Antimicrobial Lock Therapy: Is it a real savior in pediatric hematopoetic stem cell transplant (HSCT) patients?

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Manolya Kara, Murat Sutcu, Basak Adakli Aksoy, Gizem Zengin Ersoy, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4540053/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Central line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Antimicrobial lock treatment (ALT), when utilized alongside systemic antibiotics, may be lifesaving when catheter removal (CR) is not feasible. Methods This retrospective study analyzed the clinical, laboratory, and microbiologic characteristics of CLABSI episodes of pediatric patients who underwent HSCT and applied ALT. Results There were 137 cases of CLABSI (63.5 male) who were given ALT. The median age was 48 (3-204) months. The most common causative microorganism was Gram-negative bacteria, encountered in 85 patients (62%). Forty-six patients (33.6%) had Gram-positive bacterial growth, whereas 6 had (4.4%) fungal infection. ALT was successful in 77.4% of the patients (n = 106). CR was required in 25 patients (18.2%). The CLABSI-related mortality rate was 12.4%. When the outcome of ALT was evaluated, post-transplantation cyclophosphamide (PTCy) use, fungal growth, persistent bacteremia/fungemia, re-HSCT, inappropriate empirical antibiotic use, hypotension, and pediatric intensive care unit admission were significantly more common in the “unsuccessful” ALT group. The patients in the unsuccessful group had higher C-reactive protein [110.2 (1.10-323.5) mg/L] levels when compared to the successful ALT group [58 (0.2-450.3) mg/L] (p = 0.029). The presence of hypotension, HLA-mismatch transplantation, and persistent bacteremia/fungemia were independent risk factors for ALT failure. Conclusion ALT can be an effective catheter-saving strategy in HSCT pediatric patients. Nevertheless, patients should be monitored very closely during ALT, and the presence of certain risk factors should be taken into account. Central line-associated bloodstream infection pediatric hematopoietic stem cell transplantation antimicrobial lock therapy Introduction Central line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Approximately 27–68% of HSCT recipients experience CLABSI, with a rate of 12–25% increase in mortality [ 1 – 3 ]. CLABSI occurs when microorganisms form a biofilm layer inside the central catheter [ 4 ]. Overgrowing bacteria then enter the bloodstream and cause bloodstream infection. The intravenous antibiotic application can not permanently eradicate the bacteria that adhere tightly to the central line (CL). Catheter removal (CR) is rational in that case. However, the CL is critical for several reasons, such as the application of chemotherapy, transfusion, parenteral nutrition, etc, especially in young children where vascular access is problematic [ 5 ]. Antimicrobial lock treatment (ALT), the application of an antimicrobial solution at high concentrations into the lumen of the CL for some time, is recommended to combat CLABSIs [ 6 ]. When utilized alongside systemic antibiotics, ALT may serve as a lifesaving approach whenever CL removal is not feasible. A continuum of access to CL, cost-effectiveness, and the capacity to provide high doses of effective antibiotics with minimal risk of systemic toxicity and resistance constitute some of the advantages of ALT [ 7 ]. On the other hand, it is also possible that ALT may raise physicians' thresholds for catheter withdrawal, resulting in prolonged treatment time or increased catheter-related complications (such as septic embolism). Very few publications show the efficacy of ALT in pediatric oncology patients [ 8 – 12 ]. Data regarding the HSCT population, a particularly delicate group where infection control may be compromised rapidly, is even rarer [ 13 ]. The objective of the present study was to evaluate the characteristics and outcomes of ALT among pediatric HSCT patients with CLABSIs. Materials and Methods Study design This study was conducted at a pediatric tertiary HSCT center in Istanbul, Turkey, between June 2018 and June 2022. The CLABSI episodes of HSCT patients were analysed and the patients who received ALT were included in the study. The medical records of the patients were evaluated retrospectively. Demographics, primary illnesses, the duration of HSCT, immunosuppressive therapy, the presence of graft versus host disease (GvHD), CL-specific details, clinical and laboratory parameters at the onset of CLABSI, the course of the infection, components of antimicrobial treatment (systemic and ALT; the agent, dose, and duration) and the outcome were all documented. To analyze the ALT-related adverse effects, complications such as bleeding, occlusion of the catheter, or possible antibiotic-related toxicity symptoms were also investigated. Approval for the study was obtained from the Istinye University School of Medicine Clinical Research Ethical Committee. This study was conducted in accordance with the principles of the Declaration of Helsinki. Because of the study's retrospective nature, no informed consent was taken. Clinical Setting & Central Line Procedure Our facility comprises a 32-bed Hematology-Oncology and Pediatric HSCT unit that serves as a reference center for auto and allo-HSCT in Turkey. Since 2015, around 100 transplants have been performed each year. All allogeneic HSCT recipients are placed in single rooms with > 12 air exchanges per hour and high-efficiency (> 99%) particulate air (HEPA) filters capable of eliminating particles larger than 0.3 m in diameter. One nurse is assigned to every three transplant beds. Preferably, the pediatric surgeon inserts double-lumen tunneled Hickman catheters routinely under elective conditions in the operating room before the HSCT protocol. Standard practices for catheter care include bathing every other day and cleaning the insertion site with chlorhexidine after every shower, followed by a suitable dressing change. When the catheter is not in use, a heparin lock (50U in 5 mL heparinized saline) is applied once a week. Definitions According to the National Healthcare Safety Network (NHSN) of the Centers for Disease Control and Prevention (CDC) criteria, primary bloodstream infection in a patient with a CL and the isolation of a recognized pathogen with associated fever (> 38 ºC), hypotension, and chills, on at least one blood culture or two or more blood cultures on separate occasions if a common skin contaminant was isolated, were accepted as CLABSI [ 14 ]. The growth of an organism in culture drawn from any catheter lumen (as a part of surveillance) in the absence of clinical findings was noted as “colonization”; these were excluded from the study. To determine the efficacy of ALT, "no positive culture" of the same pathogen after 72 hours of treatment was the criterion. Persistent bacteremia/fungemia (after 72 hours of appropriate therapy) and the requirement of CR were accepted as “ALT failure”. “Relapse” was defined as the growth of the same pathogen in blood culture within three months. Microbial identification In the suspicion of CLABSIs, blood samples were drawn from the peripheral vein and CLs (from each lumen of the catheter, in the presence of multiple lumens). Following the manufacturer's recommendations, the bacteriological culture was performed using the BACT/ALERT® Blood Culture System (BIOMERIEUX, Durham, USA). Samples from blood culture bottles with positive results were inoculated on 5% sheep blood agar, chocolate agar, and Eosin Methylene Blue (EMB) agar media. After an overnight incubation, samples were obtained from the purely grown microorganism colonies in the media, and pre-diagnostic procedures were completed. Advanced diagnostic and antibiotic susceptibility tests were initiated depending on the Gram stain, catalase, and oxidase test results. BD Phoenix TM Automated Microbiology (BD Diagnostics Sparks, MD, USA) was used according to the manufacturer's