Abstract
Selective Digestive Decontamination (SDD) and Selective Oropharyngeal Decontamination (SOD) are applied to prevent infections amongst Intensive Care Unit (ICU) patients and have proven to reduce mortality and infection rates. However, concerns about the development of antimicrobial resistance persists, specifically after ICU discharge. The aim of this study was to assess the occurrence of antimicrobial resistance during ICU stay and after ICU discharge in patients who had received SDD, or SOD compared to control, explicitly at individual-patient level. A previous systematic review, which included studies on antimicrobial resistance after SDD or SOD published before 01-02-2012, was updated. All studies analyzing antimicrobial resistance during and after ICU stay, were included. All outcomes related to resistant pathogens, whether detected through colonization or infection, were included. Pooled odds ratios and 95% confidence intervals were calculated using the Mantel-Haenszel method with random effects. Analyses were done separately for SDD and SOD. Twenty-seven studies were included in the meta-analysis on the occurrence of antimicrobial resistance during ICU stay, yielding a protective association in patients receiving SDD; OR 0.73 (95%-CI 0.54;0.98, I2 75%), which consisted of significant heterogeneity. Four studies investigated antimicrobial resistance after ICU discharge, of which two demonstrated protective results and two observed an increase in resistance in patients who had received SDD or SOD. A prospective long-term follow-up study is required to investigate the long-term effect of SDD and SOD on antimicrobial resistance. During ICU stay, SDD was not associated with increased antimicrobial resistance to specific antibiotics, consistent with previous findings, although study heterogeneity was considerable. This current review emphasizes the limited amount of data on the long-term effect of antimicrobial decontamination strategies on antimicrobial resistance, without addressing the population level effects on resistance rates and changes in gut-microbiome. Understanding this long-term effect is essential when deciding whether to implement preventative antibiotics.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-57127-8.
Keywords: Intensive care medicine, Infections, Antimicrobial resistance, Selective digestive decontamination
Subject terms: Antimicrobials, Bacteria, Health care
Introduction
Infections are a major cause of mortality and morbidity in patients admitted to Intensive Care Units (ICUs)1. A substantial part of these infections is hospital-acquired and can therefore potentially be prevented1.
Selective Digestive Decontamination (SDD) and Selective Oropharyngeal Decontamination (SOD) are applied to prevent infections among ICU patients. These two approaches have been extensively studied and demonstrate a reduction in mortality, infection rates, and duration of mechanical ventilation2. SDD consists of the application of nonabsorbable antimicrobial agents in the oropharyngeal and gastrointestinal tract. Systemic antimicrobial prophylaxis is administered in addition to SDD during the first four days of ICU admission2–4.
SOD consists of the application of nonabsorbable antimicrobial agents in the oropharynx. SOD and SDD were introduced to prevent endogenous infections caused by pathogens colonizing the oropharynx or gastrointestinal tract of ICU patients4. The choice of antibiotics is targeted against potential pathogens and should avoid targeting the anaerobic part of the flora4.
Despite the effect of SDD on ICU mortality, there is a persistent concern about the risk of antimicrobial resistance5. Bacterial antimicrobial resistance is a major cause of mortality6. Therefore, standardized preventative antibiotic administration should be critically reviewed. The resistance occurring after SDD and SOD may arise after ICU discharge. Thus, the main aim of this research was to assess the occurrence of antimicrobial resistance after ICU discharge. Antimicrobial resistance during ICU admission was also investigated, as new studies have been performed since the last systematic review in 20137–10.
Methods
Protocol and registration
The study protocol was registered in the PROSPERO International prospective register of systematic reviews under the ID CRD4201912814311. Because of substantial heterogeneity in study designs and outcome measures, several sensitivity analyses were added to the initial protocol to assess the impact of this heterogeneity. Moreover, the analyses were conducted separately for SDD and SOD. The reporting of this article followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline12. This study received no financial support and the authors declare no competing interests.
Information sources
A comprehensive literature search in Medline, Embase, and Cochrane was performed, see Fig. S1 for the search terms that were used. A previously performed systematic review by Daneman et al., which included all articles on antimicrobial resistance after SDD or SOD published before 01-02-2012, was taken as the basis7,13. A search string was developed and tested for the 2010–2012 period. This yielded complete agreement with the studies found by Daneman et al.7 for this period. All studies identified by Daneman et al. were reviewed to determine whether they met the eligibility criteria for this current study. The search was expanded with studies from after 2012. Moreover, a cross-reference check of all included articles was performed. No additional studies were found. The last search was conducted on 08-05-24.
Study selection
All studies that analyzed the antimicrobial resistance of bacteria in ICU patients who received SDD or SOD were included, regardless of whether infections or colonization was studied. SDD and SOD regimens were defined as the application of topical regimens to the oropharyngeal and or the digestive tract. Studies were included regardless of which antimicrobial agents were used in the topical paste and whether systemic antimicrobial agents were administered. The primary outcome was the occurrence of antimicrobial resistance after ICU discharge, and the secondary outcome was the occurrence of antimicrobial resistance during ICU stay. Both routine samples and samples used for diagnosing infectious complications, which were tested on antimicrobial resistance, were included. Studies investigating both antimicrobial resistance after ICU discharge and during ICU stay were included. There were no restrictions regarding study design, country, publication status, date of publication, or study quality. Studies investigating only non-antimicrobial interventions (i.e. only washing with chlorhexidine), or only eradication rates rather than occurrence of new colonization with resistant bacteria were excluded. Only publications in English were included. When studies used overlapping data, the study which commenced first, or which investigated the most relevant outcomes was included. Study selection was performed by two reviewers (F.E. and J.P.). A third and fourth reviewer (F.H. and V.S) were consulted when consensus could not be reached. Eventually, consensus was reached through discussion.
