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Background: We examined whether long-term use of selective digestive tract decontamination (SDD) was effective in reducing intensive care unit (ICU)-acquired infection and antibiotic consumption while decreasing colistin-, tobramycin-, and most of the antibiotic-resistant colonization rates in a mixed ICU with a high endemic level of multidrug-resistant bacteria (MDRB). Methods: In this cohort study, which was conducted in a 30-bed medical-surgical ICU, clinical outcomes before (1 year, non-SDD group) and after (4 years) implementation of SDD were compared. ICU patients who were expected to require tracheal intubation for > 48 hours were given a standard prophylactic SDD regimen. Oropharyngeal and rectal swabs were obtained on admission and once weekly thereafter. Results: ICU-acquired infections occurred in 110 patients in the non-SDD group and in 258 in the SDD group. A significant (P < 0.001) reduction of infections caused by MDRB (risk ratio [RR], 0.31; 95% CI, 0.23–0.41) was found after SDD and was associated with low rates of colistin- and tobramycin-resistant colonization. Colistin- and tobramycin- acquired increasing rate of ICU colonization resistance by 1000 days, adjusted by the rate of resistances at admission, was nonsignificant (0.82; 95% CI, 0.56 to 1.95; 1.13; 95% CI, 0.75 to 1.70, respectively). SDD was also a protective factor for ICU-acquired infections caused by MDR gram-negative pathogens and Acinetobacter baumannii in the multivariate analysis. In addition, a significant (P < 0.001) reduction of ventilator-associated pneumonia (VAP) (RR, 0.43; 95% CI, 0.32–0.59) and secondary bloodstream infection (BSI) (RR, 0.35; 95% CI, 0.24–0.52) was found. A decrease in antibiotic consumption was also observed. Conclusions: Treatment with SDD during 4 years was effective in an ICU setting with a high level of resistance, with clinically relevant reductions of infections caused by MDRB, and with low rates of colistin- and tobramycin-resistant colonization with nonsignificant increasing rate of ICU colonization resistance by 1000 days, adjusted by the rate of resistances at ICU admission. In addition, VAP and secondary BSI rates were significantly lower after SDD. Notably, a decrease in antimicrobial consumption was also observed. Keywords: Selective digestive decontamination, Drug resistance, ICU-acquired infection, Ventilator-associated pneumonia, Multidrug-resistant pathogens, Bloodstream infection, Colistin, Tobramycin * Correspondence: firstname.lastname@example.org Intensive Care Unit, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, La Ballena s/n, E-35010 Las Palmas, Spain Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 2 of 11 Background bundle . The primary objective was to compare out- Selective digestive decontamination (SDD) is a prophylactic come measures between the non-SDD and SDD cohorts. treatment for critically ill patients that is based on an oro- pharyngeal paste and enteral suspension containing antimi- SDD protocol crobials, usually tobramycin, colistin, and an antifungal as SDD was started on the day of tracheal intubation and well as an intravenous antibiotic, administered during the was given throughout the length of the ICU stay and first 4 days of intensive care unit (ICU) admission (usually a until discharge from the ICU. Patients were treated three second-generation cephalosporin). The aim of SDD is to times daily with 1 g of an oral paste applied to the oral prevent or eradicate, if present, the oropharyngeal and in- cavity. The composition per 1 g was 20 mg of 2% colis- testinal abnormal carriage of potentially pathogenic micro- tin, 30 mg of 3% tobramycin, and 20 mg of 2% nystatin. organisms, such as aerobic gram-negative bacilli (AGNB), The patients also received a 14-ml suspension contain- methicillin-sensitive Staphylococcus aureus, and yeasts, in ing 140 mg of 1% colistin, 180 mg of 2% tobramycin, patients at risk for nosocomial infections [1, 2]. Once a pa- and 453.6 mg of 3.2% nystatin , which was adminis- tient has been successfully decolonized, the unaffected an- tered into the gut through a nasogastric tube. In tra- aerobic flora would offer prevention against new cheostomized patients, the oral paste was also applied colonization with potential pathogenic microorganisms. In on the skin surrounding the tracheostomy three times critically ill patients, SDD has been proven to prevent daily. Enteral vancomycin, 40 mg of 4% oropharyngeal severe infections [1–3] and to reduce mortality [3, 4], paste, and 700 mg of vancomycin in digestive solution particularly in settings with a low prevalence of were added at the same 8-hour interval to all multidrug-resistant bacteria. However, the use of SDD methicillin-resistant Staphylococcus aureus (MRSA) car- is still a matter of debate, largely because of concerns