recommendations. Management of the patients In the HSCT unit, the antimicrobial treatment protocol in the suspicion of CLABSI included a systemic antipseudomonal antibiotic (piperacillin-tazobactam, cefepime, or meropenem) with a glycopeptide (teicoplanin/vancomycin). A specific agent may be preferred depending on the patient's prior infection and colonization state. In cases where there is hypotension or other signs of septicemia, vancomycin is favored over teicoplanin. Empirical therapy was adjusted according to the antimicrobial susceptibility results of the CLABSI pathogen. Bacteremia/fungemia is monitored by collecting blood cultures every other day. Catheter removal is applied for patients with hemodynamic instability, persistent bacteremia, and non-improving clinical conditions despite adequate treatment. After removal, the catheter tip is sent for culture analysis. ALT was utilized together with systemic therapy based on the culture sensitivity pattern of the isolated pathogen. In line with antimicrobial susceptibility, only one antibiotic was selected. Before ALT, the fill volume was calculated first. This was accomplished by flushing the line with normal saline and then withdrawing the content until blood was visible at the syringe tip. The amount to be administered was completed to the fill volume, ensuring the antibiotic concentration remained as recommended (Table 1). Peripheral vascular access was established in eligible patients, and CL was only used once catheter sterilization was achieved. The ALT has been renewed based on the dwell time indicated in Table 1. The duration of antibiotic treatment varied depending on the causative microorganism: 7–14 days for Enterococcus spp., 10–14 days for CoNS, and 10–14 days for gram-negative bacilli [ 6 ]. After 72 hours of treatment, the control catheter and peripheral blood cultures were taken. All patients were followed for at least three months after the CLABSI episode. Statistical analysis Statistical analysis was performed with SPSS version 26.0 (IBM). The χ2 test and Fisher exact test compared categorical data. For variables not distributed normally, the Mann-Whitney U test was used. Significance was considered when P < .05. The most significant predictors of mortality by univariate analysis were chosen. Variables with a P ≤ .05 in univariate analysis were chosen to perform a logistic regression analysis to estimate independent risk factors for unsuccessful ALT treatment. Results During the study period, 207 pediatric patients experienced CLABSIs, an incidence of 3.7/1000 catheter days. A total of 137 patients were given ALT together with systemic antibiotics. Patient characteristics: Of 137 patients, 87 (63.5%) were male. The median age was 48 (3-204) months. The underlying illnesses were thalassemia major [n = 36, (26.3%)], acute lymphocytic leukemia [ALL; n = 25, (18.2%)], severe combined immune deficiency [SCID; n = 22, (16.1%)], aplastic anemia [n = 18, (13.1%)], acute myeloid leukemia [AML;n = 6, (4.4%)] and others [n = 30; (21.9%)]. Auto-HSCT was performed in 19 (13.9%) patients, and identical (n = 68, %49,6), mismatch (n = 35, %25,5), and haploidentical donor (n = 15, %10,9)] was performed in 118 patients. Twenty-eight (20.4%) patients had re-HSCT. Ninety (65.7%) patients had neutropenia with a median time of 9 (3-180) days at the onset of infectious episodes. Thirty-four patients (24.8%) had GvHD. Post-transplantation cyclophosphamide (PTCy) use was encountered in 47 (34.3%) patients. CLABSI episode The median duration from CL insertion to the day of infection (DOI) was 25 (3-252) days. The CL preference was Hickman in all patients. The most common causative microorganism was Gram-negative (GN) bacteria, encountered in 85 patients (62%). Forty-six patients (33.6%) had Gram-positive (GP) bacterial growth, whereas 6 had fungal infection (4.4%). The median time of parenteral antibiotic use before ALT was 4 (2–11) days. Fifty-six patients (40.9%) had prior inappropriate empirical systemic antibiotic use. The antimicrobial regimen for lock therapy included meropenem (n = 57, 41.7%), teicoplanin (n = 27, 20.4%), vancomycin (n = 13, 9.5%), colistin (n = 13, 9.5%), ciprofloxacin (n = 7, 5.1%), liposomal amphotericin- B (n = 6, 4.4%), tigecycline (n = 5, 3.6%), linezolid (n = 4, 2.9%), ceftazidime (n = 4, 2.9%) and amikacin (n = 1, 0.7%). Microbiologic distribution and ALT treatment are detailed in Table 2. ALT was successful in 77.4% of the patients (n = 106). CR was required in 25 patients (18.2%) due to persistent bacteremia/fungemia (n = 18), unexplained tachycardia (n = 2), and persistent hypotension(n = 5). Six patients had relapse within three months. The median CR day was 3 (3–5) days. Adverse events that occured during ALT were catheter displacement (n = 2), occlusion (n = 1) and skin tethering (n = 1). Comparison of CLABSI episodes according to ALT success When the outcome of ALT was evaluated, there was no significant difference regarding the median age, gender, primary disease, presence, and duration of neutropenia between the ALT successful and unsuccessful groups (Table 3). PTCy use, fungal growth, persistent bacteremia/fungemia, re-HSCT, inappropriate empirical antibiotic use, hypotension, and pediatric intensive care unit (PICU) admission were significantly more common in the “unsuccessful” ALT group. Likewise, the patients in the unsuccessful group had higher C-RP [110.2 (1.10-323.5) mg/L] levels when compared to the successful ALT group [58 (0.2-450.3) mg/L] (p = 0.029). Considering ALT success, a double-lumen catheter was more common among the successful ALT group (p < 0.001). The haploidentical human leucyte antigen (HLA) match was significantly more common among the successful ALT group, whereas mismatch was significantly higher in the unsuccessful ALT group. The presence of hypotension, HLA-mismatch transplantation, and persistent bacteremia/fungemia were independent risk factors for ALT failure (Table 4). Outcome Twenty-four patients (17.5%) were admitted to the PICU, and 21 patients (15.3%) were given inotropes. Mortality occurred in 17 (12.4%) patients due to septic shock (n = 7), acute renal failure (n = 3), acute respiratory distress syndrome (n = 3), arrhythmia (n = 1), and pulmonary hemorrhage (n = 2). The diagnosis of mortality cases was aplastic anemia (n = 5), thalassemia major (n = 4), SCID (n = 3), AML (n = 2), MDS (n = 1), hemophagocytic lymphohistiocytosis (n = 1) and non-Hodgkin lymphoma (n = 1). Responsible microorganisms were K.pneumonia (n = 11), A.baumanii (n = 1), S.maucibalis (n = 1), S.maltophilia (n = 1), S.aureus (n = 1), S.epidermidis (n = 1) and C.albicans (n = 1). The relapse rate within three months was 5.8%. Discussion Antimicrobial lock therapy, when used with systemic antibiotics, is an effective strategy to combat CLABSIs and salvage catheters. Although guidelines favor ALT, standardized prescriptions are lacking, particularly for children who underwent HSCT [ 6 , 15 , 16 ]. Thus, the decision to use ALT rather than CR is critical and mainly depends on the clinician's preference for this group of high-risk patients. To corroborate this, being a bone marrow transplant recipient and having neutropenia were identified as risk factors associated with CR among children with varied illnesses [ 17 , 18 ]. This study evaluated the ALT success rate among pediatric HSCT patients, contributing to the limited literature resources. The CLABSI incidence was 3.7/1000 catheter days in the present study. This ratio is similar to the previously reported analysis of Tural Kara et al [ 8 ], which is 4.2/1000 catheter days. However, the most prevalent microorganisms varied between these two studies. In the present study, GN bacteria, mainly K pneumonia , predominated. The most common causative agent in that study was methicillin-resistant coagulase negative Staphylococcus (MR-CoNS) [ 8 ]. It has been noted that GP cocci, members of skin flora, have dominated in recent years [ 19 , 20 ]. Nonetheless, it is noteworthy that GNs have been reported in increased frequencies among children with malignancies, particularly in nations with limited resources [ 19 – 22 ]. In the present study, the successful ALT rate was 77.4%, which is in the range of previously reported (46%-86.6%) [ 8 – 10 , 13 ]. However, these studies show variety in terms of diagnoses, catheter subtypes, ALT regimens, and causative microorganisms. Tural Kara et al. [ 8 ] reported the ALT success rate as 81% among pediatric patients with hematologic, oncologic, or immunologic diseases. In a pediatric HSCT report, Zanwer et al.