- Email: [email protected]
A randomized trial on chlorhexidine dressings for the prevention of catheter-related bloodstream infections in neutropenic patients
Annals of Oncology Advance Access published July 25, 2016
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A randomized trial on chlorhexidine dressings for the prevention of catheter-related bloodstream infections in neutropenic patients
L. M. Biehl1,12, A. Huth1, J. Panse2, C. Krämer2, M. Hentrich3, M. Engelhardt4, K. Schäfer-Eckart5, G. Kofla6, M. Kiehl7, C.-M. Wendtner8, M. Karthaus9, A. J. Ullmann10, M. Hellmich11, H. Christ11, M. J.G.T. Vehreschild1,12 Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
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Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Medical Faculty,
RWTH Aachen University Hospital, Aachen, Germany 3
Department of Medicine III, Red Cross Hospital, Munich, Germany
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Department of Medicine I, Hematology, Oncology and Stem Cell Transplantation, University of Freiburg
Medical Center, Freiburg im Breisgau, Germany 5
Medical Clinic 5, Hematology and Oncology, Klinikum Nuernberg, Nuernberg, Germany
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Charitè University Medicine, Department of Medicine, Division of Oncology/ Hematology, Charitè Campus
Mitte, Berlin, Germany 7
Medical Clinic I, Hematology and Medical Oncology, Hemostaseology, Clinical Center Frankfurt/Oder,
Frankfurt/Oder, Germany 8
Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine,
Klinikum Schwabing, Munich, Germany 9
Department of Hematology and Oncology, Klinikum Neuperlach and Klinikum Harlaching, Munich, Germany
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Division of Infectious Diseases, Department of Internal Medicine II, University Hospital Wuerzburg,
Wuerzburg, Germany 11
Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany
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German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Corresponding author: Dr. Maria J.G.T. Vehreschild, Department I of Internal Medicine, University Hospital of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany, phone: +49 221 478 88794, e-mail: [email protected]
Abstract
cause of morbidity and mortality in patients with chemotherapy-induced neutropenia. Chlorhexidine containing catheter securement dressings may prevent CRBSI. Patients and methods: A multicenter randomized controlled trial was conducted at 10 German hematology departments. We compared chlorhexidine containing dressings with nonchlorhexidine control dressings in neutropenic patients. The primary endpoint was incidence of definite CRBSI within the first 14 days (dCRBSI14) of central venous catheter (CVC) placement. Secondary endpoints included combined incidence of definite or probable CRBSI within 14 days (dpCRBSI14), overall (dpCRBSI), incidence of unscheduled dressing changes and adverse events. Results: From Feb 2012 to Sept 2014, 613 evaluable patients were included in the study. Incidence of dCRBSI14 was 2.6% (8/307) in the chlorhexidine and 3.9% (12/306) in the control group (p=0.375). Both dpCRBSI14 and dpCRBSI were significantly less frequent in the study group with dpCRBSI14 in 6.5% (20/307) of the chlorhexidine group as compared to 11% (34/306) in the control group (p=0.047), and dpCRBSI in 10.4% (32/307) vs. 17% (52/306), respectively (p=0.019). The frequency of dressing intolerance with cutaneous and soft tissue abnormalities at the contact area was similar in both groups (12.4% and 11.8%; p=0.901).
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Background: Central venous catheter-related bloodstream infections (CRBSI) are a frequent
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Conclusions: Although the trial failed its’ primary end point, the application of chlorhexidine containing catheter securement dressings reduces the incidence of definite or probable CRBSI in neutropenic patients.
Clinical Trials number: NCT01544686 (Clinicaltrials.gov) Keywords: catheter-related bloodstream infections, catheter dressings, neutropenia,
Key message: Chlorhexidine dressings reduced the incidence of definite and probable catheter-related bloodstream infections in neutropenic patients. In contrast to previous studies, tolerance to chlorhexidine and control dressings was similar.
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chlorhexidine
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Introduction The administration of intensive chemotherapy for a hematological malignancy frequently requires the insertion of a central venous catheter (CVC). Particularly during long-term use of non-tunneled CVC, catheter-related bloodstream infections (CRBSI) may occur [1], ranging
to CRBSI has been reported to be as high as 36% [5]. Previous studies have highlighted the role of skin colonization as a predisposition for catheter colonization and subsequent CRBSI [3]. Consequently, effective reduction of skin colonization may be an important preventive factor. A few randomized trials have shown reduction of CRBSI by use of dressings with chlorhexidine gluconate (CHG) impregnated sponges [6-8] or a CHG containing gel pad [9]. The transparent gel pad has the advantage of allowing visual evaluation of the CVC insertion site without dressing removal. The two largest studies were conducted in intensive care unit patients [7, 9]; only one study evaluated the clinical efficacy of CHG CVC dressings in patients undergoing chemotherapy [6]. All three studies showed reduced CVC-related infection rates for CHG dressings. The application of CHG dressings is recommended by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) [10], but not by the American Society of Clinical Oncology (ASCO) [11]. The Centers for Disease Control considers chlorhexidine dressings other than those with impregnated sponges an unresolved issue [1]. Due to the limited body of evidence and the conflicting recommendations, a multicenter randomized controlled trial investigating CVC dressings with CHG containing gel pads in the setting of high-risk neutropenic patients was conducted.
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from 2.5 to 7.5 infections per 1000 catheter days [2-4]. In neutropenic patients, mortality due
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Methods Study design We conducted an open-label, randomized, multicenter trial in 10 German hematological departments. We compared two securement dressings with regard to their safety and efficacy in preventing CRBSI. The study product 3M™ Tegaderm™ CHG I.V. is a transparent CVC dressing with a chlorhexidine-containing gel pad. The comparator, 3M™ Tegaderm™ I.V.