Data extraction
The following information was extracted from each study: author, year of publication, years of study population inclusion, country, study design, number of participating ICUs, number of patients, duration of ICU stay, nature of topical agents and systemic antibiotics, total duration of decontamination, total duration of follow-up after ICU discharge, antimicrobial resistance outcome, definitions of antimicrobial resistance, and whether surveillance samples were performed routinely. A structured data extraction form was used. Authors of the reviewed articles were contacted for additional information if necessary. Data that were unclear or not apparent were considered missing. Where possible, unreported information was derived from available data, for example by calculating absolute numbers from percentage of patients colonized with antimicrobial resistant pathogens.
Risk of bias assessment
Two reviewers (F.E. and J.P.) assessed risk of bias using the MINORS checklist14. A third and fourth reviewer were consulted when consensus could not be reached (F.H. and V.S.). Consensus was reached on all studies. The MINORS checklist allowed assessment of the risk of bias of interventional studies, both observational studies and randomized trials.
Data synthesis of studies assessing the antimicrobial resistance during ICU admission
The analyses of resistance development during ICU admission were conducted separately for studies using SOD and SDD. All studies assessing the antimicrobial resistance rates of bacteria in individual patients after ICU discharge were included in the meta-analysis. Only studies with a control group not receiving SDD or SOD, and reporting outcomes as the proportion of patients with new colonization or infection with an antimicrobial resistant pathogen relative to total number of patients, were pooled (details below). Studies presenting outcomes using isolates or pathogens numbers instead of patients were excluded from the meta-analysis, as patients could be colonized with multiple pathogens. Moreover, outcomes reported as the proportion of resistant pathogens relative to total positive isolates were excluded.
Analyses were performed using the “rmeta”, “metaviz”, “meta”, and “metafor” packages in R software for statistical computing (V.3.3.2.)15. The symmetry of the funnel plot was assessed independently by three researchers (F.E., J.P. and V.S.)16,17. To evaluate the presence of publication bias, the trim-and-fill analysis was performed. This analysis estimated the number of studies, risk ratios, and standard errors needed to achieve symmetry of the funnel plot18. The impact of possible publication bias was assessed by randomly producing multiple funnel plots with null hypothesis of no publication bias and blindly assessing whether the true funnel plot could be distinguished from the other funnel plots16,17.
Pooled odds ratios (OR) and 95% confidence intervals on the occurrence of antimicrobial resistance after SDD or SOD were calculated using the DerSimonian and Laird method with random effects. Random effects were used to account for variability in treatment effect across studies, for example due to different study populations19. A continuity correction of 0.5 was applied to cell counts with zero events. The heterogeneity of the effect estimates regarding the occurrence of antimicrobial resistance after SDD or SOD across studies was quantified by means of the I2 statistic.
Data synthesis of studies assessing the antimicrobial resistance during ICU admission
Due to limited data, outcomes of studies investigating the occurrence of antimicrobial resistance after ICU discharge were described narratively rather than pooled in a meta-analysis.
Outcomes to specific antibiotic groups and per multi-resistant bacteria type
Moreover, outcomes on resistance to specific antibiotic groups (aminoglycosides, polymyxin B and E, fluoroquinolones, and third-generation cephalosporins) and per multi-resistant bacteria type (Methicillin-Resistant S aureus (MRSA), Vancomycin Resistant Enterococcus spp. (VRE), and multi-resistant bacteria) were separately investigated. Due to limited data, only outcomes on MRSA in the SDD group were pooled. The other outcomes (MRSA in SOD, VRE and multi-resistant bacteria in both SDD and SOD) were only described narratively. Definitions of multi-resistant bacteria used by the studies included in this sensitivity analysis are specified in Table S5. Resistance to third-generation cephalosporins also included extended-spectrum beta-lactamase (ESBL) producing bacteria.
Sensitivity analyses
To investigate the effect of methodology, three sensitivity analyses were performed, combining results of studies using SDD or SOD: (A) IV antibiotics as part of SDD or SOD versus no IV antibiotics as part of SDD or SOD; (B) To explore the possible effect of cross-over contamination in individually randomized trials, a sensitivity analysis on studies with an individually randomized versus cluster randomized and observational design was conducted; When patients were individually randomized on the same ICU units, risk of cross-over contamination was higher than when patients were randomized in clusters on different ICU wards, or in observational designs such as before- and after designs; and (C) follow-up ≥ 14 days versus a < 14 days of follow-up. When studies did not report median follow-up duration, median length of ICU stay was used for this analysis.
Results
The search
In total, 65 studies were identified3,4,8–10,20–79, of which 33 studies were included in addition to the studies identified by Daneman et al.7. In total, 27 studies were included in the meta-analysis (Fig. 1), of which six were included in addition to Daneman et al.7. Of these 27 studies, there were 25 studies included in the meta-analysis on SDD, which included 181,052 patients in total. Moreover, four studies were included in the meta-analysis on SOD, including a total of 11,532 patients. Thirty-eight studies were excluded from the meta-analyses, because they had no control group or had overlapping data with previous studies (Table S1). Specific details on the reason for exclusion of studies can be found in Table S2.
Fig. 1.

Flowchart of systematic review on antibiotic resistance after SSD/SOD in ICU patients.
Lastly, four studies reported follow-up after ICU discharge.
