Clinical Nutrition xxx (2014) 1e5
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
A comparison of two methods of treatment for catheter-related bloodstream infections in patients on home parenteral nutrition ski a, *, Krystyna Majewska a, Łukasz Gradowski b, Iwona Fołtyn a, Michał Ławin Pierre Singer c _ Department of General Surgery and Clinical Nutrition, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, Poland Interdisciplinary Center for Applied Cognitive Studies, University of Social Sciences and Humanities, Chodakowska 19/31, 03-815 Warsaw, Poland c General Intensive Care Department and Institute for Nutrition Research, Rabin Medical Center, Beilinson Hospital, 49100 Petah Tikva, Israel a
b
a r t i c l e i n f o
s u m m a r y
Article history: Received 10 February 2014 Accepted 22 September 2014
Background & aims: Home parenteral nutrition (HPN) enables patients who cannot eat normally to survive and function. Catheter-related bloodstream infections (CRBSIs) are the most dangerous complication, which may be fatal if left untreated or if treatment is delayed. For over 20 years CRBSIs were managed by catheter removal and implantation of a new one after completion of antibiotic treatment. However, frequent catheter replacements put the patient at risk of large vein thrombosis, which may render parenteral nutrition impossible. The management of CRBSIs evolved into antibiotic treatment without catheter removal. The effectiveness of this approach was, however, limited by the low penetration of the antibiotics into the biofilm. Filling catheters with concentrated ethanol destroys the biofilm and does not result in the emergence of drug resistance. The aim of our study was to assess the remote outcomes of CRBSI treatment using two approaches: antibiotic-ethanol lock therapy and catheter replacement. Methods: We retrospectively analysed the treatment outcomes of CRBSI diagnosed and managed in HPN patients. During the analysed period, a total of 428 patients between 13 and 96 years of age were on HPN and a total of 181 of them suffered a total of 352 CRBSI episodes managed with one of the two approaches. Results: We showed no significant differences between the two approaches in terms of survival likelihood or duration of catheter use after an episode of CRBSI caused by various bacterial species. Conclusion: The use of antibiotic-ethanol lock therapy in the management of CRBSI is equally effective as catheter replacement. © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: HPN CRBSI Antibiotic-ethanol lock therapy
1. Introduction Parenteral nutrition involves the supply of all nutrients intravenously, thus bypassing the gastrointestinal tract [1]. The success of long-term parenteral nutrition, which is often a lifetime intervention, is conditional upon the avoidance of complications related to access to the venous system and upon the selection of nutrients that is appropriate to the patient's needs and metabolic capacity. Everyday administration of a nutrient mixture into the venous system requires at least two manipulations at the catheter end/ transfusion set interface. Following aseptic technique while performing between 25 and 40 actions each day is a condition of avoiding the contamination and colonisation of the catheter end
* Corresponding author. Tel.: þ48 501702899. ski). E-mail address: [email protected] (M. Ławin
and lumen by microorganisms [2]. Catheter colonisation leads to catheter-related bloodstream infections (CRBSIs) with all the possible sequelae of a systemic infection, which is fatal if left untreated or if treatment is delayed [3,4]. Although a number of methods to reduce the risk of colonisation and infection have been developed, it is not possible to avoid them completely. Recently, the use of taurolidine 2% (taurolidine citrate) has shown to decrease significantly the number of CRBI (5a Quarello F et al. Blood Purification 2002) in hemodialyis catheter for haemodialysis patients. Taurolidine citrate lock therapy reduced the CRBI's number from 1.3 to 0.3 infections per 1000 catheter days (J Hosp inf 2012). The traditional approach to the management of CRBSI involves removing the catheter which is the source of infection and administering an appropriate antibiotic [5]. A new catheter is implanted after the infection has been controlled. However, each subsequent catheter implantation into a large vein is more difficult and poses a risk of complications related to very catheter
http://dx.doi.org/10.1016/j.clnu.2014.09.013 0261-5614/© 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
ski et al. / Clinical Nutrition xxx (2014) 1e5 M. Ławin
2
implantation procedure and thrombotic complications which lead to the loss of vena cava access [6]. The management of CRBSIs is of dual nature and involves systemic management, including systemic antibiotics, and catheter management [12]. The traditional management of CRBSIs involves administration of antibiotics, removal of the catheter responsible for the infection, and implantation of a new catheter after the infection has been cured. However, in patients with recurrent catheter-related infections, each subsequent catheterization of a large vein is increasingly difficult and risky, and may lead to the loss of venous access. Therefore, in patients requiring parenteral nutrition, maintenance of venous access is as important as controlling and curing the infection. Because of that, attempts have been made to treat CRBSIs without catheter removal. This method has been used in many modifications but it turned out that its effectiveness is limited due to the low penetration of most antibiotics into the biofilm formed by the microorganisms in the catheter [7]. While the patients improved and the symptoms of infection resolved during hospitalisation, the infection recurred after the patients were discharged home [8,9]. In their search for agents penetrating into the biofilm, Ball et al. suggested using concentrated ethanol, previously used to restore catheter patency [10,11]. The Infectious Disease Society of America does not unequivocally recommend ethanol lock therapy as a method for endoluminal eradication of microorganisms in cases of catheter colonisation [5]. It is, however, widely believed that the use of ethanol to destroy the biofilm, followed by the use of antibiotic lock therapy to completely cure catheter contamination, may be beneficial. The aim of