designed and planned according to the Declaration of Helsinki in the version of October 2008 (59th WMA General Assembly, Seoul). Ethical approval was obtained from all competent ethics committees and registration completed at Clinicaltrials.gov (NCT01544686). Study patients Patients undergoing chemotherapy with an expected duration of chemotherapy-induced neutropenia of ≥5 days and an expected CVC use of ≥10 days were eligible for inclusion. Patients could be enrolled only once. Exclusion criteria included use of tunneled CVC, shaldon catheters, femoral insertion and suspected or confirmed bacterial infection at randomization. Trial conduct After informed consent, patients received a non-tunneled CVC in the subclavian or internal jugular vein. The type of CVC used depended on local standards, insertion followed a strict antiseptic regimen in accordance with respective guidelines [1, 12]. Dressings were applied within two hours of CVC placement and changed every 3+/-1 days. In case of neutropenic fever, central and peripheral blood cultures were drawn. If there was a suspicion of CRBSI, the CVC was removed and the tip sent in for microbiological culture. Antimicrobial prophylaxis or treatment depended on local standards, antimicrobial stewardship programs were not conducted during the study period. End of treatment (EOT)
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Advanced is a transparent CVC dressing without an antimicrobial gel pad. The study was
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was determined as CVC change or removal for any reason, definite CRBSI with or without CVC removal, maximum treatment duration of 42 days as per protocol, intolerance to the study product or death. Adverse events (AE) and severe adverse events (SAE) were assessed until follow-up on day 14 after EOT. Independent data monitors reviewed documentation. Variables and definitions Documented variables included demographics, underlying disease, chemotherapeutic
and antibiotic or antifungal administration during study treatment. In patients with CRBSI, results from blood and CVC tip cultures, presence of clinical signs according to the applied definitions and presence of an alternative focus were recorded. CRBSI were defined according to the AGIHO-DGHO guidelines [12]. Definite CRBSI required either a differential time to positivity (DTTP) over 2 hours in a pair of peripheral and central blood cultures or the detection of the same pathogen with the same susceptibility pattern in a blood culture and at the catheter tip. For probable CRBSI, one of the following three scenarios needed to be fulfilled: the presence of local infection at the insertion site with at least two signs of inflammation coupled with a positive blood culture; remission of previously refractory fever within 48 hours after catheter removal plus a positive blood culture; or a positive catheter tip culture. Definition of severe sepsis as modified from the guidelines by American College of Chest Physicians and the Society of Critical Care Medicine [13] required the following two criteria: (1) systemic inflammatory response (SIRS) and (2) at least one organ dysfunction. Since this study investigated an already approved medical product within its licensed indication, assessment of AE and SAE was not mandatory by applicable local law. Thus, AE were restricted to cutaneous and soft tissue abnormalities, AE in relation with systemic allergic reactions and AE in relation with coagulation disorders not related to chemotherapyassociated thrombocytopenia.
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regimen, CVC characteristics, dressing changes, neutropenia, occurrence of neutropenic fever
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End points The primary end point was incidence of definite CRBSI within 14 days (dCRBSI14) of CVC placement. Secondary end points were overall definite CRBSI (dCRBSI), definite and probable CRBSI within 14 days of CVC placement (dpCRBSI14), overall definite and probable CRBSI (dpCRBSI), dCRBSI14-related severe sepsis, dCRBSI14-related mortality, dpCRBSI-related severe sepsis, dpCRBSI-related mortality, overall mortality, time to removal of CVC or EOT, time to dpCRBSI, time to first neutropenic fever and the frequency and
Sample size and statistical analysis A group-sequential design using O’Brien and Fleming bounds at information fractions 0.5 and 1 was chosen to allow for early termination of the trial due to futility or success. We assumed a reduction of dCRBSI14 from 12% in the control group to 7.2% in the CHG group. Based on a two-sided type I error α = 0.05, 1190 evaluable patients were calculated to reach a power of 1 - β = 0.8 (chi-square test without continuity correction). Compensating for a percentage of about 5% non-evaluable patients, we planned to include 1260 patients. Analysis of the intention-to-treat (ITT) population included all randomized and evaluable subjects: all who received a CVC and did not withdraw consent directly after randomization. The primary end point dCRBSI14 was evaluated by a Mantel-Haenszel test stratified by study center, testing if the combined odds ratio equals 1. Characteristics of patients, catheters, and dressings were described as count (%) or median (interquartile range [IQR]) for qualitative and quantitative variables and compared between treatment groups using chi-square test, Wilcoxon rank sum test or log rank test as appropriate. Corresponding confidence intervals (CI) were calculated if possible. Subgroup analyses referred to CVC insertion site (jugular or subclavian vein) and CVC type (coated vs. non-coated). P values smaller 5% were considered “statistically significant”. SPSS Statistics software (Version 22, IBM Corp., Armonk, NY, USA) was used.
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reasons of unscheduled dressing changes (UDC).
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Results Between 02/2012 and 09/2014, 630 patients were included at 10 study sites. Results were subjected to an interim analysis. Thereafter, enrolment was discontinued, because a statistically significant difference in the primary end point was not met and was anticipated
17 inclusions (2.7%; 8 CHG and 9 controls) were screening failures. Of 613 evaluable patients, 307 were in the CHG and 306 in the control group. Patient characteristics Patient characteristics are shown in table 1. The groups did not differ significantly with respect to distribution of age, gender, Eastern Cooperative Oncology Group score (ECOG), duration of neutropenia, CVC insertion site and type. There was a higher proportion of AML patients in the control group. While there were significantly more patients in the CHG group (289, 94.8%) receiving any antimicrobial than in the control group (272, 90.3%; p=0.044), the mean cumulative days of antimicrobial treatment per patient were similar with 25.1 days in the CHG and 25.2 days in the control group (p=0.223). Primary and secondary end points For dCRBSI14, the rates were not significantly different between groups (CHG: 2.6% vs. control: 3.9%; odds ratio: 0.676; 95% CI: 0.270-1.693). Both, dpCRBSI14 (CHG: 6.5% vs. control: 11.1%; p=0.047) and dpCRBSI (CHG: 10.4% vs. control: 17.3%; p=0.014) were significantly less frequent in the study than in the control group. Respective CRBSI rates per 1000 catheter days (table S1), a differentiation of the CRBSI criteria applied (S2) and incidences per center (S3) are shown in the supplementary material. Regarding frequencies of
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not to be reached even after enrolment of further 630 patients. Of the included 630 patients,
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CRBSI-related severe sepsis and mortality, overall mortality, time to removal of CVC, time to dpCRBSI and time to first neutropenic fever, there were no significant differences (table 2). There were significantly fewer UDC in the study than in the control group reflected in the mean number of UDCs per patient (CHG: 0.9 vs. control: 1.2) and the difference in total UDC (CHG: 269 vs. control: 362; p=0.030). The most frequent reason for a UDC was intensive bleeding documented in 73 (23.8%) CHG and 83 (27.1%) control patients (p=0.355),
patients (p=0.003). Safety and tolerability In total, 56 AEs in 51 patients (16.6%) were observed in the CHG and 57 AEs in 52 patients (17.0%) in the control group (p=0.914). AEs concerning cutaneous and soft tissue abnormalities were observed in 38 patients (12.4%) in the CHG and 36 (11.8%) in the control group (p=0.901). In 22 cases (7.2%) in the CHG and 24 cases (7.8%) in the control group, this intolerance lead to study discontinuation and definite change to different dressing (p=0.762). In 33 study (10.7%) and 32 control patients (10.5%), an AE was classified as certainly or probably related to the respective dressing. All of these related AEs were cutaneous and soft tissue abnormalities. Regarding SAEs, 42 events were documented in 39 CHG (12.7%) and 36 events in 32 control patients (11.8%). The most frequently reported SAEs were organ failures related to severe sepsis. None of the SAEs were assessed as certainly or probably related to the study treatment (table 3).
