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Active surveillance testing to reduce transmission of carbapenem-resistant, gram-negative bacteria in intensive care units: a pragmatic, randomized cross-over trial

Active surveillance testing to reduce transmission of carbapenem-resistant, gram-negative... Background In intensive care unit (ICU) settings, the transmission risk of carbapenem‑resistant, gram‑negative bac‑ teria (CRGNB) is high. There is a paucity of data regarding the effectiveness of interventions, including active screen‑ ing, preemptive isolation, and contact precautions, to reduce transmission of CRGNB. Methods We conducted a pragmatic, cluster‑randomized, non‑blinded cross‑ over study in 6 adult ICUs in a tertiary care center in Seoul, South Korea. ICUs were randomly assigned to perform active surveillance testing with preemp‑ tive isolation and contact precautions (intervention) or standard precautions (control) during the initial 6‑month study period, followed by a 1‑month washout period. During a subsequent 6‑month period, departments that used standard precautions switched to using interventional precautions and vice versa. The incidence rates of CRGNB were compared between the two periods using Poisson regression analysis. Results During the study period, there were 2268 and 2224 ICU admissions during the intervention and control periods, respectively. Because a carbapenemase‑producing Enterobacterales outbreak occurred in a surgical ICU (SICU), we excluded admissions to the SICU during both the intervention and control periods and performed a modi‑ fied intention‑to ‑treat (mITT ) analysis. In mITT analysis, a total of 1314 patients were included. The acquisition rate of CRGNB was 1.75 cases per 1000 person‑ days during the intervention period versus 3.33 cases per 1000 person‑ days during the control period (IRR, 0.53 [95% confidence interval (CI) 0.23–1.11]; P = 0.07). Conclusions Although this study was underpowered and showed borderline significance, active surveillance testing and preemptive isolation could be considered in settings with high baseline prevalence of CRGNB. Trial registration Clinicaltrials.gov Identifier: NCT03980197. Keywords Active surveillance testing, Carbapenem‑resistant, Gram‑negative bacteria, Contact precautions Jiwon Jung, Joung Ha Park and Hyejin Yang have contributed equally to this work *Correspondence: Sung‑Han Kim kimsunghanmd@hotmail.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jung et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 2 of 8 Patients with histories of CRGNB colonization or infec- Introduction tion were placed under contact precautions at the time Carbapenem-resistant, gram-negative bacteria (CRGNB), of admission. including Pseudomonas aeruginosa, Acinetobacter bau- mannii, and Enterobacterales, have been leading causes of healthcare-associated infections and intensive care unit (ICU)-acquired infections [1]. In Korea, the pro- Active surveillance and contact precautions portion of carbapenem resistance rates in A. bauman- In the intervention period, stool or perirectal swabs for nii (CRAB) and P. aeruginosa (CRPA) have increased; CRPA, CRAB, and CRE surveillance cultures and spu- in a 2015 surveillance program by the Korea Centers tum, or endotracheal cultures for CRPA or CRAB, were for Disease Control and Prevention, 85% of A. bauman- obtained from patients within 2  days of their admission nii and 35% of P. aeruginosa were carbapenem-resistant to the ICU and weekly thereafter. In the intervention [2]. In addition, carbapenem-resistant Enterobacterales period, preemptive isolation and contact precautions (CRE) and carbapenemase-producing Enterobacterales were implemented at admission, and if the initial sur- have also increased exponentially [3]. Transmission of veillance test was negative, contact precautions were CRGNB is a great burden in hospitals because there are ceased, and standard precautions were continued. If the limited treatment options for CRGNB infections, and it initial surveillance test or subsequent surveillances or has high morbidity and mortality. To prevent transmis- clinical culture tests were positive for CRGNB, isolation sion of CRGNB, infection-control measures, including and contact precautions were continued until 3 nega- promotion of hand hygiene, environmental cleaning, and tive consecutive test results were obtained. In the con- screening for carriers, have been implemented. However, trol period, surveillance testing was not performed, and there is limited evidence that screening for identification if clinical specimens were positive for CRGNB, contact of CRGNB carriers is useful. For methicillin-resistant precautions were implemented. During both the inter- Staphylococcus aureus (MRSA), several studies found vention and control periods, daily chlorhexidine-bathing that screening and isolation were not effective for reduc - was performed in all ICUs, and contact precautions were ing its transmission [4] with good hand hygiene compli- required in patients with MRSA and VRE colonization or ance and daily chlorhexidine-bathing. Thus, we aimed to infection. In period 2 (from April to June 2020), universal evaluate the effectiveness of active surveillance testing for use of personal protective equipment (PPE) (gown, glove, identifying CRGNB carriers to reduce its transmission in KF94 mask, and face shield or goggle) was implemented ICUs in the chlorhexidine-bathing era. for response to COVID-19 pandemic when caring patients in ICUs. During the whole study period, hand hygiene compliance was observed 4 times by a year by the Methods infection control team staff, and the results by units were Study design disclosed to all hospital staffs. Promotions for improving We conducted a pragmatic, cluster-randomized, non- the compliance of hand hygiene included frequent moni- blinded cross-over study in the included randomized toring and real-time feedback by infection control leader ICUs between June 2019 and June 2020. We included in ICU nursing team, and hospital-wide rewards given to 6 adult ICUs in a tertiary care hospital, Seoul, South the units with high hand hygiene compliance. Korea: two medical ICUs (23 beds), two surgical ICUs If outbreaks of CRGNB occurred, surveillance and (26 beds), a cardiac ICU (16 beds), and a cardiothoracic post-outbreak surveillance in the control period were surgery ICU (15 beds) in a tertiary care hospital. The permitted. study was approved by the physicians and nurse team leaders of each ICU and the institutional review board Definition (IRB no. 2019–0274). The requirements for informed An event was defined as a positive result for CRGNB consent were waived. ICUs were randomly assigned from a clinical culture. The event date was the date of to perform active surveillance testing (intervention) the earliest positive clinical culture. A patient was clas- or use standard precautions (control) during the ini- sified as having a new event if they had stayed in the tial 6-month study period (period 1), followed by a ICU > 2 days, had no history of colonization or infection 1-month washout period, and alternative during the during the previous year, had no positive clinical culture second 6-month period (period 2). Randomization of within 2  days after admission to the ICU, and if admit- ICU was performed by SPSS for Windows software, ted to an intervention ICU, a negative surveillance cul- version 21 (SPSS Inc., Chicago, IL, USA). The micro - ture was obtained within 2 