWK, and fi ndings confi rm the results from a single-centre study5 MJMB wrote the fi rst draft of the report. All authors reviewed and revised the report.
in the Netherlands, in which SDD was also associated
with smaller proportions of patients colonised with Confl icts of interest
JAWJK has been a consultant to 3M, Destiny Pharma, Cepheid, and resistant pathogens in the respiratory tract.
Phico Therapeutics and has received grants from Pfi zer and Cepheid. Our patient-based analysis supports the results of our MJMB has participated in advisory boards of 3M, Aventis, and Novartis previous ecological analysis,11 in which we reported unit- and has received lecture fees from 3M, Novartis, Pfi zer, and wide reductions in prevalence of antibiotic-resistant Kimberly Clark. All other authors declare no confl icts of interest.
Gram-negative bacteria in the respiratory tract during References
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fi ndings. However, there are two important diff erences 3 Vincent J-L, Rello J, Marshall J, et al. International study of the between the analyses. In the ecological analysis,11 we used prevalence and outcomes of infection in intensive care units. point-prevalence surveys in which all patients in the unit JAMA 2009; 302: 2323–29.
D’Amico R, Piff eri S, Leonetti C, Torri V, Tinazzi A, Liberati A. (whether or not enrolled in the trial) were included and Eff ectiveness of antibiotic prophylaxis in critically ill adult resistance trends were analysed over time. Many of these patients: systemic review of randomised controlled trials. BMJ patients were in the intensive-care unit for a very short 1998; 316: 1275–85.
amount of time (≤3 days), and did, therefore, not receive de Jonge E, Schultz M, Spanjaard L, et al. Eff ects of selective decontamination of the digestive tract on mortality and SDD or SOD and were not included in the present acquisition of resistant bacteria in intensive care: a randomised patient-based analysis. Furthermore, as we did not have controlled trial. Lancet 2003; 362: 1011–16.
control units without SDD and SOD, we could not 6 Pugin J, Auckenthaler R, Lew DP, Suter PM. Oropharyngeal decontamination decreases incidence of ventilator- associated establish to what extent the reported increase of resistance pneumonia: a randomized, placebo-controlled, double-blind in time developed independent of either intervention. clinical trial. JAMA 1991; 265: 2704–10.
www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4
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www.thelancet.com/infection Published online March 21, 2011 DOI:10.1016/S1473-3099(11)70035-4

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Synthesis of a-L-Threofuranosyl Nucleoside TriphosphatesKeyong Zou,1 Allen Horhota,3 Biao Yu,2 Jack W. Szostak,1 Larry W. 1Howard Hughes Medical Institute, and Department of Molecular Biology,Massachusetts General Hospital, Boston, Massachusetts 02184, and 2State KeyLaboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of OrganicChemistry, Chinese Academy of Sciences, 3

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