riers, as well as to patients referred from elsewhere until that it may promote the emergence of antibiotic-resistant MRSA noncarrier status was documented . All pa- strains [5, 6]. Also, the effect of SDD in ICUs with endemic tients received systemic cefotaxime, 1 g every 8 hours, circulation of multidrug-resistant gram-negative bacilli during the first 4 days of SDD therapy, except patients MDR-GNB) remains controversial [7, 8]. We investigated with infections on admission, who were treated with whether long-term use of SDD was efficacious in reducing their antibiotics. ICU-acquired MDR-GNB infection and also sought to determine its effect, including colistin- and Endpoints tobramycin-resistant colonization as well as other The primary endpoints of the study were the incidence nosocomial infections and subsequent antibiotic con- of ICU-acquired infection caused by MDRB, the evolu- sumption, in a mixed ICU with a high endemic level tion of colistin- and tobramycin-resistant colonization, of multidrug-resistant bacteria (MDRB). and the clinical impact of SDD on MDRB infections. Secondary endpoints were VAP, central line-associated Methods primary bloodstream infection (CLABSI), secondary Study design and patients bloodstream infection (BSI), urinary tract infection, and We conducted a prospective cohort study in a 30-bed antibiotic consumption. medical-surgical ICU of an acute care tertiary hospital in Las Palmas de Gran Canaria, Canary Islands, Spain. All consecutive patients admitted to the ICU between Sep- Study procedures and definitions tember 1, 2010, and September 30, 2015, were included. Surveillance samples from the throat, rectum, tracheos- They were grouped into two consecutive cohorts before tomy, and pressure sores were collected on ICU admis- and after implementation of SDD. Data of both cohorts sion and once weekly thereafter. Diagnostic samples were collected prospectively. Patients admitted between from tracheal aspirates, peripheral blood, urine, or September 1, 2010, and September 30, 2011, were in- wounds were obtained at the physician’s discretion. cluded in the non-SDD cohort, and patients admitted Antimicrobial susceptibility testing was performed with between October 1, 2011, and September 30, 2015, were the VITEK-2 system (bioMérieux, Inc., Durham, NC, included in the SDD cohort. Since October 1, 2011, USA) , with breakpoints defined according to the SDD measures have been systematically applied to all Clinical and Laboratory Standards Institute  and the ICU patients expected to require tracheal intubation for European Committee on Antimicrobial Susceptibility more than 48 hours (SDD cohort). SDD was started Testing  guidelines. Infections caused by MDRB in- when the “Pneumonia Zero” project began to be imple- cluded the following: mented among Spanish ICUs. In the “Pneumonia Zero” project, SDD was a highly recommended component of 1. Enterobacteriaceae spp. resistant to ceftazidime the ventilator-associated pneumonia (VAP) prevention and/or aminoglycosides and/or ciprofloxacin with Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 3 of 11 extended-spectrum β-lactamase (ESBL) producing started in 2010. The ENVIN-HELICS registry was approved bacteria by the ethics committees of the majority of participating 2. Pseudomonas aeruginosa resistant to ceftazidime ICUs and was declared a registry of healthcare interest by and/or aminoglycosides and/or ciprofloxacin and/or the Spanish Ministry of Health, Social Services and Equality imipenem in 2014. The ENVIN-HELICS registry was also approved 3. MRSA by our hospital’s ethics committee. We applied SDD in the 4. Any strain of Acinetobacter spp. resistant to context of the Spanish national “Pneumonia Zero” project carbapenems , the framework for implementing SDD, which is sup- 5. Gram-negative bacteria resistant to three or more ported by the Spanish Ministry of Health, Social Policy and antimicrobial families Equality through a contract with the Spanish Society of 6. Clostridium difficile Critical Care Medicine and Coronary Units (number 0100/ 7. Vancomycin-resistant Enterococcus spp. 2010/0784). The study protocol was approved by the Clin- ical Research Ethics Committee of Hospital del Mar Imported MDRB infection was considered when cultures (Barcelona, Spain), which was the national reference of surveillance or diagnostic samples were positive within committee. 