[ 13 ] found the catheter salvage rate as high as 86.6% in the ALT-added CLABSI group, significantly higher than in patients without ALT. Similarly, Ohoro et al. [ 23 ] concluded that combining systemic antibiotics and culture-guided ALT was superior to the systemic antibiotic alone. In Tsai et al.'s [ 11 ] study, the overall success rate of ALT was 71.6%. When detailed, the success of ALT in Enterobacteriaceae infections (78.3%) was greater than that of CoNS (58.6%). Older age, elevated C-RP levels, ALL as a primary disease, and candidemia were found to be the factors associated with ALT failure [ 11 ]. In a national study by Asrak et al. [ 24 ], the rate of success for ALT was found to be 68.8% among pediatric cancer patients. The study also found that younger age was an independent risk factor for the ALT failure. In the present study, HLA-mismatch, re-HSCT and PTCy use were significantly more common among the patients with unsuccessful ALT. This situation appears to be linked to HSCT failure, resulting in extended immunosuppression, hospitalization, and complications. According to recent research, PTCy was linked to higher rates of bacterial infections, regardless of the donor [ 25 ]. Furthermore, bacterial infections were associated with increased mortality rates [ 25 ]. On the other hand, Wolf et al. [ 9 ] reported that they were unable to find any advantage of using adjunctive ALT in pediatric oncology patients with CLABSIs. This is because the treatment failure rate was similar in both groups, i.e. the group that received only systemic treatment (ST, 38.4%) and the group that received ALT in addition to ST (50%). Patients who received ALT had delayed CR and relapse of infection, resulting in later treatment failure. This study holds immense value as it stands in contrast to the opposing view presented in literature. The definition of treatment failure used in the study design is different from ours. In the study, treatment failure was defined as CR or mortality attributable to an infection within 14 days of the onset of CLABSI, or relapse of infection caused by the same microorganism species within 252 days. These variations in study design may have caused the difference. In their study, similar to ours, treatment failure due to CR within the first three days was significantly more common in the only ST group. Guidelines recommend CR in the presence of S.aureus, P.aeruginosa , and fungemia [ 4 , 6 ]. However, inserting a new CL can be challenging, and the replacement significantly increases the risk of bloodstream infection and other issues depending on where the catheter is inserted (arterial puncture, pneumothorax, etc.) [ 26 ]. Furthermore, not all patients are eligible for catheter replacement. These include critically ill individuals who may be coagulopathic, thrombocytopenic or have restricted venous access [ 26 , 27 ]. In the present study, the ALT success rate for S. aureus and P.aeroginosa was nearly 91% and 88%, respectively. Although there was a limited case of fungal ALT experience, the success rate was far below the bacterial salvage ratio, 33.3%. We succeeded in two cases with C.albicans and C. parapsilosis -related CLABSI with L-AMB. The literature contains very limited data on antifungal lock treatment [ 27 – 30 ]. In in-vivo studies with either fluconazole, echinocandin derivatives, or L-AMB (single or in combination), the therapeutic success rate varies between 17% and 100% [ 28 – 30 ]. In these studies, administered drug doses, the ingredients of lock solution, and dwell times vary significantly. Although ethanol-based lock solutions showed the highest activity, they were found to lead to potential risks, particularly concentrations above 28–30%, such as clotting, dizziness, protein precipitation, and compromised catheter integrity [ 28 , 31 ]. We opted for heparin instead of using ethanol in any of the lock solutions. The potential risk of systemic circulation of heparin after application in small infants is a crucial concern [ 4 ]. Besides, there is some evidence that heparin might promote the formation of S. aureus biofilm, although this claim is not universally agreed upon [ 32 ]. In our experience, we did not observe any heparin-related side effects, and ALT produced an overall safe treatment profile. The therapeutic success of L-AMB, reaching 83%, has also been reported in case series [ 28 ]. Castagnola et al. [ 33 ] reported a successful antifungal lock therapy experience related to C.parapsilosis CLABSI in an infant with L-AMB. Systemic antifungal treatment also included L-AMB for 14 days. Paul DiMondi et al [ 34 ] applied L-AMB lock therapy for C.albicans and succeeded in a 64-year-old female patient. However, they preferred micafungin as a parenteral agent. For our cases, we administered L-AMB both parenteral and as lock therapy. Strengths and limitations of the study It is important to acknowledge that our study has limitations as it is retrospective in nature. As with other studies on this topic, the preference and procedure of ALT rely on the clinician's judgment, as there are no clear guidelines in the literature. On the other hand, the current study has many strengths, such as the fact that it includes a significant patient group, such as pediatric HSCT, the high number of cases, and it provides a broad perspective regarding microorganism diversity and antimicrobial drug experience. Conclusion To summarize, ALT can be an effective catheter-saving strategy in HSCT pediatric patients. Nevertheless, patients should be monitored very closely during ALT, and the presence of certain risk factors should be considered. We believe that, the results of this investigation will contribute to the architecture of further studies. Declarations Conflict of Interest No conflict of interest was declared by the authors. Financial Disclosure The authors declared that this study has received no financial support. None of the authors has any potential financial conflict of interest related to this manuscript. Author Contribution MK and MS wrote the main manuscript. BAA and GZE collected the patient data. 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Infect Immun 73:4596 Castagnola E, Marazzi MG, Tacchella A, Giacchino R (2005) Broviac catheter-related candidemia. Pediatr Infect Dis J 24:747 Paul DiMondi V, Townsend ML, Johnson M, Durkin M (2014) Antifungal catheter lock therapy for the management of a persistent Candida albicans bloodstream infection in an adult receiving hemodialysis. Pharmacotherapy 34:e120–e127 Tables Table 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4540053","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":318366614,"identity":"d6cf4064-4ecd-4785-a64d-547cafcc0da6","order_by":0,"name":"Manolya Kara","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYLCCB0AsAWJ8YGBIIE5LAlQL4wyStTDzEKNFt/3swQeJbXYMku1nH362bbPL42dvYPzwMQe3FrMzeckGiW3JDNI86cbSuW3JxZI9B5glZ27Do+VAjplEYhszgxxDGgNQC3PihhsJbMy8+LScfwPSUs8gx/+M+bdlWz0RWm6AbTnMIC2RxibN2HaYGC1vjA0Szh1nkJzxjM2y59zxxJk9B5vx++V8juGDD2XVDBLn05hv/CirTuxnbz744SMeLWDAyMZQ3wBlgMgGAupB4A8GYxSMglEwCkYBAgAAF4RQXU+fZQUAAAAASUVORK5CYII=","orcid":"","institution":"Yeditepe University","correspondingAuthor":true,"prefix":"","firstName":"Manolya","middleName":"","lastName":"Kara","suffix":""},{"id":318366616,"identity":"bb9e8e81-dd61-4b3b-a4ac-da13c3dcc3d4","order_by":1,"name":"Murat