J Antimicrob Chemother 2014; 69: 1665 – 1668 doi:10.1093/jac/dku017 Advance Access publication 12 February 2014
Adjunctive management of central line-associated bloodstream infections with 70% ethanol-lock therapy David W. Kubiak1*, Erin T. Gilmore1, Mary W. Buckley1, Robert Lynch1, Francisco M. Marty1–3 and Sophia Koo1–3 1
Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA; 2Dana–Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; 3Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA *Corresponding author. Tel: +1-617-525-2255; Fax: +1-617-731-1541; E-mail: [email protected]
Objectives: Ethanol is bactericidal against most pathogens implicated in central line-associated bloodstream infections (CLABSIs) and biofilms. Current Infectious Diseases Society of America guidelines cite insufficient evidence to support adjunctive ethanol-lock therapy (ELT) for central venous catheter (CVC) salvage in patients with CLABSI in combination with systemic antimicrobial treatment. We evaluated the safety and potential efficacy of 70% ELT for CLABSI at our institution after implementation of a hospital ELT protocol. Methods: We collected data on all patients treated with adjunctive 70% ELT for catheter salvage from September 2009 to September 2011 and assessed clinical outcomes and adverse events associated with ELT. Results: Sixty-eight hospitalized patients received 70% ELT for CVC salvage: 45 (66%) met the criteria for CLABSI. Five (11%) had persistent or recurrent bacteraemia triggering CVC removal; 28 (62%) preserved their CVC long term. There were no documented adverse events associated with ELT. Discussion: Adjunctive 70% ELT is an inexpensive, well-tolerated option for CVC salvage in patients with CLABSI and warrants further investigation. Keywords: catheter-related infections, biofilms, salvage therapy
Introduction In 2011, the US CDC estimated that 41000 central line-associated bloodstream infections (CLABSIs) occur in hospitalized patients across the USA annually, with an excess cost of up to $56 000 per episode.1,2 Current Infectious Diseases Society of America (IDSA) guidelines recommend antimicrobial lock therapy as an option for central venous catheter (CVC) salvage in patients with CLABSI.3 There are drawbacks to antibiotic lock therapy, however, including poor biofilm penetration, with partial killing of microbial populations embedded in an extracellular polymeric substance matrix, selection of antibiotic resistance and recrudescent bacterial growth after cessation of antibiotic therapy.4,5 Ethanol is an inexpensive, readily available antiseptic agent that exerts its broad-spectrum bactericidal and fungicidal activity by non-specific denaturing of proteins and dissolution of lipids.6 Ethanol is effective at eradicating biofilm-embedded bacteria.7 Prolonged exposure to 70% ethanol solutions does not appreciably alter the integrity or mechanical properties of polyurethane and silicone intravascular catheters.8 Ethanol-lock therapy (ELT) is safe and effective in CLABSI prophylaxis in oncology patients and total parenteral nutrition recipients,9
but clinical data supporting the use of ELT for CVC salvage in CLABSI are sparse and limited to paediatric populations.10 – 12 Current IDSA guidelines do not endorse the use of adjunctive ELT for CVC salvage in CLABSI, citing insufficient evidence.3 In September 2009, we implemented an institutional ELT protocol for CVC salvage in CLABSI. We sought to evaluate the safety and outcomes associated with the use of ELT for CVC salvage at our institution.
Patients and methods Patient population We reviewed the medical records of patients with a bloodstream infection who received ELT for CVC salvage at our institution from September 2009 through September 2011. All patients prescribed ELT over this period were identified through electronic pharmacy records. The decision to initiate ELT was at the discretion of each patient’s clinical care team.
ELT protocol For CVC salvage in patients with long-term CVCs and suspected CLABSI, our institutional ELT protocol (available as Supplementary data at JAC Online) recommends the instillation of up to 2 mL of a 70% ethanol
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1665
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
Received 19 June 2013; returned 23 September 2013; revised 16 January 2014; accepted 17 January 2014
Kubiak et al.
solution to fill the intraluminal CVC volume for 4 – 12 h per day for 5 days. After the dwell period, the ethanol solution is either aspirated or flushed with 0.9% sodium chloride. The protocol recommends CVC removal in patients with Staphylococcus aureus or Candida CLABSI and if blood cultures are positive after 5 days of ELT. The only patients for whom ELT is contraindicated in the ELT protocol are pregnant women and neonates.
