The Effect of Selective Decontamination on Antimicrobial Resistance in Intensive Care Patients: A Systematic Review and Meta-analysis

The Effect of Selective Decontamination on Antimicrobial Resistance in Intensive Care Patients: A Systematic Review and Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Effect of Selective Decontamination on Antimicrobial Resistance in Intensive Care Patients: A Systematic Review and Meta-analysis Frederique van Eerten, Joost Plate, Rolf Groenwold, Valentijn Schweitzer, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5368003/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background 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 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 received SDD, or SOD compared to control. Methods A previous systematic review, which included studies on antimicrobial resistance after SDD or SOD from before 01-02-2012, was updated. All studies analyzing antimicrobial resistance during and after ICU stay, 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. Results 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, I 2 75%), less resistance to fluoroquinolones in patients receiving SDD OR 0.29 (95%-CI 0.12;0.68, I 2 30%) and less multi-resistant bacteria; OR 0.53 (95%-CI 0.33; 0.87, I 2 0%), compared to control treatment. Four studies investigated antimicrobial resistance after ICU discharge of which two were eligible for pooling, which yielded no significant effect; OR 1.20 (95%-CI 0.23;6.36, I 2 90%). Conclusion During ICU stay, SDD is associated with reduced antimicrobial resistance to specific antibiotics, in line with a previous review. More specifically combined with intravenous (IV) component, in settings with low prevalence of resistance and in a cluster design. This current review emphasizes the limited amount of data on the long-term effect of antimicrobial decontamination strategies to antimicrobial resistance. Understanding this long-term effect is essential when deciding whether to implement preventative antibiotics in specific subgroups. This could be done by means of a prospective long-term follow-up study. Biological sciences/Microbiology/Antimicrobials Biological sciences/Microbiology/Bacteria Health sciences/Health care intensive care medicine infections antimicrobial resistance selective digestive decontamination. Figures Figure 1 Figure 2 Figure 3 Figure 4 Background 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 prevented [ 1 ]. Selective Digestive Decontamination (SDD) and Selective Oropharyngeal Decontamination (SOD) are applied to prevent infections amongst ICU patients. These two approaches have extensively been studied and demonstrate a reduction in mortality rate, infection rate, and length of mechanical ventilation [ 2 ]. SDD consists of the application of nonabsorbable antimicrobial agents in the oropharyngeal and gastrointestinal tract. Systemic antimicrobial prophylaxis is given in addition to SDD during the first 4 days of ICU admission [ 2 – 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 patients [ 4 ]. The choice of antibiotics is targeted against potential pathogens and should not be targeted against the anaerobic part of the flora [ 4 ]. Despite the effect of SDD and SOD on ICU mortality, there is a persistent concern of the possible risk of antimicrobial resistance [ 5 ]. Bacterial antimicrobial resistance is a major cause of mortality [ 6 ]. 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 2013 [ 7 – 10 ]. Methods Protocol and registration The study protocol was registered in the PROSPERO International prospective register of systematic reviews under the ID CRD42019128143 [11]. Because of substantial heterogeneity in study designs and outcome measures, several sensitivity analyses and a mixed-effects meta regression model on study characteristics have been added to the initial protocol to investigate the influence of this heterogeneity. Moreover, the analyses were separated for SDD and SOD. The reporting of this article followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [12]. There was no financial support or competing interests of the authors of this study. Information sources A comprehensive literature search in Medline, Embase, and Cochrane was performed. A previous performed systematic review performed by Daneman et al., which included all articles on antimicrobial resistance after SDD or SOD from before 01-02-2012, was taken as basis [7,13]. A search string was made, which was tested on the 2010-2012 period. A 100% agreement was found with the studies found by Daneman et al [7] for this period. All studies identified by Daneman et al. were reviewed for meeting 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 done. No additional studies were found. The last search was performed 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 systemic antimicrobial agents were used. The primary outcome was occurrence of antimicrobial resistance after ICU discharge, secondary outcome was occurrence of antimicrobial resistance during ICU stay. Both routine samples and samples used for diagnosing infectious complication, which were tested on antimicrobial resistance, were included. Both studies investigating antimicrobial resistance after ICU discharge and studies investigating antimicrobial resistance during ICU stay were included. There were no restrictions regarding study design, country, publication status, date of publication, or study quality. Studies only investigating non-antimicrobial interventions (i.e. only washing with chlorhexidine) were excluded. Studies only investigating 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 done by two reviewers (F.E. and J.P.). A third and fourth reviewer (F.H. and V.S) were asked 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 or not. A structured data extraction form was used. Authors of the reviewed articles were contacted for additional information if necessary. If data were unclear or not apparent, it was deemed missing. If possible, information that was not reported was calculated using available data, such as calculation of absolute numbers using 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 checklist [14]. A third and fourth reviewer were asked when consensus could not be reached (F.H. and V.S.). Consensus was reached on all studies. The MINORS checklist allowed to assess the risk of bias of interventional studies, both observational studies and randomized trials. Data synthesis of studies assessing the antimicrobial resistance during and after ICU discharge The analyses on development of resistance during ICU admission and after ICU discharge were done 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 the results of studies with a control group that did not receive SDD or SOD and studies presenting data as number of patients with new antimicrobial resistance colonization or infection with an antimicrobial resistant pathogen were pooled (details below). Studies presenting outcome using isolates or pathogens numbers instead of patients were excluded from the meta-analysis, as patients could be colonized with multiple pathogens. Moreover, outcomes were presented as percentage of resistant pathogens in relation to total positive isolates were not considered. Analyses were performed using the “rmeta”, “metaviz”, “meta”, and “metafor” packages in R software for statistical computing (V.3.3.2.) [15]. To evaluate the risk of publication bias, the symmetry of the funnel plot was assessed by three researchers (F.E., J.P. and V.A.) [16,17]. This was done by randomly producing multiple funnel plots and blindly assessing whether the true funnel plot could be distinguished from the other funnel plots. [16,17]. Pooled odds ratios (OR) and 95% confidence intervals on the occurrence of antimicrobial resistance after SDD or SOD were calculated using the Mantel-Haenszel method with random effects. Random effects were used because the treatment effect varied across studies, e.g., due to different study populations [18]. The heterogeneity of the effect estimates regarding the occurrence of antimicrobial resistance after SDD or SOD across studies was quantified by means of the I 2 statistic. Sensitivity analyses Two analyses for different outcome measures were performed separately for studies investigating SDD or SOD: A. resistance to specific antibiotic groups (aminoglycosides, polymyxin E, and B, fluoroquinolones, and third generation cephalosporines) and B. per multi-resistant bacteria type (Methicillin-Resistant S aureus (MRSA), Vancomycin Resistant Enterococcus spp. ( VRE ), and multi-resistant bacteria). Definitions of multi-resistant bacteria used by the studies included in this sensitivity analysis are specified in Appendix table 3. Resistance to third generation cephalosporines also included extended-spectrum beta-lactamase (ESBL) producing bacteria. To investigate the effect of methodology, seven sensitivity analyses were performed, taking results of studies using SDD or SOD together: ( A ) IV antibiotics as part of SDD or SOD versus no IV antibiotics as part of SDD or SOD; ( B ) studies conducted in countries with low vs. intermediate or high prevalence of antimicrobial resistance. S. aureus isolates resistant to methicillin prevalence was taken as a reflection of antimicrobial resistance rates in a country. Studies were divided into studies conducted in countries with <3% vs. ≥3% S. aureus isolates resistant to methicillin [19]; ( C ) studies with versus without routine surveillance swabs in both intervention and control study groups; ( D ) randomized (botch cluster randomized and individually randomized) versus observational design; ( E ) To test the effect of herd-protection a sensitivity analyses on studies with an individually randomized versus cluster randomized and observational design was done; ( F ) studies before 2012 versus after 2012; and ( G ) follow-up ≥14 days versus a shorter follow-up. When studies did not report median days of follow-up, median length of ICU stay was used for this analysis. To examine the simultaneous effect of multiple study characteristics on the outcome, a mixed-effects meta regression model with variables was fitted, including type of antibiotic agents administered (per antibiotic), intravenous (IV) or non-IV antibiotic administration, whether studies performed routine surveillance swabs in both intervention and control study groups (yes/no), year of study performance, randomization of study participants (yes/no), median ICU/follow-up days. Outcome measurement with multi-resistant bacteria (yes/no) was not included in the meta regression due to collinearity. Results The search In total, 65 studies were identified [3,4,8–10,20–79], of which 33 studies were from >2012 and were included in addition to the studies identified by Daneman et al [7]. The meta-analyses included 27 studies (Figure 1), of which six were included in addition to Daneman et al [7]. Twenty-five studies were included in the meta-analysis on SDD and four studies in the meta-analysis on SOD. Thirty-eight studies were excluded from the meta-analyses, because they had no control group or had overlapping data with previous studies (Appendix Table 1A). Specific details on reason of exclusion of studies can be found in Appendix Table 1B. Characteristics of included studies Characteristics of each study are reported in Table 1A and B. Of all 27 studies included in the meta-analysis; most of the studies investigated ICUs in France (22.2%), Spain (18.5%), and in Germany, Netherlands and USA (all 11.1%). The designs of the studies were individually randomized (37.0%), before-after comparison (25.9%), observational (18.5%) and cluster randomized (18.5%). Most of the data studied were from before 2012 (77.8%), and 6 (22.2%) studies investigated data collected after 2012. Aminoglycosides (96.3% of the studies) and Polymyxin E and B (81.5% of the studies) were the most frequently used topical antibiotics. Third generation cephalosporines were most frequently used systemic antibiotics (44.4% of the studies). Eleven (40.7%) studies did not use additional systemic antibiotics in their decontamination regimen (Appendix Table 2A-B). 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 had a follow-up of ≥14 days. Six (22.2%) studies presented usable data on antimicrobial resistance as resistance to aminoglycosides, 5 (18.5%) studies as resistance to polymyxin E and B, 3 (11.1%) studies as resistance to fluoroquinolones, and 4 (14.8%) as resistance to third generation cephalosporines. 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. Moreover, 11 (40.7%) studies presented usable data ≥1 of the abovementioned definitions of antimicrobial resistance as outcome. One author was contacted for additional information. however, no response was received. In case of Hammond 1992 [40], de Jonge 2003 [3], Quinio 1996 [63], and Verwaest 1997 [74], information that was not reported was calculated using available data. Risk of bias assessment The risk of bias assessment is illustrated in Appendix Figure 2. All studies were deemed of sufficient quality to be included in the analyses. The funnel plot was asymmetrical, with missing studies in the right lower section of the plot. This indicated that studies which found more antimicrobial resistance after SDD or SOD and which had larger confidence intervals were missing, which means a possible reporting bias was present. (Appendix Figure 8) The true funnel plot was not identified as outstanding in the visual inference plot. 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. (Appendix Figure 9) 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 SOD [3,8,40,44]. The follow-up after ICU discharge ranged from four days after ICU discharge to four weeks after initial ICU admission. No longer follow-up was available. There were two studies eligible for meta-analysis, both using SDD as their intervention [3,40]. Hammond et al. (1992) found a causative outcome until 4 weeks after first admission; OR 3.01 (95%-CI 1.12;8.04) [40]. De Jonge et al. (2003), found a protective outcome until 10 days after discharge; OR 0.55 (95%-CI 0.38;0.78) [3]. Meta-analysis of these two studies resulted in; OR 1.20 (95%-CI 0.23;6.36, I 2 90%) (Figure 2B). The study of Humphreys et al. (1992) found no difference in minimal inhibitory concentrations (MIC) of bacteria to antibiotics up to four days after ICU discharge in patients who had received SDD [44]. De Jonge et al. (2018) found more rectal carriage with resistant gram-negative bacteria in patients who received SOD versus patients who received SDD until 10 days after ICU discharge [8]. Antimicrobial resistance during ICU admission A significant association between SDD and developing antimicrobial resistance during ICU admission was found; OR 0.73 (95%-CI 0.54;0.98, I 2 75% n = 25), while no significant association between SOD and developing antimicrobial resistance during ICU admission was found; OR 0.89 (95%-CI 0.48;1.64, I 2 67%, n =4) (Figure 2A-B). Sensitivity analyses The additional analyses on the outcome groups onantimicrobial resistance during ICU admission are illustrated in Figure 3A-D. SDD was significantly associated with less resistance to fluoroquinolones; OR 0.29 (95%-CI 0.12;0.68, I 2 30%) and developing multi-resistant bacteria; OR 0.53 (95%-CI 0.33;0.87, I 2 0%) (Figures 3C and 4C respectively). SOD was not significantly associated with developing antimicrobial resistance to one of the antibiotic groups, MRSA , VRE or multi-resistant bacteria (Figure 3A-D and 4A-C). Studies using IV antibiotics in their regimen yielded a significant association with less antimicrobial resistance in patients receiving SDD or SOD, while no significant association was found in studies not using IV antibiotics; respectively OR 0.71 (95%-CI 0.52;0.96, I 2 76%) and OR 0.86 (95%-CI 0.47;1.57, I 2 75%) (Appendix Figure 3A-B). There was a significant association with less antimicrobial resistance found in studies conducted in countries with low antimicrobial resistance prevalence. A similar trend was found in studies conducted in countries with intermediate to high prevalence but this was not statistical significant; OR 0.62 (95%-CI 0.51;0.75, I 2 54%) and OR 0.77 (95%-CI 0.55;1.09, I 2 77%) (Appendix Figure 4A-B) Studies who performed routine surveillance swabs in both intervention and control study groups found no significant association between SDD and SOD and developing antimicrobial resistance, while studies who did not perform routine swabs, but only measured antibiotic resistance in samples used for purpose of diagnosing infectious complications did find a significant association; respectively OR 0.86 (95%-CI 0.60;1.25, I 2 76%) and OR 0.65 (95%-CI 0.45;0.92, I 2 0%) (Appendix Figure 5A-B). The studies not performing routine swabs investigated swabs which were taken because of clinical suspicion of infection. SDD or SOD were significantly associated with less antimicrobial resistance in studies with an observational design; OR 0.57 (95%-CI 0.43;0.76, I 2 68%). No association was found between SDD or SOD and antimicrobial resistance in studies with a randomized design, OR 1.04 (95%-CI 0.64;1.68, I 2 80%) (Appendix Figure 6A-B). 