48 hours of ICU admission. ICU-acquired MDRB infection was defined as isolation of a new strain that was not recov- Statistical analysis ered in any of the samples taken during the first 48 hours Categorical variables are expressed as frequencies and of admission. Also, secondary endogenous infections were percentages, and quantitative variables are expressed as thoseprecededbygastrointestinalcarriageofMDRBwith mean ± SD or median and IQR (25th–75th percentiles) identical antibiotic susceptibility patterns and exogenous in- as appropriate. Percentages were compared with the χ fections when the infecting MDRB was isolated in diagnos- test, means with Student’s t test, and medians with the tic samples without previous colonization . Wilcoxon test for independent data. Statistically signifi- ICU-acquired infections were collected from the cant variables in the univariate analysis were introduced ENVIN-HELICS registry (National Nosocomial Infection in a multivariate logistic regression model, with selection Surveillance Study–HospitalsinEuropeLinkfor Infection of variables based on a complete enumeration algorithm Control through Surveillance), which is a nationwide on- and the Bayes information criterion. The models were going multicenter data collection system designed to record summarized as coefficients (β), SE, P values (likelihood invasive device-related infections in ICU patients (http:// ratio test), and ORs, which were estimated by 95% CIs. hws.vhebron.net/envin-helics/). Diagnostic criteria estab- For each ICU-acquired infection, the incidence per lished by the ENVIN-HELICS project were used . The 1000 days of exposure in each cohort and the corre- diagnosis of VAP included the following: sponding relative risks (RRs) were obtained by Poisson 1. Sequential chest x-rays or computed tomographic regression analysis. Specifically, for the ith cohort deter- (CT) scans with an image suggestive of pneumonia mined by hospital, year, and month, we denote by m the (two or more radiographs or CT scans in the pres- number of events and by d the number of days of ence of underlying cardiac or pulmonary disease) exposition (for all patients). A random effects Poisson 2. Fever (> 38 °C) and/or leukocytosis (≥ 12,000 white model  was considered, which assumes that, blood cells [WBC]/mm ) or leukopenia (≤ 4000 m ~Poisson(υ μ )is: i i i WBC/mm ) 3. At least one of the following: logμ ¼ logd þ α þ β∙SDD i i a. New-onset purulent sputum or change in the char- acteristics of sputum where υ , …, υ are continuous positive valued idd ran- 1 k b. Cough, dyspnea, or tachycardia dom variables such that E[υ ] = 1 and var(υ )= τ. SDD is i i c. Rales or bronchial breath sounds on auscultation, 1/0 according presence/absence of SDD. The parameter ronchi, wheezing τ is the overdispersion. The RR deduced from the model d. Worsening gas exchange is RR = exp β. The model was estimated by the likelihood Other infections were diagnosed according to the Cen- method and summarized by the RRs, which were ters for Disease Control and Prevention definitions  estimated by 95% CIs. Statistical significance was set at when applicable to ICU patients. P ≤ 0.05. Data were analyzed using the R package, version 3.3.1 (R Development Core Team, 2016) . Ethics Our ICU participated in the ENVIN-HELICS national Results registry, and we used this registry for prospective data col- During the 5-year study period, 3948 critically ill pa- lection during the study . Baseline data collection tients were admitted to the ICU, and ICU-acquired Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 4 of 11 infection (VAP, CLABSI, secondary BSI, urinary tract in- infection, renal replacement therapy (OR, 2.130; 95% CI, fection) was diagnosed in 368 of them (7.8%). Of a total 1.346–3.372; P = 0.001) was an independent risk factor of 994 patients admitted to the ICU between September for MDRB infection, whereas SDD was a protective fac- 2010 and September 2011, 110 patients had tor (OR, 0.491; 95% CI, 0.305–0.790; P < 0.001). ICU-acquired infection in the non-SDD cohort. Of the Treatment with SDD was associated with a significant 3948 patients admitted between October 2011 and reduction of the RR for ICU-acquired infections caused September 2015, SDD was administered to 1998 (50.6%), by MDRB, VAP, and secondary BSI (Table 3). The prob- and 258 developed an ICU-acquired infection (SDD abilities of acquiring infections caused by MDRB, VAP, cohort) (Fig. 1). No complications related to the use of and secondary BSI were 69%, 57%, and 66% lower, re- SDD were recorded. spectively, in the SDD cohort than in the non-SDD Results of univariate analysis are shown in Table 1. cohort. Demographic data and the distribution of most variables The consumption of nine antimicrobial agents com- were similar in both cohorts. In the non-SDD cohort, monly used in critically ill patients for treating MDRB, the percentage of patients with chronic obstructive pul- expressed as defined daily dose per 100 bed-days in the monary disease and CLABSI was significantly lower than ICU, also showed a marked reduction after implementa- in the SDD cohort. However, we observed significantly tion of the SDD prophylactic strategy (Table 4). During lower rates of infections caused by MRDB, including the study period, other maneuvers directed toward redu- Acinetobacter spp., other