our study was to assess the remote outcomes of CRBSI treatment in patients on long-term home parenteral nutrition (HPN) using two approaches: antibiotic-ethanol lock therapy and the traditional approach involving replacement of the contaminated catheter with a new one. 2. Material and methods 2.1. Material Between 1 January 2005 and 31 December 2010, HPN was provided to 428 patients from our hospital outpatient clinic: 240 females (56%) aged 16e92 years (mean age: 56.5 ± 16 years) and 188 males (44%) aged 13e96 years (mean age: 54 ± 17 years). Indications for parenteral nutrition in this patient group included: short bowel syndrome, multilevel bowel obstruction, postoperative gastrointestinal fistulas, malabsorption syndrome, gastrointestinal motility abnormalities, cachexia, radiation enteritis. The patients were fed through 5 kind of permanent venous accesses: tunnelized single lumen catheters the name of Broviac (n ¼ 305), Groshong (n ¼ 67), Broviac-Lifecath Expert 19, Cook Redo TPN (n ¼ 29), ports (n ¼ 8). Data was obtained from the hospital database and retrospective study was approved 20.09.2011 by the ethics committee of the Medical University of Warsaw. 2.2. Management of suspected catheter-related infection In each case of suspected catheter-related infection, the patient was hospitalized for evaluation and treatment. Throughout that period, the catheter was excluded from use and the patient was being fed and hydrated via peripheral veins. In patients in grave condition and patients with catheter exit-site or tunnel infection, the catheter was removed. Cultures for microbial evaluation were obtained from skin smears around the entry of the catheter, hemocultures taken from CV catheter, peripheral vein. Final decision on the course of management was made after obtaining the culture results for blood collected from the central catheter and
after the diagnosis of CRBSI was established. After confirming that colonisation of the inner surface of the catheter was the source of bacteraemia, the justifiability of using antibiotic and ethanol lock with or without systemic antibiotic therapy to sterilize the catheter was considered. This antibiotic-ethanol lock therapy was compared to the group of patients in whom the catheter was removed if contraindications for antibiotic-ethanol lock therapy was identified. The following were considered to be the contraindications to antibiotic-ethanol lock therapy:
a Groshong catheter (due to its design), a previously repaired catheter, a ruptured catheter hub, colonisation with fungi or bacterial strains of: Staphylococcus aureus, Staphylococcus haemolyticus, Corynebacterium spp., Mycobacterium spp., Pseudomonas aeruginosa, Micrococcus spp., Bacillus spp., colonisation with strains resistant to most antibiotics or strains whose antibiotic susceptibility could not be established.
2.3. Establishment of the antibiotic-ethanol lock The residual content and blood were aspirated from the catheter, the catheter hub and lumen were flushed to remove the residual blood using a 0.9% saline solution and the catheter was filled with a 95% ethanol solution. The solution was left in the catheter for 24 h. The next day blood was aspirated, the catheter lumen and hub were flushed and the catheter was filled with ethanol again. Four days later, the ethanol solution was replaced with an antibiotic solution, which was administered according to the same procedure for the next four days. The antibiotic was selected according to culture results. Twenty-four hours after the last dose of the antibiotic, the patient was started on his/her nutrient mixture and the next day blood from the central catheter was drawn for follow-up culture. If the patient had remained asymptomatic for the past 48 h and the culture was negative, he/she was discharged home. The following antibiotic solutions at the following concentrations were used to fill the catheters: amikacin 100 mg/ml, teicoplanin: 40 mg/ml, vancomycin: 50 mg/ml. If the patient developed fever and/or chills or if his/her condition deteriorated, the treatment was discontinued, the catheter was removed and a new catheter was implanted after completion of antibiotic treatment.
2.4. Statistical analysis The antibiotic lock therapy group was compared to the catheter removed group. Data were expressed as median with a 25the75th percentile interquartile range. The median time of new catheter use after catheter replacement and after antibiotic-ethanol lock therapy was compared using the U ManneWhitney test. Time to recurrence of infection and survival for each of the two analysed treatments were compared with the KaplaneMeier method and the significance of the results was assessed with the CoxeMantel test. The rates of recurrent infections with the same strains were assessed with the chi-square test and, for low number of cases, with the Yates continuity correction. The mean follow-up time to recurrence was assessed with the U ManneWhitney test. In order to identify the effect of factors associated with infection recurrence, multivariate logistic regression analysis of factors identified as potentially relevant in univariate analysis was performed. The IBM SPSS Statistic software package (version 21.0) was used for statistical analysis.
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
ski et al. / Clinical Nutrition xxx (2014) 1e5 M. Ławin
3. Results The total duration of parenteral nutrition in 428 patients on HPN between 1 January 2005 and 31 December 2010 was 404,808 days. During the follow-up period, 34 (7.9%) patients discontinued the treatment due to regained nutritional autonomy, 214 (50.0%) continued treatment, 178 (41.6%) died and 2 (0.5%) transferred to other facilities. 247 (57.5%) patients did not suffer any CRBSI episode, while 181 (42.5%) suffered a total of 352 CRBSI episodes. The demographic date are presented in Table 1. The number of patients who suffered 1, 2, 3, 4, and more than 4 episodes was 98, 43, 17, 13, and 10, respectively. The incidence rate of CRBSIs was 0.87 per 1000 days, which corresponds to 0.31 episode of CRBSI per year of treatment. A total of 335 CRBSIs were cured. In 331 cases parenteral nutrition was continued and in 4 cases parenteral nutrition was terminated, as the patient regained nutritional autonomy or enteric nutrition was sufficient. Catheter-related infection was attributable to the death in 16 of the hospitalised patients.