Characteristics of included studies
Study characteristics are reported in Tables 1 and 2. Characteristics of the 27 studies that were included in the meta-analysis are described in Table 1. Most studies were conducted in in France (22.2%), Spain (18.5%), and in Germany, the Netherlands and the USA (all 11.1%). Study designs included individually randomized (37.0%), before-after design (25.9%), observational (18.5%) and cluster randomized (18.5%). The majority of the studies analyzed data collected from before 2012 (77.8%), and 6 (22.2%) studies investigated data collected after 2012. Aminoglycosides (96.3% of the studies) and Polymyxin B and E (81.5% of the studies) were the most frequently used topical antibiotics. Third-generation cephalosporins was the most frequently used systemic antibiotics (44.4% of the studies). Eleven (40.7%) studies did not use additional systemic antibiotics in their decontamination regimen (Table S3-4). SDD was used in 23 (85.2%), SOD in 2 (7.4%) studies, and both interventions in 2 (7.4%) studies. Seven (25.9%) of the studies used additional chlorhexidine body wash, and one (3.7%) used chlorhexidine mouthwash. Of these, five (18.5%) also administered chlorhexidine body wash in the control group, and one (3.7%) chlorhexidine mouthwash. Finally, 13 (48.1%) studies reported a follow-up of ≥ 14 days.
Table 1.
Characteristics of studies included in systematic review and meta-analysis on antimicrobial resistance after SSD/SOD in ICU patients.
| Study | Country | Study design | Study years | Routinely swab regimen | Systemic antibiotics | Number of ICUs | Number of patients | Outcome gram + or - bacteria | Antimicrobial resistance as primary outcome | Endpoint colonization or infection | Intention to Treat (ITT) vs. Per Protocol (PP) | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | SOD | SDD | Control | |||||||||||
| Brun-Buisson 198924 | France | Individual randomization | 1987 - 1987 | Every 4 days | No | 1 | 86 | 0 | 36 | 50 | - | Yes | Colonization**** | PP |
| de la Cal 200426 | Spain | Before and after | 1997 - 2000 | 1x/week | Yes | 1 | 659 | 0 | 401 | 258 | + | Yes | Both | |
| Camus 200528 | France | Cluster randomization | 1996 - 1998 | 1x/2weeks | No | 3 | 256 | 130 | 0 | 126 | +/- | No | Infection | ITT |
| Camus 201430 | France | Before and after | 2006 - 2008 | 1x/week | No | 1 | 1947 | 0 | 1022 | 925 | +/- | No | Infection | |
| Canter 201432 | UK | Observational | 2008 - 2011 | - | Yes | 199 | 284,690 | 0 | 12,270 | 272,420 | - | Yes | Infection | |
| Dahms 200033 | USA | Observational | 1996 - 1999 | No | No | 1 | 596 | 0 | 54 | 542 | + | Yes | Both | |
| Ferrer 199435 | Spain | Individual randomization | 12 months | 3x/week | Yes | 1 | 79 | 0 | 39 | 40 | + | No | Colonization**** | PP |
| Flaherty 199036 | USA | Individual randomization | 8 months | 2x/week | No | 1 | 107 | 0 | 51 | 56 | - | No | Infection**** | ITT |
| Garcin 201237 | France | Observational | - | No | Yes | 1 | 218 | 0 | 146 | 125 | + | No | Infection | |
| Hammond 199240 | South Africa | Individual randomization | 1989 - 1990 | 2x/week | Yes | 1 | 239 | 0 | 114 | 125 | - | No | Colonization | PP |
| de Jonge 20033 | Netherlands | Cluster randomization | 1999 - 2001 | 1x/week | Yes | 1 | 773 | 0 | 378 | 395 | +/- | Yes | Colonization | ITT |
| Katchman 201446 | Canada | During and after | 2007 - 2011 | 1x/week | No | 1 | 148 | 0 | 111 | 37 | +/- | No | Both | |
| Krueger 200247 | Germany | Individual randomization | 2.5 years | 2x/week | Yes | 2 | 454 | 0 | 265 | 262 | +/- | No | Colonization | PP |
| Perez-Granda 201861 | Spain | Before and after | 2012 - 2015 | No | No | 1 | 1746 | 0 | 892 | 854 | +/- | Yes | Colonization**** | |
| Quinio 199663 | France | Individual randomization | - | 2x/week | No | 1 | 148 | 0 | 76 | 72 | +/- | No | Colonization | ITT |
| Reizine 202364 | France | Observational | 2017 - 2023 | - | Yes | 220 | 5862 | 0 | 2931 | 2931 | +/- | No | Both | |
| Righi 201465 | Italy | Before and after | 2004 - 2010 | No | Yes | 1 | 1372 | 0 | 674 | 698 | +/- | No | Infection | |
| Sánchez García 199868 | Spain | Individual randomization | - | 2x/week | Yes | 1 | 271 | 0 | 131 | 140 | + | No | Infection**** | ITT |
| Sánchez-Ramîrez 201810 | Spain | Before and after | 2010 - 2015 | 1x/week | Yes | 1 | 2992 | 0 | 1998 | 994 | +/- | Yes | Infection**** | |
| de Smet 201169 | Netherlands | Cluster randomization | 2004 - 2006 | 2x/week | Yes | 13 | 2595 | 886 | 828 | 881 | +/- | Yes | Colonization | PP |
| SuDDICU 202270 | Australia | Cluster randomization | 2017-2021 | 1week/ month | Yes | 19 | 5982 | 0 | 2791 | 3191 | +/- | No | Both | ITT |
| Unertl 198773 | Germany | Individual randomization | 1984 - 1985 | 1x/day | No | 1 | 39 | 0 | 19 | 20 | +/- | No | Colonization**** | ITT |
| Verwaest 19974 | Belgium | Individual randomization | 19 months | 2x/week | Yes | 1 | 578 | 0 | 393 | 185 | +/- | Yes | Infection | PP |
| van der Voort 200475 | Netherlands | Before and after | 2 years | 2x/week | Yes | 1 | 732 | 0 | 219 | 513 | +/- | Yes | Colonization | |
| Wang 202276 | Germany | Case control | 2012-2016 | Routinely ** | No | 11 | 5034 | 3340 | 0 | 1694 | +/- | Yes | Both | |
| Wiener 199577 | USA | Individual randomization | 8 months | 1x/week | No | 1 | 61 | 0 | 30 | 31 | +/- | Yes | Infection**** | PP |
| Wittekamp 20189 | Multi* | Cluster randomization | 2013 - 2017 | 2x/week | No | 13 | 8665 | 2224 | 2082 | 4359 | +/- | Yes | Infection | ITT |
* Belgium, Spain, Portugal, Italy, Slovenia and UK ** Frequency unknown ***Multi drug resistant, unspecified gram positive or negative **** Studies investigated both infection and colonization, but only the outcome reported in the table was used in the meta-analysis N/A. Not applicable -. Missing data (except for column depicting gram negative or positive outcome where – indicates gram negative).