GNB and ESBL-producing cing the use of antimicrobials were not applied. multidrug-resistant bacteria, VAP, and secondary BSI, in Of a total of 3948 patients admitted to the ICU during the SDD cohort than in the non-SDD cohort. A signifi- the 4-year period of implementation of the SDD treat- cantly higher number of patients with CLABSI in the ment, 285 showed surveillance samples colonized by co- SDD cohort than in the non-SDD cohort was found. listin- or tobramycin-resistant pathogens. As shown in ICU-acquired infections caused by C. difficile or Table 5, there were increases of colonization resistance vancomycin-resistant Enterococcus spp. did not occur. In to colistin and tobramycin at ICU admission. Also, as the multivariate analysis, SDD was found to be a pro- shown in Table 5, the estimated rates adjusted to 100 pa- tective factor against ICU-acquired infections caused by tients with SDD decreased in the fourth year for Acinetobacter spp. and MDR-GNB (Table 2). In the tobramycin-resistant colonization and increased from multivariate logistic regression model for MDRB 1.6 to 1.8 for colistin-resistant colonization in the third and fourth years of the study. The colistin- and tobramycin-acquired increasing rates of colonization re- sistance in the ICU by 1000 days and adjusted by the rate of resistances at admission were 0.82 (95% CI, 0.56 to 1.95; not statistically significant [NS]) and 1.13 (95% CI, 0.75 to 1.70; NS), respectively. The highest estimated rates of colistin- and tobramycin-resistant colonization by 1000 days in the ICU were 1.2 and 1.1 per 1000 days of ICU stay, respectively (Table 6). A summary of the study findings is shown in Fig. 2. Discussion Themainfinding ofthepresent studyisa significant reduction in the incidence of infections caused by MDRB, including Acinetobacter spp., and other GNB- and ESBL-producing pathogens after 4 years of implementation of SDD in the daily care of ICU patients. Additionally, low rates of colistin- and tobramycin-resistant colonization were also observed in surveillance samples, with no significant increasing rate of ICU colonization resistance, by 1000 days, adjusted by the rate of resistances at ICU admission. In addition, VAP and secondary BSI infection rates declined. These findings were associated with a reduction in antibiotic Fig. 1 Patient flowchart. SDD Selective digestive consumption, which is a remarkable aspect of the tract decontamination present results. Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 5 of 11 Table 1 Results of univariate analysis Variables Non-SDD cohort SDD cohort P value (n = 110) (n = 258) Male sex 74 (67.3) 166 (64.3) 0.589 Age, years, mean ± SD 59.5 ± 15.8 60.7 ± 16.4 0.539 APACHE II score on admission, mean ± SD 21.2 ± 7.7 22.0 ± 7.7 0.345 Glasgow Coma Scale score, median (IQR) 15 (8–15) 14.5 (8–15) 0.098 Diagnosis on ICU admission 0.289 Medical 79 (71.8) 190 (73.6) Scheduled surgery 10 (9.1) 33 (12.8) Emergency surgery 21 (19.1) 35 (13.6) Septic response 0.399 Sepsis 57 (52.8) 110 (45.45) Septic shock 51 (47.2) 132 (54.55) Prior surgery 18 (16.4) 37 (14.3) 0.618 Urgent surgery 34 (30.9) 70 (27.1) 0.461 Trauma patients 17 (15.5) 31 (12.0) 0.370 Current smokers 21 (19.1) 31 (27.4) 0.141 Underlying illness Diabetes mellitus 34 (30.9) 86 (33.3) 0.650 Coronary artery disease 19 (17.3) 45 (17.4) 0.969 Chronic liver disease 6 (5.5) 18 (7.0) 0.588 Chronic obstructive lung disease 9 (8.2) 43 (16.7) 0.032 Solid neoplasm 10 (9.1) 26 (10.1) 0.771 Chronic renal failure 40 (36.4) 56 (21.7) 0.003 Renal replacement therapy 34 (30.9) 91 (35.3) 0.419 Parenteral nutrition 26 (23.6) 50 (19.4) 0.356 Immunosuppression 8 (7.3) 22 (8.5) 0.687 Malnutrition 12 (10.9) 24 (9.3) 0.635 ICU-acquired infection VAP 59 (53.6) 102 (39.5) 0.013 CLABSI 26 (23.6) 106 (41.1) 0.001 Secondary BSI 31 (28.2) 47 (18.2) 0.023 Urinary tract infection 29 (26.4) 73 (28.3) 0.705 Infections caused by MDRB Gram-negative bacilli 12 (10.9) 8 (3.1) 0.002 Acinetobacter spp. 13 (11.8) 3 (1.2) < 0.001 ESBL-producing MDRB 38 (34.5) 62 (24.0) 0.038 Pseudomonas aeruginosa 10 (9.1) 23 (8.9) 0.957 Methicillin-resistant Staphylococcus aureus 4 (3.6) 5 (1.9) 0.460 ICU stay, days, median (IQR) 28 (16–45) 33 (17–50) 0.192 ICU mortality 36 (32.7) 85 (33.2) 0.929 Abbreviations: SDD Selective digestive tract decontamination, ICU Intensive care unit, APACHE Acute Physiology and Chronic Health Evaluation, VAP Ventilator-associated pneumonia, CLABSI Central line-associated bloodstream infection, BSI Bloodstream infection, MDRB Multidrug-resistant bacteria, ESBL Extended-spectrum β-lactamase Data are expressed as frequency and percent unless otherwise stated Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 6 of 11 Table 2 Results of multivariate logistic regression analysis Table 4 Antibiotic consumption during the study period for selective digestive tract decontamination Drug