Sutcu","email":"","orcid":"","institution":"Istinye University","correspondingAuthor":false,"prefix":"","firstName":"Murat","middleName":"","lastName":"Sutcu","suffix":""},{"id":318366618,"identity":"8e3779cd-ff65-4b0f-b186-80825ba82d4d","order_by":2,"name":"Basak Adakli Aksoy","email":"","orcid":"","institution":"Altinbas University","correspondingAuthor":false,"prefix":"","firstName":"Basak","middleName":"Adakli","lastName":"Aksoy","suffix":""},{"id":318366621,"identity":"04644aad-c43c-4df1-b5cf-86b6802344b1","order_by":3,"name":"Gizem Zengin Ersoy","email":"","orcid":"","institution":"Altinbas University","correspondingAuthor":false,"prefix":"","firstName":"Gizem","middleName":"Zengin","lastName":"Ersoy","suffix":""},{"id":318366622,"identity":"e75c4c94-a3da-4ab6-8d2e-cfc8d2e3be4b","order_by":4,"name":"Ozlem Basoglu Oner","email":"","orcid":"","institution":"Altinbas University","correspondingAuthor":false,"prefix":"","firstName":"Ozlem","middleName":"Basoglu","lastName":"Oner","suffix":""},{"id":318366623,"identity":"ebcf600f-b631-4cbe-be0a-6f721e810e3f","order_by":5,"name":"Ayhan Yaman","email":"","orcid":"","institution":"Istinye University","correspondingAuthor":false,"prefix":"","firstName":"Ayhan","middleName":"","lastName":"Yaman","suffix":""},{"id":318366624,"identity":"2e45d28f-164e-41ce-a999-e0a0df268091","order_by":6,"name":"Ahmet Ozbek","email":"","orcid":"","institution":"Altinbas University","correspondingAuthor":false,"prefix":"","firstName":"Ahmet","middleName":"","lastName":"Ozbek","suffix":""},{"id":318366625,"identity":"8bc9c98e-fbdd-4dde-9f1f-ca03e2257e76","order_by":7,"name":"Ceyhun Bozkurt","email":"","orcid":"","institution":"Istinye University","correspondingAuthor":false,"prefix":"","firstName":"Ceyhun","middleName":"","lastName":"Bozkurt","suffix":""},{"id":318366626,"identity":"adde6ffb-4d9e-4843-80ac-68c90fbe12b4","order_by":8,"name":"Tunç Fisgin","email":"","orcid":"","institution":"Altinbas University","correspondingAuthor":false,"prefix":"","firstName":"Tunç","middleName":"","lastName":"Fisgin","suffix":""}],"badges":[],"createdAt":"2024-06-06 11:36:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4540053/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4540053/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63481847,"identity":"04d342ba-f005-43f5-90b4-416b232b7c5c","added_by":"auto","created_at":"2024-08-28 15:07:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":443307,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4540053/v1/009b37db-87d0-4c77-be69-6f917ddd9ace.pdf"},{"id":58993962,"identity":"617096c3-a8a4-4aef-ac25-bee911c9a7a0","added_by":"auto","created_at":"2024-06-25 05:42:25","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":27792,"visible":true,"origin":"","legend":"","description":"","filename":"table.docx","url":"https://assets-eu.researchsquare.com/files/rs-4540053/v1/bdbafdd4764013e5dd42144d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Antimicrobial Lock Therapy: Is it a real savior in pediatric hematopoetic stem cell transplant (HSCT) patients?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCentral line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Approximately 27\u0026ndash;68% of HSCT recipients experience CLABSI, with a rate of 12\u0026ndash;25% increase in mortality [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCLABSI occurs when microorganisms form a biofilm layer inside the central catheter [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Overgrowing bacteria then enter the bloodstream and cause bloodstream infection. The intravenous antibiotic application can not permanently eradicate the bacteria that adhere tightly to the central line (CL). Catheter removal (CR) is rational in that case. However, the CL is critical for several reasons, such as the application of chemotherapy, transfusion, parenteral nutrition, etc, especially in young children where vascular access is problematic [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAntimicrobial lock treatment (ALT), the application of an antimicrobial solution at high concentrations into the lumen of the CL for some time, is recommended to combat CLABSIs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. When utilized alongside systemic antibiotics, ALT may serve as a lifesaving approach whenever CL removal is not feasible. A continuum of access to CL, cost-effectiveness, and the capacity to provide high doses of effective antibiotics with minimal risk of systemic toxicity and resistance constitute some of the advantages of ALT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. On the other hand, it is also possible that ALT may raise physicians' thresholds for catheter withdrawal, resulting in prolonged treatment time or increased catheter-related complications (such as septic embolism).\u003c/p\u003e \u003cp\u003eVery few publications show the efficacy of ALT in pediatric oncology patients [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Data regarding the HSCT population, a particularly delicate group where infection control may be compromised rapidly, is even rarer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The objective of the present study was to evaluate the characteristics and outcomes of ALT among pediatric HSCT patients with CLABSIs.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis study was conducted at a pediatric tertiary HSCT center in Istanbul, Turkey, between June 2018 and June 2022. The CLABSI episodes of HSCT patients were analysed and the patients who received ALT were included in the study. The medical records of the patients were evaluated retrospectively.\u003c/p\u003e \u003cp\u003eDemographics, primary illnesses, the duration of HSCT, immunosuppressive therapy, the presence of graft versus host disease (GvHD), CL-specific details, clinical and laboratory parameters at the onset of CLABSI, the course of the infection, components of antimicrobial treatment (systemic and ALT; the agent, dose, and duration) and the outcome were all documented.\u003c/p\u003e \u003cp\u003eTo analyze the ALT-related adverse effects, complications such as bleeding, occlusion of the catheter, or possible antibiotic-related toxicity symptoms were also investigated.\u003c/p\u003e \u003cp\u003e Approval for the study was obtained from the Istinye University School of Medicine Clinical Research Ethical Committee. This study was conducted in accordance with the principles of the Declaration of Helsinki. Because of the study's retrospective nature, no informed consent was taken.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical Setting \u0026amp; Central Line Procedure\u003c/h2\u003e \u003cp\u003eOur facility comprises a 32-bed Hematology-Oncology and Pediatric HSCT unit that serves as a reference center for auto and allo-HSCT in Turkey. Since 2015, around 100 transplants have been performed each year. All allogeneic HSCT recipients are placed in single rooms with \u0026gt;\u0026thinsp;12 air exchanges per hour and high-efficiency (\u0026gt;\u0026thinsp;99%) particulate air (HEPA) filters capable of eliminating particles larger than 0.3 m in diameter. One nurse is assigned to every three transplant beds.\u003c/p\u003e \u003cp\u003ePreferably, the pediatric surgeon inserts double-lumen tunneled Hickman catheters routinely under elective conditions in the operating room before the HSCT protocol. Standard practices for catheter care include bathing every other day and cleaning the insertion site with chlorhexidine after every shower, followed by a suitable dressing change. When the catheter is not in use, a heparin lock (50U in 5 mL heparinized saline) is applied once a week.