Data collection
CLABSI adjudication We evaluated each bloodstream infection episode according to CDC/ National Healthcare Safety Network (NHSN) CLABSI criteria and classified each episode as CLABSI or secondary bloodstream infection from another anatomical site.13
Outcome measures CVCs were removed at the discretion of each patient’s clinical care team. We recorded the duration of CVC retention following the initiation of ELT and the reasons for CVC removal. The Partners Healthcare Human Research Committee approved this study.
Results We identified 68 first bloodstream infection episodes in patients treated with adjunctive ELT for CVC salvage. Forty-five (66%) of these episodes met CDC/NHSN criteria for CLABSI.13 These patients had a median age of 53 years and most had an underlying malignancy (Table 1). Administration of chemotherapy (56%) and total parenteral nutrition (20%) were the most common CVC indications. Most patients (67%) received ELT for CLABSI associated with a tunnelled catheter. Coagulase-negative Staphylococcus (44%) was the most commonly implicated aetiological organism, followed by Gram-negative bacilli (22%) and Enterococcus faecium (7%). Patients were bacteraemic or fungaemic for a median of 3 days (IQR 2 – 4; range 0 – 7) prior to the initiation of ELT. Patients received a median of 5 days (IQR 3 – 6; range 1 – 21) of adjunctive ELT with systemic antimicrobial therapy. In 35 (78%) patients, blood cultures became sterile prior to ELT initiation; in 4 patients, blood cultures became sterile on the date of ELT initiation; and for 1 patient each, blood cultures became sterile 1, 2 and 3 days after ELT initiation. The remaining three patients were bacteraemic for 4, 6 and 7 days, respectively, after initiation of ELT, with sterilization of blood cultures after CVC removal. Two patients had recurrent bacteraemia after ELT treatment. Sixteen (36%) CLABSI patients underwent removal of their infected CVCs within 7 days of ELT treatment, 3 due to persistent bacteraemia (2 coagulase-negative Staphylococcus and 1 Bacillus cereus) and the remainder because the CVC was no longer
1666
Characteristic Patients, n
45
Age (years), median (IQR; range)
53 (41 –65; 21–90)
Female, n (%)
23 (51)
Malignancy, n (%)
34 (76)
Primary CVC indication, n (%) chemotherapy total parenteral nutrition other parenteral medications blood product transfusions haemodialysis
25 (56) 9 (20) 6 (13) 3 (7) 2 (4)
Type of CVC, n (%) tunnelled CVC (silicone) implanted port (polyurethane) PICC (polyurethane) both implanted port and PICC
30 (67) 10 (22) 4 (9) 1 (2)
Causative pathogen, n (%) coagulase-negative staphylococci Gram-negative bacillia E. faecium Streptococcus mitis S. aureus Candida spp.b B. cereus Corynebacterium jeikeium polymicrobial bacteraemiac
20 (44) 10 (22) 3 (7) 1 (2) 1 (2) 2 (4) 1 (2) 1 (2) 6 (13)
PICC, peripherally inserted central catheter. Three Escherichia coli, two S. maltophilia, two Pantoea agglomerans, one Pseudomonas aeruginosa, one Enterobacter aerogenes and one Citrobacter freundii. b One C. albicans and one C. parapsilosis. c Two S. mitis and coagulase-negative staphylococci (CoNS), two CoNS and methicillin-susceptible S. aureus, one CoNS and methicillin-resistant S. aureus and one CoNS and Enterococcus faecalis. a
clinically necessary (7), not functioning well (3) or clinician preference despite the absence of persistent CLABSI (3). One patient died of complications of an underlying malignancy 7 days after initiation of ELT without evidence of persistent CLABSI. The remaining 28 (62%) CLABSI patients retained their CVCs for a median of 71 days (IQR 34–162; range 11–569), for a total of 3274 additional patient CVC-days after ELT treatment. One patient with Stenotrophomonas maltophilia CLABSI had recurrent S. maltophilia bacteraemia 51 days after her initial CLABSI. A second patient with S. maltophilia CLABSI developed Candida parapsilosis fungaemia 115 days after the initial CLABSI and 50 colonies of S. maltophilia grew from cultures of the CVC tip. No other patients had evidence of recurrent CLABSI after ELT. Of 45 CLABSI patients, 9 (20%) had a CVC for administration of total parenteral nutrition. One patient’s CVC was removed due to persistent bacteraemia with B. cereus despite 6 days of ELT. Three
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
Demographics and details of each bloodstream infection were recorded, including the aetiological organism, duration of bacteraemia or fungaemia, concomitant systemic antibiotics and CVC type and site. The frequency and duration of repeat blood cultures after the initiation of ELT was determined at the discretion of clinical care teams. We collected details of ELT, including ELT duration and adverse events potentially related to ELT administration (CNS depression, headaches, light-headedness, dizziness, arrhythmias, fatigue, nausea, local venous irritation or flushing requiring premature cessation of ELT). Data were censored on 1 November 2011.