Non- SDD period (4 years) SDD Variable P value OR (95% CI) 1st year 2nd year 3rd year 4th year period CLABSI 0.003 2.218 (1.307 to 3.764) (1 year) Acinetobacter spp. < 0.001 0.091 (0.025 to 0.329) Levofloxacin 59.01 38.10 50.79 43.96 13.89 MDR-GNB 0.001 0.204 (0.079 to 0.527) Meropenem 43.09 32.46 32.30 27.9 11.10 CLABSI Central line-associated bloodstream infection, MDR-GNB Multidrug- Imipenem 25.08 10.20 12.57 6.06 3.15 resistant gram-negative bacilli Colistin 19.17 10.78 12.13 4.98 0.43 We found a significant reduction of ICU-acquired Vancomycin 7.23 4.95 6.96 6.56 2.47 infections caused by MDR-GNB following SDD in our Tobramycin 10.32 3.69 1.89 1.87 0.55 ICU with a high level of antibiotic resistance before Amikacin 3.13 4.28 3.10 3.08 2.47 implementation of the SDD strategy. There is limited Ceftazidime 7.29 5.48 5.12 10.93 5.80 information on the effects of SDD in settings with Ciprofloxacin 9.61 12.85 8.50 8.62 8.45 high levels of MDRB. Four observational studies [7, Cefotaxime 6.01 22.6 22.3 22.7 22.7 21–23] and one small randomized controlled trial  have been performed in ICUs where MDR-GNB were SDD Selective digestive tract decontamination Data are expressed as defined daily dose per 100 bed-days in the intensive endemic or that had an outbreak of certain species of care unit MDR-GNB. In these studies, SDD was applied either as a systematic treatment [21–23] or as a targeted ap- found to be useful in three studies [7, 21, 23]and proach for identified carriers [7, 8]. Most of these failed in two of them [8, 22]. Brun-Buisson et al.  previous studies examined the effect of SDD on elim- reported that SDD reduced colonization or carrier ination or persistence of carriage of resistant strains, status and infection during an outbreak of but ecological outcomes were not reported. Moreover, ESBL-producing Klebsiella pneumoniae.Our study heterogeneity regarding settings and designs prevented confirms that SDD can be useful in an environment clear interpretation of the findings; in fact, SDD was with high levels of MDR-GNB. Table 3 Intensive care unit-acquired infection rates Non-SDD cohort (n = 110) SDD cohort (n = 258) P value Risk ratio (95% CI) VAP/MV days Number of VAP 63 110 < 0.001 0.437 (0.320 to 0.595) Days of MV 6112 24,432 VAP/1000 MV days 10.3 4.5 Urinary tract infection/urinary catheter days Number of urinary tract infections 33 97 0.110 0.725 (0.488 to 1.076) Days of indwelling urinary catheter 8707 35,312 Urinary infections/1000 catheter days 3.79 2.75 CLABSI/CVC days Number of CLABSI 0.802 1.056 (0.690 to 1.615) Days of CVC 7249 30,631 CLABSI/1000 CVC days 3.59 3.9 Secondary BSI/ICU days Number of secondary BSI 43 57 < 0.001 0.349 (0.237 to 0.516) ICU days of stay 9176 37,857 Secondary BSI/1000 ICU days 4.69 1.64 MDRB/ICU days Number of MDRB infections 88 112 < 0.001 0.308 (0.233 to 0.408) ICU days of stay 9176 37,857 MDRB infections/1000 ICU days 9.59 2.96 Abbreviations: SDD Selective digestive tract decontamination, VAP Ventilator-associated pneumonia, MV Mechanical ventilation, CLABSI Central line-associated bloodstream infection, CVC Central venous catheter, BSI Bloodstream infection, MDRB Multidrug-resistant bacteria Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 7 of 11 Table 5 Colonization in surveillance samples by colistin- and tobramycin-resistant pathogens Variables SDD period (between October 2011 and September 2015) Total 1st year 2nd year 3rd year 4th year (n = 285) (n = 59) (n = 56) (n = 69) (n = 101) Male sex, % 66.7 67.8 71.4 60.9 67.2 Age, years, mean ± SD 60.7 ± 15.0 56.2 ± 14.4 61.0 ± 16.0 61.3 ± 12.4 62.4 ± 16.1 Total patients 3948 1067 1069 851 961 Patients with SDD 1998 522 381 430 665 Colistin Resistance at ICU admission 113 (39.6) 5 (8.5) 17 (30.4) 30 (43.5) 61 (60.4) Development of resistance 30 (10.5) 3 (5.1) 8 (14.3) 7 (10.1) 12 (11.9) Observed (at ICU admission) Rate/100 patients 2.86 0.47 1.59 3.53 6.35 Rate/100 patients SDD 5.66 0.96 4.46 6.98 9.17 Estimated (acquired in ICU) Rate/100 patients 0.76 0.28 0.75 0.82 1.25 Rate/100 patients SDD 1.5 0.57 2.1 1.63 1.8 Tobramycin Resistance at ICU admission 151 (52.9) 17 (6.0) 32 (11.2) 34 (11.9) 68 (23.9) Development of resistance 30 (10.5) 1 (0.4) 3 (1.1) 15 (5.3) 11 (3.9) Observed (at ICU admission) Rate/100 patients 3.82 1.59 2.99 3.99 7.08 Rate/100 patients SDD 7.56 3.26 8.4 7.91 10.23 Estimated (acquired in ICU) – Rate/100 patients 0.76 0.09 0.28 1.76 1.14 Rate/100 patients SDD 1.5 0.19 0.79 3.49 1.65 ICU Intensive care unit, SDD Selective digestive tract decontamination Table 6 Evolution of rates of resistance to colistin and tobramycin in ICU, by 1000 days Resistance Period 1st year 2nd year 3rd year 4th year (n = 59) (n = 56) (n = 69) (n = 101) Patient-days 9228 8583 10,731 9315 Colistin At admission 5 (8.5) 17 (30.4) 30 (43.5) 61 (60.4) Acquired in ICU 3 (5.1) 8 (14.3) 7 (10.1) 12 (11.9) Acquired in