Table 2.
Characteristics of studies included only in systematic review on antimicrobial resistance after SSD/SOD in ICU patients.
| Study | Country | Study design | Study years | Routinely swab regimen | Systemic antibiotics | Number of ICUs | Number of patients | Outcome gram + or - bacteria | Antimicrobial resistance as primary outcome |
Endpoint colonization or infection | Intention to Treat (ITT) vs. Per Protocol (PP) | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | SOD | SDD | Control | |||||||||||
| Abele-Horn 199720 | Germany | Individual randomization | - | 2x/week | Yes | 1 | 85 | 58 | 0 | 30 | + | Yes | Colonization | PP |
| Benus 201021 | Netherlands | Observational | 2004 - 2006 | no | Yes | 1 | 57 | 19 | 17 | 21 | + | No | Colonization | |
| Bergmans 200122 | Netherlands | Individual randomization | 1994 - 1996 | 2x/week | No | 3 | 226 | 87 | 0 | 139 | +/- | No | Both | PP |
| van der Bij 201623 | Netherlands | Observational | 2008 - 2013 | - | Yes | 42 | - | - | - | - | + | Yes | Both | |
| Buitinck 201925 | Multi* | Observational | 1997 - 2017 |
2x/week Aspirates 3x/week |
Yes | 1 | 12,054 | 0 | 12,054 | 0 | - | Yes | Both | |
| de la Cal 200527 | Spain | Individual randomization | 1997 - 2000 | 2x/week | Yes | 1 | 107 | 0 | 53 | 54 | + | No | Infection | PP |
| Camus 201429 | France | Cluster randomization | 1996 - 1999 | 1x/week | No | 3 | 515 | 259 | 0 | 256 | + | Yes | Both | ITT |
| Camus 201631 | France | Observational | 2008 - 2012 | 1x/week | No | 1 | 6175 | 0 | 5250 | 925 | +/- | Yes | Both | |
| Dautzenberg 201834 | Netherlands | Observational | 2005 - 2014 | 2x/week | Yes | 2 | 2448 | 0 | 2448 | 0 | - | Yes | Both | |
| Godard 199038 | France | Cluster randomization | 1988 | 1x/week | No | 1 | 181 | 0 | 97 | 84 | - | No | Both | PP |
| Halaby 201339 | Netherlands | Before and after | 2001 - 2008 | 2x/week | No | 1 | 134 | 0 | 106 | 28 | - | Yes | Both | |
| Hammond 199541 | South Africa | Before and after | 1988 – 1991 | 2x/week | Yes | 1 | 1528 | 0 | 719 | 809 | +/- | Yes | Infection | |
| Heininger 200642 | Germany | Observational | 2000 - 2004 | 2x/week | No | 34 | 7270 | 0 | 1913 | - | +/- | Yes | Both | |
| Houben 201443 | Netherlands | Observational | 2008 - 2012 | - | Yes | 38 | - | - | - | - | - | Yes | Both | |
| Humphreys 199244 | UK | Individual randomization | 17 months | 3x/week | Yes | 1 | 267 | 0 | 92 | 175 | + | Yes | Colonization | ITT |
| Janssen 202045 | Netherlands | Observational | 2018 - 2019 | 2x/week | Yes | 1 | 428 | 0 | 428 | 0 | - | Yes | Colonization | |
| de Jonge 20188 | Netherlands | Observational | 2010 - 2013 | 4x after ICU discharge | Yes | 3 | 835 | 409 | 426 | 0 | - | Yes | Colonization | |
| Landelle 201848 | Switzerland | Pre, during and after | 2014 - 2016 | No | No | 1 | 1060 | 769 | 0 | 291 | - | No | Both | |
| Lendingham 198849 | Scotland | Before and after | 1985 - 1986 | 3x/week | Yes | 1 | 324 | 0 | 163 | 161 | - | No | Both | |
| Leone 200350 | France | Case control | 6 years | 2x/week | Yes | 1 | 5987 | 0 | 360 | 360 | +/- | Yes | Both | |
| Lloréns-Villar 201951 | Spain | Before and after | 1998 - 2013 | No | Yes | 8 | - | - | 0 | - | +/- | Yes | Both | |
| Massart 202252 | France | Observational | 2020-2021 | 1x/week | No | 15 | 461 | 0 | 89 | 372 | +/- | No | Infection | |
| Massart 202353 | France | Observational | 2017-2021 | 1x/week | No | 3 | 241 | 0 | 69 | 172 | +/- | No | Colonization | |
| Mathieu 202054 | France | Before and after | 2014 - 2018 | No | Yes | 1 | 447 | 0 | 447 | 0 | MDR** | No | Both | |
| Muruzabal -Lecumberri 201555 | Spain | Observational | 2010 - 2011 | 2x/week | Yes | 1 | 24 | 0 | 24 | 0 | + | Yes | Both | |
| Noteboom 201556 | Netherlands | Observational | 2009 - 2013 | 2x/week | Yes | 16 | 8067 | 8067 | 0 | - | Yes | Colonization | ||
| Ochoa-Ardila 201157 | Spain | Observational | 2002 - 2007 | 1x/week | Yes | 1 | 1588 | 0 | 1588 | 0 | +/- | Yes | Both | |
| Oostdijk 201058 | Netherlands | Cluster randomization | 2004 - 2006 | 2x/week | Yes | 13 | - | - | - | - | Yes | Colonization | ITT | |
| Oostdijk 201359 | Netherlands | Cluster randomization | 2004 - 2009 | 2x/week | Yes | 13 | 1246 | 476 | 455 | 315 | - | Yes | Colonization | ITT |
| Oostdijk 201460 | Netherlands | Cluster randomization | 2009 - 2013 | 2x/week | Yes | 16 | 11,997 | 5957 | 6040 | 0 | +/- | Yes | Colonization | PP |