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followed by insufficient cutaneous adhesion in 43 (14%) CHG and 72 (23.5%) control
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Pathogens causing CRBSI The distribution of causative pathogens in dpCRBSI did not differ significantly between groups with coagulase-negative staphylococci being the most frequently isolated pathogens (table S4). CVC insertion site and type The distribution of CVC insertion site and CVC type was similar between groups (see table
examined the CRBSI rates according to CVC insertion site and CVC type irrespective of randomization (S6). Rates were significantly higher in patients with a subclavian vein as compared to a jugular internal vein CVC both, for dCRBSI14 (4.8% vs. 1.2%; p=0.019) and dCRBSI (8.1% vs. 3.1%; p=0.010). Comparing coated vs. uncoated CVC, patients with coated CVC had higher rates of dCRBSI14 (4.2% vs. 1.1%; p=0.048), dCRBSI (7.9% vs. 1.6%; p=0.001) and dpCRBSI (16.4% vs. 8.1%; p=0.007).
Discussion To our knowledge, this is the first randomized trial evaluating a transparent CVC dressing with a chlorhexidine gel pad in neutropenic patients. A trend towards reduction was seen for the primary end point of definite CRBSI within 14 days of CVC placement, but due to a lower than expected event rate, the study was underpowered with respect to its primary endpoint. Application of the study dressing in comparison to a transparent non-CHG dressing significantly reduced the incidence of definite and probable CRBSI overall from 17.3% to 10.4% (p=0.014) and within 14 days of CVC placement from 11.1% to 6.5% (p=0.047), respectively. These results are consistent with those of previous studies investigating
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S5 for frequencies per center). To further assess a possible influence of these variables, we
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chlorhexidine containing CVC dressings in different settings [6-9] and thus complement the evidence in favor of application of transparent CHG dressings for non-tunneled CVC in the setting of neutropenia. Given that the identified etiological agents were mostly skin colonizers, the more marked preventive efficacy in overall CRBSI rates as compared to rates within 14 days of CVC placement suggests that the effect of the dressing in reducing skin colonization is not limited to the first 14 days of its use. The risk of extraluminal contamination of the CVC, most likely not affected by our study product, is an independent,
We observed no difference in the rates of CRBSI-related severe sepsis or mortality between the two groups. However, the infrequency of these clinical outcomes limited the ability of a study of this size in detecting a possible difference. Furthermore, both, severe sepsis and overall mortality, are – obviously – not merely influenced by the applied CVC dressing in these high-risk patients. It is noteworthy, that intolerance to the study product as a reason for end of treatment as well as adverse events concerning skin and soft tissue abnormalities did not occur significantly more frequent in the study group. Skin defects were observed in only few cases in both groups. This opposes findings of previous studies reporting increased rates of contact dermatitis during the application of CHG containing dressings [9, 14]. We hypothesize that the comparatively short interval between dressing changes (3+/-1 days) might have prevented skin reactions triggered by moisture accumulating between skin and dressing. Unexpectedly, the incidence of CRBSI was lower in patients with internal jugular as compared to subclavian insertion site and in those with uncoated CVCs as compared to coated, irrespective of dressing randomization. Regarding CVC insertion site, results are contradictory to previous studies reporting lower CRBSI rates for subclavian insertion site [15, 16]. However, a Cochrane review found similar infection rates for subclavian and
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additional risk factor for CRBSI.
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internal jugular insertion sites [17]. Regarding CVC type, our results contradict various studies and literature reviews favoring coated CVCs with respect to CRBSI [18-21]. Antimicrobial or antiseptic coated CVCs are recommended in German [10] and American [11] guidelines. However, the advantage of coated CVCs might be more pronounced in ICU settings [22], in short-term catheterization under 7 days [23], and was not confirmed in a meta-analysis evaluating CVCs for parenteral nutrition and chemotherapy [24]. Of note, the present study was not designed and the study population not stratified for analyzing the
site depended on the standard of care of the respective study center. Our study has some limitations. First, the study was terminated after the interim analysis due to the low rate of primary end point events. Therefore, the study lacks adequate power, particularly regarding the conservative O’Brien-Fleming bound 0.002583 (one-sided). The incidence of the primary end point dCRBSI14 was lower than anticipated from previous observations [6] - possibly being a result of improved antiseptic routine. Second, due to a lack of a control product including a gel pad without antimicrobial activity, blinding was not feasible. Nevertheless, the microbiological department was blinded as blood cultures and CVC tips were analyzed within routine diagnostics. The substantial sample size within this special setting of neutropenic patients, the multicenter design and the thorough assessment of adverse events are key strengths of the presented study. In summary, the study was not able to demonstrate a reduction in the primary end point of definite CRBSI within 14 days of CVC placement by the application of transparent CVC dressings with a chlorhexidine containing gel pad in patients undergoing intensive chemotherapy. The presented results show that the dressings were well tolerated and significantly reduced definite and probable CRBSI. Whether the observed risk reduction for definite and probable CRBSI justifies the application of CHG dressings in the routine care of
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impact of CVC insertion site and coating on CRBSI. The choice of CVC type and insertion
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long-term neutropenic patients also depends on further factors such as local CRBSI rates and related costs.
Acknowledgements
We would like to thank the study nurses of all study sites and the staff of the wards involved in the conduct of the trial.
This work was supported by a research grant by 3M (no grant number applicable).
Disclosure LMB is supported by the German center for Infection Research (DZIF). LMB has received lecture honoraria from Astellas and MSD and travel grants from 3M and Gilead. JP has served at the speakers’ bureau and received lecture honoraria/ore travel grants of/from, Celgene, Gilead Sciences Merck/MSD, Astellas Pharma and Pfizer. AJU reports personal fees from MSD, personal fees from Pfizer, personal fees from Astellas, personal fees from Basilea and personal fees from Gilead outside the submitted work. MJGTV has served at the speakers’ bureau of Pfizer, Merck, Gilead Sciences, and Astellas Pharma, received research funding from 3M, DaVolterra, MSD/Merck, Astellas Pharma and Gilead Sciences and is a consultant to Berlin Chemie and DaVolterra. All other authors report no conflicts of interest.