ICU, by 1000 days 0.325 0.932 0.652 1.288 Acquired in ICU, by 1000 days and adjusted 0.278 0.228 0.187 0.153 by rate of resistance at admission Tobramycin At admission 17 (6.0) 32 (11.2) 34 (11.9) 68 (23.9) Acquired in ICU 1 (0.4) 3 (1.1) 15 (5.3) 11 (3.9) Acquired in ICU, by 1000 days 0.108 0.350 1.398 1.181 Acquired in ICU, by 1000 days and adjusted 0.144 0.162 0.182 0.205 by rate of resistance at admission ICU Intensive care unit The increasing rate of colistin- and tobramycin-acquired colonization resistance in the ICU by 1000 days and adjusted by the rate of resistance at admission was 0.82 (95% CI, 0.56 to 1.95; not statistically significant [NS]). P value for the goodness-of-fit test was 0.427. For tobramycin, the increasing rate was 1.13 (95% CI, 0.75 to 1.70; nonsignificant). P value for the goodness-of-fit test was 0.159 Adjusted for values corresponding to first year, namely number of patients, number of resistances at admission, and exposure days Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 8 of 11 Fig. 2 Summary of study findings. ESBL Extended-spectrum β-lactamase However, the present results are in accord with data of of 81% by Enterobacteriaceae, and these reductions were studies carried out in settings with low levels of anti- not accompanied by increases in intrinsic MDR-GNB biotic resistance, including findings of systematic reviews colonization or infection . A further analysis showed that of randomized controlled trials [3, 4] and long-term ob- development of ICU-acquired bacteremia caused by highly servational studies [24–27], confirming that SDD does resistant microorganisms was 59% less frequent with SDD not increase resistance. We also observed a significant than with standard care and 63% less frequent with SDD reduction of infections caused by ESBL-producing than with SOD . Recently, Camus et al. found that MDRB. Similarly, Saidel-Odes and coworkers  re- the incidence rate of multidrug-resistant AGNB was lower ported that SDD decreased intestinal overgrowth of during SDD (1.59 per 1000 patient-days versus preinterven- carbapenem-resistant K. pneumoniae. Zandstra et al. tion 5.43%; P < 0.001) and also declined with time, con-  also found that SDD is efficacious in controlling cluding that a decontamination regimen did not favor the colonization with ESBL-producing bacteria, and Tascini emergence of multidrug-resistant AGNB. In agreement et al.  showed that oral administration of gentamicin with other studies, infections caused by C. difficile and decontaminated the gastrointestinal tract and prevented vancomycin-resistant Enterococcusspp.werenot infections caused by carbapenem-resistant K. pneumo- registered. niae strains producing K. pneumoniae carbapenemase The use of SDD resulted in a significant reduction of (KPC)-type β-lactamase. VAP, which is consistent with previous observations. In a We also found a significant reduction of the incidence of systematic review of randomized controlled trials of anti- infections caused by Acinetobacter baumannii and biotic prophylaxis in 6914 ICU patients collected from 36 MDR-GNB. Similarly, in a randomized controlled study of trials, there was a significant reduction of respiratory tract 934 patients admitted to a surgical and medical ICU, of infections in the treated group (OR, 0.28; 95% CI, 0.65 to whom 466 were assigned to SDD and 468 to standard treat- 0.87) . Also, in a study of 4945 mechanically ventilated ment (control subjects), colonization with gram-negative patients admitted between 2005 and 2013, the incidence of bacteria resistant to ceftazidime, ciprofloxacin, imipenem, VAP per 1000 ventilator days declined significantly from polymyxin E, or tobramycin occurred in 16% of SDD pa- 4.38 ± 1.64 before to 1.64 ± 0.43 after introduction of SOD/ tients and in 26% in the control group (P = 0.001) . In a SDD in December 2010 (P = 0.007) . Implementation crossover study using cluster randomization in 13 ICUs in of SDD as the standard of care in ICUs is thus effective in the Netherlands, the rate of isolation of gram-negative bac- preventing VAP. teria from rectal swabs was lower with SDD than with se- A further remarkable finding of the study was a signifi- lective oropharyngeal decontamination (SOD) . Also, cant reduction of secondary BSI associated with the use SDD, as compared with standard care, was associated with of SDD. In a randomized study involving 16 Dutch a reduction of 57% of ICU-acquired bacteremia caused by ICUs, the proportion of ICU-acquired bacteremia by En- glucose-nonfermenting gram-negative rods (P. aeruginosa, terobacteriaceae was lower for SDD than for SOD (OR, Stenotrophomonas maltophilia,and Acinetobacter spp.) and 0.38; 95% CI, 0.26 to 0.55; P < 0.001) . In a systematic Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 9 of 11 review of 51 randomized controlled trials conducted be- Colistin- and