days of admission. Days at risk biology laboratory processed surveillance specimens were calculated from the date of the third day in the ICU using standard culture-based identification of CRGNB. Jung  et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 3 of 8 through the event date or the date two days after dis- Results charge from the ICU, whichever was later. Characteristics of ICUs and patients The primary outcome was the ICU-level incidence of A total of 4492 admissions to the 6 ICUs occurred during new events per 1000 ICU patient-days at risk. Secondary the study period, and 1884 (42%) with ICU stays ≥ 3 days ICU-level outcomes were the incidences of new events were enrolled in this study (Fig.  1). Two hundred and with CRPA, CRAB, or CRE calculated separately and sixty patients in the intervention period and 98 patients the incidences of hospital-acquired bloodstream infec- in the control period were excluded for ITT analysis, tions, catheter-related bloodstream infections, urinary respectively. A CRE outbreak occurred in SICU2 during tract infections, catheter-associated urinary tract infec- the intervention period, and post-outbreak surveillance tions, pneumonia, ventilator-associated pneumonia, and of CRE was performed in the control period; thus, we in-ICU mortality. We also performed subgroup analysis excluded the 212 patients admitted to SICU2 from the of individual ICUs for new events per 1000 ICU patient- mITT analysis. The original and revised study designs are days at risk. In addition, we compared new events per shown in Additional file  1: Figure S1. There were no sig - 1000 ICU patient-days at risk between periods 1 and 2. nificant differences in characteristics between patients in For the evaluation of economic impacts, we also com- the intervention period and those in the control period pared the lengths of hospital and ICU stays and the costs (Table  1). During the total study period, the observed of hospitalization between the intervention and control hand hygiene compliance was 96%. The number of clini - periods. cal specimens submitted to the laboratory was not differ - Outbreak was defined as ≥ 3 cases of acquisition of ent between intervention and control periods in mITT CRGNB within 2  weeks. If surveillance and post-out- analysis (mean [IQR], 3634 [2824–5568] in intervention break surveillance were performed in the control period period vs. 2767 [1902–4378] in control period; P = 0.35). because of a CRGNB outbreak, we excluded the ICU in the modified intention-to-treat (mITT) analysis. Results of the acquisition rate of CRGNB according to clinical culture Statistical analysis In the mITT analysis, the acquisition rate of CRGNB Based on the acquisition rate of CRGNB from 2016 to was 1.75 cases per 1,000 person-days in the intervention 2018 in ICUs of our hospital, we assumed a mean base- period versus 3.33 cases per 1000 person-days in the con- line incidence of CRGNB colonization or infection of 8 trol period (incidence rate ratio [IRR], 0.53; 95% confi - per 1000 patient-days; between-cluster variance would dence interval [CI] 0.23–1.11; P = 0.07) (Table 2). be 0.4, and the average amount of time a patient spent in the ICU would be 10 days. This study was designed to Secondary outcomes achieve 80% power for detecting a reduction in acquisi- There were no significant differences in the acquisition tion of 40% in the intervention period with a 2-sided type rates of CRPA, CRAB, and CRE in the intervention and I error of 5%. According to these assumptions, the esti- control periods (CRPA, 0.32 vs. 1.07 per 1,000 person- mated sample size was 2400 patients (200 per cluster; a days; IRR, 0.30 [95% CI 0.03–1.50]; P = 0.10; CR AB, total of 12 clusters with one cross-over of 6 ICUs) [5]. 0.80 vs. 1.73 per 1000 person-days; IRR, 0.46 [95% CI Categorical variables were analyzed using the chi- 0.13–1.37]; P = 0.13; CRE, 0.80 vs. 0.93; IRR, 0.85 [95% square or Fisher’s exact test, as appropriate. Normally CI 0.21–3.12]; P = 0.79) (Table 2). In addition, there were and non-normally distributed continuous variables were no significant differences in the rates of hospital-acquired analyzed by Student’s t test and the Mann–Whitney U bloodstream infections, catheter-related bloodstream test, respectively. The primary analysis was a compari - infections, urinary tract infections, catheter-associated son of the primary outcomes between the intervention urinary tract infections, pneumonia, ventilator-associ- and control periods using an unadjusted Poisson regres- ated pneumonia, and in-ICU mortality (Table 3). sion model according to the mITT. All statistical analy- The subgroup analysis of the CRGNB acquisition rate ses were performed using SPSS for Windows software, by ICU is shown in Additional file  1: Table S1. The acqui - version 21 (SPSS Inc., Chicago, IL, USA) and MedCalc sition rates of CRGNB were significantly higher in the Statistical Software version 18.10.2 (MedCalc Software control period than in the intervention period in MICU2, bvba, Sotend, Belgium) with P < 0.05 considered statisti- SICU1, and the cardiac ICU, while the rates were higher cally significant. in the intervention period than in the control period in MICU1 and SICU2; there was no difference between the rates in the intervention and control periods in the car- diothoracic surgery ICU. In ITT analysis, the acquisition rate of CRGNB was 2.94 cases per 1000 person-days in Jung et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 4 of 8 6 ICUs were enrolled 2268 ICU admissions occurred 2224 ICU admissions occurred during the intervention period during the control period 1300 (57%)involvedICU stays≤2days 1308 (59%)involvedICU stays≤2days 968 (43%) involved ICU stays 916 (41%) involved ICU stays ≥3 days ≥3 days 260(11%) were excluded -No surveillance culture ≤2 days (n=104) -Previous colonization with CRPA, 98 (4%) were excluded CRAB, or CRE (n=75) -PreviouscolonizationofCRPA, CRAB, - CRPA, CRAB, or CRE isolation based or CRE (n=78) on surveillance culture ≤2 days (n=75) - CRPA, CRAB, CRE isolation based on - CRPA, CRAB, or CRE isolation based clinical culture ≤2 days (n=20) on clinical culture ≤2 days (n=6) 818 (37%) were eligible for Intention-to-treat analysis 708 (31%) were eligible for intention-to-treat analysis intention-to treat analysis Exclusion Exclusion -94(4%)who were admitted to SICU2 -118 (5%) whowereadmittedtoSICU2 were excluded from modified intention- were excluded frommodifiedintention- to-treat analysis to-treat analysis 724 (33%) were eligible for Modified intention-to-treat 590 (26%) were eligible for analysis modified intention-to-treat modified intention-to-treat analysis analysis Fig. 1 Schematic flow chart of the study. ICU intensive care unit; CRPA carbapenem‑resistant P. aeruginosa; CRAB carbapenem‑resistant A. baumannii; CRE carbapenem‑resistant Enterobacterales Table 1 Demographic and baseline characteristics of the study population Intervention period (n = 590) Control period (n = 724) P value Male sex 338 (57.3) 439 (60.6) 0.22 Age, mean ± SD 66.1 ± 13.3 65.8 ± 13.5 0.69 Underlying diseases Solid cancer 143 (24.2) 183 (25.3) 0.66 Hematologic malignancy 33 (5.6) 47 (6.5) 0.46 Solid organ transplant 34 (5.8) 49 (6.8) 0.46 Hematopoietic stem cell transplant 9 (1.5) 15 (2.1) 0.46 End‑stage renal disease, on dialysis 33 (5.6) 36 (5.0) 0.62 Antibiotics used within the previous 3 months Cefazolin 73 (12.4) 79 (10.9) 0.41 3rd cephalosporin 95 (16.1) 143 (19.8) 0.09 Piperacillin/tazobactam 177 (30.0) 198 (27.3) 0.29 Fluoroquinolone 168 (28.5) 198 (27.3) 0.65 Carbapenem 90 (15.3) 120 (16.6) 0.52 Glycopeptide (vancomycin or teicoplanin) 113 (19.2) 142 (19.6) 0.83 Other 180 (30.5) 210 (29.0) 0.55 ICU stay, days (mean ± SD) 11.0 ± 12.0 11.2 ± 13.7 0.73 The data are shown as no. (%) unless otherwise indicated SD standard deviation Jung  et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 5 of 8 Table 2 Acquisition rates of CRPA, CRAB, and CRE in clinical the intervention period versus 3.46 cases per 1000 person specimens between the intervention and control periods days in the control period (IRR, 0.85; 95% CI 0.46–1.54; P = 0.56) (Additional file 1: Table S2). Intervention Control period, Incidence rate P value period, per 1000 ratio (95% CI) The acquisition rate of CRGNB was significantly higher per 1000 person-days in period 1 than in period 2 (3.68 cases per 1000 per- person-days (95% CI) son-days vs. 0.52 cases per 1000 person-days; P < 0.001) (95% CI) (Additional file 1: Table S3). Modified intention-to-treat analysis Of 104 patients who admitted to ICU during the inter- Total 1.75 (0.87–3.13) 3.33 (2.16–4.92) 0.53 (0.23–1.11) 0.07 vention period but did not perform surveillance culture CRPA 0.32 (0.04–1.15) 1.07 (0.46–2.10) 0.30 (0.03–1.50) 0.10 within 2  days after ICU admission, 15 were admitted to CRAB 0.80 (0.26–1.86) 1.73 (0.92–2.96) 0.46 (0.13–1.37) 0.13 SICU2. We compared the baseline characteristics of the CRE 0.80 (0.26–1.86) 0.93 (0.38–1.92) 0.85 (0.21–3.12) 0.79 remaining 89 patients and those enrolled in interven- CRPA carbapenem-resistant P. aeruginosa; CRAB carbapenem-resistant A. tion group of mITT analysis (n = 590) (Additional file  1: baumannii; CRE carbapenem-resistant Enterobacterales; CI confidence interval Table  S4). Solid organ transplant recipient (16.9% vs. Excluding SICU2 in both periods 1 and 2 5.8%, P < 0.001) and patients with end-stage renal dis- ease (12.4% vs. 5.6%, P = 0.01) were more common in patients without surveillance culture than in intervention group of mITT analysis. Patients with solid cancer was Table 3 Clinical manifestations and outcomes between the intervention and control periods Intervention period Control period P value (n = 590) (n = 724) Clinical diagnosis of infectious diseases Hospital‑acquired bloodstream infection 0 1 (0.1) 0.37 CRPA 0 0 – CRAB 0 1 (0.1) 0.37 CRE 0 0 – Catheter‑related bloodstream infection 0 1 (0.1) 0.37 CRPA 0 0 – CRAB 0 1 (0.1) 0.37 CRE 0 0 ‑ Urinary tract infection 0 1 (0.1) 0.37 CRPA 0 0 ‑ CRAB 0 0 ‑ CRE 0 1 (0.1) 0.37 Catheter‑associated urinary tract infection 0 1 (0.1) 0.37 CRPA 0 0 – CRAB 0 0 – CRE 0 1 (0.1) 0.37 Pneumonia 0 4 (0.6) 0.07 CRPA 0 2 (0.3) 0.20 CRAB 0 2 (0.3) 0.20 CRE 0 1 (0.1) 0.37 Ventilator‑associated pneumonia 0 3 (0.4) 0.12 CRPA 0 2 (0.3) 0.20 CRAB 0 1 (0.1) 0.37 CRE 0 1 (0.1) 0.37 Death – In‑ICU mortality 70 (11.9) 76 (10.5) 0.43 CRPA carbapenem-resistant P. aeruginosa; CRAB carbapenem-resistant A. baumannii; CRE carbapenem-resistant Enterobacterales The data are shown as no. (%) unless otherwise indicated Death during the follow-up periods (until 2 days after ICU discharge) Jung et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 6 of 8 less common in those without surveillance culture than testing is associated with reducing CRGNB transmission, in intervention group of mITT analysis (12.4% vs. 24.2%, but many hospitals have implemented active surveillance P = 0.01). The type of ICU was significantly different testing for identifying CRGNB. Recent studies showed between two groups (P < 0.001), which reflects the differ - that screening and isolation of colonized patients do not ence of compliance of study protocol by ICUs. reduce multidrug-resistant bacteria, especially MRSA, In mITT analysis, 39 (7%) cases in intervention period when compliance with hand hygiene and chlorhexidine- were detected in surveillance culture. Of these, 31 were bathing is high [10–13]. We conducted this study to pro- detected in surveillance culture only, and 8 were detected vide evidence of the effectiveness of active surveillance in in both surveillance and clinical culture. Five were the chlorohexidine-bathing and high hand hygiene com- detected in surveillance culture earlier than in clinical pliance era. Our study had low power because only 79% culture. Therefore, 36 (6%) were actually detected in sur - (1884/2400) of patients were enrolled in the target sam- veillance culture (only or earlier than in clinical culture). ple size, and the baseline acquisition rate was lower than expected. Although it had borderline significance, we Evaluation of the economic impact of active surveillance showed that about half of CRGNB acquisition can be pre- testing vented through active surveillance testing. Therefore, this For the economic impact evaluation of active surveil- strategy may be beneficial in high-baseline-prevalence lance testing of CRGNB, we compared the lengths of settings. A large, multicenter study is needed to confirm hospital and ICU stays and the total cost of hospitaliza- our findings. tion between the intervention and control periods in the The incidence of CRGNB acquisition was higher in the mITT population (Table  4). The mean length of hospi - period 1 (before COVID-19 pandemic) than in period 2 tal stays was 0.9  day shorter in the intervention period (after COVID-19 pandemic). The lower acquisition rate than in the control period, but the difference was not in period 2 may be associated with additional infection statistically significant (P = 0.73). Although there was an prevention measure to respond COVID-19 pandemic, additional cost of $5666 for hospitalization in the inter- especially universal donning of gown and glove. Previous vention period than in the control period, the cost differ - cluster randomized study showed that universal glove ence was also not statistically significant (P = 0.43). and gown use was associated with decrease in acquisition of antibiotic-resistant gram-negative bacteria, although Discussion it was not statistically significant [14]. As we excluded This pragmatic, cluster-randomized, cross-over study SICU2 in the analysis, more patients were allocated to showed that active surveillance testing to identify the control group in the first period, and we may overesti - patients colonized with CRGNB was associated with mate the positive effect of the intervention. Further study non-statistically significant decrease in the acquisition of for evaluating the effectiveness of active surveillance in CRGNB in clinical specimens. the setting of identical infection prevention measures Early detection of patients colonized or infected with between intervention and control period is needed. CRGNB is important for implementing timely interven- In our subgroup analysis, the CRGNB acquisition rate tions to prevent subsequent spread. However, active sur- was higher in the intervention period than in the control veillance testing is a complicated and resource-intensive period in MICU1 and SICU2. Although a CPE outbreak intervention that has the potential for several adverse occurred in SICU2, there was no outbreak of CRGNB in consequences, including reduced contact between MICU1, and the reason for this unanticipated finding is healthcare workers and patients due to contact precau- unclear. It may be a seasonal effect, or more enhanced tions [6]. Previous studies have reported that active environmental cleaning might have been performed dur- surveillance testing in combination with