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, I 2 67%). No such effect was found in individually randomized studies, OR 1.31 (95%-CI 0.66;2.61, I 2 63%) (Appendix Figure 7A-B). No significant association between SDD and SOD and antimicrobial resistance was found in studies investigating data 2012; OR 0.52 (95%-CI 0.40;0.69, I 2 57%) (Appendix Figure 8A-B) as well as in studies with a follow-up <14 days; OR 0.57 (95%-CI 0.42;0.78, I 2 61%). Studies with a follow-up ≥14 days found no such association; OR 1.11 (95%-CI 0.66;1.87, I 2 82%) (Appendix Figure 9A-B). In addition, meta-regression did not yield a significant effect of the study characteristics on the occurrence of antimicrobial resistance (Table 2). Discussion In total, 4 studies investigated the occurrence of antimicrobial resistance after SDD or SOD and after ICU discharge. One study found less, and one study found more antimicrobial resistance after SDD [ 3 , 40 ]. One study found no difference in MICs in bacteria after ICU discharge in patients who had received SDD and one study found more rectal carriage with resistant gram-negative bacteria in patients who received SOD versus patients who received SDD [ 8 , 44 ]. There were significantly less patients during ICU stay with antimicrobial resistance after receiving SDD, based on observational studies from > 2012 with a median length of ICU stay of < 14 days, administrating IV antibiotics as part of the SDD or SOD regimen and not performing routine follow-up swabs. Moreover, during ICU stay there was significantly less resistance to fluoroquinolones and there were significantly less multi-resistant bacteria in patients receiving SDD. However, the definition of multi-resistant bacteria varied between studies which makes the interpretation of this finding difficult. There were only five studies investigating SOD, which 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. When comparing the two studies included in the meta-analysis, de Jonge et al. (2003) was performed 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 group [ 3 , 44 ]. The resistant rates in South-Africa are higher than in the Netherlands, which makes the occurrence of MRSA more common in South-Africa than in the Netherlands [ 80 , 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 are not solely resistance rates occurring after ICU discharge. Only 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 4 [ 40 ]. 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 showed positive results [ 7 , 82 – 84 ]. Moreover, overall total antibiotic consumption when using SDD or SOD versus control was comparable or even lower in 20 of the 21 studies investigating this [ 3 , 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 control [ 76 ]. 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 infections [ 6 ]. Currently, there is little knowledge on the long-term effect of preventative antibiotics in general on antimicrobial resistance. This could possibly be explained because long-term investigation is costly and prone to loss of follow-up. It should be noted that this is specifically about long-term effect in specific patients rather than overall 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 discharge [ 25 ]. On the short term, it is known that preventative antibiotics influence the composition of the gut-microbiome [ 85 ]. Interestingly, the gut-microbiome possesses recovery capacity of the microbiota several days after exposure to antibiotics [ 86 , 87 ]. Whether this recovery is accompanied by antimicrobial resistance is not yet excluded [ 88 ]. However, both Hammond et al. and de Jonge et al. showed that it is possible to obtain antibiotic resistance after ICU discharge [ 8 , 40 ]. To investigate this possible long-term effect of preventative antibiotics, one must discriminate clearly between the effect of preventative and therapeutic administered 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 ICU [ 37 ]. Hence, the SDD or SOD administration is usually the first exposure to antibiotics on a previously unaffected microbiome [ 37 ]. 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. 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 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 administrate preventative antimicrobial agents. Antimicrobial resistance during ICU stay The significant less 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 decreased use of other antibiotics [ 79 ]. 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 the studies), in which it is important to acknowledge the inter-country differences in prevalence of these bacteria [ 80 , 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. However, this is not seen in the sensitivity analyses. 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 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% was considerable, which was most likely due to between-study differences in antibiotic use, ICU settings and study design. The sensitivity analyses showed the influence of different study characteristics. Firstly, studies with IV antibiotics in their SDD or SOD regimen found significantly less 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 systemically eradication of bacteria in patients receiving IV antibiotics in comparison to no IV antibiotics. Secondly, studies conducted in countries with low antimicrobial resistant rates showed significant reduction in antimicrobial resistance during ICU stay. This is in line with previous studies [ 4 , 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, when swabs were taking routinely in both intervention and control study groups, no significant association between SDD or SOD and antimicrobial resistance was found, which could be due to surveillance bias where more resistance was found in the studies performing routine swabs rather than on indication only. Fourthly, observational studies found significantly less antibiotic resistance as opposed to studies with a randomized design. This could be because of herd-effects where clusters of patients acquire herd-protection against antimicrobial resistant pathogens whereas individually randomized patients may have contaminated each other. This is strengthened by the sensitivity analysis where 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. Fifthly, the six studies investigating data from after 2012 yielded significantly less antibiotic resistance after SDD or SOD. The main outcome of these studies was multi-resistant bacteria in contrast to MRSA as the main outcome in studies before 2012. As showed in the additional analyses on multi-resistant bacteria, SDD is protective of acquiring multi-resistant bacteria. Therefore, it is tempting to speculate that the significant effect in this sensitivity analysis is due to outcome measure. Lastly, 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, that this would be 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 the generalizability of the results due to large heterogeneity in countries of studies, the variations in SDD and SOD regimens used, local antimicrobial resistance rates, and standard hygiene measures. The funnel plot was asymmetrical as it seemed smaller studies who reported more antimicrobial resistance after SDD or SOD were missing, indicating a possible reporting bias. In case of minimal reporting bias, the actual protective effect of SDD on the occurrence of antimicrobial resistance might have been lower than the result from this meta-analysis. 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 is significantly associated with reduced antimicrobial resistance to specific antibiotics, more specifically this is found when an IV component is added, in settings with a low prevalence of resistance and in studies using a cluster design i.e. without risk of cross-contamination, which is in line with previous reviews. This was not observed for SOD. Moreover, this current review shows there is limited data available on the long-term effect of SDD and SOD to antimicrobial resistance. Knowledge of the long-term effect of SDD and SOD on antimicrobial resistance as well as the effect on the gut microbiome is a fundamental contributor in the consideration on 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 a prospective long-term follow-up study in patients receiving SDD or SOD without prior exposure to antibiotics such as trauma and elective surgery patients. Abbreviations Intensive Care Unit (ICU) Intravenous (IV) Methicillin-Resistant S. aureus (MRSA) Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Selective Digestive Decontamination (SDD) Selective Oropharyngeal Decontamination (SOD) Vancomycin Resistant Enterococcus spp. (VRE) Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials All data generated or analyzed during this study are included in this published article [and its supplementary information files]. Competing interests The authors declare that they have no competing interests Funding There are no financial, or non-financial conflicts of interest to declare for all authors Authors' 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. Acknowledgements Not applicable References Vincent J-L, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA. 2009;302:2323–9. Hammond NE, Myburgh J, Seppelt I, Garside T, Vlok R, Mahendran S, et al. Association between Selective Decontamination of the Digestive Tract and In-Hospital Mortality in Intensive Care Unit Patients Receiving Mechanical Ventilation: A Systematic Review and Meta-analysis. JAMA. 2022;328:1922–34. de Jonge E, Schultz M J, Spanjaard L, Bossuyt P M M, Vroom M B, Dankert J, et al. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: A randomised controlled tria. Lancet. 2003;362:1011–6. de Smet AMGA, Kluytmans JAWJ, Cooper BS. Decontamination of the Digestive Tract and Oropharynx in ICU Patients. New Engl J Med. 2009;360:20–31. Kesecioglu J, Eggimann P. What is new in selective decontamination of the digestive tract? Intensive Care Med. 2016;42:1270–5. Antimicrobial Resistance Collaborators*, Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399:629–55. Daneman N, Sarwar S, Fowler RA, Cuthbertson BH. Effect of selective decontamination on antimicrobial resistance in intensive care units: A systematic review and meta-analysis. Lancet Infect Dis. 2013;13:328–41. de Jonge E, de Wilde RBP, Juffermans NP, Oostdijk EAN, Bernards AT, Van Essen EHR, et al. Carriage of antibiotic-resistant Gram-negative bacteria after discontinuation of selective decontamination of the digestive tract (SDD) or selective oropharyngeal decontamination (SOD). Crit Care. 2018;22:1–10. Wittekamp BH, Plantinga NL, Cooper BS, Lopez-Contreras J, Coll P, Mancebo J, et al. Decontamination Strategies and Bloodstream Infections with Antibiotic-Resistant Microorganisms in Ventilated Patients: A Randomized Clinical Trial. JAMA. 2018;320:2087–98. Sánchez-Ramírez C, Hípola-Escalada S, Cabrera-Santana M, Hernández-Viera MA, Caipe-Balcázar L, Saavedra P, et al. Long-term use of selective digestive decontamination in an ICU highly endemic for bacterial resistance. Crit Care. 2018;22:141. PROSPERO International prospective register of systematic reviews. [Internet]. [cited 2024 Jun 5]. Available from: https://www.crd.york.ac.uk/prospero Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1-34. Garner P, Hopewell S, Chandler J, MacLehose H, Schünemann HJ, Akl EA, et al. When and how to update systematic reviews: Consensus and checklist. BMJ. 2016;354. Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological Index for Non-Randomized Studies (MINORS) : Development and Validation of a New Instrument. ANZ J Surg. 2003;73:712–6. R Core Team. A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria 2017. Vienna, Austria; 2017. Addressing reporting biases. [Internet]. [cited 2024 Jun 5]. Available from: https://handbook-5-1.cochrane.org/chapter_10/10_addressing_reporting_biases.htm Kossmeier M, Tran US, Voracek M. Visual Inference for the Funnel Plot in Meta-Analysis. Z Psychol. 2019;227:83–9. Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:964–7. OneHealthTrust. ResistanceMap: Antibiotic resistance. https://resistancemap.onehealthtrust.org/AntibioticResistance.php. 2024. Abele-Horn M, Dauber A, Bauernfeind A, Russwurm W, Seyfarth-Metzger I, Gleich P, et al. Decrease in nosocomial pneumonia in ventilated patients by selective oropharyngeal decontamination (SOD). Intensive Care Med. 1997;23:187–95. Benus RF, Harmsen HJ, Welling GW, Spanjersberg R, Zijlstra JG, Degener JE, et al. Impact of digestive and oropharyngeal decontamination on the intestinal microbiota in ICU patients. Intensive Care Med. 2010;36:1394–402. Bergmans DCJJ, Bonten MJM, Gaillard CA, Paling JOHAN C., van der Geest S, van Tiel FH, et al. Prevention of Ventilator-associated Pneumonia by Oral Decontamination. Am J Respir Crit Care Med. 2001;164:382–8. van der Bij AK, Frentz D, Bonten MJM, Cohen Stuart JWT, Van Hees BC, Vijfhuizen J, et al. Gram-positive cocci in Dutch ICUs with and without selective decontamination of the oropharyngeal and digestive tract: A retrospective database analysis. J Antimicrob Chemother. 2016;71:816–20. Brun-Buisson C, Legrand P, Rauss A, Richard C, Montravers F, Besbes M, et al. Intestinal decontamination for control of nosocomial multiresistant gram-negative bacilli. Study of an outbreak in an intensive care unit. Ann Intern Med. 1989;110:873–81. Buitinck S, Jansen R, Rijkenberg S, Wester JPJ, Bosman RJ, Van Der Meer NJM, et al. The ecological effects of selective decontamination of the digestive tract (SDD) on antimicrobial resistance: A 21-year longitudinal single-centre study. Crit Care. 2019;23:208. de la Cal MA, Cerdá E, van Saene HKF, García-Hierro P, Negro E, Parra ML, et al. Effectiveness and safety of enteral vancomycin to control endemicity of methicillin-resistant Staphylococcus aureus in a medical/surgical intensive care unit. J Hosp Infect. 2004;56:175–83. de La Cal MA, Cerdá E, García-Hierro P, van Saene HKF, Gómez-Santos D, Negro E, et al. Survival Benefit in Critically Ill Burned Patients Receiving Selective Decontamination of the Digestive Tract. Ann Surg. 2005;241:424–30. Camus C, Bellissant E, Sebille V, Perrotin D, Garo B, Legras A, et al. Prevention of acquired infections in intubated patients with the combination of two decontamination regimens. Crit Care Med. 2005;33:307–14. Camus C, Sebille V, Legras A, Garo B, Renault A, Le Corre P, et al. Mupirocin/chlorexidine to prevent methicillin-resistant Staphylococcus aureus infections: Post hoc analysis of a placebo-controlled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin for the prevention of acquired infections in intubated patients. Infection. 2014;42:493–502. Camus C, Salomon S, Bouchigny C, Gacouin A, Lavoué S, Donnio PY, et al. Short-term decline in all-cause acquired infections with the routine use of a decontamination regimen combining topical polymyxin, tobramycin, and amphotericin B with mupirocin and chlorhexidine in the ICU: A single-center experience. Crit Care Med. 2014;42:1121–30. Camus C, Sauvadet E, Tavenard A, Piau C, Uhel F, Bouju P, et al. Decline of multidrug-resistant Gram negative infections with the routine use of a multiple decontamination regimen in ICU. Journal of Infection. 2016;73:200–9. Canter RR, Harvey SE, Harrison DA, Campbell MK, Rowan KM, Cuthbertson BH, et al. Observational study of current use of selective decontamination of the digestive tract in UK Critical Care units. Br J Anaesth. 2014;113:610–7. Dahms R, Carlson M, Lohr B, Beilman G. Selective digestive tract decontamination and vancomycin-resistant enterococcus isolation in the surgical intensive care unit. Shock. 2000;14:343–6. Dautzenberg MJD, Bayjanov JR, Leverstein-van Hall MA, Muller AE, Gelinck LBS, Jansen CL, et al. Dynamics of colistin and tobramycin resistance among Enterobacter cloacae during prolonged use of selective decontamination of the digestive tract. Antimicrob Resist Infect Control. 2018;7:67. Ferrer M, Torres a, Gonzalez J, Puig De La Bellacasa J, Gatell JM, Roca M, et al. Utility of selective digestive decontamination general population of mechanically ventilated patients. Ann Intern Med. 1994;120:389–95. Flaherty J, Nathan C, Kabins SA, Weinstein RA. Pilot trial of selective decontamination for prevention of bacterial infection in an intensive care unit. J Infect Dis. 1990;162:1393–7. Garcin F, Textoris J, Ragonnet B, Antonini F, Martin C, Leone M. Selective digestive decontamination and empirical antimicrobial therapy of late–onset ventilator–associated pneumonia in trauma. J Acute Dis. 1994;1:1–6. Godard J, Guillaume C, Reverdy M E, Herriot E, Received F. Intestinal decontamination in a polyvalent ICU. A double-blind study. Intensive Care Med. 1990;16:307–11. Halaby T, Naiemi N Al, Kluytmans J, Van Der Palen J, Vandenbroucke-Grauls CMJE. Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimicrob Agents Chemother. 2013;57:3224–9. Hammond JMJ, Potgieter PD, Hammond JMJ. Double-blind study of selective decontamination of the digestive tract in intensive care. JAMA. 1992;340:5–9. Hammond J M, Potgieter P D. Long-term effects of selective decontamination on antimicrobial resistance. Crit Care Med. 1995;23:637–45. Heininger A, Meyer E, Schwab F, Marschal M, Unertl K, Krueger WA. Effects of long-term routine use of selective digestive decontamination on antimicrobial resistance. Intensive Care Med. 2006;32:1569–76. Houben AJM, Oostdijk EAN, van der Voort PHJ, Monen JCM, Bonten MJM, van der Bij AK, et al. Selective decontamination of the oropharynx and the digestive tract, and antimicrobial resistance: A 4 year ecological study in 38 intensive care units in the Netherlands. J Antimicrob Chemother. 2014;69:797–804. Humphreys H, Winter R, Pick A. The effect of selective decontamination of the digestive tract on gastrointestinal enterococcal colonization in ITU patients. Intensive Care Med. 1992;18:459–63. Janssen AB, van Hout D, Bonten MJM, Willems RJL, van Schaik W. Microevolution of acquired colistin resistance in enterobacteriaceae from ICU patients receiving selective decontamination of the digestive tract. J Antimicrob Chemother. 