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Funding
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Table 1: Demographic and clinical characteristics of included patients Characteristics
Control group, n=306 58 (18-82; 18) 172/134
105 (34.2) 23 (7.5) 60 (19.5) 14 (4.6) 88 (28.7) 17 (5.5)
140 (45.8) 11 (3.6) 53 (17.3) 10 (3.3) 81 (26.5) 11 (3.6)
p 0.594# 0.190† 0.036†
0.183† 178 (58.0) 100 (32.6) 27 (8.8) 2 (0.7)
173 (56.5) 91 (29.7) 34 (11.1) 8 (2.6) 0.056†
89 (29.0) 10 (3.3) 21 (6.8) 2 (0.7) 155 (50.5) 0
104 (34.0) 22 (7.2) 12 (3.9) 4 (1.3) 133 (43.5) 1 (0.3)
27 (8.8)
23 (7.5)
2 (0.7) 1 (0.3)
6 (2.0) 1 (0.3) 0.624†
175 (57.0) 132 (43.0)
181 (59.2) 125 (40.8) 0.930†
92 (30.0) 215 (70.0) 8 (0-42; 8)
93 (30.4) 213 (69.6) 7 (0-41; 8)
0.176#
289 (94.8) 25.1/18 (28)
272 (90.3) 25.2/15 (27)
0.044† 0.223†
CHG: chlorhexidine gluconate; IQR. Interquartile range; AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; NHL: non-Hodgkin lymphoma; ECOG: European Cooperative Oncology Group; HSCT: hematopoietic stem cell transplantation; CVC: central venous catheter. # t-test for independent samples; † Pearson’s χ² test a Other conditions (CHG/control): amyloidosis (1/1), aplastic anemia (2/0), chronic lymphocytic leukemia (0/2), chronic myelogenous leukemia (0/1), testicular cancer (7/4), myelodysplastic syndrome (5/1), myeloproliferative neoplasms (2/2) b Other chemotherapy (CHG/control): anti-thymocyte globulin for aplastic anemia (1/0), hydroxycarbamide monotherapy for AML (0/1)
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Age – median years (range; IQR) Gender (male/female) Underlying condition (%) AML ALL NHL Hodgkin’s lymphoma Multiple myeloma/ plasmocytoma Othera ECOG score at randomization (%) 0 1 2 3 Chemotherapy (%) AML induction AML consolidation ALL induction ALL consolidation Autologous HSCT chemotherapy (%) Allogeneic HSCT, myeloablativ conditioning Allogeneic HSCT; reduced intensity conditioning Relapse chemotherapy for lymphoma Otherb CVC insertion site (%) Subclavian vein Internal jugular vein CVC type (%) Uncoated Silver/CHG coated Median number of neutropenic days during study treatment (range; IQR) Antimicrobial consumption Patients with any antimicrobials (%) Mean/median cumulative days per patientc (IQR)
CHG group, n=307 58 (18-83; 21) 189/118
c
Days of antimicrobials total are cumulative, meaning that days per antimicrobial class are summed up by patient regardless of overlap of timeframes.
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Table 2: Primary and secondary end points End point
group, Control n=306
group, p
8 (2.6) 13 (4.2) 20 (6.5) 32 (10.4)
12 (3.9) 24 (7.8) 34 (11.1) 53 (17.3)
0.375† 0.064† 0.047† 0.014†
2 (0.7) 1 (0.3) 5 (1.6) 1 (0.3) 19 (6.2)
2 (0.7) 0 (0.0) 6 (2.0) 2 (0.7) 17 (5.6)
1.0† 1.0† 0.772† 0.624† 0.864†
17 (0-42; 10) 13 (4-39; 7.5) 11 (0-41; 4) 0/0.9 (0-10; 1)
16 (0-42; 11) 13 (0-40; 8) 10 (0-39; 5) 1/1.2 (0-14; 2)
0.074# 0.956# 0.253# 0.030#
CHG: chlorhexidine gluconate; CRBSI: catheter-related bloodstream infection; dCRBSI14: definite CRBSI within 14 days of catheter placement; dCRBSI: definite CRBSI overall; dpCRBSI14: definite and probable CRBSI within 14 days of catheter placement; dpCRBSI: definite and probable CRBSI overall; IQR: interquartile range; CVC: central venous catheter; EOT: end of treatment; UDC: unscheduled dressing change. # t-test for independent samples; † Pearson’s χ² test
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CRBSI end points (%) dCRBSI14 (primary end point) dCRBSI dpCRBSI14 dpCRBSI Outcome end points (%) dCRBSI14-related severe sepsis dCRBSI14-related mortality dpCRBSI-related severe sepsis dpCRBSI-related mortality Overall mortality Median time to … in days (range, IQR) …removal of CVC or EOT …dpCRBSI …first neutropenic fever Median/mean number of UDC per patient (range; IQR)
CHG n=307
Table 3: Adverse and severe adverse events
CHG: chlorhexidine gluconate; AE: adverse event; SAE: severe adverse event. a All AEs with certain or probable causal relationship to the respective treatment were cutaneous and soft tissue abnormalities. † Pearson’s χ² test b Other AEs: generalized itching (1xCHG group), anaphylaxis (1xCHG group). c Other SAEs in CHG group (12 events in 10 patients): bleeding; central nervous system alterations in context of sepsis; death of unknown cause; disseminated intravascular coagulation; dyspnea; lung hemorrhage (2x); pneumonia; generalized cerebral seizures; subdural bleeding; tachyarrhythmia absoluta. d Other SAEs in control group (12 events in 10 patients): acute kidney injury in context of sepsis; atypical pneumonia; death of unknown cause; disseminated zygomycosis; gastral bleeding; intermittent atrial fibrillation; rehospitalisation due to C. difficile associated diarrhea; respiratory insufficiency of unknown origin (2x); RSV pneumonia.