contact precau- ing the control period due to the COVID-19 pandemic, tions for colonized patients contributed to the decline which occurred in the latter 6-month period (Additional of MRSA or vancomycin-resistant Enterococcus [7–9]. file 1: Table S3). However, there is limited evidence that active surveillance Table 4 Lengths of hospital and ICU stays and cost of hospitalizations in the intervention and control periods (mITT population) Intervention period (n = 590) Control period (n = 724) P value Length of hospital stay, mean (± SE) days 44.7 (1.9) 45.6 (1.9) 0.73 Length of ICU stay, mean (± SE) days 11.0 (0.5) 11.2 (0.5) 0.73 Cost of hospitalization ($), mean (± SE) 93,491 (6034) 87,825 (4,252) 0.43 Jung  et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 7 of 8 Author contributions The acquisition rates of CRPA, CRAB, and CRE did JJ and SHK designed the study. JJ, JHP, and HY collected and analyzed the not differ between the intervention and control periods. data. JJ wrote the main manuscript text and JHP prepared figure. YJL, EOK, Because this trial was designed to identify the effective - CML, MNK, MWJ, SCY, and SHK reviewed and revised the manuscript. This study was presented in part in ASM Microbe, 2022, Jun 12, Washington ness of reducing the total CRGNB acquisition rate, fur- DC (Abstract number CIV‑2578). All authors read and approved the final ther study is needed to identify the effectiveness of active manuscript. surveillance testing for each organisms. Funding Our study has some limitations. First, it was a single- This work was supported by grants from the research fund donation for center study with a low prevalence of CRGNB. A mul- COVID‑19 research to Asan Medical Center by Kyu‑Kang Cho. ticenter study with variable prevalences of CRGNB is Availability of data and materials warranted to generalize our findings. Despite this limi - Data and materials are not available. tation, well-monitored infection control practices and policies to minimize unmeasured confounding factors by Declarations different centers during the study period is a strength of our study. Second, as this study was not blinded, the dif- Ethics approval and consent to participate The study was approved by the physicians and nurse team leaders of each ICU ference in the number of clinical specimens submitted to and the institutional review board (IRB no. 2019–0274). The requirements for the laboratory may be present, and this may have affected informed consent were waived. the chance to detect CRGNB. However, the number of Consent for publication clinical specimen was not different between interven - Not applicable. tion and control periods in mITT analysis. Third, we did not perform surveillance testing during the control Competing interests The authors have no competing interests as defined by BMC, or other interests period, which may have biased our findings. However, that might be perceived to influence the results and/or discussion reported in we performed a pragmatic trial that reflects actual clini - this paper. cal practices, and we evaluated the outcomes of CRGNB Author details acquisition in clinical specimens. Fourth, data regarding Department of Infectious Disease, Asan Medical Center, University of Ulsan immunosuppressant use was absent. Use of immunosup- College of Medicine, Seoul, South Korea. Division of Infectious Diseases, pressant is associated with exposure to antimicrobials Department of Internal Medicine, Chung‑Ang University Gwangmyeong Hos‑ pital, Gwangmyeong, South Korea. Office for Infection Control, Asan Medical and acquisition of MDR gram-negative organism [15– Center, Seoul, South Korea. Department of Pulmonary and Critical Care 17]. However, there was no significant difference of the Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, recent antibiotics exposure between the intervention South Korea. Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Depar tment period and the control period. Therefore, this limitation of Preventive Medicine, University of Ulsan College of Medicine, Seoul, South may not substantially affect our main findings. Finally, we Korea. Department of Clinical Epidemiology and Biostatistics, Asan Medical performed a conventional culture method for active sur- Center, University of Ulsan College of Medicine, Seoul, South Korea. veillance, and the turnaround time is longer than rapid Received: 18 October 2022 Accepted: 21 February 2023 PCR testing. Therefore, further study to evaluate active surveillance testing using PCR testing is needed. References Conclusions 1. Tacconelli E, Cataldo MA, Dancer SJ, De AG, Falcone M, Frank U, et al. ESC‑ In conclusion, active surveillance testing for CRGNB may MID guidelines for the management of the infection control measures to reduce transmission of multidrug‑resistant Gram‑negative bacteria in reduce its acquisition in clinical specimens in the ICU hospitalized patients. Clin Microbiol Infect. 2014;20(S1):1–55. without additional costs. Individual hospitals should con- 2. Kim D, Ahn JY, Lee CH, Jang SJ, Lee H, Yong D, et al. 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Multidrug‑resistant Gram‑negative bacterial infections in solid organ transplant recipients—Guidelines from the American Society of Trans‑ plantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13594. 16. Aguilar‑ Guisado M, Espigado I, Martin’Pena A, Gudiol C, Royo‑ Cebrecos C, Falantes J, et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open‑label, randomized, controlled phase 4 trial. Lancet Haematol. 2017;4(12):e573‑83. 17. Anderson DJ, Jenkins TC, Evans SR, Harris AD, Weinstein RA, Tamma PD, Han JH, et al. The role of stewardship in addressing antibacterial resist‑ ance: stewardship and infection control committee of the antibacterial resistance leadership group. Clin Infect Dis. 2017;64:S36‑40. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. 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Active surveillance testing to reduce transmission of carbapenem-resistant, gram-negative bacteria in intensive care units: a pragmatic, randomized cross-over trial

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10.1186/s13756-023-01222-2
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Abstract

Background In intensive care unit (ICU) settings, the transmission risk of carbapenem‑resistant, gram‑negative bac‑ teria (CRGNB) is high. There is a paucity of data regarding the effectiveness of interventions, including active screen‑ ing, preemptive isolation, and contact precautions, to reduce transmission of CRGNB. Methods We conducted a pragmatic, cluster‑randomized, non‑blinded cross‑ over study in 6 adult ICUs in a tertiary care center in Seoul, South Korea. ICUs were randomly assigned to perform active surveillance testing with preemp‑ tive isolation and contact precautions (intervention) or standard precautions (control) during the initial 6‑month study period, followed by a 1‑month washout period. During a subsequent 6‑month period, departments that used standard precautions switched to using interventional precautions and vice versa. The incidence rates of CRGNB were compared between the two periods using Poisson regression analysis. Results During the study period, there were 2268 and 2224 ICU admissions during the intervention and control periods, respectively. Because a carbapenemase‑producing Enterobacterales outbreak occurred in a surgical ICU (SICU), we excluded admissions to the SICU during both the intervention and control periods and performed a modi‑ fied intention‑to ‑treat (mITT ) analysis. In mITT analysis, a total of 1314 patients were included. The acquisition rate of CRGNB was 1.75 cases per 1000 person‑ days during the intervention period versus 3.33 cases per 1000 person‑ days during the control period (IRR, 0.53 [95% confidence interval (CI) 0.23–1.11]; P = 0.07). Conclusions Although this study was underpowered and showed borderline significance, active surveillance testing and preemptive isolation could be considered in settings with high baseline prevalence of CRGNB. Trial registration Clinicaltrials.gov Identifier: NCT03980197. Keywords Active surveillance testing, Carbapenem‑resistant, Gram‑negative bacteria, Contact precautions Jiwon Jung, Joung Ha Park and Hyejin Yang have contributed equally to this work *Correspondence: Sung‑Han Kim kimsunghanmd@hotmail.