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eAccording to the National Healthcare Safety Network (NHSN) of the Centers for Disease Control and Prevention (CDC) criteria, primary bloodstream infection in a patient with a CL and the isolation of a recognized pathogen with associated fever (\u0026gt;\u0026thinsp;38 \u0026ordm;C), hypotension, and chills, on at least one blood culture or two or more blood cultures on separate occasions if a common skin contaminant was isolated, were accepted as CLABSI [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The growth of an organism in culture drawn from any catheter lumen (as a part of surveillance) in the absence of clinical findings was noted as \u0026ldquo;colonization\u0026rdquo;; these were excluded from the study.\u003c/p\u003e \u003cp\u003eTo determine the efficacy of ALT, \"no positive culture\" of the same pathogen after 72 hours of treatment was the criterion. Persistent bacteremia/fungemia (after 72 hours of appropriate therapy) and the requirement of CR were accepted as \u0026ldquo;ALT failure\u0026rdquo;. \u0026ldquo;Relapse\u0026rdquo; was defined as the growth of the same pathogen in blood culture within three months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eMicrobial identification\u003c/h2\u003e \u003cp\u003eIn the suspicion of CLABSIs, blood samples were drawn from the peripheral vein and CLs (from each lumen of the catheter, in the presence of multiple lumens). Following the manufacturer's recommendations, the bacteriological culture was performed using the BACT/ALERT\u0026reg; Blood Culture System (BIOMERIEUX, Durham, USA).\u003c/p\u003e \u003cp\u003eSamples from blood culture bottles with positive results were inoculated on 5% sheep blood agar, chocolate agar, and Eosin Methylene Blue (EMB) agar media. After an overnight incubation, samples were obtained from the purely grown microorganism colonies in the media, and pre-diagnostic procedures were completed. Advanced diagnostic and antibiotic susceptibility tests were initiated depending on the Gram stain, catalase, and oxidase test results. BD Phoenix \u003csup\u003eTM\u003c/sup\u003e Automated Microbiology (BD Diagnostics Sparks, MD, USA) was used according to the manufacturer's recommendations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eManagement of the patients\u003c/h2\u003e \u003cp\u003eIn the HSCT unit, the antimicrobial treatment protocol in the suspicion of CLABSI included a systemic antipseudomonal antibiotic (piperacillin-tazobactam, cefepime, or meropenem) with a glycopeptide (teicoplanin/vancomycin). A specific agent may be preferred depending on the patient's prior infection and colonization state. In cases where there is hypotension or other signs of septicemia, vancomycin is favored over teicoplanin. Empirical therapy was adjusted according to the antimicrobial susceptibility results of the CLABSI pathogen. Bacteremia/fungemia is monitored by collecting blood cultures every other day.\u003c/p\u003e \u003cp\u003eCatheter removal is applied for patients with hemodynamic instability, persistent bacteremia, and non-improving clinical conditions despite adequate treatment. After removal, the catheter tip is sent for culture analysis.\u003c/p\u003e \u003cp\u003eALT was utilized together with systemic therapy based on the culture sensitivity pattern of the isolated pathogen. In line with antimicrobial susceptibility, only one antibiotic was selected. Before ALT, the fill volume was calculated first. This was accomplished by flushing the line with normal saline and then withdrawing the content until blood was visible at the syringe tip. The amount to be administered was completed to the fill volume, ensuring the antibiotic concentration remained as recommended (Table\u0026nbsp;1). Peripheral vascular access was established in eligible patients, and CL was only used once catheter sterilization was achieved. The ALT has been renewed based on the dwell time indicated in Table\u0026nbsp;1. The duration of antibiotic treatment varied depending on the causative microorganism: 7\u0026ndash;14 days for Enterococcus spp., 10\u0026ndash;14 days for CoNS, and 10\u0026ndash;14 days for gram-negative bacilli [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. After 72 hours of treatment, the control catheter and peripheral blood cultures were taken. All patients were followed for at least three months after the CLABSI episode.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed with SPSS version 26.0 (IBM). The χ2 test and Fisher exact test compared categorical data. For variables not distributed normally, the Mann-Whitney U test was used. Significance was considered when P\u0026thinsp;\u0026lt;\u0026thinsp;.05. The most significant predictors of mortality by univariate analysis were chosen. Variables with a P\u0026thinsp;\u0026le;\u0026thinsp;.05 in univariate analysis were chosen to perform a logistic regression analysis to estimate independent risk factors for unsuccessful ALT treatment.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period, 207 pediatric patients experienced CLABSIs, an incidence of 3.7/1000 catheter days. A total of 137 patients were given ALT together with systemic antibiotics.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics:\u003c/h2\u003e \u003cp\u003eOf 137 patients, 87 (63.5%) were male. The median age was 48 (3-204) months. The underlying illnesses were thalassemia major [n\u0026thinsp;=\u0026thinsp;36, (26.3%)], acute lymphocytic leukemia [ALL; n\u0026thinsp;=\u0026thinsp;25, (18.2%)], severe combined immune deficiency [SCID; n\u0026thinsp;=\u0026thinsp;22, (16.1%)], aplastic anemia [n\u0026thinsp;=\u0026thinsp;18, (13.1%)], acute myeloid leukemia [AML;n\u0026thinsp;=\u0026thinsp;6, (4.4%)] and others [n\u0026thinsp;=\u0026thinsp;30; (21.9%)].\u003c/p\u003e \u003cp\u003eAuto-HSCT was performed in 19 (13.9%) patients, and identical (n\u0026thinsp;=\u0026thinsp;68, %49,6), mismatch (n\u0026thinsp;=\u0026thinsp;35, %25,5), and haploidentical donor (n\u0026thinsp;=\u0026thinsp;15, %10,9)] was performed in 118 patients. Twenty-eight (20.4%) patients had re-HSCT.\u003c/p\u003e \u003cp\u003eNinety (65.7%) patients had neutropenia with a median time of 9 (3-180) days at the onset of infectious episodes. Thirty-four patients (24.8%) had GvHD. Post-transplantation cyclophosphamide (PTCy) use was encountered in 47 (34.3%) patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCLABSI episode\u003c/h2\u003e \u003cp\u003eThe median duration from CL insertion to the day of infection (DOI) was 25 (3-252) days. The CL preference was Hickman in all patients. The most common causative microorganism was Gram-negative (GN) bacteria, encountered in 85 patients (62%). Forty-six patients (33.6%) had Gram-positive (GP) bacterial growth, whereas 6 had fungal infection (4.4%).\u003c/p\u003e \u003cp\u003eThe median time of parenteral antibiotic use before ALT was 4 (2\u0026ndash;11) days. Fifty-six patients (40.9%) had prior inappropriate empirical systemic antibiotic use. The antimicrobial regimen for lock therapy included meropenem (n\u0026thinsp;=\u0026thinsp;57, 41.7%), teicoplanin (n\u0026thinsp;=\u0026thinsp;27, 20.4%), vancomycin (n\u0026thinsp;=\u0026thinsp;13, 9.5%), colistin (n\u0026thinsp;=\u0026thinsp;13, 9.5%), ciprofloxacin (n\u0026thinsp;=\u0026thinsp;7, 5.1%), liposomal amphotericin- B (n\u0026thinsp;=\u0026thinsp;6, 4.4%), tigecycline (n\u0026thinsp;=\u0026thinsp;5, 3.6%), linezolid (n\u0026thinsp;=\u0026thinsp;4, 2.9%), ceftazidime (n\u0026thinsp;=\u0026thinsp;4, 2.9%) and amikacin (n\u0026thinsp;=\u0026thinsp;1, 0.7%).\u003c/p\u003e \u003cp\u003eMicrobiologic distribution and ALT treatment are detailed in Table\u0026nbsp;2.