Table 1. Patient, CVC and bloodstream infection characteristics of patients with CLABSI who received adjuvant 70% ELT
JAC
Ethanol-lock therapy for central venous catheter salvage
of these patients had their catheters removed after 2 days of ELT, one because the CVC was no longer clinically necessary for the patient’s nutrition and two because the CVC was not functioning well despite the absence of persistent CLABSI. The remaining five patients had sterilization of blood cultures and retained their CVCs for a median of 82 days.
Safety and adverse events
Discussion The use of 70% ELT for adjunctive therapy of CLABSI appeared to be well tolerated and potentially effective in a cohort comprised predominantly of cancer patients requiring long-term indwelling CVCs for chemotherapy and supportive care. Only five (11%) patients had persistent or recurrent bacteraemia triggering CVC removal after ELT: three patients had persistent bacteraemia with coagulase-negative Staphylococcus or B. cereus during the initial CLABSI episode, while two patients had evidence of recurrent S. maltophilia infection several weeks after the initial CLABSI episode. While 36% of CVCs were removed within 1 week of ELT initiation, mostly in patients whose CVCs were no longer clinically necessary, 28 of 45 (62%) patients retained their CVCs for a median of 71 additional CVC-days without recrudescent bloodstream infection. While this study is relatively small in size and retrospective in nature, with substantial heterogeneity in the length of bacteraemia prior to ELT, the duration of ELT exposure and each clinician’s threshold for CVC removal, it is the largest and most comprehensive assessment of the clinical safety and efficacy of ELT in adult CLABSI patients to date, with a relatively long duration of follow-up after ELT exposure. Our findings should be interpreted cautiously: prior to initiation of this ELT protocol, the majority of patients with CLABSI at our institution had prompt removal of their CVCs, so it was not possible to define a comparable control group where CVC salvage was attempted with systemic antimicrobial therapy alone, making it challenging to draw definitive conclusions about the efficacy and safety of exposure to adjunctive ELT. Also, due to the retrospective nature of this analysis, the assessment of adverse events associated with ELT depended on the quality of physician and nursing clinical documentation, which was variable. However, no patients in this cohort were reported to have any symptoms theoretically associated with ethanol toxicity, namely CNS depression, arrhythmias, fatigue, headaches, dizziness, nausea, lightheadedness, local venous irritation or flushing, that triggered discontinuation of ELT. Additionally, there were no documented reports of CVC malfunction or diminished integrity attributed to ELT. Ethanol is comparable or superior to antibiotic agents in sterilizing catheter-associated biofilms in vitro. Sherertz et al.14
Acknowledgements Results from this study were presented in part at the Forty-ninth Annual Meeting of the Infectious Diseases Society of America, Boston, MA, USA, 2011 (Abstract 670).
1667
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
There were no documented adverse events potentially associated with ELT in the 45 CLABSI patients. Two of the 23 patients treated with ELT for secondary bloodstream infection discontinued ELT therapy after 3 and 5 days, respectively, because of recurrent CVC lumen occlusion. No patients were reported to have experienced CNS depression, arrhythmias, fatigue, headaches, dizziness, nausea, light-headedness, local venous irritation or flushing, attributed clinically to ELT.