2020;75:3135–43. Katchman E, Marquez M, Bazerbachi F, Grant D, Cattral M, Low CY, et al. A comparative study of the use of selective digestive decontamination prophylaxis in living-donor liver transplant recipients. Transpl Infect Dis. 2014;16:539–47. Krueger WA, Lenhart FP, Neeser G, Ruckdeschel G, Schreckhase H, Eissner HJ, et al. Influence of combined intravenous and topical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortality in critically III surgical patients: A prospective, stratified, randomized, double-blind, placebo-controlled clinical tr. Am J Respir Crit Care Med. 2002;166:1029–37. Landelle C, Nocquet Boyer V, Abbas M, Genevois E, Abidi N, Naimo S, et al. Impact of a multifaceted prevention program on ventilator-associated pneumonia including selective oropharyngeal decontamination. Intensive Care Med. 2018;44:1777–86. Ledingham IM, Alcock SR, Eastaway AT, McDonald JC, McKay IC, Ramsay G. Triple regimen of selective decontamination of the digestive tract, systemic cefotaxime, and microbiological surveillance for prevention of acquired infection in intensive care. Lancet. 1988;331:785–90. Leone M, Albanese J, Antonini F, Nguyen-Michel A, Martin C. Long-term (6-year) effect of selective digestive decontamination on antimicrobial resistance in intensive care, multiple-trauma patients. Crit Care Med. 2003;31:2090–5. Lloréns-Villar Y, Tusell F, Canut A, Barrasa H, Corral E, Martín A, et al. Antibiotic susceptibility trend before and after long-term use of selective digestive decontamination: a 16 year ecological study. J Antimicrob Chemother. 2019;74:2289–94. Massart N, Reizine F, Fillatre P, Seguin P, La Combe B, Frerou A, et al. Multiple-site decontamination regimen decreases acquired infection incidence in mechanically ventilated COVID-19 patients. Ann Intensive Care. 2022;12:84. Massart N, Camus C, Nesseler N, Fillâtre P, Flecher E, Mansour A, et al. Multiple-site decontamination to prevent acquired infection in patients with veno-venous ECMO support. Ann Intensive Care. 2023;13. Mathieu C, Abbate R, Meresse Z, Hammad E, Duclos G, Antonini F, et al. Decreased duration of intravenous cephalosporins in intensive care unit patients with selective digestive decontamination: a retrospective before-and-after study. Eu J Clin Microbiol Infect Dis. 2020;39:2115–20. Muruzábal-Lecumberri I, Girbau C, Canut A, Alonso R, Fernández-Astorga A. Spread of an Enterococcus faecalis sequence type 6 (CC2) clone in patients undergoing selective decontamination of the digestive tract. APMIS. 2015;123:245–51. Noteboom Y, Ong DSY, Oostdijk EA, Schultz MJ, De Jonge E, Purmer I, et al. Antibiotic-induced within-host resistance development of gram-negative bacteria in patients receiving selective decontamination or standard care. Crit Care Med. 2015;43:2582–8. Ochoa-Ardila ME, García-Cañas A, Gómez-Mediavilla K, González-Torralba A, Alía I, García-Hierro P, et al. Long-term use of selective decontamination of the digestive tract does not increase antibiotic resistance: A 5-year prospective cohort study. Intensive Care Med. 2011;37:1458–65. Oostdijk EAN, de Smet AMGA, Blok HEM, Thieme Groen ES, van Asselt GJ, Benus RFJ, et al. Ecological Effects of Selective Decontamination on Resistant Gram-negative Bacterial Colonization. Am J Respir Crit Care Med. 2010;181:452–7. Oostdijk EAN, Smits L, De Smet AMGA, Leverstein-Van Hall MA, Kesecioglu J, Bonten MJM. Colistin resistance in gram-negative bacteria during prophylactic topical colistin use in intensive care units. Intensive Care Med. 2013;39:653–60. Oostdijk EAN, Kesecioglu J, Schultz MJ, Visser CE, De Jonge E, Van Essen EHR, et al. Effects of decontamination of the oropharynx and intestinal tract on antibiotic resistance in icus a randomized clinical trial. JAMA. 2014;312:1429–37. Pérez-Granda MJ, Barrio JM, Hortal J, Burillo A, Muñoz P, Bouza E. Impact of selective digestive decontamination without systemic antibiotics in a major heart surgery intensive care unit. J Thorac Cardiovasc Surg. 2018;156:685–93. Plantinga NL, Wittekamp BHJ, Brun-Buisson C, Bonten MJM, Cooper BS, Coll P, et al. The effects of topical antibiotics on eradication and acquisition of third-generation cephalosporin and carbapenem-resistant Gram-negative bacteria in ICU patients; a post hoc analysis from a multicentre cluster-randomized trial. Clin Microbiol Infect. 2020;26:485–91. Quinio B, Albanese J, Bues CM, Viviand X, Martin C. Selective decontamination of the digestive tract in multiple trauma patients. A prospective double-blind, randomized, placebo-controlled study. Chest. 1996;109:765–72. Reizine F, Massart N, Joussellin V, Machut A, Vacheron CH, Savey A, et al. Association between selective digestive decontamination and decreased rate of acquired candidemia in mechanically ventilated ICU patients: a multicenter nationwide study. Crit Care. 2023;27:494. Righi E, Aggazzotti G, Ferrari E, Giovanardi C, Busani S, Rinaldi L, et al. Trends in ventilator-associated pneumonia: Impact of a ventilator care bundle in an Italian tertiary care hospital intensive care unit. Am J Infect Control. 2014;42:1312–6. Rocha LA, Martln MJ, Pita S, Paz J, Seco C, Margusino L, et al. Intensive Care Medicine Prevention of nosocomial infection in critically ill patients by selective decontamination of the digestive tract A randomized, double blind, placebo-controlled study. Intensive Care Med. 1992;18:398–404. Rodríguez-Gascón A, Lloréns-Villar Y, Solinís MÁ, Barrasa H, Canut-Blasco A. Does selective digestive decontamination (SDD) increase antibiotic resistance? Long-term comparison of two intensive care units (with and without SDD) of the same tertiary hospital. Eu J Clin Microbiol Infect Dis. 2024;43:885–93. Sánchez-García M, Cambronero Galache J, Diaz JL, Cerdá EC, Blasco JR, Gómez Aguinaga MA, et al. Effectiveness and Cost of Selective Decontamination of the Digestive Tract in Critically Ill Intubated Patients. Am J Respir Crit Care Med. 1998;158:908–16. de Smet AMGA, Kluytmans JAJW, Blok HEM, Mascini EM, Benus RFJ, Bernards AT, et al. 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. Lancet Infect Dis. 2011;11:372–80. SuDDICU Investigators, Myburgh JA, Seppelt IM, Goodman F, Billot L, Correa M, et al. Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2022;328:1911–21. Tetteroo G W M, Wagenvoort J H T, Mulder P G H, Ince C, Bruining H A. Decreased mortality rate and length of hospital stay in surgical intensive care unit patients with successful selective decontamination of the gut. Crit Care Med. 1993;21:1692–8. Ulrich C, Harinck-de Weerd JE, Bakker NC, Jacz K, Doornbos L, de Ridder VA. Selective decontamination of the digestive tract with norfloxacin in the prevention of ICU-acquired infections: a prospective randomized study. Intensive Care Med. 1989;15:424–31. Unertl K, Ruckdeschel G, Selbmann HK, Jensen U, Forst H, Lenhart FP, et al. Prevention of colonization and respiratory infections in long- term ventilated patients by local antimicrobial prophylaxis. Intensive Care Med. 1987;13:106–13. Verwaest C, Verhaegen J, Ferdinande P, et al. Randomised, controlled trial of selective digestive deconatmination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med. 1997;25:63–71. van der Voort PHJ, van Roon EN, Kampinga GA, Boerma EC, Gerritsen RT, Egbers NHM, et al. A before-after study of multi-resistance and cost of selective decontamination of the digestive tract. Infection. 2004;32:271–7. Wang B, Briegel J, Krueger WA, Draenert R, Jung J, Weber A, et al. Ecological effects of selective oral decontamination on multidrug-resistance bacteria acquired in the intensive care unit: a case–control study over 5 years. Intensive Care Med. 2022;48:1165–75. Wiener J, Itokazu G, Nathan C, Kabins SA, Weinstein RA. A Randomized, Double-Blind, Placebo-Controlled Trial of Selective Digestive Decontamination in a Medical-Surgical Intensive-Care Unit. Clin Infect Dis. 1995;20:861–7. Wittekamp BHJ, Oostdijk EAN, De Smet AMGA, Bonten MJM. Colistin and tobramycin resistance during long- term use of selective decontamination strategies in the intensive care unit: A post hoc analysis. Crit Care. 2015;19. Young PJ, Devaux A, Li Q, Billot L, Davis JS, Delaney A, et al. Selective digestive tract decontamination in critically ill adults with acute brain injuries: a post hoc analysis of a randomized clinical trial. Intensive Care Med. 2024;50:56–67. Jurke A, Daniels-Haardt I, Silvis W, Berends MS, Glasner C, Becker K, et al. Changing epidemiology of meticillin-resistant Staphylococcus aureus in 42 hospitals in the Dutch–German border region, 2012 to 2016: Results of the search-and-follow-policy. Euro surveill. 2019;24:1800244. Perovic O, Iyaloo S, Kularatne R, Lowman W, Bosman N, Wadula J, et al. Prevalence and trends of staphylococcus aureus bacteraemia in hospitalized patients in South Africa, 2010 to 2012: Laboratory-based surveillance mapping of antimicrobial resistance and molecular epidemiology. PLoS One. 2015;10:e0145429. Zhu D, Zhao Q, Guo S, Bai L, Yang S, Zhao Y, et al. Efficacy of preventive interventions against ventilator-associated pneumonia in critically ill patients: an umbrella review of meta-analyses. J Hosp Infect. 2024;145:174–86. Oostdijk EA, de Wit GA, Bakker M, Marie A de Smet AG, M Bonten MJ. Selective decontamination of the digestive tract and selective oropharyngeal decontamination in intensive care unit patients: a cost-effectiveness analysis. BMJ Open. 2013;3:e002529. Minozzi S, Pifferi S, Brazzi L, Pecoraro V, Montrucchio G, D’Amico R. Topical antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving mechanical ventilation. Cochrane Database Syst Rev. 2021;1:CD000022. Tan G, Tay H, Tan S, Lee T, Ng T, Lye D. Gut Microbiota Modulation: Implications for Infection Control and Antimicrobial Stewardship. Adv Ther. 2020;37:4054–67. Huttner B, Haustein T, Uçkay I, Renzi G, Stewardson A, Schaerrer D, et al. Decolonization of intestinal carriage of extended-spectrum Β-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: A randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother. 2013;68:2375–82. Aardema H, Lisotto P, Kurilshikov A, Diepeveen JRJ, Friedrich AW, Sinha B, et al. Marked Changes in Gut Microbiota in Cardio-Surgical Intensive Care Patients: A Longitudinal Cohort Study. Front Cell Infect Microbiol. 2020;9:467. Buelow E, Bello González TDJ, Fuentes S, de Steenhuijsen Piters WAA, Lahti L, Bayjanov JR, et al. Comparative gut microbiota and resistome profiling of intensive care patients receiving selective digestive tract decontamination and healthy subjects. Microbiome. 2017;5:88. A.M.G.A. DS, M.J.M. B, J.A.J.W. K, de Smet AMGA, Bonten MJM, Kluytmans JAJW. For whom should we use selective decontamination of the digestive tract? Curr Opin Infect Dis [Internet]. 2012;25:211–7. Available from: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L364397746 Tables Table 1A 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 Total SOD SDD Control Brun-Buisson 1989 [24] France Individual randomization 1987 - 1987 Every 4 days No 1 86 0 36 50 - de la Cal 2004 [26] Spain Before and after 1997 - 2000 1x/week Yes 1 659 0 401 258 + Camus 2005 [28] France Cluster randomization 1996 - 1998 1x/2weeks No 3 256 130 0 126 +/- Camus 2014 [30] France Before and after 2006 - 2008 1x/week No 1 1947 0 1022 925 +/- Canter 2014 [32] UK Observational 2008 - 2011 - Yes 199 284690 0 12270 272420 - Dahms 2000 [33] USA Observational 1996 - 1999 No No 1 596 0 54 542 + Ferrer 1994 [35] Spain Individual randomization 12 months 3x/week Yes 1 79 0 39 40 + Flaherty 1990 [36] USA Individual randomization 8 months 2x/week No 1 107 0 51 56 - Garcin 2012 [37] France Observational - No Yes 1 218 0 146 125 + Hammond 1992 [40] South Africa Individual randomization 1989 - 1990 2x/week Yes 1 239 0 114 125 - de Jonge 2003 [3] Netherlands Cluster randomization 1999 - 2001 1x/week Yes 1 773 0 378 395 +/- Katchman 2014 [46] Canada During and after 2007 - 2011 1x/week No 1 148 0 111 37 +/- Krueger 2002 [47] Germany Individual randomization 2.5 years 2x/week Yes 2 454 0 265 262 +/- Perez-Granda 2018 [61] Spain Before and after 2012 - 2015 No No 1 1746 0 892 854 +/- Quinio 1996 [63] France Individual randomization - 2x/week No 1 148 0 76 72 +/- Reizine 2023 [64] France Observational 2017 - 2023 - Yes 220 5862 0 2931 2931 +/- Righi 2014 [65] Italy Before and after 2004 - 2010 No Yes 1 1372 0 674 698 +/- Sánchez-García 1998 [68] Spain Individual randomization - 2x/week Yes 1 271 0 131 140 + Sánchez-Ramîrez 2018 [10] Spain Before and after 2010 - 2015 1x/week Yes 1 2992 0 1998 994 +/- de Smet 2011 [69] Netherlands Cluster randomization 2004 - 2006 2x/week Yes 13 2595 886 828 881 +/- SuDDICU 2022 [70] Australia Cluster randomization 2017-2021 1week/ month Yes 19 5982 0 2791 3191 +/- Unertl 1987 [73] Germany Individual randomization 1984 - 1985 1x/day No 1 39 0 19 20 +/- Verwaest 1997 [74] Belgium Individual randomization 19 months 2x/week Yes 1 578 0 393 185 +/- van der Voort 2004 [75] Netherlands Before and after 2 years 2x/week Yes 1 732 0 219 513 +/- Wang 2022 [76] Germany Case control 2012-2016 Routinely ** No 11 5034 3340 0 1694 +/- Wiener 1995 [77] USA Individual randomization 8 months 1x/week No 1 61 0 30 31 +/- Wittekamp 2018 [9] Multi * Cluster randomization 2013 - 2017 2x/week No 13 8665 2224 2082 4359 +/- * Belgium, Spain, Portugal, Italy, Slovenia and UK ** Frequency unknown ***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). Table 1B 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 Total SOD SDD Control Abele-Horn 1997 [20] Germany Individual randomization - 2x/week Yes 1 85 58 0 30 + Benus 2010 [21] Netherlands Observational 2004 - 2006 no Yes 1 57 19 17 21 + Bergmans 2001 [22] Netherlands Individual randomization 1994 - 1996 2x/week No 3 226 87 0 139 +/- van der Bij 2016 [23] Netherlands Observational 2008 - 2013 - Yes 42 - - - - + Buitinck 2019 [25] Multi * Observational 1997 - 2017 2x/week Aspirates 3x/week Yes 1 12054 0 12054 0 - de la Cal 2005 [27] Spain Individual randomization 1997 - 2000 2x/week Yes 1 107 0 53 54 + Camus 2014 [29] France Cluster randomization 1996 - 1999 1x/week No 3 515 259 0 256 + Camus 2016 [31] France Observational 2008 - 2012 1x/week No 1 6175 0 5250 925 +/- Dautzenberg 2018 [34] Netherlands Observational 2005 - 2014 2x/week Yes 2 2448 0 2448 0 - Godard 1990 [38] France Cluster randomization 1988 1x/week No 1 181 0 97 84 - Halaby 2013 [39] Netherlands Before and after 2001 - 2008 2x/week No 1 134 0 106 28 - Hammond 1995 [41] South Africa Before and after 1988 – 1991 2x/week Yes 1 1528 0 719 809 +/- Heininger 2006 [42] Germany Observational 2000 - 2004 2x/week No 34 7270 0 1913 - +/- Houben 2014 [43] Netherlands Observational 2008 - 2012 - Yes 38 - - - - - Humphreys 1992 [44] UK Individual randomization 17 months 3x/week Yes 1 267 0 92 175 + Janssen 2020 [45] Netherlands Observational 2018 - 2019 2x/week Yes 1 428 0 428 0 - de Jonge 2018 [8] Netherlands Observational 2010 - 2013 4x after ICU discharge Yes 3 835 409 426 0 - Landelle 2018 [48] Switzerland Pre, during and after 2014 - 2016 No No 1 1060 769 0 291 - Lendingham 1988 [49] Scotland Before and after 1985 - 1986 3x/week Yes 1 324 0 163 161 - Leone 2003 [50] France Case control 6 years 2x/week Yes 1 5987 0 360 360 +/- Lloréns-Villar 2019 [51] Spain Before and after 1998 - 2013 No Yes 8 - - 0 - +/- Massart 2022 [52] France Observational 2020-2021 1x/week No 15 461 0 89 372 +/- Massart 2023 [53] France Observational 2017-2021 1x/week No 3 241 0 69 172 +/- Mathieu 2020 [54] France Before and after 2014 - 2018 No Yes 1 447 0 447 0 MDR ** Muruzabal -Lecumberri 2015 [55] Spain Observational 2010 - 2011 2x/week Yes 1 24 0 24 0 + Noteboom 2015 [56] Netherlands Observational 2009 - 2013 2x/week Yes 16 8067 8067 0 - Ochoa-Ardila 2011 [57] Spain Observational 2002 - 2007 1x/week Yes 1 1588 0 1588 0 +/- Oostdijk 2010 [58] Netherlands Cluster randomization 2004 - 2006 2x/week Yes 13 - - - - Oostdijk 2013 [59] Netherlands Cluster randomization 2004 - 2009 2x/week Yes 13 1246 476 455 315 - Oostdijk 2014 [60] Netherlands Cluster randomization 2009 - 2013 2x/week Yes 16 11997 5957 6040 0 +/- Plantinga 2020 [62] Netherlands Cluster randomization 2013 - 2017 2x/week No 13 8665 - - - - Rocha 1992 [66] Spain Individual randomization 14 months 2x/week Yes 1 101 0 47 54 +/- Rodríguez-Gascón 2024 [67] Spain Observational 2014-2018 2x/week Yes 2 - 0 - - +/- de Smet 2009 [4] Netherlands Cluster randomization 2004 - 2006 2x/week Yes 13 5939 1904 2045 1990 - Tetteroo 1993 [71] Netherlands Observational 18 months 1x/week Yes 1 97 0 97 0 + Ulrich 1989 [72] Netherlands Individual randomization 1986 - 1987 2x/week Yes 1 100 0 48 52 +/- Wittekamp 2015 [78] Netherlands Cluster randomization 2004 - 2013 1x/month Yes 5 1865 - - +/- Young 2024 [79] Australia Cluster randomization 2017 - 2021 1x/month Yes 19 2061 0 968 1093 +/- * 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). Table 2 Meta regression on the influence of specific study characteristics to the odds ratio of occurrence of antibiotic resistance in patients after receiving SDD or SOD Ratio of Odds Ratio (95% confidence interval) P-value Study characteristic Regimen* Aminoglycosides 0.64 (0.12 - 3.40) 0.60 Glycopeptides 0.38 (0.11 - 1.30) 0.12 Polyenes 0.52 (0.08 - 3.18.) 0.48 Cephalosporins 3.67 (0.15 - 90.0) 0.43 Fluoroquinolones 0.87 (0.30 - 2.55) 0.80 I.V. antibiotics 0.33 (0.02 - 6.95) 0.47 Year of study performance 0.98 (0.94 - 1.02) 0.34 Design (randomized) 1.36 (0.49 - 3.78) 0.56 Median length of follow-up (days) 1.00 (0.94 - 1.06) 0.88 Routine swabs performed 1.74 (0.57 - 5.36) 0.33 Study conducted in countries with low antimicrobial resistant rates 0.60 (0.18 - 2.03) 0.41 Ratio of Odds Ratio Ratio representing with which factor each study characteristic influences the overall odds ratio on occurrence of antibiotic resistance after SDD or SOD as calculated in Figure 1B. *Originally, macrolides and polymyxins were also taken as a regimen characteristic, however since only Canter et al. [32] used macrolides and all studies except Dahms et al. [33] used polymyxins combined with other antibiotic agents, macrolides were deemed a redundant predictor. Additional Declarations No competing interests reported. Supplementary Files AppendixAntimicrobialresistanceSDDSOD.docx PRISMA2020.