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CHG group, Control p n=307 (%) group, n=306 (%) At least one AE – no. of patients 51 (16.6) 52 (17.0) 0.914† At least one AE with certain causal relationship to 4 (1.3) 1 (0.3) 0.373† a the treatment – no. of patients At least one AE with probable causal relationship 29 (9.4) 31 (10.1) 0.788† a to the treatment – no. of patients AE type – no. of patients Cutaneous and soft tissue abnormalities in the 38 (12.4) 36 (11.8) 0.901† area in contact with the study treatment Systemic allergic reactions 14 (4.6) 20 (6.5) 0.296† Disseminated intravascular coagulation 1 (0.3) 1 (0.3) 1.000† Otherb 2 (0.7) 00.352† Symptoms of AEs with cutaneous and soft tissue 0.669† abnormalities – no. of patients Erythema alone 2 (0.7) 5 (1.6) Pruritus alone 5 (1.6) 3 (1.0) Erythema and pruritus 8 (2.6) 9 (2.9) Blisters/ vesiculae 7 (2.3) 4 (1.3) Skin defect alone 4 (1.3) 2 (0.7) Skin defect and erythema/ pruritus or both 7 (2.3) 5 (1.6) Other/ unknown symptoms 5 (1.6) 8 (2.6) At least one SAE – no. of patients 39 (12.7) 32 (10.5) 0.449† SAE type – no. of patients Multi-organ failure in context of sepsis 23 (7.5) 19 (6.2) 0.632† Heart failure in the context of sepsis 2 (0.7) 1 (0.3) 1.000† Respiratory failure in the context of sepsis 2 (0.7) 3 (1.0) 0.686† Acute coronary syndrome or myocardial 2 (0.7) 1 (0.3) 1.000† infarction Other 10 (3.3) c 10 (3.3) d 1.000†
1
A randomized trial on chlorhexidine dressings for the prevention of catheter-related bloodstream infections in neutropenic patients
L. M. Biehl1,12, A. Huth1, J. Panse2, C. Krämer2, M. Hentrich3, M. Engelhardt4, K. Schäfer-Eckart5, G. Kofla6, M. Kiehl7, C.-M. Wendtner8, M. Karthaus9, A. J. Ullmann10, M. Hellmich11, H. Christ11, M. J.G.T. Vehreschild1,12 Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
2
Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Medical Faculty,
RWTH Aachen University Hospital, Aachen, Germany 3
Department of Medicine III, Red Cross Hospital, Munich, Germany
4
Department of Medicine I, Hematology, Oncology and Stem Cell Transplantation, University of Freiburg
Medical Center, Freiburg im Breisgau, Germany 5
Medical Clinic 5, Hematology and Oncology, Klinikum Nuernberg, Nuernberg, Germany
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Charitè University Medicine, Department of Medicine, Division of Oncology/ Hematology, Charitè Campus
Mitte, Berlin, Germany 7
Medical Clinic I, Hematology and Medical Oncology, Hemostaseology, Clinical Center Frankfurt/Oder,
Frankfurt/Oder, Germany 8
Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine,
Klinikum Schwabing, Munich, Germany 9
Department of Hematology and Oncology, Klinikum Neuperlach and Klinikum Harlaching, Munich, Germany
10
Division of Infectious Diseases, Department of Internal Medicine II, University Hospital Wuerzburg,
Wuerzburg, Germany 11
Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany
12
German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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2
Corresponding author: Dr. Maria J.G.T. Vehreschild, Department I of Internal Medicine, University Hospital of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany, phone: +49 221 478 88794, e-mail: [email protected]
Abstract
cause of morbidity and mortality in patients with chemotherapy-induced neutropenia. Chlorhexidine containing catheter securement dressings may prevent CRBSI. Patients and methods: A multicenter randomized controlled trial was conducted at 10 German hematology departments. We compared chlorhexidine containing dressings with nonchlorhexidine control dressings in neutropenic patients. The primary endpoint was incidence of definite CRBSI within the first 14 days (dCRBSI14) of central venous catheter (CVC) placement. Secondary endpoints included combined incidence of definite or probable CRBSI within 14 days (dpCRBSI14), overall (dpCRBSI), incidence of unscheduled dressing changes and adverse events. Results: From Feb 2012 to Sept 2014, 613 evaluable patients were included in the study. Incidence of dCRBSI14 was 2.6% (8/307) in the chlorhexidine and 3.9% (12/306) in the control group (p=0.375). Both dpCRBSI14 and dpCRBSI were significantly less frequent in the study group with dpCRBSI14 in 6.5% (20/307) of the chlorhexidine group as compared to 11% (34/306) in the control group (p=0.047), and dpCRBSI in 10.4% (32/307) vs. 17% (52/306), respectively (p=0.019). The frequency of dressing intolerance with cutaneous and soft tissue abnormalities at the contact area was similar in both groups (12.4% and 11.8%; p=0.901).
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Background: Central venous catheter-related bloodstream infections (CRBSI) are a frequent
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Conclusions: Although the trial failed its’ primary end point, the application of chlorhexidine containing catheter securement dressings reduces the incidence of definite or probable CRBSI in neutropenic patients.
Clinical Trials number: NCT01544686 (Clinicaltrials.gov) Keywords: catheter-related bloodstream infections, catheter dressings, neutropenia,
Key message: Chlorhexidine dressings reduced the incidence of definite and probable catheter-related bloodstream infections in neutropenic patients. In contrast to previous studies, tolerance to chlorhexidine and control dressings was similar.
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chlorhexidine
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Introduction The administration of intensive chemotherapy for a hematological malignancy frequently requires the insertion of a central venous catheter (CVC). Particularly during long-term use of non-tunneled CVC, catheter-related bloodstream infections (CRBSI) may occur [1], ranging
to CRBSI has been reported to be as high as 36% [5]. Previous studies have highlighted the role of skin colonization as a predisposition for catheter colonization and subsequent CRBSI [3]. Consequently, effective reduction of skin colonization may be an important preventive factor. A few randomized trials have shown reduction of CRBSI by use of dressings with chlorhexidine gluconate (CHG) impregnated sponges [6-8] or a CHG containing gel pad [9]. The transparent gel pad has the advantage of allowing visual evaluation of the CVC insertion site without dressing removal. The two largest studies were conducted in intensive care unit patients [7, 9]; only one study evaluated the clinical efficacy of CHG CVC dressings in patients undergoing chemotherapy [6]. All three studies showed reduced CVC-related infection rates for CHG dressings. The application of CHG dressings is recommended by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) [10], but not by the American Society of Clinical Oncology (ASCO) [11]. The Centers for Disease Control considers chlorhexidine dressings other than those with impregnated sponges an unresolved issue [1]. Due to the limited body of evidence and the conflicting recommendations, a multicenter randomized controlled trial investigating CVC dressings with CHG containing gel pads in the setting of high-risk neutropenic patients was conducted.
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from 2.5 to 7.5 infections per 1000 catheter days [2-4]. In neutropenic patients, mortality due
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Methods Study design We conducted an open-label, randomized, multicenter trial in 10 German hematological departments. We compared two securement dressings with regard to their safety and efficacy in preventing CRBSI. The study product 3M™ Tegaderm™ CHG I.V. is a transparent CVC dressing with a chlorhexidine-containing gel pad. The comparator, 3M™ Tegaderm™ I.V.