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jung et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 2 of 8 Patients with histories of CRGNB colonization or infec- Introduction tion were placed under contact precautions at the time Carbapenem-resistant, gram-negative bacteria (CRGNB), of admission. including Pseudomonas aeruginosa, Acinetobacter bau- mannii, and Enterobacterales, have been leading causes of healthcare-associated infections and intensive care unit (ICU)-acquired infections [1]. In Korea, the pro- Active surveillance and contact precautions portion of carbapenem resistance rates in A. bauman- In the intervention period, stool or perirectal swabs for nii (CRAB) and P. aeruginosa (CRPA) have increased; CRPA, CRAB, and CRE surveillance cultures and spu- in a 2015 surveillance program by the Korea Centers tum, or endotracheal cultures for CRPA or CRAB, were for Disease Control and Prevention, 85% of A. bauman- obtained from patients within 2  days of their admission nii and 35% of P. aeruginosa were carbapenem-resistant to the ICU and weekly thereafter. In the intervention [2]. In addition, carbapenem-resistant Enterobacterales period, preemptive isolation and contact precautions (CRE) and carbapenemase-producing Enterobacterales were implemented at admission, and if the initial sur- have also increased exponentially [3]. Transmission of veillance test was negative, contact precautions were CRGNB is a great burden in hospitals because there are ceased, and standard precautions were continued. If the limited treatment options for CRGNB infections, and it initial surveillance test or subsequent surveillances or has high morbidity and mortality. To prevent transmis- clinical culture tests were positive for CRGNB, isolation sion of CRGNB, infection-control measures, including and contact precautions were continued until 3 nega- promotion of hand hygiene, environmental cleaning, and tive consecutive test results were obtained. In the con- screening for carriers, have been implemented. However, trol period, surveillance testing was not performed, and there is limited evidence that screening for identification if clinical specimens were positive for CRGNB, contact of CRGNB carriers is useful. For methicillin-resistant precautions were implemented. During both the inter- Staphylococcus aureus (MRSA), several studies found vention and control periods, daily chlorhexidine-bathing that screening and isolation were not effective for reduc - was performed in all ICUs, and contact precautions were ing its transmission [4] with good hand hygiene compli- required in patients with MRSA and VRE colonization or ance and daily chlorhexidine-bathing. Thus, we aimed to infection. In period 2 (from April to June 2020), universal evaluate the effectiveness of active surveillance testing for use of personal protective equipment (PPE) (gown, glove, identifying CRGNB carriers to reduce its transmission in KF94 mask, and face shield or goggle) was implemented ICUs in the chlorhexidine-bathing era. for response to COVID-19 pandemic when caring patients in ICUs. During the whole study period, hand hygiene compliance was observed 4 times by a year by the Methods infection control team staff, and the results by units were Study design disclosed to all hospital staffs. Promotions for improving We conducted a pragmatic, cluster-randomized, non- the compliance of hand hygiene included frequent moni- blinded cross-over study in the included randomized toring and real-time feedback by infection control leader ICUs between June 2019 and June 2020. We included in ICU nursing team, and hospital-wide rewards given to 6 adult ICUs in a tertiary care hospital, Seoul, South the units with high hand hygiene compliance. Korea: two medical ICUs (23 beds), two surgical ICUs If outbreaks of CRGNB occurred, surveillance and (26 beds), a cardiac ICU (16 beds), and a cardiothoracic post-outbreak surveillance in the control period were surgery ICU (15 beds) in a tertiary care hospital. The permitted. study was approved by the physicians and nurse team leaders of each ICU and the institutional review board Definition (IRB no. 2019–0274). The requirements for informed An event was defined as a positive result for CRGNB consent were waived. ICUs were randomly assigned from a clinical culture. The event date was the date of to perform active surveillance testing (intervention) the earliest positive clinical culture. A patient was clas- or use standard precautions (control) during the ini- sified as having a new event if they had stayed in the tial 6-month study period (period 1), followed by a ICU > 2 days, had no history of colonization or infection 1-month washout period, and alternative during the during the previous year, had no positive clinical culture second 6-month period (period 2). Randomization of within 2  days after admission to the ICU, and if admit- ICU was performed by SPSS for Windows software, ted to an intervention ICU, a negative surveillance cul- version 21 (SPSS Inc., Chicago, IL, USA). The micro - ture was obtained within 2 days of admission. Days at risk biology laboratory processed surveillance specimens were calculated from the date of the third day in the ICU using standard culture-based identification of CRGNB. Jung  et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 3 of 8 through the event date or the date two days after dis- Results charge from the ICU, whichever was later. Characteristics of ICUs and patients The primary outcome was the ICU-level incidence of A total of 4492 admissions to the 6 ICUs occurred during new events per 1000 ICU patient-days at risk. Secondary the study period, and 1884 (42%) with ICU stays ≥ 3 days ICU-level outcomes were the incidences of new events were enrolled in this study (Fig.  1). Two hundred and with CRPA, CRAB, or CRE calculated separately and sixty patients in the intervention period and 98 patients the incidences of hospital-acquired bloodstream infec- in the control period were excluded for ITT analysis, tions, catheter-related bloodstream infections, urinary respectively. A CRE outbreak occurred in SICU2 during tract infections, catheter-associated urinary tract infec- the intervention period, and post-outbreak surveillance tions, pneumonia, ventilator-associated pneumonia, and of CRE was performed in the control period; thus, we in-ICU mortality. We also performed subgroup analysis excluded the 212 patients admitted to SICU2 from the of individual ICUs for new events per 1000 ICU patient- mITT analysis. The original and revised study designs are days at risk. In addition, we compared new events per shown in