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 03 Apr, 2025 Reviews received at journal 03 Feb, 2025 Reviews received at journal 12 Jan, 2025 Reviewers agreed at journal 12 Jan, 2025 Reviewers agreed at journal 10 Jan, 2025 Reviewers invited by journal 25 Nov, 2024 Editor assigned by journal 25 Nov, 2024 Editor invited by journal 19 Nov, 2024 Submission checks completed at journal 15 Nov, 2024 First submitted to journal 31 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5368003","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":384657156,"identity":"63cd5f96-e068-40f7-b3d2-9faf23f42a21","order_by":0,"name":"Frederique van Eerten","email":"data:image/png;base64,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","orcid":"","institution":"University Medical Center Utrecht","correspondingAuthor":true,"prefix":"","firstName":"Frederique","middleName":"van","lastName":"Eerten","suffix":""},{"id":384657157,"identity":"84c55b4d-25b9-4697-af80-4378941f8654","order_by":1,"name":"Joost Plate","email":"","orcid":"","institution":"Canisius-Wilhelmina Ziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Joost","middleName":"","lastName":"Plate","suffix":""},{"id":384657158,"identity":"58788329-857e-465d-b975-efc09a6e430a","order_by":2,"name":"Rolf Groenwold","email":"","orcid":"","institution":"Leiden University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Rolf","middleName":"","lastName":"Groenwold","suffix":""},{"id":384657159,"identity":"b28a593a-a013-4bb7-9b11-825a72b861bf","order_by":3,"name":"Valentijn Schweitzer","email":"","orcid":"","institution":"University Medical Center Utrecht","correspondingAuthor":false,"prefix":"","firstName":"Valentijn","middleName":"","lastName":"Schweitzer","suffix":""},{"id":384657160,"identity":"b2d6337c-18e4-4dc0-84a3-69e074ac899d","order_by":4,"name":"Jan Kluytmans","email":"","orcid":"","institution":"University Medical Center Utrecht","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Kluytmans","suffix":""},{"id":384657161,"identity":"778034f9-5378-484a-a24c-a72778c80eec","order_by":5,"name":"Falco Hietbrink","email":"","orcid":"","institution":"University Medical Center Utrecht","correspondingAuthor":false,"prefix":"","firstName":"Falco","middleName":"","lastName":"Hietbrink","suffix":""}],"badges":[],"createdAt":"2024-10-31 15:53:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5368003/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5368003/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71791474,"identity":"d600537a-f912-4fd3-8474-7445d3ac26c0","added_by":"auto","created_at":"2024-12-18 15:27:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":52785,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of systematic review on antibiotic resistance after SSD/SOD in ICU patients\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5368003/v1/d5477690e906b6ef4937d21b.png"},{"id":71789972,"identity":"05039f7d-a949-4106-9748-d7eeaf4c0cdd","added_by":"auto","created_at":"2024-12-18 15:19:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":104455,"visible":true,"origin":"","legend":"\u003cp\u003eOccurrence of colonization of- or infection with resistant bacteria in patients receiving SDD, or SOD versus placebo or control group\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003e During ICU stay. \u003cstrong\u003eB. \u003c/strong\u003eAfter ICU discharge. An odds ratio \u0026lt;1 suggests a protective effect and an odds ratio \u0026gt;1 suggests a risk-inducing effect.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5368003/v1/b263a50a2ea5517b951839db.png"},{"id":71792099,"identity":"201bd9fb-a245-4b50-b4a9-7de0383620a8","added_by":"auto","created_at":"2024-12-18 15:35:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86481,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA-D\u003c/strong\u003e \u0026nbsp;Additional analyses on the occurrence \u0026nbsp;\u0026nbsp;of colonization of-, or infection with resistant bacteria in patients \u0026nbsp;\u0026nbsp;receiving SDD, or SOD versus placebo or control group\u003c/p\u003e\n\u003cp\u003eStudies are sorted on basis of outcome measurements. Divided in studies investigating the acquisition of resistance to A. aminoglycosides B. polymyxin E, and B C. fluoroquinolones, and D. third generation cephalosporines. An odds ratio \u0026lt;1 suggests a protective effect and an odds ratio \u0026gt;suggests a risk-inducing effect.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5368003/v1/3afa4da6da504acab15f0256.png"},{"id":71791481,"identity":"636382c9-a717-4e7d-9cce-75ab57cac09c","added_by":"auto","created_at":"2024-12-18 15:27:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":93875,"visible":true,"origin":"","legend":"\u003cp\u003eA-C Additional analyses on the occurrence of colonization of-, or infection of specific (multi-)resistant bacteria in patients receiving SDD, or SOD versus placebo or control group\u003c/p\u003e\n\u003cp\u003eStudies \u0026nbsp;\u0026nbsp;are sorted on basis of on the occurrence of specific (multi-)resistant \u0026nbsp;\u0026nbsp;bacteria. \u003cstrong\u003eA.\u003c/strong\u003e MRSA \u003cstrong\u003eB.\u003c/strong\u003e VRE\u003cem\u003e,\u003c/em\u003e and \u003cstrong\u003eC.\u003c/strong\u003e multi-resistant \u0026nbsp;\u0026nbsp;bacteria, other than MRSA or VRE. An odds ratio \u0026lt;1 suggests a protective \u0026nbsp;\u0026nbsp;effect and an odds ratio \u0026gt;suggests a risk-inducing effect.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinitions \u0026nbsp;\u0026nbsp;of multi-resistant bacteria used by the studies included in this sensitivity \u0026nbsp;\u0026nbsp;analysis is specified in Appendix table\u003c/strong\u003e 3\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5368003/v1/1e1389f6daec108673646890.png"},{"id":71791473,"identity":"37fb1eb5-4e48-4164-927b-70b06ec08de5","added_by":"auto","created_at":"2024-12-18 15:27:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1367521,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5368003/v1/c40d6c44-0746-47be-8d7d-2a2fafdf7e60.pdf"},{"id":71789993,"identity":"98982bad-bf93-47cf-8e82-d568a388d85f","added_by":"auto","created_at":"2024-12-18 15:19:09","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1275568,"visible":true,"origin":"","legend":"","description":"","filename":"AppendixAntimicrobialresistanceSDDSOD.docx","url":"https://assets-eu.researchsquare.com/files/rs-5368003/v1/f4b397eb2d6f1e058eaf0180.docx"},{"id":71791509,"identity":"c8f1a1b8-774e-4b93-8ec7-c61db4f54938","added_by":"auto","created_at":"2024-12-18 15:27:11","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":91541,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5368003/v1/11157c5de93a9d725d736db8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of Selective Decontamination on Antimicrobial Resistance in Intensive Care Patients: A Systematic Review and Meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eInfections are a major cause of mortality and morbidity in patients admitted to Intensive Care Units (ICUs) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. A substantial part of these infections is hospital-acquired and can therefore potentially be prevented [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSelective Digestive Decontamination (SDD) and Selective Oropharyngeal Decontamination (SOD) are applied to prevent infections amongst ICU patients. These two approaches have extensively been studied and demonstrate a reduction in mortality rate, infection rate, and length of mechanical ventilation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. SDD consists of the application of nonabsorbable antimicrobial agents in the oropharyngeal and gastrointestinal tract. Systemic antimicrobial prophylaxis is given in addition to SDD during the first 4 days of ICU admission [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSOD 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 patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The choice of antibiotics is targeted against potential pathogens and should not be targeted against the anaerobic part of the flora [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the effect of SDD and SOD on ICU mortality, there is a persistent concern of the possible risk of antimicrobial resistance [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Bacterial antimicrobial resistance is a major cause of mortality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, standardized preventative antibiotic administration should be critically reviewed. The resistance occurring after SDD and SOD may arise \u003cem\u003eafter\u003c/em\u003e ICU discharge, thus the main aim of this research was to assess the occurrence of antimicrobial resistance \u003cem\u003eafter\u003c/em\u003e ICU discharge. Antimicrobial resistance \u003cem\u003eduring\u003c/em\u003e ICU admission was also investigated, as new studies have been performed since the last systematic review in 2013 [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eProtocol and registration\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was registered in the PROSPERO International prospective register of systematic reviews under the ID CRD42019128143 [11]. Because of substantial heterogeneity in study designs and outcome measures, several sensitivity analyses and a mixed-effects meta regression model on study characteristics\u0026nbsp;have been added to the initial protocol to investigate the influence of this heterogeneity. \u0026nbsp;Moreover, the analyses were separated for SDD and SOD. The reporting of this article followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [12]. There was no financial support or competing interests of the authors of this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInformation sources\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive literature search in Medline, Embase, and Cochrane was performed. A previous performed systematic review performed by Daneman et al., which included all articles on antimicrobial resistance after SDD or SOD from before 01-02-2012, was taken as basis [7,13]. A search string was made, which was tested on the 2010-2012 period. A 100% agreement was found with the studies found by Daneman et al [7] for this period. All studies identified by Daneman et al. were reviewed for meeting 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 done. No additional studies were found. The last search was performed on 08-05-24.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy selection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll studies that analyzed the antimicrobial\u0026nbsp;resistance of bacteria in ICU patients who received SDD or SOD were included, regardless of whether systemic antimicrobial agents were used. The primary outcome was occurrence of antimicrobial resistance after ICU discharge, secondary outcome was occurrence of antimicrobial resistance during ICU stay. Both routine samples and samples used for diagnosing infectious complication, which were tested on antimicrobial resistance, were included. Both studies investigating antimicrobial resistance after ICU discharge and studies investigating antimicrobial resistance during ICU stay were included. There were no restrictions regarding study design, country, publication status, date of publication, or study quality. Studies only investigating non-antimicrobial interventions (i.e. only washing with chlorhexidine) were excluded. Studies only investigating 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 done by two reviewers (F.E. and J.P.). A third and fourth reviewer (F.H. and V.S) were asked when consensus could not be reached. Eventually, consensus was reached through discussion.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData extraction\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe 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\u0026nbsp;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 or not. A structured data extraction form was used.\u0026nbsp;Authors of the reviewed articles were contacted for additional information if necessary. If data were unclear or not apparent, it was deemed missing. \u0026nbsp;If possible, information that was not reported was calculated using available data, such as calculation of absolute numbers using percentage of patients colonized with antimicrobial resistant pathogens.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRisk of bias assessment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTwo reviewers (F.E. and J.P.) assessed risk of bias using the MINORS checklist [14]. \u0026nbsp;A third and fourth reviewer were asked when consensus could not be reached (F.H. and V.S.). Consensus was reached on all studies. The MINORS checklist allowed to assess the risk of bias of interventional studies, both observational studies and randomized trials.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData synthesis of studies assessing the\u0026nbsp;\u003c/em\u003e\u003cem\u003eantimicrobial\u003c/em\u003e\u003cem\u003e\u0026nbsp;resistance during and after ICU discharge\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe analyses on development of resistance during ICU admission and after ICU discharge were done separately for studies using SOD and SDD. All studies assessing the\u0026nbsp;antimicrobial\u0026nbsp;resistance rates of bacteria in individual patients after ICU discharge were included in the meta-analysis. Only the results of studies with a control group that did not receive SDD or SOD and studies presenting data as number of patients with new antimicrobial resistance colonization or infection with an antimicrobial resistant pathogen were pooled (details below). Studies presenting outcome using isolates or pathogens numbers instead of patients were excluded from the meta-analysis, as patients could be colonized with multiple pathogens. Moreover, outcomes were presented as percentage of resistant pathogens in relation to total positive isolates were not considered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalyses were performed using the “rmeta”, “metaviz”, “meta”, and “metafor” packages in R software for statistical computing (V.3.3.2.) [15]. To evaluate the risk of publication bias, the symmetry of the funnel plot was assessed by three researchers (F.E., J.P. and V.A.) [16,17]. This was done by randomly producing multiple funnel plots and blindly assessing whether the true funnel plot could be distinguished from the other funnel plots. [16,17].\u003c/p\u003e\n\u003cp\u003ePooled odds ratios (OR) and 95% confidence intervals\u0026nbsp;on the occurrence of antimicrobial resistance after SDD or SOD were calculated using the Mantel-Haenszel method with random effects. Random effects were used because the treatment effect varied across studies, e.g., due to different study populations [18]. The heterogeneity of the effect estimates regarding the occurrence of antimicrobial resistance after SDD or SOD across studies was quantified by means of the I\u003csup\u003e2\u003c/sup\u003e statistic.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSensitivity analyses\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTwo analyses for different outcome measures were performed separately for studies investigating SDD or SOD: \u003cstrong\u003eA.\u003c/strong\u003e resistance to specific antibiotic groups (aminoglycosides, polymyxin E, and B, fluoroquinolones, and third generation cephalosporines) and \u003cstrong\u003eB.\u0026nbsp;\u003c/strong\u003eper multi-resistant bacteria type (Methicillin-Resistant \u003cem\u003eS aureus\u0026nbsp;\u003c/em\u003e(MRSA), Vancomycin Resistant\u003cem\u003e\u0026nbsp;Enterococcus spp. (\u003c/em\u003eVRE\u003cem\u003e),\u003c/em\u003e and multi-resistant bacteria). Definitions of multi-resistant bacteria used by the studies included in this sensitivity analysis are specified in Appendix table 3. Resistance to third generation cephalosporines also included extended-spectrum beta-lactamase (ESBL) producing bacteria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo investigate the effect of methodology, seven sensitivity analyses were performed, taking results of studies using SDD or SOD together: (\u003cstrong\u003eA\u003c/strong\u003e) IV antibiotics as part of SDD or SOD versus no IV antibiotics as part of SDD or SOD; (\u003cstrong\u003eB\u003c/strong\u003e) studies conducted in countries with low vs. intermediate or high prevalence of antimicrobial resistance. \u003cem\u003eS. aureus\u003c/em\u003e isolates resistant to methicillin prevalence was taken as a reflection of antimicrobial resistance rates in a country. Studies were divided into studies conducted in countries with \u0026lt;3% vs. ≥3% \u003cem\u003eS. aureus\u003c/em\u003e isolates resistant to methicillin [19]; (\u003cstrong\u003eC\u003c/strong\u003e) studies with versus without routine surveillance swabs\u0026nbsp;in both intervention and control study groups;\u0026nbsp;(\u003cstrong\u003eD\u003c/strong\u003e) randomized (botch cluster randomized and individually randomized) versus observational design;\u0026nbsp;(\u003cstrong\u003eE\u003c/strong\u003e)\u0026nbsp;To test the effect of herd-protection a sensitivity analyses on studies with an individually randomized versus cluster randomized and observational design was done; (\u003cstrong\u003eF\u003c/strong\u003e)\u0026nbsp;studies before 2012 versus after 2012; and (\u003cstrong\u003eG\u003c/strong\u003e) follow-up ≥14 days versus a shorter follow-up. When studies did not report median days of follow-up, median length of ICU stay was used for this analysis. To examine the simultaneous effect of multiple study characteristics on the outcome, a mixed-effects meta regression model with variables was fitted, including type of antibiotic agents administered (per antibiotic), intravenous (IV) or non-IV antibiotic administration, whether studies performed routine surveillance swabs in both intervention and control study groups (yes/no), year of study performance, randomization of study participants (yes/no), median ICU/follow-up days. Outcome measurement with multi-resistant bacteria (yes/no) was not included in the meta regression due to collinearity.