3.1. Remote outcomes of treatment of catheter-related infections Among the 331 episodes after which patients continued parenteral nutrition after successful treatment, 100 had been managed with antibiotic and ethanol lock and 231 had their catheter replaced. The outcomes of treatment of catheter-related infections is expressed in Table 2, showing the duration of using the catheter after treatment, occurrence of recurrences of infection with the same microbial species and patient survival after treatment of a CRBSI episode relative to the management approach used. Recurrence of infection with the same microbial species was observed in 33 patients: in 17 patients (17%) managed with antibiotic-ethanol lock therapy (83% success) and 16 patients (6.93%) after catheter replacement (93% success) (p < 001 in chisquared test). The mean time from completion of antibioticethanol lock therapy or catheter replacement to recurrence of infection with the same microbial species was Me ¼ 265 IQR 110e516 days after antibiotic-ethanol lock therapy and Me ¼ 330 IQR 162e591 days after catheter replacement (U ¼ 6233.00; p ¼ 0.051 in the U ManneWhitney test) (Fig. 1). The antibiotic most commonly used for antibiotic lock therapy was amikacin. Recurrences of infection with the same microbial species were observed in 5 (8.47%) of the 59 patients whose catheters had been filled with amikacin. The rate of recurrences after treatment with vancomycin was 21.88% and that after treatment with teicoplanin was 57.14% (p < 0.001 in chi-squared test). The rate of infections with the same microbial species, in the absence of systemic antibiotic treatment, was 75% in patients managed with catheter replacement and 19.44% in patients managed with
3
Table 2 The treatment of catheter-related infections (median and IQR e Inter Quartile Range). Duration of using the catheter after treatment
Gram Positive Staph Epidermitis Staph Con Gram Negative
Antibiotic-ethanol lock
Catheter removal
Me ¼ 292 IQR 136 to 695 Me ¼ 290 IQR 126 to 516 Me ¼ 341 IQR 212 to 935 Me ¼ 182 IQR 114 to 547
Me ¼ 353 IQR 163 to 611 Me ¼ 261 IQR 159 to 567 Me ¼ 366 IQR 140 to 616 Me ¼ 314 IQR 135 to 569
U Manne Whitney value
p Value
5177.0
0.379
1094.0
0.949
476.5
0.467
740.0
0.254
antibiotic-ethanol lock therapy (p < 0.0001 vs. patients receiving systemic antibiotic treatment). Much fewer infections were observed in patients who received empirical treatment consisting of 2 or 3 antibiotics irrespective of the management of the catheterrelated infection compared to patients who received just one systemic antibiotic (p < 001). The analysis (Multivariate Logistic Regression) of the relationships of factors that could potentially affect the recurrence of infection with the same microbial species showed that the absence of systemic antibiotic treatment was the only factor that was significantly associated with the recurrence of infection with the same microbial species in patients managed by catheter replacement (b ¼ 0.36; p < 0.0001) (Fig. 2). Recurrence of CRBSI with the same microbial species after an episode managed with antibiotic-ethanol lock therapy was, on the other hand, associated with the person servicing the parenteral nutrition catheter (b ¼ 0.32; p < 0.0001) (Fig. 3). No differences were observed when the cumulative survival of patients from the first CRBSI episode according to the management approach employed (Fig. 4). Comparison of late results of treatment with catheter replacement and ethanol/antibiotic lock shows both methods as equally efficient. Early CRBSI recurrence (until 60 days) were observed in 2 (1%) treated by catheter replacement and 4 (4%) treated by ethanol/ antibiotic lock (chi-square test p ¼ 0.13) and until 120 days respectively in 5 (2.2%) and 7 (7%), treated (chi-square test p ¼ 0.66).
Table 1 Demographic data of antibiotic-ethanol and catheter removal groups (n ¼ 181). Treatment
Gender Age ± SD Catheter care Place of residence
Male Female Independent Caregiver Urban Rural
Antibiotic-ethanol lock
Catheter removal
23 25 54.8 ± 15 28 (58.3%) 20 (41.7%) 30 (62.5%) 18 (37.5%)
75 58 55.1 ± 18 66 (49.7%) 67 (50.3%) 98 (73.7%) 35 (26.3%)
Fig. 1. Likelihood of using the catheter without recurrence of infection with the same microbial species according to the treatment approach (p ¼ 0.00169 [NS] in CoxeMantel test).
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
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4
Fig. 2. Effect of various factors on the development of recurrent CRBSI with the same microbial species after treatment with catheter removal.
Fig. 4. Patient survival likelihood according to the treatment approach employed during the first episode of CRBSI (p ¼ 0.48663[NS] in CoxeMantel test).
4. Discussion When evaluating the effectiveness of treatment of catheterrelated infections, one should not only take into account the immediate outcomes (control of the acute infection and eradication of the source of infection) but also patient survival after treatment, duration of fault-free use of the catheter and the rate of infection recurrences. If the goal of the treatment is to preserve a permanent catheter, then antibiotic lock therapy or ethanol lock therapy becomes the only option. The body of experience gained so far and the resulting current recommendations confirm the justifiability of antibiotic lock therapy for the treatment of catheter-related infections without the need to remove the catheter in patients requiring longterm venous access [5,13,14]. Rannem et al. successfully managed some of the infections solely with antibiotics administered through the catheter and Buchman et al., in patients treated between 1986 and 1989, managed to preserve 87% catheters using this method
Fig. 3. Effect of various factors on the development of recurrent CRBSI with the same microbial species after antibiotic-ethanol lock therapy.