tobramycin-resistant colonization rates tween 1987 and 2005, comprising 4079 patients treated in our study were lower than 2.5/1000 patients days at with SDD and 3986 control subjects, SDD was associ- risk, as shown in the study by Oostdijk et al. . Using ated with a reduction of overall and gram-negative BSIs two large cohorts of ICU patients, Oostdijk et al. dem- of 27% and 61%, respectively, without affecting onstrated that the prolonged use of colistin, as part of gram-positive BSIs . Furthermore, prophylactic treat- SDD and SOD, was not associated with increased acqui- ment with SDD was a protective factor for infections sition of colistin-resistant GNB in the respiratory tract. caused by MRDB. In a systematic review and Moreover, acquisition rates of colistin-resistant GNB in meta-analysis of 64 studies assessing the effect of SDD the intestinal tract during SDD ranged from 1.2 to 3.2 and SOD on antimicrobial resistance, no differences per 1000 patient-days at risk. The overall conversion rate were found in the prevalence of colonization or infection from colistin susceptibility to resistance in the intestinal with gram-positive antimicrobial-resistant pathogens tract was below 1 conversion per 1000 patient-days at (MRSA, vancomycin-resistant enterococci) and risk. During SDD, though, these conversion rates ranged gram-negative bacilli resistant to aminoglycosides and from 3.2 to 5.4 per 1000 days of colonization with GNB fluoroquinolones . However, there was a reduction and from 15.5 to 12.6 per 1000 days of colonization with in polymyxin-resistant and third-generation tobramycin-resistant GNB. Also, the use of meropenem cephalosporin-resistant gram-negative bacilli in recipi- appeared to be strongly associated with the development ents of SDD compared with those who did not receive of meropenem resistance in P. aeruginosa with an ad- the intervention. According to these data, the perceived justed HR of 11.1 (95% CI, 2.4–51.5), corresponding to risk of long-term harm related to SDD cannot be justi- 23 events of resistance acquisition per 1000 patient-days fied. The authors also conclude that the effect of SDD at risk. . On the basis of these findings, we con- on ICU-level antimicrobial resistance rates is probably cluded, as Oostdijk et al.  did, that the rates of resist- understudied. However, emergence of antimicrobial re- ance acquisition for frequently used antibiotics were sistance is still a main objection to the widespread use of considerably higher than for acquisition of colistin resist- SDD in ICUs [5, 6, 8]. ance during topical use of this agent. Also, there is a controversy regarding the emergence of an Our findings differ from those of previous studies increased resistance to colistin and tobramycin used as part showing no increase in acquisition of resistant flora to of SDD. We found low rates of colistin- and these agents over a 5-year period  or no increases in tobramycin-resistant colonization in cultures of surveillance the prevalence of resistance against colistin and tobra- samples during the 4-year SDD. It is known that there may mycin among gram-negative isolates during a mean of be nosocomial transmission of highly resistant microorgan- 7 years of SDD or SOD use . Noteboom et al.  isms from one patient infected to another, with or without also observed that the percentages of antibiotic resist- SDD, and that this can increase the number of patients with ance with SDD and standard care were similar. GNB-resistant colonization . As shown in Table 5,there However, in a short course of SDD with colistin are increases of colonization resistance to colistin and tobra- and gentamicin during an outbreak due to a mycin at ICU admission. Also, the estimated rates adjusted KPC-2-producing K. pneumoniae strain, development to 100 patients with SDD decreased in the fourth year for of secondary resistance to colistin (19% increase in tobramycin-resistant colonization and showed a small in- resistance rate) and gentamicin (45% increase) was crease from 1.6 to 1.8 for colistin-resistant colonization in found . Halaby et al.  reported a significant relation- the third and fourth years of the study. The colistin- and ship between use of SDD and tobramycin resistance as tobramycin-acquired increasing rates of colonization resist- well as resistance to colistin among ESBL-producing ance in the ICU by 1000 days and adjusted by the rate of re- pathogens. Brink et al.  showed the emergence of sistances at admission were 0.82 (95% CI, 0.56 to 1.95; NS) KPC in Enterobacteriaceae and the selection of strains and 1.13 (95% CI, 0.75 to 1.70; NS), respectively. These find- resistant to colistin. Of note, Silvestri et al. , regard- ings mean that although there were increases in the rates of ing data reported by Brink et al. , argued that an in- colistin- and tobramycin-resistant colonization, these in- adequate