designed and planned according to the Declaration of Helsinki in the version of October 2008 (59th WMA General Assembly, Seoul). Ethical approval was obtained from all competent ethics committees and registration completed at Clinicaltrials.gov (NCT01544686). Study patients Patients undergoing chemotherapy with an expected duration of chemotherapy-induced neutropenia of ≥5 days and an expected CVC use of ≥10 days were eligible for inclusion. Patients could be enrolled only once. Exclusion criteria included use of tunneled CVC, shaldon catheters, femoral insertion and suspected or confirmed bacterial infection at randomization. Trial conduct After informed consent, patients received a non-tunneled CVC in the subclavian or internal jugular vein. The type of CVC used depended on local standards, insertion followed a strict antiseptic regimen in accordance with respective guidelines [1, 12]. Dressings were applied within two hours of CVC placement and changed every 3+/-1 days. In case of neutropenic fever, central and peripheral blood cultures were drawn. If there was a suspicion of CRBSI, the CVC was removed and the tip sent in for microbiological culture. Antimicrobial prophylaxis or treatment depended on local standards, antimicrobial stewardship programs were not conducted during the study period. End of treatment (EOT)
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Advanced is a transparent CVC dressing without an antimicrobial gel pad. The study was
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was determined as CVC change or removal for any reason, definite CRBSI with or without CVC removal, maximum treatment duration of 42 days as per protocol, intolerance to the study product or death. Adverse events (AE) and severe adverse events (SAE) were assessed until follow-up on day 14 after EOT. Independent data monitors reviewed documentation. Variables and definitions Documented variables included demographics, underlying disease, chemotherapeutic
and antibiotic or antifungal administration during study treatment. In patients with CRBSI, results from blood and CVC tip cultures, presence of clinical signs according to the applied definitions and presence of an alternative focus were recorded. CRBSI were defined according to the AGIHO-DGHO guidelines [12]. Definite CRBSI required either a differential time to positivity (DTTP) over 2 hours in a pair of peripheral and central blood cultures or the detection of the same pathogen with the same susceptibility pattern in a blood culture and at the catheter tip. For probable CRBSI, one of the following three scenarios needed to be fulfilled: the presence of local infection at the insertion site with at least two signs of inflammation coupled with a positive blood culture; remission of previously refractory fever within 48 hours after catheter removal plus a positive blood culture; or a positive catheter tip culture. Definition of severe sepsis as modified from the guidelines by American College of Chest Physicians and the Society of Critical Care Medicine [13] required the following two criteria: (1) systemic inflammatory response (SIRS) and (2) at least one organ dysfunction. Since this study investigated an already approved medical product within its licensed indication, assessment of AE and SAE was not mandatory by applicable local law. Thus, AE were restricted to cutaneous and soft tissue abnormalities, AE in relation with systemic allergic reactions and AE in relation with coagulation disorders not related to chemotherapyassociated thrombocytopenia.
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regimen, CVC characteristics, dressing changes, neutropenia, occurrence of neutropenic fever
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End points The primary end point was incidence of definite CRBSI within 14 days (dCRBSI14) of CVC placement. Secondary end points were overall definite CRBSI (dCRBSI), definite and probable CRBSI within 14 days of CVC placement (dpCRBSI14), overall definite and probable CRBSI (dpCRBSI), dCRBSI14-related severe sepsis, dCRBSI14-related mortality, dpCRBSI-related severe sepsis, dpCRBSI-related mortality, overall mortality, time to removal of CVC or EOT, time to dpCRBSI, time to first neutropenic fever and the frequency and
Sample size and statistical analysis A group-sequential design using O’Brien and Fleming bounds at information fractions 0.5 and 1 was chosen to allow for early termination of the trial due to futility or success. We assumed a reduction of dCRBSI14 from 12% in the control group to 7.2% in the CHG group. Based on a two-sided type I error α = 0.05, 1190 evaluable patients were calculated to reach a power of 1 - β = 0.8 (chi-square test without continuity correction). Compensating for a percentage of about 5% non-evaluable patients, we planned to include 1260 patients. Analysis of the intention-to-treat (ITT) population included all randomized and evaluable subjects: all who received a CVC and did not withdraw consent directly after randomization. The primary end point dCRBSI14 was evaluated by a Mantel-Haenszel test stratified by study center, testing if the combined odds ratio equals 1. Characteristics of patients, catheters, and dressings were described as count (%) or median (interquartile range [IQR]) for qualitative and quantitative variables and compared between treatment groups using chi-square test, Wilcoxon rank sum test or log rank test as appropriate. Corresponding confidence intervals (CI) were calculated if possible. Subgroup analyses referred to CVC insertion site (jugular or subclavian vein) and CVC type (coated vs. non-coated). P values smaller 5% were considered “statistically significant”. SPSS Statistics software (Version 22, IBM Corp., Armonk, NY, USA) was used.
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reasons of unscheduled dressing changes (UDC).
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Results Between 02/2012 and 09/2014, 630 patients were included at 10 study sites. Results were subjected to an interim analysis. Thereafter, enrolment was discontinued, because a statistically significant difference in the primary end point was not met and was anticipated
17 inclusions (2.7%; 8 CHG and 9 controls) were screening failures. Of 613 evaluable patients, 307 were in the CHG and 306 in the control group. Patient characteristics Patient characteristics are shown in table 1. The groups did not differ significantly with respect to distribution of age, gender, Eastern Cooperative Oncology Group score (ECOG), duration of neutropenia, CVC insertion site and type. There was a higher proportion of AML patients in the control group. While there were significantly more patients in the CHG group (289, 94.8%) receiving any antimicrobial than in the control group (272, 90.3%; p=0.044), the mean cumulative days of antimicrobial treatment per patient were similar with 25.1 days in the CHG and 25.2 days in the control group (p=0.223). Primary and secondary end points For dCRBSI14, the rates were not significantly different between groups (CHG: 2.6% vs. control: 3.9%; odds ratio: 0.676; 95% CI: 0.270-1.693). Both, dpCRBSI14 (CHG: 6.5% vs. control: 11.1%; p=0.047) and dpCRBSI (CHG: 10.4% vs. control: 17.3%; p=0.014) were significantly less frequent in the study than in the control group. Respective CRBSI rates per 1000 catheter days (table S1), a differentiation of the CRBSI criteria applied (S2) and incidences per center (S3) are shown in the supplementary material. Regarding frequencies of
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not to be reached even after enrolment of further 630 patients. Of the included 630 patients,
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CRBSI-related severe sepsis and mortality, overall mortality, time to removal of CVC, time to dpCRBSI and time to first neutropenic fever, there were no significant differences (table 2). There were significantly fewer UDC in the study than in the control group reflected in the mean number of UDCs per patient (CHG: 0.9 vs. control: 1.2) and the difference in total UDC (CHG: 269 vs. control: 362; p=0.030). The most frequent reason for a UDC was intensive bleeding documented in 73 (23.8%) CHG and 83 (27.1%) control patients (p=0.355),
patients (p=0.003). Safety and tolerability In total, 56 AEs in 51 patients (16.6%) were observed in the CHG and 57 AEs in 52 patients (17.0%) in the control group (p=0.914). AEs concerning cutaneous and soft tissue abnormalities were observed in 38 patients (12.4%) in the CHG and 36 (11.8%) in the control group (p=0.901). In 22 cases (7.2%) in the CHG and 24 cases (7.8%) in the control group, this intolerance lead to study discontinuation and definite change to different dressing (p=0.762). In 33 study (10.7%) and 32 control patients (10.5%), an AE was classified as certainly or probably related to the respective dressing. All of these related AEs were cutaneous and soft tissue abnormalities. Regarding SAEs, 42 events were documented in 39 CHG (12.7%) and 36 events in 32 control patients (11.8%). The most frequently reported SAEs were organ failures related to severe sepsis. None of the SAEs were assessed as certainly or probably related to the study treatment (table 3).