[15,16]. More recent studies, however, showed a greater efficacy of antibiotic lock therapy compared to antibiotic infusion through the catheter [17,18] and a longer survival of the dialysis catheter after lock therapy versus catheter replacement (154 and 71 days, respectively) [19]. A number of factors contributing to infection recurrence after antibiotic lock therapy have been identified. It is believed that the principal factor that interferes with successful eradication of microorganisms colonising the catheter and contributing to recurrences of infections with these microorganisms is the biofilm and its resistance to antibiotics [6,7]. Studies were therefore conducted to investigate the use of substances along with the antibiotic that would destroy the biofilm or facilitate penetration of antibiotics into the biofilm: N-acetylcysteine, macrolide antibiotics (especially erythromycin) and ethanol [20e22]. The properties of ethanol, such as good penetration into the biofilm, no risk of selection of resistant strains, low cost, low risk of recurrences and low risk of emergence of resistance, make it an ideal agent to eradicate microorganisms from catheters [23]. Experimental studies show, however, that the older the biofilm is and the shorter the exposure time, the less effective ethanol is [24]. These two methods were combined into one, antibiotic-ethanol lock therapy, on the premise that after four days of exposure ethanol would destroy the biofilm, which would facilitate penetration of the antibiotic and eradication of the remaining microorganisms from the inner surface of the catheter. The low number of recurrences and the long follow-up period confirm that this premise was correct. The comparison of the remote outcomes in the group of patients managed with catheter replacement with the outcomes in the group of patients managed with antibiotic lock therapy showed that both methods are generally equally effective. Survival of patients after antibiotic-ethanol lock therapy compared to survival of patients managed with catheter replacement, after excluding cancer patients from the analysis, were similar. The median duration HPN from the first episode of CRBSI was 1193 days (IQR: 631e1524) in patients managed with antibiotic and ethanol lock therapy and 1026 days (IQR: 566e1580) in patients managed with catheter replacement. Our study has several limitations. The first is that taurolidine use for prevention was not a possible alternative since the study was started in 2005, when taurolidine lock was not a true alternative for prevention of CRBIs. Second, the groups were not randomly chosen
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
ski et al. / Clinical Nutrition xxx (2014) 1e5 M. Ławin
but according to a protocol making the value of our study weaker. However, the large number of patients followed for a long time is giving a strong signal of the equal value of the 2 strategies. [6]
5. Conclusions We conclude that the use of antibiotic-ethanol lock therapy in the management of CRBSI is equally effective as catheter replacement, after exclusion of absolute indications of catheter removal. No complications associated with catheter filling with ethanol were observed. The duration of catheter use and survival after treatment of a CRBSI episode and patient survival did not differ relative to the approach employed. Recurrences of CRBSIs with the same microbial species over a period of up to 120 days after the completion of treatment were observed in 7% of patients managed with antibiotic-ethanol lock therapy and 2.2% of patients managed with catheter replacement. Development of recurrences of CRBSIs was associated with the absence of systemic antibiotic treatment. Statement of authorship MŁ is responsible for planned the article and manuscript preparation. ŁG performed statistical analysis KM, IF collections and analysed data, PS reviewed the data and revised the manuscript. All authors read and approved the final manuscript. Conflict of interest statement Each author declared no conflict of financial or personal interests in this study.
[7] [8]
[9]
[10]
[11] [12] [13]
[14]
[15]
[16]
[17]
[18]
References [19] _ [1] Pertkiewicz M, Korta T, Ksia˛ zyk J, Łyszkowska M, Matczuk M, Spodaryk M, _ et al. Standardy Zywienia Pozajelitowego i Dojelitowego PZWL 2005;1:1e76. _ _ [2] Pertkiewicz M, Majewska K, Korta T. Doste˛ p zylny do zywienia pozajelito . Warswego. In: Zasady, zapobieganie, rozpoznawanie i leczenie powikłan zawa; 1997. p. 5e61. [3] Arnow PM, Quimosing EM, Beach M. Consequences of intravascular catheter sepsis. Clin Infect Dis 1993 Jun;16(6):778e84. ~ ares J, Pe rez JL, Farrero N, Jaurrieta E, et al. Hub [4] Sitges-Serra A, Puig P, Lin colonization as the initial step in an outbreak of catheter-related sepsis due to coagulase negative staphylococci during parenteral nutrition. J Parenter Enteral Nutr 1984, NoveDec;8(6):668e72. [5] Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, et al. Clinical practice guidelines for the diagnosis and management of intravascular
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catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009 Jul 1;49(1):1e45. No abstract available. Erratum in: Clin Infect Dis. 2010 Feb 1;50(3):457. Clin Infect Dis. 2010 Apr 1;50(7): 1079. Del Pozo JL. Role of antibiotic lock therapy for the treatment of catheterrelated bloodstream infections. Int J Artif Organs 2009 Sep;32(9):678e88. Donlan RM. Biofilms on central venous catheters: is eradication possible? Curr Top Microbiol Immunol 2008;322:133e61. Guedon C, Nouvellon M, Lalaude O, Lerebours E. Efficacy of antibiotic-lock technique with teicoplanin in staphylococcus epidermidis catheter-related sepsis during long-term parenteral nutrition. J Parenter Enteral Nutr 2002 MareApr;26(2):109e13. Opilla MT, Kirby DF, Edmond MB. Use of ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients. J Parenter Enteral Nutr 2007 JuleAug;31(4):302e5. Ball PA, Brokenshire E, Parry B, Merrie A, Gillanders L, McIlroy K, et al. Ethanol locking as a possible treatment for microbial contamination of long-term central venous catheters. Nutrition 2003 Jun;19(6):570. Johnston DA, Walker K, Richards J, Pennington CR. Ethanol flush for the prevention of catheter occlusion. Clin Nutr 1992 Apr;11(2):97e100. Pagani JL, Eggimann P. Management of catheter-related infection. Expert Rev Anti Infect Ther 2008 