| Plantinga 202062 | Netherlands | Cluster randomization | 2013 - 2017 | 2x/week | No | 13 | 8665 | - | - | - | - | Yes | Colonization | ITT |
| Rocha 199266 | Spain | Individual randomization | 14 months | 2x/week | Yes | 1 | 101 | 0 | 47 | 54 | +/- | Yes | Both | PP |
| Rodríguez-Gascón 202467 | Spain | Observational | 2014-2018 | 2x/week | Yes | 2 | - | 0 | - | - | +/- | Yes | Both | |
| de Smet 20094 | Netherlands | Cluster randomization | 2004 - 2006 | 2x/week | Yes | 13 | 5939 | 1904 | 2045 | 1990 | - | No | Colonization | ITT |
| Tetteroo 199371 | Netherlands | Observational | 18 months | 1x/week | Yes | 1 | 97 | 0 | 97 | 0 | + | No | Colonization | |
| Ulrich 198972 | Netherlands | Individual randomization | 1986 - 1987 | 2x/week | Yes | 1 | 100 | 0 | 48 | 52 | +/- | No | Colonization | PP |
| Wittekamp 201578 | Netherlands | Cluster randomization | 2004 - 2013 | 1x/month | Yes | 5 | 1865 | - | - | +/- | Yes | Colonization | ITT | |
| Young 202479 | Australia | Cluster randomization | 2017 - 2021 | 1x/month | Yes | 19 | 2061 | 0 | 968 | 1093 | +/- | No | Both | ITT |
* Belgium, Spain, Portugal, Italy, Slovenia and UK **Multi drug resistant, unspecified gram positive or negative N/A. Not applicable -. Missing data (except for column depicting gram negative or positive outcome where – indicates gram negative).
Six (22.2%) studies presented usable data on antimicrobial resistance as resistance to aminoglycosides, 5 (18.5%) studies as resistance to polymyxin B and E, 3 (11.1%) studies as resistance to fluoroquinolones, and 4 (14.8%) as resistance to third-generation cephalosporins. Antimicrobial resistance was defined as infection or colonization with MRSA in 16 (59.3%) studies, VRE in 5 (18.5%) studies, and multi-resistant bacteria in 6 (22.2%) studies. In total, 11 (40.7%) studies presented usable data for ≥ 1 of these definitions of antimicrobial resistance. The occurrence of antimicrobial resistance was the primary outcome in 13 (48.1%) studies.
One author was contacted for additional information; however, no response was received. In case of Hammond et al. (1992)40, de Jonge et al. (2003)3, Quinio et al. (1996)63, and Verwaest et al. (1997)74, unreported information derived from available data. Absolute numbers of outcomes were calculated using reported percentages of patients with acquired antimicrobial resistant pathogens.
Risk of bias assessment
The risk of bias assessment is illustrated in Fig. S2. All studies were deemed of sufficient quality to be included in the analyses.
The funnel plot was asymmetrical (Fig. 2). When conducting the trim-and-fill analysis, two missing studies were added, one in the lower left section and one in the upper left section (Fig. S3). This indicated that two studies which found lower antimicrobial resistance after SDD or SOD were missing, which means a possible reporting bias was present. The true funnel plot was not identified as outstanding in the visual inference plot (Fig. S4). This indicated that a possible bias did not significantly influence the outcome of the forest plot. In case of reporting bias, the true effect might have been less protective than what was found in the meta-analyses (Fig. 2).
Fig. 2.

Funnelplot of identified studies included in the meta-analysis on antibiotic resistance after SDD or SOD in ICU patients. X-axis Risk ratio Y-axis Standard Error Dark grey area is a p-value between 0.1 and 0.05 Medium grey area is a p-value between 0.05 and 0.01 Light grey area is a p-value less than 0.01.
Antimicrobial resistance during ICU admission
All 27 studies which were described above were included in the meta-analysis on the occurrence of resistance during ICU stay. Of these, 25 studies were included in the analysis on SDD and four studies were included in the analysis on SOD. A significant association between SDD and the development of antimicrobial resistance during ICU admission was found; OR 0.72 (95%-CI 0.53;0.98, I2 75% n = 25, p < 0.01). The four studies included in the analysis on SOD yielded no significant association between SOD and developing antimicrobial resistance during ICU admission; OR 0.89 (95%-CI 0.48;1.64, I2 67%, n = 4, p = 0.03) (Fig. 3).
Fig. 3.

Occurrence of colonization of- or infection with resistant bacteria during ICU stay in patients receiving SDD, or SOD versus placebo or control group. Studies are divided into SDD or SOD as decontamination regimen. An odds ratio <1 suggests a protective effect and an odds ratio >1 suggests a risk-inducing effect.