\u003c/p\u003e \u003cp\u003eALT was successful in 77.4% of the patients (n\u0026thinsp;=\u0026thinsp;106). CR was required in 25 patients (18.2%) due to persistent bacteremia/fungemia (n\u0026thinsp;=\u0026thinsp;18), unexplained tachycardia (n\u0026thinsp;=\u0026thinsp;2), and persistent hypotension(n\u0026thinsp;=\u0026thinsp;5). Six patients had relapse within three months. The median CR day was 3 (3\u0026ndash;5) days. Adverse events that occured during ALT were catheter displacement (n\u0026thinsp;=\u0026thinsp;2), occlusion (n\u0026thinsp;=\u0026thinsp;1) and skin tethering (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eComparison of CLABSI episodes according to ALT success\u003c/h2\u003e \u003cp\u003eWhen the outcome of ALT was evaluated, there was no significant difference regarding the median age, gender, primary disease, presence, and duration of neutropenia between the ALT successful and unsuccessful groups (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003ePTCy use, fungal growth, persistent bacteremia/fungemia, re-HSCT, inappropriate empirical antibiotic use, hypotension, and pediatric intensive care unit (PICU) admission were significantly more common in the \u0026ldquo;unsuccessful\u0026rdquo; ALT group. Likewise, the patients in the unsuccessful group had higher C-RP [110.2 (1.10-323.5) mg/L] levels when compared to the successful ALT group [58 (0.2-450.3) mg/L] (p\u0026thinsp;=\u0026thinsp;0.029).\u003c/p\u003e \u003cp\u003eConsidering ALT success, a double-lumen catheter was more common among the successful ALT group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The haploidentical human leucyte antigen (HLA) match was significantly more common among the successful ALT group, whereas mismatch was significantly higher in the unsuccessful ALT group. The presence of hypotension, HLA-mismatch transplantation, and persistent bacteremia/fungemia were independent risk factors for ALT failure (Table\u0026nbsp;4).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eOutcome\u003c/h2\u003e \u003cp\u003eTwenty-four patients (17.5%) were admitted to the PICU, and 21 patients (15.3%) were given inotropes. Mortality occurred in 17 (12.4%) patients due to septic shock (n\u0026thinsp;=\u0026thinsp;7), acute renal failure (n\u0026thinsp;=\u0026thinsp;3), acute respiratory distress syndrome (n\u0026thinsp;=\u0026thinsp;3), arrhythmia (n\u0026thinsp;=\u0026thinsp;1), and pulmonary hemorrhage (n\u0026thinsp;=\u0026thinsp;2). The diagnosis of mortality cases was aplastic anemia (n\u0026thinsp;=\u0026thinsp;5), thalassemia major (n\u0026thinsp;=\u0026thinsp;4), SCID (n\u0026thinsp;=\u0026thinsp;3), AML (n\u0026thinsp;=\u0026thinsp;2), MDS (n\u0026thinsp;=\u0026thinsp;1), hemophagocytic lymphohistiocytosis (n\u0026thinsp;=\u0026thinsp;1) and non-Hodgkin lymphoma (n\u0026thinsp;=\u0026thinsp;1). Responsible microorganisms were \u003cem\u003eK.pneumonia\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;11), \u003cem\u003eA.baumanii\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1), \u003cem\u003eS.maucibalis\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1), \u003cem\u003eS.maltophilia\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1), \u003cem\u003eS.aureus\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1), \u003cem\u003eS.epidermidis\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1) and \u003cem\u003eC.albicans\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1). The relapse rate within three months was 5.8%.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAntimicrobial lock therapy, when used with systemic antibiotics, is an effective strategy to combat CLABSIs and salvage catheters. Although guidelines favor ALT, standardized prescriptions are lacking, particularly for children who underwent HSCT [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Thus, the decision to use ALT rather than CR is critical and mainly depends on the clinician's preference for this group of high-risk patients. To corroborate this, being a bone marrow transplant recipient and having neutropenia were identified as risk factors associated with CR among children with varied illnesses [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This study evaluated the ALT success rate among pediatric HSCT patients, contributing to the limited literature resources.\u003c/p\u003e \u003cp\u003eThe CLABSI incidence was 3.7/1000 catheter days in the present study. This ratio is similar to the previously reported analysis of Tural Kara et al [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which is 4.2/1000 catheter days. However, the most prevalent microorganisms varied between these two studies. In the present study, GN bacteria, mainly \u003cem\u003eK pneumonia\u003c/em\u003e, predominated. The most common causative agent in that study was methicillin-resistant coagulase negative Staphylococcus (MR-CoNS) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It has been noted that GP cocci, members of skin flora, have dominated in recent years [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Nonetheless, it is noteworthy that GNs have been reported in increased frequencies among children with malignancies, particularly in nations with limited resources [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the present study, the successful ALT rate was 77.4%, which is in the range of previously reported (46%-86.6%) [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, these studies show variety in terms of diagnoses, catheter subtypes, ALT regimens, and causative microorganisms. Tural Kara et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] reported the ALT success rate as 81% among pediatric patients with hematologic, oncologic, or immunologic diseases. In a pediatric HSCT report, Zanwer et al.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] found the catheter salvage rate as high as 86.6% in the ALT-added CLABSI group, significantly higher than in patients without ALT. Similarly, Ohoro et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] concluded that combining systemic antibiotics and culture-guided ALT was superior to the systemic antibiotic alone. In Tsai et al.'s [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] study, the overall success rate of ALT was 71.6%. When detailed, the success of ALT in \u003cem\u003eEnterobacteriaceae\u003c/em\u003e infections (78.3%) was greater than that of CoNS (58.6%). Older age, elevated C-RP levels, ALL as a primary disease, and candidemia were found to be the factors associated with ALT failure [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In a national study by Asrak et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], the rate of success for ALT was found to be 68.8% among pediatric cancer patients. The study also found that younger age was an independent risk factor for the ALT failure.\u003c/p\u003e \u003cp\u003eIn the present study, HLA-mismatch, re-HSCT and PTCy use were significantly more common among the patients with unsuccessful ALT. This situation appears to be linked to HSCT failure, resulting in extended immunosuppression, hospitalization, and complications. According to recent research, PTCy was linked to higher rates of bacterial infections, regardless of the donor [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Furthermore, bacterial infections were associated with increased mortality rates [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOn the other hand, Wolf et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] reported that they were unable to find any advantage of using adjunctive ALT in pediatric oncology patients with CLABSIs. This is because the treatment failure rate was similar in both groups, i.e. the group that received only systemic treatment (ST, 38.4%) and the group that received ALT in addition to ST (50%). Patients who received ALT had delayed CR and relapse of infection, resulting in later treatment failure. This study holds immense value as it stands in contrast to the opposing view presented in literature. The definition of treatment failure used in the study design is different from ours. In the study, treatment failure was defined as CR or mortality attributable to an infection within 14 days of the onset of CLABSI, or relapse of infection caused by the same microorganism species within 252 days. These variations in study design may have caused the difference. In their study, similar to ours, treatment failure due to CR within the first three days was significantly more common in the only ST group.