dose of enteral antimicrobials in the SDD creases could not be associated with SDD and may have protocol was responsible for the failure of K. pneumo- been linked to the progressive rise of MDR-GNB at ICU ad- niae to decolonize and eventually become resistant to mission over the 4 years of the study and also may have been colistin. Failure associated with subtherapeutic doses of due to a higher degree of nosocomial transmission of highly SDD may cause overgrowth of MDR-GNB, with in- resistant microorganisms among ICU patients. The highest creased spontaneous mutation leading to polyclonality estimated rates of colistin- and tobramycin-resistant and resistance . colonization by 1000 days at risk were 1.2 and 1.1 per Associations between prolonged intravenous colistin 1000 days, respectively (Table 6). use and development of colistin resistance have been Sánchez-Ramírez et al. Critical Care (2018) 22:141 Page 10 of 11 reported from settings with high levels of MAHV collected data and supervised the registry. LCB collected data and supervised the registry. PS performed statistical analysis and interpreted data. carbapenemase-producing GNB [44, 45]. In contrast to NSM collected data and critically reviewed the manuscript. FAC collected facilitating resistance, SDD has been used successfully as data and critically reviewed the manuscript. CFLV collected data. SRS a control measure in outbreak situations with designed the study, drafted the manuscript, analyzed results, interpreted data, and provided general supervision of the study. MCS collection of data ESBL-producing GNB [7, 46]. High intraluminal levels and supervision of the registry. All authors read and approved the final of topical antibiotics exceed minimum inhibitory con- manuscript. centrations of resistant pathogens, leading at least to Ethics approval and consent to participate temporary suppression, which reduces the risk of over- The ENVIN registry was approved by the ethics committees of the majority growth and cross-transmission. However, there are sev- of participating ICUs, including our hospital, and was declared a registry of eral factors aside from SDD that produce GNB-resistant healthcare interest by the Spanish Ministry of Health, Social Services and Equality in 2014. colonization. We did not find any MDR-GNB suscep- tible only to colistin in our study. Also, we observed de- Consent for publication creased ICU global mortality over the course of the Not applicable, given the noninterventional nature of the study, because data were collected from the ENVIN-HELICS registry. 4-year application of SDD. Nevertheless, we think that SDD must be accompanied Competing interests by careful monitoring of tobramycin and colistin resist- The authors declare that they have no competing interests. ance in GNB. We do so, as described in our protocol. We recommended screening weekly throughout the ICU stay. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Conclusions SDD in an ICU setting with a high level of resistance Author details Intensive Care Unit, Hospital Universitario de Gran Canaria Dr. Negrín, Las was associated with a clinically relevant reduction of in- Palmas de Gran Canaria, La Ballena s/n, E-35010 Las Palmas, Spain. fections caused by MDRB, with low rates of colistin- and 2 Mathematics Department, Universidad de las Palmas de Gran Canaria, Las tobramycin-resistant colonization and a nonsignificant Palmas, Spain. Microbiology Department, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Las Palmas, Spain. Pharmacy increasing rate of ICU colonization resistance by Department, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de 1000 days, adjusted by the rate of resistance at ICU ad- Gran Canaria, Las Palmas, Spain. mission. SDD was also a protective factor against MDRB Received: 26 February 2018 Accepted: 9 May 2018 infection. Furthermore, VAP and secondary BSI were significantly decreased after SDD. Notably, a decrease in antimicrobial consumption was also observed. References 1. Oostdijk EAN, Kesecioglu J, Schultz MJ, Visser CE, de Jonge E, van Essen Abbreviations HER, et al. Effects of decontamination of the oropharynx and intestinal tract AGNB: Aerobic gram-negative bacilli; APACHE: Acute Physiology and Chronic on antibiotic resistance in ICUs: a randomized clinical trial. JAMA. 2014;312: Health Evaluation; BSI: Bloodstream infection; CLABSI: Central line-associated 1429–37. bloodstream infection; CLSI: Clinical and Laboratory Standards Institute; 2. Silvestri L, van Saene HK, Milanese M, Gregori D, Gullo A. Selective CT: Computed tomographic; CVC: Central venous catheter; ENVIN: National decontamination of the digestive tract reduces bacterial bloodstream Nosocomial Infection Surveillance Study; ESBL: Extended-spectrum β- infection and mortality in critically ill patients. 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