Antimicrobial resistance after ICU discharge
There were four studies that investigated antimicrobial resistance both during ICU stay and after discharge in individual patients after receiving SDD or SOD3,8,40,44. The study performed by Hammond et al. (1992) was conducted in South Africa and comprised 239 patients, of whom 114 (48%) patients received SDD40. Hammond et al. (1992) found higher antimicrobial resistance rates until 4 weeks after first admission; 13% in the intervention group, versus 5% in the control group (p < 0.05)40. The study of Humphreys et al. (1992) was conducted in the UK and included 267 patients, of which 92 (34%) received SDD, but did not include a control group44. Humphreys et al. (1992) found no difference in minimal inhibitory concentrations (MIC) of bacteria to antibiotics up to four days after ICU discharge among patients who had received SDD44. De Jonge et al. (2003) investigated 773 patients in a Dutch ICU, of which 378 (49%) received SDD3. De Jonge et al. (2003) found lower antimicrobial resistance until 10 days after discharge; 16% in the intervention group, versus 26% in the control group (p = 0.001)3. De Jonge et al. (2018) investigated 835 patients from a Dutch ICU, of whom 409 (49%) patients received SOD and 426 (51%) received SDD8. De Jonge et al. (2018) compared SDD group to SOD group. The study found slightly more rectal carriage with resistant gram-negative bacteria in patients who received SOD (13%), versus patients who received SDD (11%) until 10 days after ICU discharge, however, this difference was statistically significant (p = 0.7)8.
Resistance to specific antimicrobial agents
There were ten studies that reported analyses on the occurrence of resistance to specific antimicrobial agents3,10,28,36,47,61,69,73,76,77. Five studies investigating the occurrence of resistance to aminoglycosides after SDD or SOD found no significant difference between the groups28,36,69,73,77. The study of de Jonge et al. (2003) found occurrence of tobramycin resistance in gram-negative bacteria in 5% in the SDD group, and 12% in the control group, with a relative risk (RR) of 0.4 (95%-CI; 0.3;0.7)3.
Four studies found no significant difference in the occurrence of resistance to polymyxin B and E after administration of SDD or SOD3,28,36,73. Whereas the study of de Smet et al. (2011) found significantly lower resistance to polymyxin B and E after SDD, 7% versus 15% respectively (crude OR; 0.41 (95%-CI; 0.29;0.57))69.
Two studies did not find significant differences in the occurrence of resistance to fluoroquinolones after SDD or SOD47,76. De Jonge et al. (2003) found significantly lower resistance to ciprofloxacin in gram-negative bacteria in the SDD group (2%) versus the control group (8%) (RR; 0.3 (95%-CI 0.1;0.6))3.
Lastly, de Smet et al. (2011) found lower resistance to third-generation cephalosporins in the SDD group (2%) versus the control group (6%) (crude OR; 0.36 (95%-CI; 0.22;0·0.1))69. Wang et al. (2022) found a lower incidence density / 1000 days with versus without SOD of colonization with ESBL-producing K. pneumonia; 0.22 versus 0.56 (p < 0.01)76. The two other studies investigating this specific occurrence of antimicrobial resistance did not find significant differences between SDD or SOD and the control group10,61.
Occurrence of VRE, MRSA and multi-resistant pathogens
Fourteen studies investigated the acquisition of MRSA in patients who received SDD. Pooling of these studies yielded no significant result; OR 1.02 (95%-CI 0.76;1.38, I2 42%, p = 0.05) (Fig. 4). Three studies investigated the acquisition of MRSA after SOD, with no significant differences between intervention and control group9,28,76.
Fig. 4.

Additional analysis on the occurrence of colonization of-, or infection of MRSA. An odds ratio <1 suggests a protective effect and an odds ratio > 1 suggests a risk-inducing effect.
Four studies investigated the occurrence of VRE after SDD or SOD, with no significant differences between SDD or SOD and control group3,9,32,33. However, Wang et al. (2022) found a higher incidence density / 1000 days with versus without SOD of colonization with VRE; 0.72 versus 0.31 (p < 0.01)76.
Lastly, six studies investigated the occurrence of multi-resistant bacteria other than MRSA or VRE, of which two studies described less multi-resistant bacteria in the SDD group versus control group9,30,61,64,65,75. These studies included Camus et al. (2014); (1% vs. 2%, respectively. Adjusted OR; 0.33 (95%-CI 0.15–0.74; p = 0.008))30, and Reizine et al. (2023); (1% vs. 5%, respectively, p < 0.001)64. Definitions of multi-resistant bacteria used by the studies are specified in Table S5.
Sensitivity analyses
All 27 studies that were included in the meta-analysis were subdivided in the sensitivity analyses on different study characteristics. In total, 15 (55%) studies included IV antibiotics in their study regimen, and 12 (45%) studies did not. Studies using IV antibiotics in their regimen yielded a significant association with lower antimicrobial resistance in patients receiving SDD, while no significant association was found in studies not using IV antibiotics; respectively OR 0.70 (95%-CI 0.52;0.96, I2 76%, p < 0.0001) and OR 0.86 (95%-CI 0.47;1.57, I2 75%, p < 0.01) (Figure S5).
There were 10 (37%) studies with individual randomization, i.e. studies with patients who received SDD or SOD and control patients in the same ICU. There were 17 (63%) studies with cluster randomization or an observational design, i.e. studies where intervention patients were in separate ICUs than control patients. When observational and cluster-randomized design studies were pooled together, there was a significant protective effect of SDD and SOD to the occurrence of antimicrobial resistance, OR 0.61 (95%-CI 0.49;0.75, I2 67%, p < 0.01). No such effect was found in individually randomized studies, OR 1.31 (95%-CI 0.66;2.61, I2 63%, p < 0.01) (Fig. S6).