Feb;6(1):31e7. Gillanders L, Angstmann K, Ball P, O'Callaghan M, Thomson A, Wong T, Thomas M. A prospective study of catheter-related complications in HPN patients. Clin Nutr 2012 Feb;31(1):30e4. Pittiruti M, Hamilton H, Biffi R, MacFie J, Pertkiewicz M. ESPEN.: ESPEN guidelines on parenteral nutrition: central venous catheters (access, care, diagnosis and therapy of complications). Clin Nutr 2009 Aug;28(4):365e77. Buchman AL, Moukarzel A, Goodson B, Herzog F, Pollack P, Reyen L, et al. Catheter-related infections associated with home parenteral nutrition and predictive factors for the need for catheter removal in their treatment. J Parenter Enteral Nutr 1994 JuleAug;18(4):297e302. Rannem T, Ladefoged K, Tvede M, Lorentzen JE, Jarnum S. Catheter-related septicaemia in patients receiving home parenteral nutrition. Scand J Gastroenterol 1986 May;21(4):455e60. vila P, Bla zquez J, Tato M, S Fortún J, Grill F, Martín-Da anchez-Corral J, et al. Treatment of long-term intravascular catheter-related bacteraemia with antibiotic-lock therapy. J Antimicrob Chemother 2006 Oct;58(4):816e21. Rijnders BJ, Van Wijngaerden E, Vandecasteele SJ, Stas M, Peetermans WE. Treatment of long-term intravascular catheter-related bacteraemia with antibiotic lock: randomized, placebo-controlled trial. J Antimicrob Chemother 2005 Jan;55(1):90e4. Poole CV, Carlton D, Bimbo L, Allon M. Treatment of catheter-related bacteraemia with an antibiotic lock protocol: effect of bacterial pathogen. Nephrol Dial Transplant 2004 May;19(5):1237e44. Aslam S. Effect of antibacterials on biofilms. Am J Infect Control 2008 Dec;36(10):S175.e9e175.e11. Laird J, Soutar R, Butcher I. Complications of the ethanol-lock technique in the treatment of central venous catheter sepsis. J Infect 2005 Nov;51(4):338. Wu CY, Lee PI. Antibiotic-lock therapy and erythromycin for treatment of catheter-related Candida parapsilosis and Staphylococcus aureus infections. J Antimicrob Chemother 2007 Sep;60(3):706e7. Maiefski M, Rupp ME, Hermsen ED. Ethanol lock technique: review of the literature. Infect Control Hosp Epidemiol 2009 Nov;30(11):1096e108. Chambers ST, Peddie B, Pithie A. Ethanol disinfection of plastic-adherent micro-organisms. J Hosp Infect 2006 Jun;63(2):193e6.
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
A comparison of two methods of treatment for catheter-related bloodstream infections in patients on home parenteral nutrition ski a, *, Krystyna Majewska a, Łukasz Gradowski b, Iwona Fołtyn a, Michał Ławin Pierre Singer c _ Department of General Surgery and Clinical Nutrition, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, Poland Interdisciplinary Center for Applied Cognitive Studies, University of Social Sciences and Humanities, Chodakowska 19/31, 03-815 Warsaw, Poland c General Intensive Care Department and Institute for Nutrition Research, Rabin Medical Center, Beilinson Hospital, 49100 Petah Tikva, Israel a
b
a r t i c l e i n f o
s u m m a r y
Article history: Received 10 February 2014 Accepted 22 September 2014
Background & aims: Home parenteral nutrition (HPN) enables patients who cannot eat normally to survive and function. Catheter-related bloodstream infections (CRBSIs) are the most dangerous complication, which may be fatal if left untreated or if treatment is delayed. For over 20 years CRBSIs were managed by catheter removal and implantation of a new one after completion of antibiotic treatment. However, frequent catheter replacements put the patient at risk of large vein thrombosis, which may render parenteral nutrition impossible. The management of CRBSIs evolved into antibiotic treatment without catheter removal. The effectiveness of this approach was, however, limited by the low penetration of the antibiotics into the biofilm. Filling catheters with concentrated ethanol destroys the biofilm and does not result in the emergence of drug resistance. The aim of our study was to assess the remote outcomes of CRBSI treatment using two approaches: antibiotic-ethanol lock therapy and catheter replacement. Methods: We retrospectively analysed the treatment outcomes of CRBSI diagnosed and managed in HPN patients. During the analysed period, a total of 428 patients between 13 and 96 years of age were on HPN and a total of 181 of them suffered a total of 352 CRBSI episodes managed with one of the two approaches. Results: We showed no significant differences between the two approaches in terms of survival likelihood or duration of catheter use after an episode of CRBSI caused by various bacterial species. Conclusion: The use of antibiotic-ethanol lock therapy in the management of CRBSI is equally effective as catheter replacement. © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: HPN CRBSI Antibiotic-ethanol lock therapy
1. Introduction Parenteral nutrition involves the supply of all nutrients intravenously, thus bypassing the gastrointestinal tract [1]. The success of long-term parenteral nutrition, which is often a lifetime intervention, is conditional upon the avoidance of complications related to access to the venous system and upon the selection of nutrients that is appropriate to the patient's needs and metabolic capacity. Everyday administration of a nutrient mixture into the venous system requires at least two manipulations at the catheter end/ transfusion set interface. Following aseptic technique while performing between 25 and 40 actions each day is a condition of avoiding the contamination and colonisation of the catheter end
* Corresponding author. Tel.: þ48 501702899. ski). E-mail address: [email protected] (M. Ławin
and lumen by microorganisms [2]. Catheter colonisation leads to catheter-related bloodstream infections (CRBSIs) with all the possible sequelae of a systemic infection, which is fatal if left untreated or if treatment is delayed [3,4]. Although a number of methods to reduce the risk of colonisation and infection have been developed, it is not possible to avoid them completely. Recently, the use of taurolidine 2% (taurolidine citrate) has shown to decrease significantly the number of CRBI (5a Quarello F et al. Blood Purification 2002) in hemodialyis catheter for haemodialysis patients. Taurolidine citrate lock therapy reduced the CRBI's number from 1.3 to 0.3 infections per 1000 catheter days (J Hosp inf 2012). The traditional approach to the management of CRBSI involves removing the catheter which is the source of infection and administering an appropriate antibiotic [5]. A new catheter is implanted after the infection has been controlled. However, each subsequent catheter implantation into a large vein is more difficult and poses a risk of complications related to very catheter