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eThe search\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 65 studies were identified [3,4,8–10,20–79],\u0026nbsp;of which\u0026nbsp;33 studies were from \u0026gt;2012 and were included in addition to the studies identified by Daneman et al [7]. The meta-analyses included 27 studies (Figure 1), of which six were included in addition to Daneman et al [7]. Twenty-five studies were included in the meta-analysis on SDD and four studies in the meta-analysis on SOD. Thirty-eight studies were excluded from the meta-analyses, because they had no control group or had overlapping data with previous studies (Appendix Table 1A). Specific details on reason of exclusion of studies can be found in Appendix Table 1B.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCharacteristics of included studies\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCharacteristics of each study are reported in Table 1A and B. Of all 27 studies included in the meta-analysis; most of the studies investigated ICUs in France (22.2%), Spain (18.5%), and in Germany, Netherlands and USA (all 11.1%). The designs of the studies were individually randomized (37.0%), before-after comparison (25.9%), observational (18.5%) and cluster randomized (18.5%). Most of the data studied were from before 2012 (77.8%), and 6 (22.2%) studies investigated data collected after 2012. Aminoglycosides (96.3% of the studies) and Polymyxin E and B (81.5% of the studies) were the most frequently used topical antibiotics. Third generation cephalosporines were most frequently used systemic antibiotics (44.4% of the studies). Eleven (40.7%) studies did not use additional systemic antibiotics in their decontamination regimen (Appendix Table 2A-B). 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 had a follow-up of ≥14 days. Six (22.2%) studies presented usable data on antimicrobial resistance as resistance to aminoglycosides, 5 (18.5%) studies as resistance to polymyxin E and B, 3 (11.1%) studies as resistance to fluoroquinolones, and 4 (14.8%) as resistance to third generation cephalosporines. 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. Moreover, 11 (40.7%) studies presented usable data ≥1 of the abovementioned definitions of antimicrobial resistance as outcome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne author was contacted for additional information. however, no response was received. \u0026nbsp;In case of Hammond 1992 [40], de Jonge 2003 [3], Quinio 1996 [63], and Verwaest 1997 [74], information that was not reported was calculated using available data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRisk of bias assessment\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias assessment is illustrated in Appendix Figure 2. All studies were deemed of sufficient quality to be included in the analyses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe funnel plot was asymmetrical, with missing studies in the right lower section of the plot. This indicated that studies which found more antimicrobial resistance after SDD or SOD and which had larger confidence intervals were missing, which means a possible reporting bias was present. (Appendix Figure 8) The true funnel plot was not identified as outstanding in the visual inference plot. 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. (Appendix Figure 9)\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAntimicrobial resistance \u003cu\u003eafter\u003c/u\u003e ICU discharge\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere were four studies that investigated antimicrobial resistance both during ICU stay and after discharge in individual patients after receiving SDD or SOD [3,8,40,44]. The follow-up after ICU discharge ranged from four days after ICU discharge to four weeks after initial ICU admission. No longer follow-up was available. There were two studies eligible for meta-analysis, both using SDD as their intervention [3,40]. Hammond et al. (1992) found a causative outcome until 4 weeks after first admission; OR 3.01 (95%-CI 1.12;8.04) [40]. De Jonge et al. (2003), found a protective outcome until 10 days after discharge; OR 0.55 (95%-CI 0.38;0.78) [3]. Meta-analysis of these two studies resulted in; OR 1.20 (95%-CI 0.23;6.36, I\u003csup\u003e2\u003c/sup\u003e 90%) (Figure 2B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study of Humphreys et al. (1992) found no difference in minimal inhibitory concentrations (MIC) of bacteria to antibiotics up to four days after ICU discharge in patients who had received SDD [44]. De Jonge et al. (2018) found more rectal carriage with resistant gram-negative bacteria in patients who received SOD versus patients who received SDD until 10 days after ICU discharge [8].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAntimicrobial resistance \u003cu\u003eduring\u0026nbsp;\u003c/u\u003eICU admission\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA significant association between SDD and developing antimicrobial resistance during ICU admission was found; OR 0.73 (95%-CI 0.54;0.98, I\u003csup\u003e2\u003c/sup\u003e 75% n = 25), while no significant association between SOD and developing antimicrobial resistance during ICU admission was found; OR 0.89 (95%-CI 0.48;1.64, I\u003csup\u003e2\u003c/sup\u003e 67%, n =4) (Figure 2A-B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSensitivity analyses\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe additional analyses on the outcome groups onantimicrobial resistance \u003cu\u003eduring\u003c/u\u003e ICU admission are illustrated in Figure 3A-D. SDD was significantly associated with less resistance to fluoroquinolones; OR 0.29 (95%-CI 0.12;0.68, I\u003csup\u003e2\u003c/sup\u003e 30%) and developing multi-resistant bacteria; OR 0.53 (95%-CI 0.33;0.87, I\u003csup\u003e2\u003c/sup\u003e 0%) (Figures 3C and 4C respectively). SOD was not significantly associated with developing antimicrobial resistance to one of the antibiotic groups, MRSA\u003cem\u003e,\u0026nbsp;\u003c/em\u003eVRE or multi-resistant bacteria (Figure 3A-D and 4A-C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudies using IV antibiotics in their regimen yielded a significant association with less antimicrobial resistance in patients receiving SDD or SOD, while no significant association was found in studies not using IV antibiotics; respectively OR 0.71 (95%-CI 0.52;0.96, I\u003csup\u003e2\u003c/sup\u003e 76%) and OR 0.86 (95%-CI 0.47;1.57, I\u003csup\u003e2\u003c/sup\u003e 75%) (Appendix Figure 3A-B). There was a significant association with less antimicrobial resistance found in studies conducted in countries with low antimicrobial resistance prevalence. A similar trend was found in studies conducted in countries with intermediate to high prevalence but this was not statistical significant; OR 0.62 (95%-CI 0.51;0.75, I\u003csup\u003e2\u003c/sup\u003e 54%) and OR 0.77 (95%-CI 0.55;1.09, I\u003csup\u003e2\u003c/sup\u003e 77%) (Appendix Figure 4A-B) Studies who performed routine surveillance swabs in both intervention and control study groups found no significant association between SDD and SOD and developing antimicrobial resistance, while studies who did not perform routine swabs, but only measured antibiotic resistance in samples used for purpose of diagnosing infectious complications did find a significant association; respectively OR 0.86 (95%-CI 0.60;1.25, I\u003csup\u003e2\u003c/sup\u003e 76%) and OR 0.65 (95%-CI 0.45;0.92, I\u003csup\u003e2\u003c/sup\u003e 0%) (Appendix Figure 5A-B). The studies not performing routine swabs investigated swabs which were taken because of clinical suspicion of infection.\u003c/p\u003e\n\u003cp\u003eSDD or SOD were significantly associated with less antimicrobial resistance in studies with an observational design; OR 0.57 (95%-CI 0.43;0.76, I\u003csup\u003e2\u003c/sup\u003e 68%). No association was found between SDD or SOD and antimicrobial resistance in studies with a randomized design, OR 1.04 (95%-CI 0.64;1.68, I\u003csup\u003e2\u003c/sup\u003e 80%) (Appendix Figure 6A-B). 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, I\u003csup\u003e2\u003c/sup\u003e 67%). No such effect was found in individually randomized studies, OR 1.31 (95%-CI 0.66;2.61, I\u003csup\u003e2\u003c/sup\u003e 63%) (Appendix Figure 7A-B). No significant association between SDD and SOD and antimicrobial resistance was found in studies investigating data \u0026lt;2012; OR 0.90 (95%-CI 0.62;1.32, I\u003csup\u003e2\u003c/sup\u003e 74%). SDD and SOD was significantly associated with less antimicrobial resistance in studies investigating data \u0026gt;2012; OR 0.52 (95%-CI 0.40;0.69, I\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e57%) (Appendix Figure 8A-B) as well as in studies with a follow-up \u0026lt;14 days; OR 0.57 (95%-CI 0.42;0.78, I\u003csup\u003e2\u003c/sup\u003e 61%). Studies with a follow-up ≥14 days found no such association; OR 1.11 (95%-CI 0.66;1.87, I\u003csup\u003e2\u003c/sup\u003e 82%) (Appendix Figure 9A-B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition, meta-regression did not yield a significant effect of the study characteristics on the occurrence of antimicrobial resistance (Table 2).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn total, 4 studies investigated the occurrence of antimicrobial resistance after SDD or SOD and \u003cem\u003eafter\u003c/em\u003e ICU discharge. One study found less, and one study found more antimicrobial resistance after SDD [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. One study found no difference in MICs in bacteria after ICU discharge in patients who had received SDD and one study found more rectal carriage with resistant gram-negative bacteria in patients who received SOD versus patients who received SDD [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere were significantly less patients \u003cem\u003eduring\u003c/em\u003e ICU stay with antimicrobial resistance after receiving SDD, based on observational studies from \u0026gt;\u0026thinsp;2012 with a median length of ICU stay of \u0026lt;\u0026thinsp;14 days, administrating IV antibiotics as part of the SDD or SOD regimen and not performing routine follow-up swabs. Moreover, \u003cem\u003eduring\u003c/em\u003e ICU stay there was significantly less resistance to fluoroquinolones and there were significantly less multi-resistant bacteria in patients receiving SDD. However, the definition of multi-resistant bacteria varied between studies which makes the interpretation of this finding difficult. There were only five studies investigating SOD, which yielded no significant association between SOD and developing antimicrobial resistance during ICU stay.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAntimicrobial resistance after ICU discharge\u003c/h2\u003e \u003cp\u003eThe few studies investigating the occurrence of antimicrobial resistance \u003cem\u003eafter\u003c/em\u003e ICU discharge yielded conflicting results. When comparing the two studies included in the meta-analysis, de Jonge et al. (2003) was performed 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 group [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The resistant rates in South-Africa are higher than in the Netherlands, which makes the occurrence of MRSA more common in South-Africa than in the Netherlands [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]. 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 are not solely resistance rates occurring \u003cem\u003eafter\u003c/em\u003e ICU discharge. Only Hammond et al. had a follow-up after ICU discharge\u0026thinsp;\u0026gt;\u0026thinsp;2 weeks and showed an increasing colonization rate of 10% at week 2 and 13% at week 4 [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eClinical relevance\u003c/h2\u003e \u003cp\u003eTo 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 showed positive results [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR83\" citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]. Moreover, overall total antibiotic consumption when using SDD or SOD versus control was comparable or even lower in 20 of the 21 studies investigating this [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan additionalcitationids=\"CR78\" citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]. Only one study found a higher intravenous antibiotic consumption rate in patients receiving SOD versus control [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, 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., \u003cem\u003eafter\u003c/em\u003e ICU discharge, is important as it could lead to increased morbidity by complicating treatment of infections [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Currently, there is little knowledge on the long-term effect of preventative antibiotics in general on antimicrobial resistance. This could possibly be explained because long-term investigation is costly and prone to loss of follow-up. It should be noted that this is specifically about long-term effect in specific patients rather than overall 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 discharge [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. On the short term, it is known that preventative antibiotics influence the composition of the gut-microbiome [\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e]. Interestingly, the gut-microbiome possesses recovery capacity of the microbiota several days after exposure to antibiotics [\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e]. Whether this recovery is accompanied by antimicrobial resistance is not yet excluded [\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e]. However, both Hammond et al. and de Jonge et al. showed that it is possible to obtain antibiotic resistance after ICU discharge [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo investigate this possible long-term effect of preventative antibiotics, one must discriminate clearly between the effect of preventative and therapeutic administered 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 ICU [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Hence, the SDD or SOD administration is usually the first exposure to antibiotics on a previously unaffected microbiome [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eSuch 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 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 administrate preventative antimicrobial agents.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eAntimicrobial resistance during ICU stay\u003c/h2\u003e \u003cp\u003eThe significant less 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 decreased use of other antibiotics [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]. 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 the studies), in which it is important to acknowledge the inter-country differences in prevalence of these bacteria [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]. 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. However, this is not seen in the sensitivity analyses. 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 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.\u003c/p\u003e \u003cp\u003eMoreover, the heterogeneity of 75% was considerable, which was most likely due to between-study differences in antibiotic use, ICU settings and study design. The sensitivity analyses showed the influence of different study characteristics.\u003c/p\u003e \u003cp\u003eFirstly, studies with IV antibiotics in their SDD or SOD regimen found significantly less 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 systemically eradication of bacteria in patients receiving IV antibiotics in comparison to no IV antibiotics.\u003c/p\u003e \u003cp\u003eSecondly, studies conducted in countries with low antimicrobial resistant rates showed significant reduction in antimicrobial resistance during ICU stay. This is in line with previous studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e]. This is possibly because in countries with lower resistance rates, antimicrobial resistant bacteria are less likely to be selected through SDD or SOD.\u003c/p\u003e \u003cp\u003eThirdly, when swabs were taking routinely in both intervention and control study groups, no significant association between SDD or SOD and antimicrobial resistance was found, which could be due to surveillance bias where more resistance was found in the studies performing routine swabs rather than on indication only.\u003c/p\u003e \u003cp\u003eFourthly, observational studies found significantly less antibiotic resistance as opposed to studies with a randomized design. This could be because of herd-effects where clusters of patients acquire herd-protection against antimicrobial resistant pathogens whereas individually randomized patients may have contaminated each other. This is strengthened by the sensitivity analysis where 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.\u003c/p\u003e \u003cp\u003eFifthly, the six studies investigating data from after 2012 yielded significantly less antibiotic resistance after SDD or SOD. The main outcome of these studies was multi-resistant bacteria in contrast to MRSA as the main outcome in studies before 2012. As showed in the additional analyses on multi-resistant bacteria, SDD is protective of acquiring multi-resistant bacteria. Therefore, it is tempting to speculate that the significant effect in this sensitivity analysis is due to outcome measure.