\u003c/p\u003e \u003cp\u003eGuidelines recommend CR in the presence of \u003cem\u003eS.aureus, P.aeruginosa\u003c/em\u003e, and fungemia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, inserting a new CL can be challenging, and the replacement significantly increases the risk of bloodstream infection and other issues depending on where the catheter is inserted (arterial puncture, pneumothorax, etc.) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Furthermore, not all patients are eligible for catheter replacement. These include critically ill individuals who may be coagulopathic, thrombocytopenic or have restricted venous access [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In the present study, the ALT success rate for \u003cem\u003eS. aureus\u003c/em\u003e and \u003cem\u003eP.aeroginosa\u003c/em\u003e was nearly 91% and 88%, respectively. Although there was a limited case of fungal ALT experience, the success rate was far below the bacterial salvage ratio, 33.3%. We succeeded in two cases with \u003cem\u003eC.albicans\u003c/em\u003e and C. \u003cem\u003eparapsilosis\u003c/em\u003e-related CLABSI with L-AMB.\u003c/p\u003e \u003cp\u003eThe literature contains very limited data on antifungal lock treatment [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In in-vivo studies with either fluconazole, echinocandin derivatives, or L-AMB (single or in combination), the therapeutic success rate varies between 17% and 100% [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In these studies, administered drug doses, the ingredients of lock solution, and dwell times vary significantly. Although ethanol-based lock solutions showed the highest activity, they were found to lead to potential risks, particularly concentrations above 28\u0026ndash;30%, such as clotting, dizziness, protein precipitation, and compromised catheter integrity [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. We opted for heparin instead of using ethanol in any of the lock solutions. The potential risk of systemic circulation of heparin after application in small infants is a crucial concern [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Besides, there is some evidence that heparin might promote the formation of \u003cem\u003eS. aureus\u003c/em\u003e biofilm, although this claim is not universally agreed upon [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In our experience, we did not observe any heparin-related side effects, and ALT produced an overall safe treatment profile.\u003c/p\u003e \u003cp\u003eThe therapeutic success of L-AMB, reaching 83%, has also been reported in case series [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Castagnola et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] reported a successful antifungal lock therapy experience related to \u003cem\u003eC.parapsilosis\u003c/em\u003e CLABSI in an infant with L-AMB. Systemic antifungal treatment also included L-AMB for 14 days. Paul DiMondi et al [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] applied L-AMB lock therapy for \u003cem\u003eC.albicans\u003c/em\u003e and succeeded in a 64-year-old female patient. However, they preferred micafungin as a parenteral agent. For our cases, we administered L-AMB both parenteral and as lock therapy.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations of the study\u003c/h2\u003e \u003cp\u003eIt is important to acknowledge that our study has limitations as it is retrospective in nature. As with other studies on this topic, the preference and procedure of ALT rely on the clinician's judgment, as there are no clear guidelines in the literature. On the other hand, the current study has many strengths, such as the fact that it includes a significant patient group, such as pediatric HSCT, the high number of cases, and it provides a broad perspective regarding microorganism diversity and antimicrobial drug experience.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo summarize, ALT can be an effective catheter-saving strategy in HSCT pediatric patients. Nevertheless, patients should be monitored very closely during ALT, and the presence of certain risk factors should be considered. We believe that, the results of this investigation will contribute to the architecture of further studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eNo conflict of interest was declared by the authors.\u003c/p\u003e \u003ch2\u003eFinancial Disclosure\u003c/strong\u003e \u003cp\u003eThe authors declared that this study has received no financial support. None of the authors has any potential financial conflict of interest related to this manuscript.\u003c/p\u003e \u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMK and MS wrote the main manuscript. BAA and GZE collected the patient data. OBO, AY and AO revised the data and made statistical analyses. CB and TF made critical revision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFrom the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology (ASNR), Cardiovascular and Interventional Radiology Society of Europe (CIRSE), Canadian Interventional Radiology Association (CIRA), Congress of Neurological Surgeons (CNS), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organization (ESO), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Interventional Radiology (SIR), Society of NeuroInterventional Surgery (SNIS), and World Stroke Organization (WSO), Sacks D, Baxter B, Campbell BCV et al (2018) Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int J Stroke. ;13:612\u0026thinsp;\u0026ndash;\u0026thinsp;32\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang AK, Foca MD, Jin Z et al (2016) Bacterial bloodstream infections in pediatric allogeneic hematopoietic stem cell recipients before and after implementation of a central line-associated bloodstream infection protocol: a single-center experience. Am J Infect Control 44:1650\u0026ndash;1655\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLukenbill J, Rybicki L, Sekeres MA et al (2013) Defining incidence, risk factors, and impact on survival of central line-associated bloodstream infections following hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transpl 19:720\u0026ndash;724\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGirand HL, McNeil C Lock therapy for treatment and prevention of intravascular non-hemodialysis catheter-related infection. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.uptodate.com\u003c/span\u003e\u003cspan address=\"https://www.uptodate.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Date of access, April 2,2024].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBennett J, Cheung M (2020) Intravenous access in children. Pediatr Child Health 30:224\u0026ndash;229\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMermel LA, Allon M, Bouza E et al (2009) Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 49:1\u0026ndash;45\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerrinton A, Gould FK (2001) Use of antibiotic locks to treat colonized central venous catheters. J Antimicrob Chemother 48:597\u0026ndash;603\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKara TT, \u0026Ouml;zdemir H, Erat T et al (2019) Is antibiotic lock therapy effective for implantable long-term catheter-related bloodstream infections in children? Turk J Pediatr 61:895\u0026ndash;904\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolf J, Allison KJ, Tang L, Sun Y, Hayden RT, Flynn PM (2014) No evidence of benefit from antibiotic lock therapy in pediatric oncology patients with central line-related bloodstream infection: results of a retrospective matched cohort study and review of the literature. 