http://dx.doi.org/10.1016/j.clnu.2014.09.013 0261-5614/© 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
ski et al. / Clinical Nutrition xxx (2014) 1e5 M. Ławin
2
implantation procedure and thrombotic complications which lead to the loss of vena cava access [6]. The management of CRBSIs is of dual nature and involves systemic management, including systemic antibiotics, and catheter management [12]. The traditional management of CRBSIs involves administration of antibiotics, removal of the catheter responsible for the infection, and implantation of a new catheter after the infection has been cured. However, in patients with recurrent catheter-related infections, each subsequent catheterization of a large vein is increasingly difficult and risky, and may lead to the loss of venous access. Therefore, in patients requiring parenteral nutrition, maintenance of venous access is as important as controlling and curing the infection. Because of that, attempts have been made to treat CRBSIs without catheter removal. This method has been used in many modifications but it turned out that its effectiveness is limited due to the low penetration of most antibiotics into the biofilm formed by the microorganisms in the catheter [7]. While the patients improved and the symptoms of infection resolved during hospitalisation, the infection recurred after the patients were discharged home [8,9]. In their search for agents penetrating into the biofilm, Ball et al. suggested using concentrated ethanol, previously used to restore catheter patency [10,11]. The Infectious Disease Society of America does not unequivocally recommend ethanol lock therapy as a method for endoluminal eradication of microorganisms in cases of catheter colonisation [5]. It is, however, widely believed that the use of ethanol to destroy the biofilm, followed by the use of antibiotic lock therapy to completely cure catheter contamination, may be beneficial. The aim of our study was to assess the remote outcomes of CRBSI treatment in patients on long-term home parenteral nutrition (HPN) using two approaches: antibiotic-ethanol lock therapy and the traditional approach involving replacement of the contaminated catheter with a new one. 2. Material and methods 2.1. Material Between 1 January 2005 and 31 December 2010, HPN was provided to 428 patients from our hospital outpatient clinic: 240 females (56%) aged 16e92 years (mean age: 56.5 ± 16 years) and 188 males (44%) aged 13e96 years (mean age: 54 ± 17 years). Indications for parenteral nutrition in this patient group included: short bowel syndrome, multilevel bowel obstruction, postoperative gastrointestinal fistulas, malabsorption syndrome, gastrointestinal motility abnormalities, cachexia, radiation enteritis. The patients were fed through 5 kind of permanent venous accesses: tunnelized single lumen catheters the name of Broviac (n ¼ 305), Groshong (n ¼ 67), Broviac-Lifecath Expert 19, Cook Redo TPN (n ¼ 29), ports (n ¼ 8). Data was obtained from the hospital database and retrospective study was approved 20.09.2011 by the ethics committee of the Medical University of Warsaw. 2.2. Management of suspected catheter-related infection In each case of suspected catheter-related infection, the patient was hospitalized for evaluation and treatment. Throughout that period, the catheter was excluded from use and the patient was being fed and hydrated via peripheral veins. In patients in grave condition and patients with catheter exit-site or tunnel infection, the catheter was removed. Cultures for microbial evaluation were obtained from skin smears around the entry of the catheter, hemocultures taken from CV catheter, peripheral vein. Final decision on the course of management was made after obtaining the culture results for blood collected from the central catheter and
after the diagnosis of CRBSI was established. After confirming that colonisation of the inner surface of the catheter was the source of bacteraemia, the justifiability of using antibiotic and ethanol lock with or without systemic antibiotic therapy to sterilize the catheter was considered. This antibiotic-ethanol lock therapy was compared to the group of patients in whom the catheter was removed if contraindications for antibiotic-ethanol lock therapy was identified. The following were considered to be the contraindications to antibiotic-ethanol lock therapy:
a Groshong catheter (due to its design), a previously repaired catheter, a ruptured catheter hub, colonisation with fungi or bacterial strains of: Staphylococcus aureus, Staphylococcus haemolyticus, Corynebacterium spp., Mycobacterium spp., Pseudomonas aeruginosa, Micrococcus spp., Bacillus spp., colonisation with strains resistant to most antibiotics or strains whose antibiotic susceptibility could not be established.
2.3. Establishment of the antibiotic-ethanol lock The residual content and blood were aspirated from the catheter, the catheter hub and lumen were flushed to remove the residual blood using a 0.9% saline solution and the catheter was filled with a 95% ethanol solution. The solution was left in the catheter for 24 h. The next day blood was aspirated, the catheter lumen and hub were flushed and the catheter was filled with ethanol again. Four days later, the ethanol solution was replaced with an antibiotic solution, which was administered according to the same procedure for the next four days. The antibiotic was selected according to culture results. Twenty-four hours after the last dose of the antibiotic, the patient was started on his/her nutrient mixture and the next day blood from the central catheter was drawn for follow-up culture. If the patient had remained asymptomatic for the past 48 h and the culture was negative, he/she was discharged home. The following antibiotic solutions at the following concentrations were used to fill the catheters: amikacin 100 mg/ml, teicoplanin: 40 mg/ml, vancomycin: 50 mg/ml. If the patient developed fever and/or chills or if his/her condition deteriorated, the treatment was discontinued, the catheter was removed and a new catheter was implanted after completion of antibiotic treatment.