\u003c/p\u003e \u003cp\u003eLastly, studies in which the length of stay on the ICU was a mean or median of \u0026lt;\u0026thinsp;14 days yielded significantly less antimicrobial resistance as opposed to studies in which the length of stay on the ICU was a mean or median of \u0026gt;\u0026thinsp;14 days. It is tempting to speculate that if antimicrobial resistance occurs, that this would be 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eStrengths of this study are the addition of 33 new studies to Daneman et al [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] 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 the generalizability of the results due to large heterogeneity in countries of studies, the variations in SDD and SOD regimens used, local antimicrobial resistance rates, and standard hygiene measures. The funnel plot was asymmetrical as it seemed smaller studies who reported more antimicrobial resistance after SDD or SOD were missing, indicating a possible reporting bias. In case of minimal reporting bias, the actual protective effect of SDD on the occurrence of antimicrobial resistance might have been lower than the result from this meta-analysis. 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.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDuring ICU stay SDD is significantly associated with reduced antimicrobial resistance to specific antibiotics, more specifically this is found when an IV component is added, in settings with a low prevalence of resistance and in studies using a cluster design i.e. without risk of cross-contamination, which is in line with previous reviews. This was not observed for SOD. Moreover, this current review shows there is limited data available on the long-term effect of SDD and SOD to antimicrobial resistance. Knowledge of the long-term effect of SDD and SOD on antimicrobial resistance as well as the effect on the gut microbiome is a fundamental contributor in the consideration on whether to apply SDD or SOD.\u003c/p\u003e \u003cp\u003eTherefore, it is recommended to enlarge the data on the occurrence of antimicrobial resistance after ICU discharge by conducting a prospective long-term follow-up study in patients receiving SDD or SOD without prior exposure to antibiotics such as trauma and elective surgery patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIntensive Care Unit (ICU)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIntravenous (IV)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethicillin-Resistant \u003cem\u003eS. aureus\u003c/em\u003e (MRSA)\u003c/p\u003e\n\u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSelective Digestive Decontamination (SDD)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSelective Oropharyngeal Decontamination (SOD)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVancomycin Resistant \u003cem\u003eEnterococcus\u003c/em\u003e spp. (VRE)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere are no financial, or non-financial conflicts of interest to declare for all authors\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll 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.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVincent J-L, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA. 2009;302:2323\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eHammond NE, Myburgh J, Seppelt I, Garside T, Vlok R, Mahendran S, et al. Association between Selective Decontamination of the Digestive Tract and In-Hospital Mortality in Intensive Care Unit Patients Receiving Mechanical Ventilation: A Systematic Review and Meta-analysis. JAMA. 2022;328:1922\u0026ndash;34. \u003c/li\u003e\n\u003cli\u003ede Jonge E, Schultz M J, Spanjaard L, Bossuyt P M M, Vroom M B, Dankert J, et al. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: A randomised controlled tria. Lancet. 2003;362:1011\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003ede Smet AMGA, Kluytmans JAWJ, Cooper BS. Decontamination of the Digestive Tract and Oropharynx in ICU Patients. New Engl J Med. 2009;360:20\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eKesecioglu J, Eggimann P. What is new in selective decontamination of the digestive tract? Intensive Care Med. 2016;42:1270\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eAntimicrobial Resistance Collaborators*, Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399:629\u0026ndash;55. \u003c/li\u003e\n\u003cli\u003eDaneman N, Sarwar S, Fowler RA, Cuthbertson BH. Effect of selective decontamination on antimicrobial resistance in intensive care units: A systematic review and meta-analysis. Lancet Infect Dis. 2013;13:328\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003ede Jonge E, de Wilde RBP, Juffermans NP, Oostdijk EAN, Bernards AT, Van Essen EHR, et al. Carriage of antibiotic-resistant Gram-negative bacteria after discontinuation of selective decontamination of the digestive tract (SDD) or selective oropharyngeal decontamination (SOD). Crit Care. 2018;22:1\u0026ndash;10. \u003c/li\u003e\n\u003cli\u003eWittekamp BH, Plantinga NL, Cooper BS, Lopez-Contreras J, Coll P, Mancebo J, et al. Decontamination Strategies and Bloodstream Infections with Antibiotic-Resistant Microorganisms in Ventilated Patients: A Randomized Clinical Trial. JAMA. 2018;320:2087\u0026ndash;98. \u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez-Ram\u0026iacute;rez C, H\u0026iacute;pola-Escalada S, Cabrera-Santana M, Hern\u0026aacute;ndez-Viera MA, Caipe-Balc\u0026aacute;zar L, Saavedra P, et al. Long-term use of selective digestive decontamination in an ICU highly endemic for bacterial resistance. Crit Care. 2018;22:141. \u003c/li\u003e\n\u003cli\u003ePROSPERO International prospective register of systematic reviews. [Internet]. [cited 2024 Jun 5]. Available from: https://www.crd.york.ac.uk/prospero\u003c/li\u003e\n\u003cli\u003eLiberati A, Altman DG, Tetzlaff J, Mulrow C, G\u0026oslash;tzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1-34. \u003c/li\u003e\n\u003cli\u003eGarner P, Hopewell S, Chandler J, MacLehose H, Sch\u0026uuml;nemann HJ, Akl EA, et al. When and how to update systematic reviews: Consensus and checklist. BMJ. 2016;354. \u003c/li\u003e\n\u003cli\u003eSlim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological Index for Non-Randomized Studies (MINORS) : Development and Validation of a New Instrument. ANZ J Surg. 2003;73:712\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eR Core Team. A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria 2017. Vienna, Austria; 2017. \u003c/li\u003e\n\u003cli\u003eAddressing reporting biases. [Internet]. [cited 2024 Jun 5]. Available from: https://handbook-5-1.cochrane.org/chapter_10/10_addressing_reporting_biases.htm\u003c/li\u003e\n\u003cli\u003eKossmeier M, Tran US, Voracek M. Visual Inference for the Funnel Plot in Meta-Analysis. Z Psychol. 2019;227:83\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eRiley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:964\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eOneHealthTrust. ResistanceMap: Antibiotic resistance. https://resistancemap.onehealthtrust.org/AntibioticResistance.php. 2024. \u003c/li\u003e\n\u003cli\u003eAbele-Horn M, Dauber A, Bauernfeind A, Russwurm W, Seyfarth-Metzger I, Gleich P, et al. Decrease in nosocomial pneumonia in ventilated patients by selective oropharyngeal decontamination (SOD). Intensive Care Med. 1997;23:187\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eBenus RF, Harmsen HJ, Welling GW, Spanjersberg R, Zijlstra JG, Degener JE, et al. Impact of digestive and oropharyngeal decontamination on the intestinal microbiota in ICU patients. Intensive Care Med. 2010;36:1394\u0026ndash;402. \u003c/li\u003e\n\u003cli\u003eBergmans DCJJ, Bonten MJM, Gaillard CA, Paling JOHAN\u0026ensp;C., van\u0026ensp;der\u0026ensp;Geest S, van Tiel FH, et al. Prevention of Ventilator-associated Pneumonia by Oral Decontamination. Am J Respir Crit Care Med. 2001;164:382\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003evan der Bij AK, Frentz D, Bonten MJM, Cohen Stuart JWT, Van Hees BC, Vijfhuizen J, et al. Gram-positive cocci in Dutch ICUs with and without selective decontamination of the oropharyngeal and digestive tract: A retrospective database analysis. J Antimicrob Chemother. 2016;71:816\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eBrun-Buisson C, Legrand P, Rauss A, Richard C, Montravers F, Besbes M, et al. Intestinal decontamination for control of nosocomial multiresistant gram-negative bacilli. Study of an outbreak in an intensive care unit. Ann Intern Med. 1989;110:873\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eBuitinck S, Jansen R, Rijkenberg S, Wester JPJ, Bosman RJ, Van Der Meer NJM, et al. The ecological effects of selective decontamination of the digestive tract (SDD) on antimicrobial resistance: A 21-year longitudinal single-centre study. Crit Care. 2019;23:208. \u003c/li\u003e\n\u003cli\u003ede la Cal MA, Cerd\u0026aacute; E, van Saene HKF, Garc\u0026iacute;a-Hierro P, Negro E, Parra ML, et al. Effectiveness and safety of enteral vancomycin to control endemicity of methicillin-resistant Staphylococcus aureus in a medical/surgical intensive care unit. J Hosp Infect. 2004;56:175\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003ede La Cal MA, Cerd\u0026aacute; E, Garc\u0026iacute;a-Hierro P, van Saene HKF, G\u0026oacute;mez-Santos D, Negro E, et al. Survival Benefit in Critically Ill Burned Patients Receiving Selective Decontamination of the Digestive Tract. Ann Surg. 2005;241:424\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eCamus C, Bellissant E, Sebille V, Perrotin D, Garo B, Legras A, et al. Prevention of acquired infections in intubated patients with the combination of two decontamination regimens. Crit Care Med. 2005;33:307\u0026ndash;14. \u003c/li\u003e\n\u003cli\u003eCamus C, Sebille V, Legras A, Garo B, Renault A, Le Corre P, et al. Mupirocin/chlorexidine to prevent methicillin-resistant Staphylococcus aureus infections: Post hoc analysis of a placebo-controlled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin for the prevention of acquired infections in intubated patients. Infection. 2014;42:493\u0026ndash;502. \u003c/li\u003e\n\u003cli\u003eCamus C, Salomon S, Bouchigny C, Gacouin A, Lavou\u0026eacute; S, Donnio PY, et al. Short-term decline in all-cause acquired infections with the routine use of a decontamination regimen combining topical polymyxin, tobramycin, and amphotericin B with mupirocin and chlorhexidine in the ICU: A single-center experience. Crit Care Med. 2014;42:1121\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eCamus C, Sauvadet E, Tavenard A, Piau C, Uhel F, Bouju P, et al. Decline of multidrug-resistant Gram negative infections with the routine use of a multiple decontamination regimen in ICU. Journal of Infection. 2016;73:200\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eCanter RR, Harvey SE, Harrison DA, Campbell MK, Rowan KM, Cuthbertson BH, et al. Observational study of current use of selective decontamination of the digestive tract in UK Critical Care units. Br J Anaesth. 2014;113:610\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eDahms R, Carlson M, Lohr B, Beilman G. Selective digestive tract decontamination and vancomycin-resistant enterococcus isolation in the surgical intensive care unit. Shock. 2000;14:343\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eDautzenberg MJD, Bayjanov JR, Leverstein-van Hall MA, Muller AE, Gelinck LBS, Jansen CL, et al. Dynamics of colistin and tobramycin resistance among Enterobacter cloacae during prolonged use of selective decontamination of the digestive tract. Antimicrob Resist Infect Control. 2018;7:67. \u003c/li\u003e\n\u003cli\u003eFerrer M, Torres a, Gonzalez J, Puig De La Bellacasa J, Gatell JM, Roca M, et al. Utility of selective digestive decontamination general population of mechanically ventilated patients. Ann Intern Med. 1994;120:389\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eFlaherty J, Nathan C, Kabins SA, Weinstein RA. Pilot trial of selective decontamination for prevention of bacterial infection in an intensive care unit. J Infect Dis. 1990;162:1393\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eGarcin F, Textoris J, Ragonnet B, Antonini F, Martin C, Leone M. Selective digestive decontamination and empirical antimicrobial therapy of late\u0026ndash;onset ventilator\u0026ndash;associated pneumonia in trauma. J Acute Dis. 1994;1:1\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eGodard J, Guillaume C, Reverdy M E, Herriot E, Received F. Intestinal decontamination in a polyvalent ICU. A double-blind study. Intensive Care Med. 1990;16:307\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eHalaby T, Naiemi N Al, Kluytmans J, Van Der Palen J, Vandenbroucke-Grauls CMJE. Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimicrob Agents Chemother. 2013;57:3224\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eHammond JMJ, Potgieter PD, Hammond JMJ. Double-blind study of selective decontamination of the digestive tract in intensive care. JAMA. 1992;340:5\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eHammond J M, Potgieter P D. Long-term effects of selective decontamination on antimicrobial resistance. Crit Care Med. 1995;23:637\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003eHeininger A, Meyer E, Schwab F, Marschal M, Unertl K, Krueger WA. Effects of long-term routine use of selective digestive decontamination on antimicrobial resistance. Intensive Care Med. 2006;32:1569\u0026ndash;76. \u003c/li\u003e\n\u003cli\u003eHouben AJM, Oostdijk EAN, van der Voort PHJ, Monen JCM, Bonten MJM, van der Bij AK, et al. Selective decontamination of the oropharynx and the digestive tract, and antimicrobial resistance: A 4 year ecological study in 38 intensive care units in the Netherlands. J Antimicrob Chemother. 2014;69:797\u0026ndash;804. \u003c/li\u003e\n\u003cli\u003eHumphreys H, Winter R, Pick A. The effect of selective decontamination of the digestive tract on gastrointestinal enterococcal colonization in ITU patients. Intensive Care Med. 1992;18:459\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eJanssen AB, van Hout D, Bonten MJM, Willems RJL, van Schaik W. Microevolution of acquired colistin resistance in enterobacteriaceae from ICU patients receiving selective decontamination of the digestive tract. J Antimicrob Chemother. 2020;75:3135\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eKatchman E, Marquez M, Bazerbachi F, Grant D, Cattral M, Low CY, et al. A comparative study of the use of selective digestive decontamination prophylaxis in living-donor liver transplant recipients. Transpl Infect Dis. 2014;16:539\u0026ndash;47. \u003c/li\u003e\n\u003cli\u003eKrueger WA, Lenhart FP, Neeser G, Ruckdeschel G, Schreckhase H, Eissner HJ, et al. Influence of combined intravenous and topical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortality in critically III surgical patients: A prospective, stratified, randomized, double-blind, placebo-controlled clinical tr. Am J Respir Crit Care Med. 2002;166:1029\u0026ndash;37. \u003c/li\u003e\n\u003cli\u003eLandelle C, Nocquet Boyer V, Abbas M, Genevois E, Abidi N, Naimo S, et al. Impact of a multifaceted prevention program on ventilator-associated pneumonia including selective oropharyngeal decontamination. Intensive Care Med. 2018;44:1777\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eLedingham IM, Alcock SR, Eastaway AT, McDonald JC, McKay IC, Ramsay G. Triple regimen of selective decontamination of the digestive tract, systemic cefotaxime, and microbiological surveillance for prevention of acquired infection in intensive care. Lancet. 1988;331:785\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eLeone M, Albanese J, Antonini F, Nguyen-Michel A, Martin C. Long-term (6-year) effect of selective digestive decontamination on antimicrobial resistance in intensive care, multiple-trauma patients. Crit Care Med. 2003;31:2090\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eLlor\u0026eacute;ns-Villar Y, Tusell F, Canut A, Barrasa H, Corral E, Mart\u0026iacute;n A, et al. Antibiotic susceptibility trend before and after long-term use of selective digestive decontamination: a 16 year ecological study. J Antimicrob Chemother. 2019;74:2289\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eMassart N, Reizine F, Fillatre P, Seguin P, La Combe B, Frerou A, et al. Multiple-site decontamination regimen decreases acquired infection incidence in mechanically ventilated COVID-19 patients. Ann Intensive Care. 2022;12:84. \u003c/li\u003e\n\u003cli\u003eMassart N, Camus C, Nesseler N, Fill\u0026acirc;tre P, Flecher E, Mansour A, et al. Multiple-site decontamination to prevent acquired infection in patients with veno-venous ECMO support. Ann Intensive Care. 2023;13. \u003c/li\u003e\n\u003cli\u003eMathieu C, Abbate R, Meresse Z, Hammad E, Duclos G, Antonini F, et al. Decreased duration of intravenous cephalosporins in intensive care unit patients with selective digestive decontamination: a retrospective before-and-after study. Eu J Clin Microbiol Infect Dis. 2020;39:2115\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eMuruz\u0026aacute;bal-Lecumberri I, Girbau C, Canut A, Alonso R, Fern\u0026aacute;ndez-Astorga A. Spread of an Enterococcus faecalis sequence type 6 (CC2) clone in patients undergoing selective decontamination of the digestive tract. APMIS. 