Of all 27 meta-analyzed studies, 14 (52%) had a follow-up < 14 days, which showed lower antimicrobial resistance in the intervention group; OR 0.57 (95%-CI 0.42;0.78, I2 61%, p < 0.01). The other studies with a follow-up ≥ 14 days (12 (44%) studies) found no such association; OR 1.11 (95%-CI 0.66;1.87, I2 82%, p < 0.01) (Fig. S7). The study of the SuDDICU Investigators et al. (2022) did not specify median days of follow-up of microbiological cultures and was therefore not included in this sensitivity analysis70.
Discussion
In total, four studies investigated the occurrence of antimicrobial resistance after SDD or SOD and after ICU discharge. One study found lower, and one study found higher antimicrobial resistance after SDD3,40. One study found no difference in MICs for bacteria after ICU discharge in patients who had received SDD and one study found more rectal carriage of resistant gram-negative bacteria in patients who received SOD versus patients who received SDD8,44.
Moreover, 27 studies investigated the occurrence of antimicrobial resistance during ICU stay. There were significantly fewer patients during ICU stay with antimicrobial resistance after receiving SDD, based on studies with a median length of ICU stay of < 14 days and administering IV antibiotics as part of the SDD or SOD regimen. However, there was significant heterogeneity, which is reflected in the wide variation in outcome incidences across studies. This heterogeneity should be considered when interpreting the meta-analysis results, as it limits the generalizability of the results and indicates extensive inter-study variability. There were only four studies investigating SOD, and they yielded no significant association between SOD and developing antimicrobial resistance during ICU stay.
Antimicrobial resistance after ICU discharge
The few studies investigating the occurrence of antimicrobial resistance after ICU discharge yielded conflicting results. The two studies that included a control group showed different results. The study of De Jonge et al. (2003) was conducted in the Netherlands and did not find an increase in MRSA in both groups, whereas Hammond et al. (1992) in South Africa found more MRSA in the SDD or SOD group than in the control group3,44. The resistance rates in South Africa are higher than in the Netherlands, which makes the occurrence of MRSA more common in South Africa than in the Netherlands80,81. As MRSA is practically absent in the Netherlands it is a priori unlikely that MRSA acquisition occurs under any antibiotic regimen. Moreover, the studies also included data of antimicrobial resistance during ICU stay, therefore these outcomes do not reflect resistance rates occurring exclusively after ICU discharge. Only the study of Hammond et al. had a follow-up after ICU discharge > 2 weeks and showed an increasing colonization rate of 10% at week 2 and 13% at week 440.
Clinical relevance
To decide whether to apply preventative antibiotics, advantages and disadvantages must be weighed against each other. In case of SDD and SOD, mortality rates, infection rates, costs and short-term occurrence of resistance have all been extensively studied and have shown positive results7,82–84. Moreover, overall total antibiotic consumption when using SDD or SOD versus control was comparable to lower than in control in 20 of the 21 studies investigating this3,4,10,22,30,31,36,41,44,46–48,53,63,67,68,72,77–79. Only one study found a higher intravenous antibiotic consumption rate in patients receiving SOD versus control76.
However, the occurrence of antibiotic resistance on the long term should also be a factor in the consideration on whether to apply preventative antibiotics. Antimicrobial resistance on the long term, e.g., after ICU discharge, is important as it could lead to increased morbidity by complicating treatment of infections6. Currently, there is little knowledge on the long-term effect of preventative antibiotics in general on antimicrobial resistance. This could possibly be explained by the fact that long -term investigation is costly and prone to loss of follow-up. It should be noted that this is specifically about the long-term effect at the level of individual patients rather than population-level long-term effect. For example, an ecological study found that resistance rates in an ICU did not increase significantly during SDD administration over a period of 21 years, however this study did not analyze the long-term in patients i.e. after ICU discharge25. In the short term, it is known that preventative antibiotics influence the composition of the gut-microbiome85. Interestingly, the gut-microbiome has the capacity to recover several days after exposure to antibiotics86,87. Whether this recovery is accompanied by antimicrobial resistance remains uncertain88. However, both Hammond et al. and de Jonge et al. showed that it is possible to obtain antibiotic resistance after ICU discharge8,40.
To investigate this possible long-term effect of preventative antibiotics, one must discriminate clearly between the effect of preventative and therapeutic antibiotics. The specific patient population in which this is possible consists of trauma patients or elective complex surgery patients who receive SDD or SOD. Trauma and elective complex surgery patients are mainly a healthy population without excessive hospitalization and treatments before being admitted to the ICU37. Hence, the SDD or SOD administration is usually the first exposure to antibiotics in a previously unaffected microbiome37. Therefore, it is recommended to investigate the long-term effect of SDD or SOD on the occurrence of antimicrobial resistance specifically in trauma and elective complex surgery patients. As SDD and SOD have been extensively studied to be beneficial for outcomes on mortality and infection rates in ICU patients, it would be ethically preferable to investigate long-term occurrence of antimicrobial resistance observationally rather than initiating a randomized controlled trial.
Such a study would preferably be conducted prospectively with rectal baseline swabs at admission, followed by routine swabs during ICU stay and lastly follow-up at 6 weeks and 1 year after ICU discharge. Secondly, the outcomes of these swabs should be combined with outcomes of cultures from clinically relevant infections to gain insight into the possible risks associated with the acquisition of antimicrobial-resistant bacteria. Such prospective long-term follow-up study would provide insights regarding rectal colonization, antimicrobial resistance occurrence and its relation to the occurrence of infections with different pathogens. This information together could contribute to a patient-specific consideration on whether to administer preventative antimicrobial agents.