2.4. Statistical analysis The antibiotic lock therapy group was compared to the catheter removed group. Data were expressed as median with a 25the75th percentile interquartile range. The median time of new catheter use after catheter replacement and after antibiotic-ethanol lock therapy was compared using the U ManneWhitney test. Time to recurrence of infection and survival for each of the two analysed treatments were compared with the KaplaneMeier method and the significance of the results was assessed with the CoxeMantel test. The rates of recurrent infections with the same strains were assessed with the chi-square test and, for low number of cases, with the Yates continuity correction. The mean follow-up time to recurrence was assessed with the U ManneWhitney test. In order to identify the effect of factors associated with infection recurrence, multivariate logistic regression analysis of factors identified as potentially relevant in univariate analysis was performed. The IBM SPSS Statistic software package (version 21.0) was used for statistical analysis.
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
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3. Results The total duration of parenteral nutrition in 428 patients on HPN between 1 January 2005 and 31 December 2010 was 404,808 days. During the follow-up period, 34 (7.9%) patients discontinued the treatment due to regained nutritional autonomy, 214 (50.0%) continued treatment, 178 (41.6%) died and 2 (0.5%) transferred to other facilities. 247 (57.5%) patients did not suffer any CRBSI episode, while 181 (42.5%) suffered a total of 352 CRBSI episodes. The demographic date are presented in Table 1. The number of patients who suffered 1, 2, 3, 4, and more than 4 episodes was 98, 43, 17, 13, and 10, respectively. The incidence rate of CRBSIs was 0.87 per 1000 days, which corresponds to 0.31 episode of CRBSI per year of treatment. A total of 335 CRBSIs were cured. In 331 cases parenteral nutrition was continued and in 4 cases parenteral nutrition was terminated, as the patient regained nutritional autonomy or enteric nutrition was sufficient. Catheter-related infection was attributable to the death in 16 of the hospitalised patients.
3.1. Remote outcomes of treatment of catheter-related infections Among the 331 episodes after which patients continued parenteral nutrition after successful treatment, 100 had been managed with antibiotic and ethanol lock and 231 had their catheter replaced. The outcomes of treatment of catheter-related infections is expressed in Table 2, showing the duration of using the catheter after treatment, occurrence of recurrences of infection with the same microbial species and patient survival after treatment of a CRBSI episode relative to the management approach used. Recurrence of infection with the same microbial species was observed in 33 patients: in 17 patients (17%) managed with antibiotic-ethanol lock therapy (83% success) and 16 patients (6.93%) after catheter replacement (93% success) (p < 001 in chisquared test). The mean time from completion of antibioticethanol lock therapy or catheter replacement to recurrence of infection with the same microbial species was Me ¼ 265 IQR 110e516 days after antibiotic-ethanol lock therapy and Me ¼ 330 IQR 162e591 days after catheter replacement (U ¼ 6233.00; p ¼ 0.051 in the U ManneWhitney test) (Fig. 1). The antibiotic most commonly used for antibiotic lock therapy was amikacin. Recurrences of infection with the same microbial species were observed in 5 (8.47%) of the 59 patients whose catheters had been filled with amikacin. The rate of recurrences after treatment with vancomycin was 21.88% and that after treatment with teicoplanin was 57.14% (p < 0.001 in chi-squared test). The rate of infections with the same microbial species, in the absence of systemic antibiotic treatment, was 75% in patients managed with catheter replacement and 19.44% in patients managed with
3
Table 2 The treatment of catheter-related infections (median and IQR e Inter Quartile Range). Duration of using the catheter after treatment
Gram Positive Staph Epidermitis Staph Con Gram Negative
Antibiotic-ethanol lock
Catheter removal
Me ¼ 292 IQR 136 to 695 Me ¼ 290 IQR 126 to 516 Me ¼ 341 IQR 212 to 935 Me ¼ 182 IQR 114 to 547
Me ¼ 353 IQR 163 to 611 Me ¼ 261 IQR 159 to 567 Me ¼ 366 IQR 140 to 616 Me ¼ 314 IQR 135 to 569
U Manne Whitney value
p Value
5177.0
0.379
1094.0
0.949
476.5
0.467
740.0
0.254
antibiotic-ethanol lock therapy (p < 0.0001 vs. patients receiving systemic antibiotic treatment). Much fewer infections were observed in patients who received empirical treatment consisting of 2 or 3 antibiotics irrespective of the management of the catheterrelated infection compared to patients who received just one systemic antibiotic (p < 001). The analysis (Multivariate Logistic Regression) of the relationships of factors that could potentially affect the recurrence of infection with the same microbial species showed that the absence of systemic antibiotic treatment was the only factor that was significantly associated with the recurrence of infection with the same microbial species in patients managed by catheter replacement (b ¼ 0.36; p < 0.0001) (Fig. 2). Recurrence of CRBSI with the same microbial species after an episode managed with antibiotic-ethanol lock therapy was, on the other hand, associated with the person servicing the parenteral nutrition catheter (b ¼ 0.32; p < 0.0001) (Fig. 3). No differences were observed when the cumulative survival of patients from the first CRBSI episode according to the management approach employed (Fig. 4). Comparison of late results of treatment with catheter replacement and ethanol/antibiotic lock shows both methods as equally efficient. Early CRBSI recurrence (until 60 days) were observed in 2 (1%) treated by catheter replacement and 4 (4%) treated by ethanol/ antibiotic lock (chi-square test p ¼ 0.13) and until 120 days respectively in 5 (2.2%) and 7 (7%), treated (chi-square test p ¼ 0.66).