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J Pediatr Hematol Oncol 45:17\u0026ndash;20\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZanwar S, Jain P, Gokarn A et al (2019) Antibiotic lock therapy for salvage of tunneled central venous catheters with catheter colonization and catheter-related bloodstream infection. Transpl Infect Dis 21(1):e13017\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoran TC, Andrus M, Dudeck MA (2008) CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 36:309\u0026ndash;332\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMermel LA, Farr BM, Sherertz RJ et al (2001) Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis 32:1249\u0026ndash;1272\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Grady NP, Alexander M, Dellinger EP et al (2002) Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention. MMWR Recomm Rep 51:1\u0026ndash;29\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalker LW, Visweswaran S, Nowalk AJ (2023) Outcomes in Pediatric Central Line-associated Bloodstream Infections Treated With Antimicrobial Locks: A 14-Year Retrospective Analysis. Pediatr Infect Dis J 42:473\u0026ndash;478\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSignorino C, Fusco E, Galli L, Chiappini E (2023) Effectiveness of Antimicrobial Lock Therapy for the Treatment of Catheter-Related and Central-Line-Associated Bloodstream Infections in Children: A Single Center Retrospective Study. Antibiot (Basel) 12:800\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNorris LB, Kablaoui F, Brilhart MK, Bookstaver PB (2017) Systematic review of antimicrobial lock therapy for prevention of central-line-associated bloodstream infections in adult and pediatric cancer patients. Int J Antimicrob Agents 50:308\u0026ndash;317\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaynes R, Jacob J T.Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.uptodate.com\u003c/span\u003e\u003cspan address=\"https://www.uptodate.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. [Date of access; March 21, 2024]\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAli N, Adil SN, Shaikh MU (2014) Bloodstream and central line isolate from hematopoietic stem cell transplant recipients: data from a developing country. Transpl Infect Dis 16:98\u0026ndash;105\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButt T, Afzal RK, Ahmad RN, Hussain I, Anwar M (2004) Central venous catheter-related bloodstream infections in cancer patients. J Coll Phys Surg Pakistan 14:549\u0026ndash;552\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Horo JC, Silva GL, Safdar N (2011) Anti-infective locks for treatment of central line-associated bloodstream infection: a systematic review and meta-analysis. Am J Nephrol 34:415\u0026ndash;422\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsrak HK, Belet N, T\u0026uuml;fek\u0026ccedil;i \u0026Ouml;, \u0026Ouml;zl\u0026uuml; C, Baysal B, İnce D (2021) Investigating the risk factors for antibiotic lock therapy failure in pediatric cancer: a single center retrospective analysis. Turk J Pediatr 63:86\u0026ndash;94\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUstun C, Chen M, Kim S et al (2024) Post-transplantation cyclophosphamide is associated with increased bacterial infections. Bone Marrow Transpl 59(1):76\u0026ndash;84\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'grady NP, Alexander M, Dellinger EP et al (2002) Healthcare Infection Control Practices Advisory Committee. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 30:476\u0026ndash;489\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalraven CJ, Lee SA (2013) Antifungal lock therapy. Antimicrob Agents Chemother 57:1\u0026ndash;8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKov\u0026aacute;cs R, Majoros L (2022) Antifungal lock therapy: an eternal promise or an effective alternative therapeutic approach? Lett Appl Microbiol 74:851\u0026ndash;862\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasas J, Morer A, Ratia C et al (2016) Efficacy of anidulafungin in the treatment of experimental Candida parapsilosis catheter infection using an antifungal-lock technique. J Antimicrob Chemother 71:2895\u0026ndash;2901\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasas J, Palau M, Gomis X et al (2019) Efficacy of liposomal amphotericin B and anidulafungin using an antifungal lock technique (ALT) for catheter-related Candida albicans and Candida glabrata infections in an experimental model. PLoS ONE 14:e0212426\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMermel LA, Alang N (2014) Adverse effects associated with ethanol catheter lock solutions: a systematic review. J Antimicrob Chemother 69:2611\u0026ndash;2619\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShanks RM, Donegan NP, Graber ML et al (2005) Heparin stimulates Staphylococcus aureus biofilm formation. Infect Immun 73:4596\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastagnola E, Marazzi MG, Tacchella A, Giacchino R (2005) Broviac catheter-related candidemia. Pediatr Infect Dis J 24:747\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaul DiMondi V, Townsend ML, Johnson M, Durkin M (2014) Antifungal catheter lock therapy for the management of a persistent Candida albicans bloodstream infection in an adult receiving hemodialysis. Pharmacotherapy 34:e120\u0026ndash;e127\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Central line-associated bloodstream infection, pediatric hematopoietic stem cell transplantation, antimicrobial lock therapy","lastPublishedDoi":"10.21203/rs.3.rs-4540053/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4540053/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction\u003c/h2\u003e \u003cp\u003eCentral line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Antimicrobial lock treatment (ALT), when utilized alongside systemic antibiotics, may be lifesaving when catheter removal (CR) is not feasible.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study analyzed the clinical, laboratory, and microbiologic characteristics of CLABSI episodes of pediatric patients who underwent HSCT and applied ALT.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThere were 137 cases of CLABSI (63.5 male) who were given ALT. The median age was 48 (3-204) months. The most common causative microorganism was Gram-negative bacteria, encountered in 85 patients (62%). Forty-six patients (33.6%) had Gram-positive bacterial growth, whereas 6 had (4.4%) fungal infection. ALT was successful in 77.4% of the patients (n\u0026thinsp;=\u0026thinsp;106). CR was required in 25 patients (18.2%). The CLABSI-related mortality rate was 12.4%. When the outcome of ALT was evaluated, post-transplantation cyclophosphamide (PTCy) use, fungal growth, persistent bacteremia/fungemia, re-HSCT, inappropriate empirical antibiotic use, hypotension, and pediatric intensive care unit admission were significantly more common in the \u0026ldquo;unsuccessful\u0026rdquo; ALT group. The patients in the unsuccessful group had higher C-reactive protein [110.2 (1.10-323.5) mg/L] levels when compared to the successful ALT group [58 (0.2-450.3) mg/L] (p\u0026thinsp;=\u0026thinsp;0.029). The presence of hypotension, HLA-mismatch transplantation, and persistent bacteremia/fungemia were independent risk factors for ALT failure.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eALT can be an effective catheter-saving strategy in HSCT pediatric patients. Nevertheless, patients should be monitored very closely during ALT, and the presence of certain risk factors should be taken into account.\u003c/p\u003e","manuscriptTitle":"Antimicrobial Lock Therapy: Is it a real savior in pediatric hematopoetic stem cell transplant (HSCT) patients?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-25 05:42:20","doi":"10.21203/rs.3.rs-4540053/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0c6745a4-ddf9-4d61-b864-1232fc511312","owner":[],"postedDate":"June 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-28T14:59:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-25 05:42:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4540053","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4540053","identity":"rs-4540053","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}