Additional file  1: Figure S1. There were no sig - 1000 ICU patient-days at risk between periods 1 and 2. nificant differences in characteristics between patients in For the evaluation of economic impacts, we also com- the intervention period and those in the control period pared the lengths of hospital and ICU stays and the costs (Table  1). During the total study period, the observed of hospitalization between the intervention and control hand hygiene compliance was 96%. The number of clini - periods. cal specimens submitted to the laboratory was not differ - Outbreak was defined as ≥ 3 cases of acquisition of ent between intervention and control periods in mITT CRGNB within 2  weeks. If surveillance and post-out- analysis (mean [IQR], 3634 [2824–5568] in intervention break surveillance were performed in the control period period vs. 2767 [1902–4378] in control period; P = 0.35). because of a CRGNB outbreak, we excluded the ICU in the modified intention-to-treat (mITT) analysis. Results of the acquisition rate of CRGNB according to clinical culture Statistical analysis In the mITT analysis, the acquisition rate of CRGNB Based on the acquisition rate of CRGNB from 2016 to was 1.75 cases per 1,000 person-days in the intervention 2018 in ICUs of our hospital, we assumed a mean base- period versus 3.33 cases per 1000 person-days in the con- line incidence of CRGNB colonization or infection of 8 trol period (incidence rate ratio [IRR], 0.53; 95% confi - per 1000 patient-days; between-cluster variance would dence interval [CI] 0.23–1.11; P = 0.07) (Table 2). be 0.4, and the average amount of time a patient spent in the ICU would be 10 days. This study was designed to Secondary outcomes achieve 80% power for detecting a reduction in acquisi- There were no significant differences in the acquisition tion of 40% in the intervention period with a 2-sided type rates of CRPA, CRAB, and CRE in the intervention and I error of 5%. According to these assumptions, the esti- control periods (CRPA, 0.32 vs. 1.07 per 1,000 person- mated sample size was 2400 patients (200 per cluster; a days; IRR, 0.30 [95% CI 0.03–1.50]; P = 0.10; CR AB, total of 12 clusters with one cross-over of 6 ICUs) [5]. 0.80 vs. 1.73 per 1000 person-days; IRR, 0.46 [95% CI Categorical variables were analyzed using the chi- 0.13–1.37]; P = 0.13; CRE, 0.80 vs. 0.93; IRR, 0.85 [95% square or Fisher’s exact test, as appropriate. Normally CI 0.21–3.12]; P = 0.79) (Table 2). In addition, there were and non-normally distributed continuous variables were no significant differences in the rates of hospital-acquired analyzed by Student’s t test and the Mann–Whitney U bloodstream infections, catheter-related bloodstream test, respectively. The primary analysis was a compari - infections, urinary tract infections, catheter-associated son of the primary outcomes between the intervention urinary tract infections, pneumonia, ventilator-associ- and control periods using an unadjusted Poisson regres- ated pneumonia, and in-ICU mortality (Table 3). sion model according to the mITT. All statistical analy- The subgroup analysis of the CRGNB acquisition rate ses were performed using SPSS for Windows software, by ICU is shown in Additional file  1: Table S1. The acqui - version 21 (SPSS Inc., Chicago, IL, USA) and MedCalc sition rates of CRGNB were significantly higher in the Statistical Software version 18.10.2 (MedCalc Software control period than in the intervention period in MICU2, bvba, Sotend, Belgium) with P < 0.05 considered statisti- SICU1, and the cardiac ICU, while the rates were higher cally significant. in the intervention period than in the control period in MICU1 and SICU2; there was no difference between the rates in the intervention and control periods in the car- diothoracic surgery ICU. In ITT analysis, the acquisition rate of CRGNB was 2.94 cases per 1000 person-days in Jung et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 4 of 8 6 ICUs were enrolled 2268 ICU admissions occurred 2224 ICU admissions occurred during the intervention period during the control period 1300 (57%)involvedICU stays≤2days 1308 (59%)involvedICU stays≤2days 968 (43%) involved ICU stays 916 (41%) involved ICU stays ≥3 days ≥3 days 260(11%) were excluded -No surveillance culture ≤2 days (n=104) -Previous colonization with CRPA, 98 (4%) were excluded CRAB, or CRE (n=75) -PreviouscolonizationofCRPA, CRAB, - CRPA, CRAB, or CRE isolation based or CRE (n=78) on surveillance culture ≤2 days (n=75) - CRPA, CRAB, CRE isolation based on - CRPA, CRAB, or CRE isolation based clinical culture ≤2 days (n=20) on clinical culture ≤2 days (n=6) 818 (37%) were eligible for Intention-to-treat analysis 708 (31%) were eligible for intention-to-treat analysis intention-to treat analysis Exclusion Exclusion -94(4%)who were admitted to SICU2 -118 (5%) whowereadmittedtoSICU2 were excluded from modified intention- were excluded frommodifiedintention- to-treat analysis to-treat analysis 724 (33%) were eligible for Modified intention-to-treat 590 (26%) were eligible for analysis modified intention-to-treat modified intention-to-treat analysis analysis Fig. 1 Schematic flow chart of the study. ICU intensive care unit; CRPA carbapenem‑resistant P. aeruginosa; CRAB carbapenem‑resistant A. baumannii; CRE carbapenem‑resistant Enterobacterales Table 1 Demographic and baseline characteristics of the study population Intervention period (n = 590) Control period (n = 724) P value Male sex 338 (57.3) 439 (60.6) 0.22 Age, mean ± SD 66.1 ± 13.3 65.8 ± 13.5 0.69 Underlying diseases Solid cancer 143 (24.2) 183 (25.3) 0.66 Hematologic malignancy 33 (5.6) 47 (6.5) 0.46 Solid organ transplant 34 (5.8) 49 (6.8) 0.46 Hematopoietic stem cell transplant 9 (1.5) 15 (2.1) 0.46 End‑stage renal disease, on dialysis 33 (5.6) 36 (5.0) 0.62 Antibiotics used within the previous 3 months Cefazolin 73 (12.4) 79 (10.9) 0.41 3rd cephalosporin 95 (16.1) 143 (19.8) 0.09 Piperacillin/tazobactam 177 (30.0) 198 (27.3) 0.29 Fluoroquinolone 168 (28.5) 198 (27.3) 0.65 Carbapenem 90 (15.3) 120 (16.6) 0.52 Glycopeptide (vancomycin or teicoplanin) 113 (19.2) 142 (19.6) 0.83 Other 180 (30.5) 210 (29.0) 0.55 ICU stay, days (mean ± SD) 11.0 ± 12.0 11.2 ± 13.7 0.73 The data are shown as no. (%) unless otherwise indicated SD standard deviation Jung  et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 5 of 8 Table 2 Acquisition rates of CRPA, CRAB, and CRE in clinical the intervention period versus 3.46 cases per 1000 person specimens between the intervention and control periods days in the control period (IRR, 0.85; 95% CI 0.46–1.54; P = 0.56) (Additional file 1: Table S2). Intervention Control period, Incidence rate P value period, per 1000 ratio (95% CI) The acquisition rate of CRGNB was significantly higher per 1000 person-days in period 1 than in period 2 (3.68 cases per 1000 per- person-days (95% CI) son-days vs. 0.52 cases per 1000 person-days; P < 0.001) (95% CI) (Additional file 1: Table S3). Modified intention-to-treat analysis Of 104 patients who admitted to ICU during the inter- Total 1.75 (0.87–3.13) 3.33 (2.16–4.92) 0.53 (0.23–1.11) 0.07 vention period but did not perform surveillance culture CRPA 0.32 (0.04–1.15) 1.07 (0.46–2.10) 0.30 (0.03–1.50) 0.10 within 2  days after ICU admission, 15 were admitted to CRAB 0.80 (0.26–1.86) 1.73 (0.92–2.96) 0.46 (0.13–1.37) 0.13 SICU2. We compared the baseline characteristics of the CRE 0.80 (0.26–1.86) 0.93 (0.38–1.92) 0.85 (0.21–3.12) 0.79 remaining 89 patients and those enrolled in interven- CRPA