Table 1 Demographic data of antibiotic-ethanol and catheter removal groups (n ¼ 181). Treatment
Gender Age ± SD Catheter care Place of residence
Male Female Independent Caregiver Urban Rural
Antibiotic-ethanol lock
Catheter removal
23 25 54.8 ± 15 28 (58.3%) 20 (41.7%) 30 (62.5%) 18 (37.5%)
75 58 55.1 ± 18 66 (49.7%) 67 (50.3%) 98 (73.7%) 35 (26.3%)
Fig. 1. Likelihood of using the catheter without recurrence of infection with the same microbial species according to the treatment approach (p ¼ 0.00169 [NS] in CoxeMantel test).
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
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Fig. 2. Effect of various factors on the development of recurrent CRBSI with the same microbial species after treatment with catheter removal.
Fig. 4. Patient survival likelihood according to the treatment approach employed during the first episode of CRBSI (p ¼ 0.48663[NS] in CoxeMantel test).
4. Discussion When evaluating the effectiveness of treatment of catheterrelated infections, one should not only take into account the immediate outcomes (control of the acute infection and eradication of the source of infection) but also patient survival after treatment, duration of fault-free use of the catheter and the rate of infection recurrences. If the goal of the treatment is to preserve a permanent catheter, then antibiotic lock therapy or ethanol lock therapy becomes the only option. The body of experience gained so far and the resulting current recommendations confirm the justifiability of antibiotic lock therapy for the treatment of catheter-related infections without the need to remove the catheter in patients requiring longterm venous access [5,13,14]. Rannem et al. successfully managed some of the infections solely with antibiotics administered through the catheter and Buchman et al., in patients treated between 1986 and 1989, managed to preserve 87% catheters using this method
Fig. 3. Effect of various factors on the development of recurrent CRBSI with the same microbial species after antibiotic-ethanol lock therapy.
[15,16]. More recent studies, however, showed a greater efficacy of antibiotic lock therapy compared to antibiotic infusion through the catheter [17,18] and a longer survival of the dialysis catheter after lock therapy versus catheter replacement (154 and 71 days, respectively) [19]. A number of factors contributing to infection recurrence after antibiotic lock therapy have been identified. It is believed that the principal factor that interferes with successful eradication of microorganisms colonising the catheter and contributing to recurrences of infections with these microorganisms is the biofilm and its resistance to antibiotics [6,7]. Studies were therefore conducted to investigate the use of substances along with the antibiotic that would destroy the biofilm or facilitate penetration of antibiotics into the biofilm: N-acetylcysteine, macrolide antibiotics (especially erythromycin) and ethanol [20e22]. The properties of ethanol, such as good penetration into the biofilm, no risk of selection of resistant strains, low cost, low risk of recurrences and low risk of emergence of resistance, make it an ideal agent to eradicate microorganisms from catheters [23]. Experimental studies show, however, that the older the biofilm is and the shorter the exposure time, the less effective ethanol is [24]. These two methods were combined into one, antibiotic-ethanol lock therapy, on the premise that after four days of exposure ethanol would destroy the biofilm, which would facilitate penetration of the antibiotic and eradication of the remaining microorganisms from the inner surface of the catheter. The low number of recurrences and the long follow-up period confirm that this premise was correct. The comparison of the remote outcomes in the group of patients managed with catheter replacement with the outcomes in the group of patients managed with antibiotic lock therapy showed that both methods are generally equally effective. Survival of patients after antibiotic-ethanol lock therapy compared to survival of patients managed with catheter replacement, after excluding cancer patients from the analysis, were similar. The median duration HPN from the first episode of CRBSI was 1193 days (IQR: 631e1524) in patients managed with antibiotic and ethanol lock therapy and 1026 days (IQR: 566e1580) in patients managed with catheter replacement. Our study has several limitations. The first is that taurolidine use for prevention was not a possible alternative since the study was started in 2005, when taurolidine lock was not a true alternative for prevention of CRBIs. Second, the groups were not randomly chosen
ski M, et al., A comparison of two methods of treatment for catheter-related bloodstream infections in Please cite this article in press as: Ławin patients on home parenteral nutrition, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.09.013
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but according to a protocol making the value of our study weaker. However, the large number of patients followed for a long time is giving a strong signal of the equal value of the 2 strategies. [6]
5. Conclusions We conclude that the use of antibiotic-ethanol lock therapy in the management of CRBSI is equally effective as catheter replacement, after exclusion of absolute indications of catheter removal. No complications associated with catheter filling with ethanol were observed. The duration of catheter use and survival after treatment of a CRBSI episode and patient survival did not differ relative to the approach employed. Recurrences of CRBSIs with the same microbial species over a period of up to 120 days after the completion of treatment were observed in 7% of patients managed with antibiotic-ethanol lock therapy and 2.2% of patients managed with catheter replacement. Development of recurrences of CRBSIs was associated with the absence of systemic antibiotic treatment. Statement of authorship MŁ is responsible for planned the article and manuscript preparation. ŁG performed statistical analysis KM, IF collections and analysed data, PS reviewed the data and revised the manuscript. All authors read and approved the final manuscript. Conflict of interest statement Each author declared no conflict of financial or personal interests in this study.
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[15]
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