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followed by insufficient cutaneous adhesion in 43 (14%) CHG and 72 (23.5%) control
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Pathogens causing CRBSI The distribution of causative pathogens in dpCRBSI did not differ significantly between groups with coagulase-negative staphylococci being the most frequently isolated pathogens (table S4). CVC insertion site and type The distribution of CVC insertion site and CVC type was similar between groups (see table
examined the CRBSI rates according to CVC insertion site and CVC type irrespective of randomization (S6). Rates were significantly higher in patients with a subclavian vein as compared to a jugular internal vein CVC both, for dCRBSI14 (4.8% vs. 1.2%; p=0.019) and dCRBSI (8.1% vs. 3.1%; p=0.010). Comparing coated vs. uncoated CVC, patients with coated CVC had higher rates of dCRBSI14 (4.2% vs. 1.1%; p=0.048), dCRBSI (7.9% vs. 1.6%; p=0.001) and dpCRBSI (16.4% vs. 8.1%; p=0.007).
Discussion To our knowledge, this is the first randomized trial evaluating a transparent CVC dressing with a chlorhexidine gel pad in neutropenic patients. A trend towards reduction was seen for the primary end point of definite CRBSI within 14 days of CVC placement, but due to a lower than expected event rate, the study was underpowered with respect to its primary endpoint. Application of the study dressing in comparison to a transparent non-CHG dressing significantly reduced the incidence of definite and probable CRBSI overall from 17.3% to 10.4% (p=0.014) and within 14 days of CVC placement from 11.1% to 6.5% (p=0.047), respectively. These results are consistent with those of previous studies investigating
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S5 for frequencies per center). To further assess a possible influence of these variables, we
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chlorhexidine containing CVC dressings in different settings [6-9] and thus complement the evidence in favor of application of transparent CHG dressings for non-tunneled CVC in the setting of neutropenia. Given that the identified etiological agents were mostly skin colonizers, the more marked preventive efficacy in overall CRBSI rates as compared to rates within 14 days of CVC placement suggests that the effect of the dressing in reducing skin colonization is not limited to the first 14 days of its use. The risk of extraluminal contamination of the CVC, most likely not affected by our study product, is an independent,
We observed no difference in the rates of CRBSI-related severe sepsis or mortality between the two groups. However, the infrequency of these clinical outcomes limited the ability of a study of this size in detecting a possible difference. Furthermore, both, severe sepsis and overall mortality, are – obviously – not merely influenced by the applied CVC dressing in these high-risk patients. It is noteworthy, that intolerance to the study product as a reason for end of treatment as well as adverse events concerning skin and soft tissue abnormalities did not occur significantly more frequent in the study group. Skin defects were observed in only few cases in both groups. This opposes findings of previous studies reporting increased rates of contact dermatitis during the application of CHG containing dressings [9, 14]. We hypothesize that the comparatively short interval between dressing changes (3+/-1 days) might have prevented skin reactions triggered by moisture accumulating between skin and dressing. Unexpectedly, the incidence of CRBSI was lower in patients with internal jugular as compared to subclavian insertion site and in those with uncoated CVCs as compared to coated, irrespective of dressing randomization. Regarding CVC insertion site, results are contradictory to previous studies reporting lower CRBSI rates for subclavian insertion site [15, 16]. However, a Cochrane review found similar infection rates for subclavian and
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additional risk factor for CRBSI.
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internal jugular insertion sites [17]. Regarding CVC type, our results contradict various studies and literature reviews favoring coated CVCs with respect to CRBSI [18-21]. Antimicrobial or antiseptic coated CVCs are recommended in German [10] and American [11] guidelines. However, the advantage of coated CVCs might be more pronounced in ICU settings [22], in short-term catheterization under 7 days [23], and was not confirmed in a meta-analysis evaluating CVCs for parenteral nutrition and chemotherapy [24]. Of note, the present study was not designed and the study population not stratified for analyzing the
site depended on the standard of care of the respective study center. Our study has some limitations. First, the study was terminated after the interim analysis due to the low rate of primary end point events. Therefore, the study lacks adequate power, particularly regarding the conservative O’Brien-Fleming bound 0.002583 (one-sided). The incidence of the primary end point dCRBSI14 was lower than anticipated from previous observations [6] - possibly being a result of improved antiseptic routine. Second, due to a lack of a control product including a gel pad without antimicrobial activity, blinding was not feasible. Nevertheless, the microbiological department was blinded as blood cultures and CVC tips were analyzed within routine diagnostics. The substantial sample size within this special setting of neutropenic patients, the multicenter design and the thorough assessment of adverse events are key strengths of the presented study. In summary, the study was not able to demonstrate a reduction in the primary end point of definite CRBSI within 14 days of CVC placement by the application of transparent CVC dressings with a chlorhexidine containing gel pad in patients undergoing intensive chemotherapy. The presented results show that the dressings were well tolerated and significantly reduced definite and probable CRBSI. Whether the observed risk reduction for definite and probable CRBSI justifies the application of CHG dressings in the routine care of
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impact of CVC insertion site and coating on CRBSI. The choice of CVC type and insertion
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long-term neutropenic patients also depends on further factors such as local CRBSI rates and related costs.
Acknowledgements
We would like to thank the study nurses of all study sites and the staff of the wards involved in the conduct of the trial.
This work was supported by a research grant by 3M (no grant number applicable).
Disclosure LMB is supported by the German center for Infection Research (DZIF). LMB has received lecture honoraria from Astellas and MSD and travel grants from 3M and Gilead. JP has served at the speakers’ bureau and received lecture honoraria/ore travel grants of/from, Celgene, Gilead Sciences Merck/MSD, Astellas Pharma and Pfizer. AJU reports personal fees from MSD, personal fees from Pfizer, personal fees from Astellas, personal fees from Basilea and personal fees from Gilead outside the submitted work. MJGTV has served at the speakers’ bureau of Pfizer, Merck, Gilead Sciences, and Astellas Pharma, received research funding from 3M, DaVolterra, MSD/Merck, Astellas Pharma and Gilead Sciences and is a consultant to Berlin Chemie and DaVolterra. All other authors report no conflicts of interest.