carbapenem-resistant P. aeruginosa; CRAB carbapenem-resistant A. tion group of mITT analysis (n = 590) (Additional file  1: baumannii; CRE carbapenem-resistant Enterobacterales; CI confidence interval Table  S4). Solid organ transplant recipient (16.9% vs. Excluding SICU2 in both periods 1 and 2 5.8%, P < 0.001) and patients with end-stage renal dis- ease (12.4% vs. 5.6%, P = 0.01) were more common in patients without surveillance culture than in intervention group of mITT analysis. Patients with solid cancer was Table 3 Clinical manifestations and outcomes between the intervention and control periods Intervention period Control period P value (n = 590) (n = 724) Clinical diagnosis of infectious diseases Hospital‑acquired bloodstream infection 0 1 (0.1) 0.37 CRPA 0 0 – CRAB 0 1 (0.1) 0.37 CRE 0 0 – Catheter‑related bloodstream infection 0 1 (0.1) 0.37 CRPA 0 0 – CRAB 0 1 (0.1) 0.37 CRE 0 0 ‑ Urinary tract infection 0 1 (0.1) 0.37 CRPA 0 0 ‑ CRAB 0 0 ‑ CRE 0 1 (0.1) 0.37 Catheter‑associated urinary tract infection 0 1 (0.1) 0.37 CRPA 0 0 – CRAB 0 0 – CRE 0 1 (0.1) 0.37 Pneumonia 0 4 (0.6) 0.07 CRPA 0 2 (0.3) 0.20 CRAB 0 2 (0.3) 0.20 CRE 0 1 (0.1) 0.37 Ventilator‑associated pneumonia 0 3 (0.4) 0.12 CRPA 0 2 (0.3) 0.20 CRAB 0 1 (0.1) 0.37 CRE 0 1 (0.1) 0.37 Death – In‑ICU mortality 70 (11.9) 76 (10.5) 0.43 CRPA carbapenem-resistant P. aeruginosa; CRAB carbapenem-resistant A. baumannii; CRE carbapenem-resistant Enterobacterales The data are shown as no. (%) unless otherwise indicated Death during the follow-up periods (until 2 days after ICU discharge) Jung et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 6 of 8 less common in those without surveillance culture than testing is associated with reducing CRGNB transmission, in intervention group of mITT analysis (12.4% vs. 24.2%, but many hospitals have implemented active surveillance P = 0.01). The type of ICU was significantly different testing for identifying CRGNB. Recent studies showed between two groups (P < 0.001), which reflects the differ - that screening and isolation of colonized patients do not ence of compliance of study protocol by ICUs. reduce multidrug-resistant bacteria, especially MRSA, In mITT analysis, 39 (7%) cases in intervention period when compliance with hand hygiene and chlorhexidine- were detected in surveillance culture. Of these, 31 were bathing is high [10–13]. We conducted this study to pro- detected in surveillance culture only, and 8 were detected vide evidence of the effectiveness of active surveillance in in both surveillance and clinical culture. Five were the chlorohexidine-bathing and high hand hygiene com- detected in surveillance culture earlier than in clinical pliance era. Our study had low power because only 79% culture. Therefore, 36 (6%) were actually detected in sur - (1884/2400) of patients were enrolled in the target sam- veillance culture (only or earlier than in clinical culture). ple size, and the baseline acquisition rate was lower than expected. Although it had borderline significance, we Evaluation of the economic impact of active surveillance showed that about half of CRGNB acquisition can be pre- testing vented through active surveillance testing. Therefore, this For the economic impact evaluation of active surveil- strategy may be beneficial in high-baseline-prevalence lance testing of CRGNB, we compared the lengths of settings. A large, multicenter study is needed to confirm hospital and ICU stays and the total cost of hospitaliza- our findings. tion between the intervention and control periods in the The incidence of CRGNB acquisition was higher in the mITT population (Table  4). The mean length of hospi - period 1 (before COVID-19 pandemic) than in period 2 tal stays was 0.9  day shorter in the intervention period (after COVID-19 pandemic). The lower acquisition rate than in the control period, but the difference was not in period 2 may be associated with additional infection statistically significant (P = 0.73). Although there was an prevention measure to respond COVID-19 pandemic, additional cost of $5666 for hospitalization in the inter- especially universal donning of gown and glove. Previous vention period than in the control period, the cost differ - cluster randomized study showed that universal glove ence was also not statistically significant (P = 0.43). and gown use was associated with decrease in acquisition of antibiotic-resistant gram-negative bacteria, although Discussion it was not statistically significant [14]. As we excluded This pragmatic, cluster-randomized, cross-over study SICU2 in the analysis, more patients were allocated to showed that active surveillance testing to identify the control group in the first period, and we may overesti - patients colonized with CRGNB was associated with mate the positive effect of the intervention. Further study non-statistically significant decrease in the acquisition of for evaluating the effectiveness of active surveillance in CRGNB in clinical specimens. the setting of identical infection prevention measures Early detection of patients colonized or infected with between intervention and control period is needed. CRGNB is important for implementing timely interven- In our subgroup analysis, the CRGNB acquisition rate tions to prevent subsequent spread. However, active sur- was higher in the intervention period than in the control veillance testing is a complicated and resource-intensive period in MICU1 and SICU2. Although a CPE outbreak intervention that has the potential for several adverse occurred in SICU2, there was no outbreak of CRGNB in consequences, including reduced contact between MICU1, and the reason for this unanticipated finding is healthcare workers and patients due to contact precau- unclear. It may be a seasonal effect, or more enhanced tions [6]. Previous studies have reported that active environmental cleaning might have been performed dur- surveillance testing in combination with contact precau- ing the control period due to the COVID-19 pandemic, tions for colonized patients contributed to the decline which occurred in the latter 6-month period (Additional of MRSA or vancomycin-resistant Enterococcus [7–9]. file 1: Table S3). However, there is limited evidence that active surveillance Table 4 Lengths of hospital and ICU stays and cost of hospitalizations in the intervention and control periods (mITT population) Intervention period (n = 590) Control period (n = 724) P value Length of hospital stay, mean (± SE) days 44.7 (1.9) 45.6 (1.9) 0.73 Length of ICU stay, mean (± SE) days 11.0 (0.5) 11.2 (0.5) 0.73 Cost of hospitalization ($), mean (± SE) 93,491 (6034) 87,825 (4,252) 0.43 Jung  et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 7 of 8 Author contributions The acquisition rates of CRPA, CRAB, and CRE did JJ and SHK designed the study. JJ, JHP, and HY collected and analyzed the not differ between the intervention and control periods. data. JJ wrote the main manuscript text and JHP prepared figure. YJL, EOK, Because this trial was designed to identify the effective - CML, MNK, MWJ, SCY, and SHK reviewed and revised the manuscript. This study was presented in part in ASM Microbe, 2022, Jun 12, Washington ness of reducing the total CRGNB acquisition rate, fur- DC (Abstract number CIV‑2578). All authors read and approved the final ther study is needed to identify the effectiveness of active manuscript. surveillance testing for each organisms. Funding Our study has some limitations. First, it was a single- This work was