2015;123:245\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eNoteboom Y, Ong DSY, Oostdijk EA, Schultz MJ, De Jonge E, Purmer I, et al. Antibiotic-induced within-host resistance development of gram-negative bacteria in patients receiving selective decontamination or standard care. Crit Care Med. 2015;43:2582\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eOchoa-Ardila ME, Garc\u0026iacute;a-Ca\u0026ntilde;as A, G\u0026oacute;mez-Mediavilla K, Gonz\u0026aacute;lez-Torralba A, Al\u0026iacute;a I, Garc\u0026iacute;a-Hierro P, et al. Long-term use of selective decontamination of the digestive tract does not increase antibiotic resistance: A 5-year prospective cohort study. Intensive Care Med. 2011;37:1458\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eOostdijk EAN, de Smet AMGA, Blok HEM, Thieme Groen ES, van Asselt GJ, Benus RFJ, et al. Ecological Effects of Selective Decontamination on Resistant Gram-negative Bacterial Colonization. Am J Respir Crit Care Med. 2010;181:452\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eOostdijk EAN, Smits L, De Smet AMGA, Leverstein-Van Hall MA, Kesecioglu J, Bonten MJM. Colistin resistance in gram-negative bacteria during prophylactic topical colistin use in intensive care units. Intensive Care Med. 2013;39:653\u0026ndash;60. \u003c/li\u003e\n\u003cli\u003eOostdijk EAN, Kesecioglu J, Schultz MJ, Visser CE, De Jonge E, Van Essen EHR, et al. Effects of decontamination of the oropharynx and intestinal tract on antibiotic resistance in icus a randomized clinical trial. JAMA. 2014;312:1429\u0026ndash;37. \u003c/li\u003e\n\u003cli\u003eP\u0026eacute;rez-Granda MJ, Barrio JM, Hortal J, Burillo A, Mu\u0026ntilde;oz P, Bouza E. Impact of selective digestive decontamination without systemic antibiotics in a major heart surgery intensive care unit. J Thorac Cardiovasc Surg. 2018;156:685\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003ePlantinga NL, Wittekamp BHJ, Brun-Buisson C, Bonten MJM, Cooper BS, Coll P, et al. The effects of topical antibiotics on eradication and acquisition of third-generation cephalosporin and carbapenem-resistant Gram-negative bacteria in ICU patients; a post hoc analysis from a multicentre cluster-randomized trial. Clin Microbiol Infect. 2020;26:485\u0026ndash;91. \u003c/li\u003e\n\u003cli\u003eQuinio B, Albanese J, Bues CM, Viviand X, Martin C. Selective decontamination of the digestive tract in multiple trauma patients. A prospective double-blind, randomized, placebo-controlled study. Chest. 1996;109:765\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eReizine F, Massart N, Joussellin V, Machut A, Vacheron CH, Savey A, et al. Association between selective digestive decontamination and decreased rate of acquired candidemia in mechanically ventilated ICU patients: a multicenter nationwide study. Crit Care. 2023;27:494. \u003c/li\u003e\n\u003cli\u003eRighi E, Aggazzotti G, Ferrari E, Giovanardi C, Busani S, Rinaldi L, et al. Trends in ventilator-associated pneumonia: Impact of a ventilator care bundle in an Italian tertiary care hospital intensive care unit. Am J Infect Control. 2014;42:1312\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eRocha LA, Martln MJ, Pita S, Paz J, Seco C, Margusino L, et al. Intensive Care Medicine Prevention of nosocomial infection in critically ill patients by selective decontamination of the digestive tract A randomized, double blind, placebo-controlled study. Intensive Care Med. 1992;18:398\u0026ndash;404. \u003c/li\u003e\n\u003cli\u003eRodr\u0026iacute;guez-Gasc\u0026oacute;n A, Llor\u0026eacute;ns-Villar Y, Solin\u0026iacute;s M\u0026Aacute;, Barrasa H, Canut-Blasco A. Does selective digestive decontamination (SDD) increase antibiotic resistance? Long-term comparison of two intensive care units (with and without SDD) of the same tertiary hospital. Eu J Clin Microbiol Infect Dis. 2024;43:885\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez-Garc\u0026iacute;a M, Cambronero Galache J, Diaz JL, Cerd\u0026aacute; EC, Blasco JR, G\u0026oacute;mez Aguinaga MA, et al. Effectiveness and Cost of Selective Decontamination of the Digestive Tract in Critically Ill Intubated Patients. Am J Respir Crit Care Med. 1998;158:908\u0026ndash;16. \u003c/li\u003e\n\u003cli\u003ede Smet AMGA, Kluytmans JAJW, Blok HEM, Mascini EM, Benus RFJ, Bernards AT, et al. 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. Lancet Infect Dis. 2011;11:372\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eSuDDICU Investigators, Myburgh JA, Seppelt IM, Goodman F, Billot L, Correa M, et al. Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2022;328:1911\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eTetteroo G W M, Wagenvoort J H T, Mulder P G H, Ince C, Bruining H A. Decreased mortality rate and length of hospital stay in surgical intensive care unit patients with successful selective decontamination of the gut. Crit Care Med. 1993;21:1692\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eUlrich C, Harinck-de Weerd JE, Bakker NC, Jacz K, Doornbos L, de Ridder VA. Selective decontamination of the digestive tract with norfloxacin in the prevention of ICU-acquired infections: a prospective randomized study. Intensive Care Med. 1989;15:424\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eUnertl K, Ruckdeschel G, Selbmann HK, Jensen U, Forst H, Lenhart FP, et al. Prevention of colonization and respiratory infections in long- term ventilated patients by local antimicrobial prophylaxis. Intensive Care Med. 1987;13:106\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eVerwaest C, Verhaegen J, Ferdinande P, et al. Randomised, controlled trial of selective digestive deconatmination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med. 1997;25:63\u0026ndash;71. \u003c/li\u003e\n\u003cli\u003evan der Voort PHJ, van Roon EN, Kampinga GA, Boerma EC, Gerritsen RT, Egbers NHM, et al. A before-after study of multi-resistance and cost of selective decontamination of the digestive tract. Infection. 2004;32:271\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eWang B, Briegel J, Krueger WA, Draenert R, Jung J, Weber A, et al. Ecological effects of selective oral decontamination on multidrug-resistance bacteria acquired in the intensive care unit: a case\u0026ndash;control study over 5 years. Intensive Care Med. 2022;48:1165\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eWiener J, Itokazu G, Nathan C, Kabins SA, Weinstein RA. A Randomized, Double-Blind, Placebo-Controlled Trial of Selective Digestive Decontamination in a Medical-Surgical Intensive-Care Unit. Clin Infect Dis. 1995;20:861\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eWittekamp BHJ, Oostdijk EAN, De Smet AMGA, Bonten MJM. Colistin and tobramycin resistance during long- term use of selective decontamination strategies in the intensive care unit: A post hoc analysis. Crit Care. 2015;19. \u003c/li\u003e\n\u003cli\u003eYoung PJ, Devaux A, Li Q, Billot L, Davis JS, Delaney A, et al. Selective digestive tract decontamination in critically ill adults with acute brain injuries: a post hoc analysis of a randomized clinical trial. Intensive Care Med. 2024;50:56\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eJurke A, Daniels-Haardt I, Silvis W, Berends MS, Glasner C, Becker K, et al. Changing epidemiology of meticillin-resistant Staphylococcus aureus in 42 hospitals in the Dutch\u0026ndash;German border region, 2012 to 2016: Results of the search-and-follow-policy. Euro surveill. 2019;24:1800244. \u003c/li\u003e\n\u003cli\u003ePerovic O, Iyaloo S, Kularatne R, Lowman W, Bosman N, Wadula J, et al. Prevalence and trends of staphylococcus aureus bacteraemia in hospitalized patients in South Africa, 2010 to 2012: Laboratory-based surveillance mapping of antimicrobial resistance and molecular epidemiology. PLoS One. 2015;10:e0145429. \u003c/li\u003e\n\u003cli\u003eZhu D, Zhao Q, Guo S, Bai L, Yang S, Zhao Y, et al. Efficacy of preventive interventions against ventilator-associated pneumonia in critically ill patients: an umbrella review of meta-analyses. J Hosp Infect. 2024;145:174\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eOostdijk EA, de Wit GA, Bakker M, Marie A de Smet AG, M Bonten MJ. Selective decontamination of the digestive tract and selective oropharyngeal decontamination in intensive care unit patients: a cost-effectiveness analysis. BMJ Open. 2013;3:e002529. \u003c/li\u003e\n\u003cli\u003eMinozzi S, Pifferi S, Brazzi L, Pecoraro V, Montrucchio G, D\u0026rsquo;Amico R. Topical antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving mechanical ventilation. Cochrane Database Syst Rev. 2021;1:CD000022. \u003c/li\u003e\n\u003cli\u003eTan G, Tay H, Tan S, Lee T, Ng T, Lye D. Gut Microbiota Modulation: Implications for Infection Control and Antimicrobial Stewardship. Adv Ther. 2020;37:4054\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eHuttner B, Haustein T, U\u0026ccedil;kay I, Renzi G, Stewardson A, Schaerrer D, et al. Decolonization of intestinal carriage of extended-spectrum \u0026Beta;-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: A randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother. 2013;68:2375\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eAardema H, Lisotto P, Kurilshikov A, Diepeveen JRJ, Friedrich AW, Sinha B, et al. Marked Changes in Gut Microbiota in Cardio-Surgical Intensive Care Patients: A Longitudinal Cohort Study. Front Cell Infect Microbiol. 2020;9:467. \u003c/li\u003e\n\u003cli\u003eBuelow E, Bello Gonz\u0026aacute;lez TDJ, Fuentes S, de Steenhuijsen Piters WAA, Lahti L, Bayjanov JR, et al. Comparative gut microbiota and resistome profiling of intensive care patients receiving selective digestive tract decontamination and healthy subjects. Microbiome. 2017;5:88. \u003c/li\u003e\n\u003cli\u003eA.M.G.A. DS, M.J.M. B, J.A.J.W. K, de Smet AMGA, Bonten MJM, Kluytmans JAJW. For whom should we use selective decontamination of the digestive tract? Curr Opin Infect Dis [Internet]. 2012;25:211\u0026ndash;7. Available from: http://www.embase.com/search/results?subaction=viewrecord\u0026amp;from=export\u0026amp;id=L364397746\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"737\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" valign=\"top\" style=\"width: 737px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1A\u003c/strong\u003e Characteristics of studies included in systematic review and meta-analysis on antimicrobial resistance after SSD/SOD in ICU patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Study\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eStudy design\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eStudy years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eRoutinely swab regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eSystemic antibiotics\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNumber of ICUs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eNumber of patients \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eOutcome gram + or - bacteria\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBrun-Buisson 1989\u003c/strong\u003e\u003cstrong\u003e[24]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1987 - 1987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eEvery 4 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ede la Cal 2004\u003c/strong\u003e\u003cstrong\u003e[26]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1997 - 2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e659\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e401\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCamus 2005\u003c/strong\u003e\u003cstrong\u003e[28]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1996 - 1998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/2weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCamus 2014\u003c/strong\u003e\u003cstrong\u003e[30]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2006 - 2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1947\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e925\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCanter 2014\u003c/strong\u003e\u003cstrong\u003e[32]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2008 - 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e199\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e284690\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e12270\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e272420\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDahms 2000\u003c/strong\u003e\u003cstrong\u003e[33]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1996 - 1999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e596\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e542\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFerrer 1994\u003c/strong\u003e\u003cstrong\u003e[35]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFlaherty 1990\u003c/strong\u003e\u003cstrong\u003e[36]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e8 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGarcin 2012\u003c/strong\u003e\u003cstrong\u003e[37]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e218\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHammond 1992\u003c/strong\u003e\u003cstrong\u003e[40]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSouth Africa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1989 - 1990\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ede Jonge 2003\u003c/strong\u003e\u003cstrong\u003e[3]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1999 - 2001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e773\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e395\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKatchman 2014\u003c/strong\u003e\u003cstrong\u003e[46]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eDuring and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2007 - 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKrueger 2002\u003c/strong\u003e\u003cstrong\u003e[47]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2.5 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e265\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePerez-Granda 2018\u003c/strong\u003e\u003cstrong\u003e[61]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2012 - 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e892\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e854\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQuinio 1996\u003c/strong\u003e\u003cstrong\u003e[63]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReizine 2023\u003c/strong\u003e\u003cstrong\u003e[64]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2017 - 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e5862\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2931\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2931\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRighi 2014\u003c/strong\u003e\u003cstrong\u003e[65]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eItaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and \u0026nbsp;after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2004 - 2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1372\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e674\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e698\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eS\u0026aacute;nchez-Garc\u0026iacute;a 1998\u003c/strong\u003e\u003cstrong\u003e[68]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eS\u0026aacute;nchez-Ram\u0026icirc;rez 2018\u003c/strong\u003e\u003cstrong\u003e[10]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2010 - 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2992\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e994\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ede Smet 2011\u003c/strong\u003e\u003cstrong\u003e[69]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2004 - 2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e886\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e828\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e881\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSuDDICU 2022\u003c/strong\u003e\u003cstrong\u003e[70]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2017-2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1week/ month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e5982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2791\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e3191\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnertl 1987\u003c/strong\u003e\u003cstrong\u003e[73]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1984 - 1985\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVerwaest 1997\u003c/strong\u003e\u003cstrong\u003e[74]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eBelgium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e19 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e578\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e393\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e185\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003evan der Voort 2004\u003c/strong\u003e\u003cstrong\u003e[75]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e732\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWang 2022\u003c/strong\u003e\u003cstrong\u003e[76]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGermany\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCase control\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2012-2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eRoutinely **\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e5034\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3340\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1694\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWiener 1995\u003c/strong\u003e\u003cstrong\u003e[77]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e8 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWittekamp 2018\u003c/strong\u003e\u003cstrong\u003e[9]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMulti\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2013 - 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e8665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e2224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2082\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e4359\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" valign=\"top\" style=\"width: 737px;\"\u003e\n \u003cp\u003e* Belgium, Spain, Portugal, Italy, Slovenia and UK ** Frequency unknown ***Multi drug resistant, unspecified gram positive or negative N/A. Not applicable -. Missing data (except for column depicting gram negative or positive outcome where \u0026ndash; indicates gram negative).