examined the efficacy of ethanol and various antibiotic agents (vancomycin, ciprofloxacin, minocycline and rifampicin) in sterilizing S. aureus biofilms incubated on silicone CVCs. At concentrations of ≥30%, ethanol was superior to all other agents tested, with 3.6 – 3.9 log units of killing at 2, 4 and 24 h.14 At concentrations of ≥35%, ethanol has been shown to reduce the metabolic activity of mature Candida albicans biofilms by .99%.15 Despite these in vitro studies demonstrating the effectiveness of ethanol in sterilizing biofilms, clinical data on the efficacy of ELT for CVC salvage are sparse and most analyses have included patients who did not clearly meet CLABSI criteria. In a retrospective analysis of 28 children with 39 discrete bloodstream infections, 16 of 24 (67%) patients treated with adjunctive ELT and only 7 of 15 (47%) treated with systemic antibiotics alone were free of recurrent bloodstream infection at 4 weeks.11 Another study of 70% ELT in 51 bloodstream infection episodes in 40 children found no recurrent bloodstream infection at 30 days in 45 of 51 (88%) episodes.10 Another study prospectively examined the effects of ELT in conjunction with systemic antibiotics in 19 paediatric and adult patients with bloodstream infection, predominantly due to Gram-negative pathogens. Of 17 patients who completed 5 days of ELT, all had sterile blood cultures 6 days after completion of ELT and 12 (71%) retained their CVCs for .14 days without recrudescent bacteraemia.12 One patient in our study had persistent B. cereus CLABSI and two patients developed late recrudescent S. maltophilia infections associated with their salvaged catheters despite appropriate antimicrobial therapy and ≥5 days of adjunctive ELT. B. cereus and S. maltophilia are known to form highly tenacious biofilms in vitro that may be refractory to sterilization by even relatively high concentrations of ethanol.16,17 CLABSI due to these organisms should probably not be considered for 70% ELT. It is difficult to assess and capture all potential adverse events associated with ELT in a retrospective analysis. The amount of ethanol that may reach the systemic circulation with our ELT protocol is miniscule, as it is mostly aspirated after the dwell period, and generally well-tolerated by our study population. Whenever possible, the ethanol-lock solution instilled in the CVC should be aspirated and not flushed into the systemic circulation. Although unlikely, clinicians should monitor patients receiving ELT closely for adverse effects that may be associated with ELT, including CNS depression, cardiac arrhythmias, excessive fatigue, prolonged headaches, dizziness, severe nausea, light-headedness, local venous irritation or flushing. The development of these or other symptoms potentially attributable to ELT should warrant reconsideration of ELT therapy for CVC salvage. The removal and replacement of long-term CVCs is burdensome and costly. Further controlled studies into the effects of adjunctive ELT, an inexpensive, well-tolerated and potentially effective method for CVC salvage in CLABSI, are warranted.
Kubiak et al.
Funding The work was carried out in part with support from the National Institutes of Health (AI097225 to S. K.).
Transparency declarations None to declare.
Supplementary data Our institutional ELT protocol is available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).
1 CDC. Vital signs: central line-associated blood stream infections— United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep 2011; 60: 243–8. 2 Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clinic Proc 2006; 81: 1159–71. 3 Mermel LA, Allon M, Bouza E et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49: 1– 45.
8 Crnich CJ, Halfmann JA, Crone WC et al. The effects of prolonged ethanol exposure on the mechanical properties of polyurethane and silicone catheters used for intravascular access. Infect Control Hosp Epidemiol 2005; 26: 708–14. 9 Oliveira C, Nasr A, Brindle M et al. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012; 129: 318– 29. 10 Onland W, Shin CE, Fustar S et al. Ethanol-lock technique for persistent bacteremia of long-term intravascular devices in pediatric patients. Arch Pediatr Adolesc Med 2006; 160: 1049– 53. 11 Dannenberg C, Bierbach U, Rothe A et al. Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheter. J Pediatr Hematol Oncol 2003; 25: 616– 21. 12 Broom J, Woods M, Allworth A et al. Ethanol lock therapy to treat tunnelled central venous catheter-associated blood stream infections: results from a prospective trial. Scand J Infect Dis 2008; 40: 399– 406. 13 Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008; 36: 309–32. 14 Sherertz RJ, Boger MS, Collins CA et al. Comparative in vitro efficacies of various catheter lock solutions. Antimicrob Agents Chemother 2006; 50: 1865– 8. 15 Rane HS, Bernardo SM, Walraven CJ et al. In vitro analyses of ethanol activity against Candida albicans biofilms. Antimicrob Agents Chemother 2012; 56: 4487– 9.
4 Yahav D, Rozen-Zvi B, Gafter-Gvili A et al. Antimicrobial lock solutions for the prevention of infections associated with intravascular catheters in patients undergoing hemodialysis: systematic review and meta-analysis of randomized, controlled trials. Clin Infect Dis 2008; 47: 83– 93.
16 Karunakaran E, Biggs CA. Mechanisms of Bacillus cereus biofilm formation: an investigation of the physicochemical characteristics of cell surfaces and extracellular proteins. Appl Microbiol Biotechnol 2011; 89: 1161– 75.
5 Davies D. Understanding biofilm resistance to antibacterial agents. Nat Rev Drug Discov 2003; 2: 114– 22.
17 Passerini de Rossi B, Feldman L, Pineda MS et al. Comparative in vitro efficacies of ethanol-, EDTA- and levofloxacin-based catheter lock solutions on eradication of Stenotrophomonas maltophilia biofilms. J Med Microbiol 2012; 61: 1248 –53.
6 Maiefski M, Rupp ME, Hermsen ED. Ethanol lock technique: review of the literature. Infect Control Hosp Epidemiol 2009; 30: 1096– 108.