supported by grants from the research fund donation for center study with a low prevalence of CRGNB. A mul- COVID‑19 research to Asan Medical Center by Kyu‑Kang Cho. ticenter study with variable prevalences of CRGNB is Availability of data and materials warranted to generalize our findings. Despite this limi - Data and materials are not available. tation, well-monitored infection control practices and policies to minimize unmeasured confounding factors by Declarations different centers during the study period is a strength of our study. Second, as this study was not blinded, the dif- Ethics approval and consent to participate The study was approved by the physicians and nurse team leaders of each ICU ference in the number of clinical specimens submitted to and the institutional review board (IRB no. 2019–0274). The requirements for the laboratory may be present, and this may have affected informed consent were waived. the chance to detect CRGNB. However, the number of Consent for publication clinical specimen was not different between interven - Not applicable. tion and control periods in mITT analysis. Third, we did not perform surveillance testing during the control Competing interests The authors have no competing interests as defined by BMC, or other interests period, which may have biased our findings. However, that might be perceived to influence the results and/or discussion reported in we performed a pragmatic trial that reflects actual clini - this paper. cal practices, and we evaluated the outcomes of CRGNB Author details acquisition in clinical specimens. Fourth, data regarding Department of Infectious Disease, Asan Medical Center, University of Ulsan immunosuppressant use was absent. Use of immunosup- College of Medicine, Seoul, South Korea. Division of Infectious Diseases, pressant is associated with exposure to antimicrobials Department of Internal Medicine, Chung‑Ang University Gwangmyeong Hos‑ pital, Gwangmyeong, South Korea. Office for Infection Control, Asan Medical and acquisition of MDR gram-negative organism [15– Center, Seoul, South Korea. Department of Pulmonary and Critical Care 17]. However, there was no significant difference of the Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, recent antibiotics exposure between the intervention South Korea. Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Depar tment period and the control period. Therefore, this limitation of Preventive Medicine, University of Ulsan College of Medicine, Seoul, South may not substantially affect our main findings. Finally, we Korea. Department of Clinical Epidemiology and Biostatistics, Asan Medical performed a conventional culture method for active sur- Center, University of Ulsan College of Medicine, Seoul, South Korea. veillance, and the turnaround time is longer than rapid Received: 18 October 2022 Accepted: 21 February 2023 PCR testing. Therefore, further study to evaluate active surveillance testing using PCR testing is needed. References Conclusions 1. Tacconelli E, Cataldo MA, Dancer SJ, De AG, Falcone M, Frank U, et al. ESC‑ In conclusion, active surveillance testing for CRGNB may MID guidelines for the management of the infection control measures to reduce transmission of multidrug‑resistant Gram‑negative bacteria in reduce its acquisition in clinical specimens in the ICU hospitalized patients. Clin Microbiol Infect. 2014;20(S1):1–55. without additional costs. Individual hospitals should con- 2. Kim D, Ahn JY, Lee CH, Jang SJ, Lee H, Yong D, et al. Increasing resistance sider the cost-effectiveness of the intervention based on to extended‑spectrum cephalosporins, fluoroquinolone, and carbap ‑ enem in gram‑negative bacilli and the emergence of carbapenem non‑ the baseline acquisition rate of CRGNB and the cost of susceptibility in Klebsiella pneumoniae: analysis of Korean Antimicrobial intervention when they decide whether to adopt active Resistance Monitoring System (KARMS) data from 2013 to 2015. Ann Lab surveillance testing. Med. 2017;37(3):231–9. 3. Lee E, Lee S, Bahk H, Kim S, Lee H. Analysis of carbapenemase‑producing Enterobacteriaceae (CPE) surveillance results for 2017 in Korea: Com‑ Supplementary Information parison with the surveillance results of the previous 5 years (2012–2016). The online version contains supplementary material available at https:// doi. Korea Disease Control and Prevention Agency. Public Health Weekly org/ 10. 1186/ s13756‑ 023‑ 01222‑2. Report. Available at: http:// www. kdca. go. kr/ board/ board. es? mid= a2060 20100 00& bid= 0034& list_ no= 14190 9& act= view. Accessed 22 Nov 2018. 4. Fätkenheuer G, Hirschel B, Harbarth S. Screening and isolation to control Additional file 1. Supplemental Figure and Tables. meticillin‑resistant Staphylococcus aureus: sense, nonsense, and evidence. Lancet. 2015;385(9973):1146–9. Jung et al. Antimicrobial Resistance & Infection Control (2023) 12:16 Page 8 of 8 5. Reich NG, Myers JA, Obeng D, Milstone AM, Perl TM. Empirical power and sample size calculations for cluster‑randomized and cluster ‑randomized crossover studies. PLoS ONE. 2012;7(4): e35564. 6. Diekema DJ, Edmond MB. Look before you leap: active surveillance for multidrug‑resistant organisms. Clin Infect Dis. 2007;44:1101–7. 7. Jernigan JA, Clemence MA, Stott GA, Titus MG, Alexander CH, Palumbo CM, et al. Control of methicillin‑resistant Staphylococcus aureus at a university hospital: one decade later. Infect Control Hosp Epidemiol. 1995;16:686–96. 8. Muto CA, Jernigan JH, Ostrowsky BE, Richet HM, Jarvis WR, Boyce JM, et al. SHEA guideline Active surveillance cultures are essential to identify the reservoir for spread of MRSA and VRE infections and make control possible using the CDC’s long‑recommended contact precautions. Infect Control Hosp Epidemiol. 2003;24(5):362–86. 9. Ostrowsky BE, Trick WE, Sohn AH, Quirk SB, Holt S, Carson LA, et al. Control of vancomycin‑resistant enterococcus in health care facilities in a region. N Engl J Med. 2001;344:1427–33. 10. Troche G, Joly LM, Guibert M, Zazzo JF. Detection and treatment of antibiotic‑resistant bacterial carriage in a surgical intensive care unit: a 6‑ year prospective survey. Infect Control Hosp Epidemiol. 2005;26:161–5. 11. Nijssen S, Bonten MJ, Weinstein RA. Are active microbiological surveil‑ lance and subsequent isolation needed to prevent the spread of methicillin‑resistant Staphylococcus aureus? 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Multidrug‑resistant Gram‑negative bacterial infections in solid organ transplant recipients—Guidelines from the American Society of Trans‑ plantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13594. 16. Aguilar‑ Guisado M, Espigado I, Martin’Pena A, Gudiol C, Royo‑ Cebrecos C, Falantes J, et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open‑label, randomized, controlled phase 4 trial. Lancet Haematol. 2017;4(12):e573‑83. 17. Anderson DJ, Jenkins TC, Evans SR, Harris AD, Weinstein RA, Tamma PD, Han JH, et al. The role of stewardship in addressing antibacterial resist‑ ance: stewardship and infection control committee of the antibacterial resistance leadership group. Clin Infect Dis. 2017;64:S36‑40. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. 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Journal

Antimicrobial Resistance and Infection ControlSpringer Journals

Published: Mar 3, 2023

Keywords: Active surveillance testing; Carbapenem-resistant; Gram-negative bacteria; Contact precautions

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