Antimicrobial resistance during ICU stay
The significantly lower resistance during ICU stay in studies using SDD, especially in studies also administrating IV antibiotics as part of the SDD regimen, can be explained by the eradication of bacteria from the digestive tract or by the potentially reduction in the use of other antibiotics79. It is unlikely that the decrease in antimicrobial resistance is due to reduced external acquisition. However, most of the included studies investigated occurrence of multi-resistant bacteria and MRSA (80% of studies), and it is important to acknowledge the inter-country differences in prevalence of these bacteria80,81. In countries with a low prevalence of multi-resistant bacteria or MRSA, resistance to antimicrobial agents used in the SDD regimen may be a more clinically relevant outcome than MRSA occurrence, given the higher anticipated risk of resistance developing to these agents. Moreover, it should be noted that SDD and SOD are not intended to eradicate MRSA or bacteria intrinsically resistant to SDD or SOD components, and therefore the emergence of resistance due to SDD and SOD is unlikely. Rather, the increased occurrence of MRSA is likely due to selection under antibiotic pressure and therefore a reflection of the underlying baseline prevalence in that setting.
Moreover, the heterogeneity of 75% (I2) was considerable and should be taken into account in interpreting the results. This heterogeneity was not only reflected in the I² value itself, but also in the wide variation in endpoint incidences across studies (ranging from 1% to 49%). Such variation is explained by between-study differences in antibiotic use, ICU settings and study design. The sensitivity analyses further demonstrated the impact of these study characteristics on the pooled estimates.
Firstly, studies with IV antibiotics in their SDD or SOD regimen found significantly lower resistance during ICU stay in patients who received SDD or SOD as opposed to studies not using IV antibiotics as part of the SDD or SOD regimen. This may be caused by a more systemic eradication of bacteria in patients receiving IV antibiotics in comparison to no IV antibiotics.
Secondly, studies conducted in countries with low antimicrobial resistance rates showed significant reduction in antimicrobial resistance during ICU stay. This is in line with previous studies4,89. This is possibly because in countries with lower resistance rates, antimicrobial resistant bacteria are less likely to be selected through SDD or SOD.
Thirdly, studies with a cluster randomized and observational design pooled together yielded a significant protective effect versus no protective effect in studies with an individually randomized design. This can be explained by risk of cross-contamination in an individually randomized design, where intervention and control patients may be admitted at the same ICU. This could cause cross-contamination of pathogens from intervention group to the control group.
Lastly, studies in which the length of stay on the ICU was a mean or median of < 14 days yielded significantly lower antimicrobial resistance as opposed to studies in which the length of stay on the ICU was a mean or median of > 14 days. It is tempting to speculate that if antimicrobial resistance occurs, it would do so after two weeks. This can be explained by time needed to develop resistance as well as a prolonged period of possible external acquisition of bacteria such as MRSA for example due to prolonged ICU stay, possible interventions and foreign bodies.
Strengths and limitations
Strengths of this study are the addition of 33 new studies to Daneman et al.7, the focus on antimicrobial resistance after ICU discharge, the clear distinction between effect of SDD and SOD, and the transparency of our research process. Limitations are substantial heterogeneity in study countries, the variations in SDD and SOD regimens used, local antimicrobial resistance rates, and standard hygiene measures. Therefore, the generalizability of the results is limited. The funnel plot was asymmetrical as it seemed few studies that reported lower antimicrobial resistance after SDD or SOD were missing, indicating a possible minor reporting bias. In case of minimal reporting bias, the actual protective effect of SDD on the occurrence of antimicrobial resistance might be lower than the result from this meta-analysis.
Beyond this, it remains uncertain to what extent the observed effects reflect preventive benefits versus population-level influences. Concerns include that the apparent effects are mainly observed in studies with high event rates90. In addition, as mentioned above, reported incidence rates vary widely (1%–49%). This suggests that the effect on antimicrobial resistance may partly be driven by underlying population-level dynamics rather than a direct effect of the interventions alone90. These potential population-level effects remain insufficiently studied and warrant further investigation.
Moreover, mortality could be considered a competing event for the occurrence of antimicrobial resistance. However, conducting a sensitivity analysis on mortality as competing event would require detailed patient-level data. This sensitivity analysis was not performed as these data were not available. Lastly, correction for multiple testing was not done, yielding an increased risk of false-positive outcomes. However, this methodology was deliberately chosen, given the explorative nature of this study.
Conclusion
During ICU stay, SDD was not significantly associated with increased antimicrobial resistance to specific antibiotics, more specifically when an IV component is added, which is in line with previous reviews. This was not observed for SOD. Moreover, this current review shows there were limited data available on the long-term effect of SDD and SOD on antimicrobial resistance. Knowledge of the long-term effect of SDD and SOD on antimicrobial resistance, the potential population effect, and the effect on the gut microbiome is a fundamental contributor in the consideration of whether to apply SDD or SOD.
Therefore, it is recommended to enlarge the data on the occurrence of antimicrobial resistance after ICU discharge by conducting an observational prospective long-term follow-up study in patients receiving SDD or SOD without prior exposure to antibiotics, such as trauma and elective surgery patients.
Supplementary Information
Below is the link to the electronic supplementary material.
Abbreviations
- ICU
Intensive Care Unit
- IV
Intravenous
- MRSA
Methicillin-Resistant S. aureus
- PRISMA
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
- SDD
Selective Digestive Decontamination
- SOD
Selective Oropharyngeal Decontamination
- VRE
Vancomycin Resistant Enterococcus spp.
Author contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by F.J.C. van Eerten, J.D.J. Plate and V.A. Schweitzer. The first draft of the manuscript was written by F.J.C. van Eerten and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
There are no financial, or non-financial conflicts of interest to declare for all authors.
Data availability
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