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Funding
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Table 1: Demographic and clinical characteristics of included patients Characteristics
Control group, n=306 58 (18-82; 18) 172/134
105 (34.2) 23 (7.5) 60 (19.5) 14 (4.6) 88 (28.7) 17 (5.5)
140 (45.8) 11 (3.6) 53 (17.3) 10 (3.3) 81 (26.5) 11 (3.6)
p 0.594# 0.190† 0.036†
0.183† 178 (58.0) 100 (32.6) 27 (8.8) 2 (0.7)
173 (56.5) 91 (29.7) 34 (11.1) 8 (2.6) 0.056†
89 (29.0) 10 (3.3) 21 (6.8) 2 (0.7) 155 (50.5) 0
104 (34.0) 22 (7.2) 12 (3.9) 4 (1.3) 133 (43.5) 1 (0.3)
27 (8.8)
23 (7.5)
2 (0.7) 1 (0.3)
6 (2.0) 1 (0.3) 0.624†
175 (57.0) 132 (43.0)
181 (59.2) 125 (40.8) 0.930†
92 (30.0) 215 (70.0) 8 (0-42; 8)
93 (30.4) 213 (69.6) 7 (0-41; 8)
0.176#
289 (94.8) 25.1/18 (28)
272 (90.3) 25.2/15 (27)
0.044† 0.223†
CHG: chlorhexidine gluconate; IQR. Interquartile range; AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; NHL: non-Hodgkin lymphoma; ECOG: European Cooperative Oncology Group; HSCT: hematopoietic stem cell transplantation; CVC: central venous catheter. # t-test for independent samples; † Pearson’s χ² test a Other conditions (CHG/control): amyloidosis (1/1), aplastic anemia (2/0), chronic lymphocytic leukemia (0/2), chronic myelogenous leukemia (0/1), testicular cancer (7/4), myelodysplastic syndrome (5/1), myeloproliferative neoplasms (2/2) b Other chemotherapy (CHG/control): anti-thymocyte globulin for aplastic anemia (1/0), hydroxycarbamide monotherapy for AML (0/1)
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Age – median years (range; IQR) Gender (male/female) Underlying condition (%) AML ALL NHL Hodgkin’s lymphoma Multiple myeloma/ plasmocytoma Othera ECOG score at randomization (%) 0 1 2 3 Chemotherapy (%) AML induction AML consolidation ALL induction ALL consolidation Autologous HSCT chemotherapy (%) Allogeneic HSCT, myeloablativ conditioning Allogeneic HSCT; reduced intensity conditioning Relapse chemotherapy for lymphoma Otherb CVC insertion site (%) Subclavian vein Internal jugular vein CVC type (%) Uncoated Silver/CHG coated Median number of neutropenic days during study treatment (range; IQR) Antimicrobial consumption Patients with any antimicrobials (%) Mean/median cumulative days per patientc (IQR)
CHG group, n=307 58 (18-83; 21) 189/118
c
Days of antimicrobials total are cumulative, meaning that days per antimicrobial class are summed up by patient regardless of overlap of timeframes.
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Table 2: Primary and secondary end points End point
group, Control n=306
group, p
8 (2.6) 13 (4.2) 20 (6.5) 32 (10.4)
12 (3.9) 24 (7.8) 34 (11.1) 53 (17.3)
0.375† 0.064† 0.047† 0.014†
2 (0.7) 1 (0.3) 5 (1.6) 1 (0.3) 19 (6.2)
2 (0.7) 0 (0.0) 6 (2.0) 2 (0.7) 17 (5.6)
1.0† 1.0† 0.772† 0.624† 0.864†
17 (0-42; 10) 13 (4-39; 7.5) 11 (0-41; 4) 0/0.9 (0-10; 1)
16 (0-42; 11) 13 (0-40; 8) 10 (0-39; 5) 1/1.2 (0-14; 2)
0.074# 0.956# 0.253# 0.030#
CHG: chlorhexidine gluconate; CRBSI: catheter-related bloodstream infection; dCRBSI14: definite CRBSI within 14 days of catheter placement; dCRBSI: definite CRBSI overall; dpCRBSI14: definite and probable CRBSI within 14 days of catheter placement; dpCRBSI: definite and probable CRBSI overall; IQR: interquartile range; CVC: central venous catheter; EOT: end of treatment; UDC: unscheduled dressing change. # t-test for independent samples; † Pearson’s χ² test
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CRBSI end points (%) dCRBSI14 (primary end point) dCRBSI dpCRBSI14 dpCRBSI Outcome end points (%) dCRBSI14-related severe sepsis dCRBSI14-related mortality dpCRBSI-related severe sepsis dpCRBSI-related mortality Overall mortality Median time to … in days (range, IQR) …removal of CVC or EOT …dpCRBSI …first neutropenic fever Median/mean number of UDC per patient (range; IQR)
CHG n=307
Table 3: Adverse and severe adverse events
CHG: chlorhexidine gluconate; AE: adverse event; SAE: severe adverse event. a All AEs with certain or probable causal relationship to the respective treatment were cutaneous and soft tissue abnormalities. † Pearson’s χ² test b Other AEs: generalized itching (1xCHG group), anaphylaxis (1xCHG group). c Other SAEs in CHG group (12 events in 10 patients): bleeding; central nervous system alterations in context of sepsis; death of unknown cause; disseminated intravascular coagulation; dyspnea; lung hemorrhage (2x); pneumonia; generalized cerebral seizures; subdural bleeding; tachyarrhythmia absoluta. d Other SAEs in control group (12 events in 10 patients): acute kidney injury in context of sepsis; atypical pneumonia; death of unknown cause; disseminated zygomycosis; gastral bleeding; intermittent atrial fibrillation; rehospitalisation due to C. difficile associated diarrhea; respiratory insufficiency of unknown origin (2x); RSV pneumonia.
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CHG group, Control p n=307 (%) group, n=306 (%) At least one AE – no. of patients 51 (16.6) 52 (17.0) 0.914† At least one AE with certain causal relationship to 4 (1.3) 1 (0.3) 0.373† a the treatment – no. of patients At least one AE with probable causal relationship 29 (9.4) 31 (10.1) 0.788† a to the treatment – no. of patients AE type – no. of patients Cutaneous and soft tissue abnormalities in the 38 (12.4) 36 (11.8) 0.901† area in contact with the study treatment Systemic allergic reactions 14 (4.6) 20 (6.5) 0.296† Disseminated intravascular coagulation 1 (0.3) 1 (0.3) 1.000† Otherb 2 (0.7) 00.352† Symptoms of AEs with cutaneous and soft tissue 0.669† abnormalities – no. of patients Erythema alone 2 (0.7) 5 (1.6) Pruritus alone 5 (1.6) 3 (1.0) Erythema and pruritus 8 (2.6) 9 (2.9) Blisters/ vesiculae 7 (2.3) 4 (1.3) Skin defect alone 4 (1.3) 2 (0.7) Skin defect and erythema/ pruritus or both 7 (2.3) 5 (1.6) Other/ unknown symptoms 5 (1.6) 8 (2.6) At least one SAE – no. of patients 39 (12.7) 32 (10.5) 0.449† SAE type – no. of patients Multi-organ failure in context of sepsis 23 (7.5) 19 (6.2) 0.632† Heart failure in the context of sepsis 2 (0.7) 1 (0.3) 1.000† Respiratory failure in the context of sepsis 2 (0.7) 3 (1.0) 0.686† Acute coronary syndrome or myocardial 2 (0.7) 1 (0.3) 1.000† infarction Other 10 (3.3) c 10 (3.3) d 1.000†