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"737\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" valign=\"top\" style=\"width: 737px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1B\u003c/strong\u003e Characteristics of studies included only in systematic review on antimicrobial resistance after SSD/SOD in ICU patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Study\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eStudy design\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eStudy years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eRoutinely swab regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eSystemic antibiotics\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNumber of ICUs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eNumber of patients \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eOutcome gram + or - bacteria\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbele-Horn 1997\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e[20]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e30\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBenus 2010\u003c/strong\u003e\u003cstrong\u003e[21]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2004 - 2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eno\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBergmans 2001\u003c/strong\u003e\u003cstrong\u003e[22]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1994 - 1996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e139\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003evan der Bij 2016\u003c/strong\u003e\u003cstrong\u003e[23]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2008 - 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBuitinck 2019\u003c/strong\u003e\u003cstrong\u003e[25]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMulti\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1997 - 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003cp\u003eAspirates 3x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e12054\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e12054\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ede la Cal 2005\u003c/strong\u003e\u003cstrong\u003e[27]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1997 - 2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCamus 2014\u003c/strong\u003e\u003cstrong\u003e[29]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1996 - 1999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e515\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e259\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCamus 2016\u003c/strong\u003e\u003cstrong\u003e[31]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2008 - 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e6175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e5250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e925\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDautzenberg 2018\u003c/strong\u003e\u003cstrong\u003e[34]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2005 - 2014\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2448\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2448\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGodard 1990\u003c/strong\u003e\u003cstrong\u003e[38]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1988\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e97\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e84\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHalaby 2013\u003c/strong\u003e\u003cstrong\u003e[39]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2001 - \u0026nbsp;2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHammond 1995\u003c/strong\u003e\u003cstrong\u003e[41]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSouth Africa\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1988 \u0026ndash; 1991\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e719\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e809\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeininger 2006\u003c/strong\u003e\u003cstrong\u003e[42]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGermany\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2000 - 2004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e7270\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHouben 2014\u003c/strong\u003e\u003cstrong\u003e[43]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2008 - 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHumphreys 1992\u003c/strong\u003e\u003cstrong\u003e[44]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e17 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e267\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJanssen 2020\u003c/strong\u003e\u003cstrong\u003e[45]\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2018 - 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e428\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e428\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ede Jonge 2018\u003c/strong\u003e\u003cstrong\u003e[8]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2010 - 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4x after ICU discharge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e835\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e409\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLandelle 2018\u003c/strong\u003e\u003cstrong\u003e[48]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSwitzerland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePre, during and after\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2014 - 2016\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e769\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e291\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLendingham 1988\u003c/strong\u003e\u003cstrong\u003e[49]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eScotland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1985 - 1986\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e161\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeone 2003\u003c/strong\u003e\u003cstrong\u003e[50]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCase control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e6 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e5987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e360\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLloréns-Villar 2019\u003c/strong\u003e\u003cstrong\u003e[51]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1998 - 2013\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMassart 2022\u003c/strong\u003e\u003cstrong\u003e[52]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2020-2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e372\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMassart 2023\u003c/strong\u003e\u003cstrong\u003e[53]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2017-2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e241\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMathieu 2020\u003c/strong\u003e\u003cstrong\u003e[54]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBefore and after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2014 - 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e447 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eMDR\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMuruzabal -Lecumberri 2015\u003c/strong\u003e\u003cstrong\u003e[55]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2010 - 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNoteboom 2015\u003c/strong\u003e\u003cstrong\u003e[56]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2009 - 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e8067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e8067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOchoa-Ardila 2011\u003c/strong\u003e\u003cstrong\u003e[57]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2002 - 2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1588\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1588\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOostdijk 2010\u003c/strong\u003e\u003cstrong\u003e[58]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2004 - 2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOostdijk 2013\u003c/strong\u003e\u003cstrong\u003e[59]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2004 - 2009\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1246\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e476\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e455\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e315\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOostdijk 2014\u003c/strong\u003e\u003cstrong\u003e[60]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2009 - 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e11997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e5957\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e6040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlantinga 2020\u003c/strong\u003e\u003cstrong\u003e[62]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2013 - 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e8665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRocha 1992\u003c/strong\u003e\u003cstrong\u003e[66]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e14 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRodr\u0026iacute;guez-Gasc\u0026oacute;n 2024\u003c/strong\u003e\u003cstrong\u003e[67]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2014-2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ede Smet 2009\u003c/strong\u003e\u003cstrong\u003e[4]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2004 - 2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e5939\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1904\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1990\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTetteroo 1993\u003c/strong\u003e\u003cstrong\u003e[71]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eObservational\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e18 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUlrich 1989\u003c/strong\u003e\u003cstrong\u003e[72]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIndividual randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1986 - 1987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWittekamp 2015\u003c/strong\u003e\u003cstrong\u003e[78]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2004 - 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1865\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYoung 2024\u003c/strong\u003e\u003cstrong\u003e[79]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCluster randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2017 - 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1x/month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e2061\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e968\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e1093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" valign=\"top\" style=\"width: 737px;\"\u003e\n \u003cp\u003e* 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 \u0026ndash; indicates gram negative).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 633px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Meta regression on the influence of specific study characteristics to the odds ratio of occurrence of antibiotic resistance in patients after receiving SDD or SOD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRatio of Odds Ratio (95% confidence interval)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy characteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cem\u003eRegimen*\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eAminoglycosides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e0.64 (0.12 - 3.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eGlycopeptides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e0.38 (0.11 - 1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003ePolyenes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e0.52 (0.08 - 3.18.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eCephalosporins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e3.67 (0.15 - 90.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eFluoroquinolones\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e0.87 (0.30 - 2.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eI.V. antibiotics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e0.33 (0.02 - 6.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eYear of study performance\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e0.98 (0.94 - 1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eDesign (randomized)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e1.36 (0.49 - 3.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eMedian length of follow-up (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e1.00 (0.94 - 1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eRoutine swabs performed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e1.74 (0.57 - 5.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eStudy conducted in countries with low antimicrobial resistant rates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e0.60 (0.18 - 2.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 633px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRatio of Odds Ratio\u003c/strong\u003e Ratio representing with which factor each study characteristic influences the overall odds ratio on occurrence of antibiotic resistance after SDD or SOD as calculated in Figure 1B.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e*Originally, macrolides and polymyxins were also taken as a regimen characteristic, however since only Canter et al.\u003cstrong\u003e[32]\u003c/strong\u003e used macrolides and all studies except Dahms et al.\u003cstrong\u003e[33]\u003c/strong\u003e used polymyxins combined with other antibiotic agents, macrolides were deemed a redundant predictor. \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"intensive care medicine, infections, antimicrobial resistance, selective digestive decontamination.","lastPublishedDoi":"10.21203/rs.3.rs-5368003/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5368003/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSelective 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 development of antimicrobial resistance persists, specifically after ICU discharge. The aim of this study was to assess the occurrence of antimicrobial resistance \u003cem\u003eduring\u003c/em\u003e ICU stay and \u003cem\u003eafter\u003c/em\u003e ICU discharge in patients who received SDD, or SOD compared to control.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA previous systematic review, which included studies on antimicrobial resistance after SDD or SOD from before 01-02-2012, was updated. All studies analyzing antimicrobial resistance during and after ICU stay, 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.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTwenty-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, I\u003csup\u003e2\u003c/sup\u003e 75%), less resistance to fluoroquinolones in patients receiving SDD OR 0.29 (95%-CI 0.12;0.68, I\u003csup\u003e2\u003c/sup\u003e 30%) and less multi-resistant bacteria; OR 0.53 (95%-CI 0.33; 0.87, I\u003csup\u003e2\u003c/sup\u003e 0%), compared to control treatment. Four studies investigated antimicrobial resistance after ICU discharge of which two were eligible for pooling, which yielded no significant effect; OR 1.20 (95%-CI 0.23;6.36, I\u003csup\u003e2\u003c/sup\u003e 90%).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDuring ICU stay, SDD is associated with reduced antimicrobial resistance to specific antibiotics, in line with a previous review. More specifically combined with intravenous (IV) component, in settings with low prevalence of resistance and in a cluster design. This current review emphasizes the limited amount of data on the long-term effect of antimicrobial decontamination strategies to antimicrobial resistance. Understanding this long-term effect is essential when deciding whether to implement preventative antibiotics in specific subgroups. This could be done by means of a prospective long-term follow-up study.\u003c/p\u003e","manuscriptTitle":"The Effect of Selective Decontamination on Antimicrobial Resistance in Intensive Care Patients: A Systematic Review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 15:18:59","doi":"10.21203/rs.3.rs-5368003/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-03T06:42:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-03T15:54:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-12T09:45:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4443568448184600727653901943890383203","date":"2025-01-12T08:10:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"297228851883980899238574981036069666911","date":"2025-01-10T13:30:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-25T16:49:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-25T07:34:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-19T07:27:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-15T10:12:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-10-31T15:50:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5fdd3e62-4d17-4d27-b623-09ab8521d446","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":40979104,"name":"Biological sciences/Microbiology/Antimicrobials"},{"id":40979105,"name":"Biological sciences/Microbiology/Bacteria"},{"id":40979106,"name":"Health sciences/Health care"}],"tags":[],"updatedAt":"2026-04-29T04:53:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-18 15:18:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5368003","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5368003","identity":"rs-5368003","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}