1668
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
References
7 Peters BM, Ward RM, Rane HS et al. Efficacy of ethanol against Candida albicans and Staphylococcus aureus polymicrobial biofilms. Antimicrob Agents Chemother 2013; 57: 74– 82.
Adjunctive management of central line-associated bloodstream infections with 70% ethanol-lock therapy David W. Kubiak1*, Erin T. Gilmore1, Mary W. Buckley1, Robert Lynch1, Francisco M. Marty1–3 and Sophia Koo1–3 1
Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA; 2Dana–Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; 3Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA *Corresponding author. Tel: +1-617-525-2255; Fax: +1-617-731-1541; E-mail: [email protected]
Objectives: Ethanol is bactericidal against most pathogens implicated in central line-associated bloodstream infections (CLABSIs) and biofilms. Current Infectious Diseases Society of America guidelines cite insufficient evidence to support adjunctive ethanol-lock therapy (ELT) for central venous catheter (CVC) salvage in patients with CLABSI in combination with systemic antimicrobial treatment. We evaluated the safety and potential efficacy of 70% ELT for CLABSI at our institution after implementation of a hospital ELT protocol. Methods: We collected data on all patients treated with adjunctive 70% ELT for catheter salvage from September 2009 to September 2011 and assessed clinical outcomes and adverse events associated with ELT. Results: Sixty-eight hospitalized patients received 70% ELT for CVC salvage: 45 (66%) met the criteria for CLABSI. Five (11%) had persistent or recurrent bacteraemia triggering CVC removal; 28 (62%) preserved their CVC long term. There were no documented adverse events associated with ELT. Discussion: Adjunctive 70% ELT is an inexpensive, well-tolerated option for CVC salvage in patients with CLABSI and warrants further investigation. Keywords: catheter-related infections, biofilms, salvage therapy
Introduction In 2011, the US CDC estimated that 41000 central line-associated bloodstream infections (CLABSIs) occur in hospitalized patients across the USA annually, with an excess cost of up to $56 000 per episode.1,2 Current Infectious Diseases Society of America (IDSA) guidelines recommend antimicrobial lock therapy as an option for central venous catheter (CVC) salvage in patients with CLABSI.3 There are drawbacks to antibiotic lock therapy, however, including poor biofilm penetration, with partial killing of microbial populations embedded in an extracellular polymeric substance matrix, selection of antibiotic resistance and recrudescent bacterial growth after cessation of antibiotic therapy.4,5 Ethanol is an inexpensive, readily available antiseptic agent that exerts its broad-spectrum bactericidal and fungicidal activity by non-specific denaturing of proteins and dissolution of lipids.6 Ethanol is effective at eradicating biofilm-embedded bacteria.7 Prolonged exposure to 70% ethanol solutions does not appreciably alter the integrity or mechanical properties of polyurethane and silicone intravascular catheters.8 Ethanol-lock therapy (ELT) is safe and effective in CLABSI prophylaxis in oncology patients and total parenteral nutrition recipients,9
but clinical data supporting the use of ELT for CVC salvage in CLABSI are sparse and limited to paediatric populations.10 – 12 Current IDSA guidelines do not endorse the use of adjunctive ELT for CVC salvage in CLABSI, citing insufficient evidence.3 In September 2009, we implemented an institutional ELT protocol for CVC salvage in CLABSI. We sought to evaluate the safety and outcomes associated with the use of ELT for CVC salvage at our institution.
Patients and methods Patient population We reviewed the medical records of patients with a bloodstream infection who received ELT for CVC salvage at our institution from September 2009 through September 2011. All patients prescribed ELT over this period were identified through electronic pharmacy records. The decision to initiate ELT was at the discretion of each patient’s clinical care team.
ELT protocol For CVC salvage in patients with long-term CVCs and suspected CLABSI, our institutional ELT protocol (available as Supplementary data at JAC Online) recommends the instillation of up to 2 mL of a 70% ethanol
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1665
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
Received 19 June 2013; returned 23 September 2013; revised 16 January 2014; accepted 17 January 2014
Kubiak et al.
solution to fill the intraluminal CVC volume for 4 – 12 h per day for 5 days. After the dwell period, the ethanol solution is either aspirated or flushed with 0.9% sodium chloride. The protocol recommends CVC removal in patients with Staphylococcus aureus or Candida CLABSI and if blood cultures are positive after 5 days of ELT. The only patients for whom ELT is contraindicated in the ELT protocol are pregnant women and neonates.
Data collection
CLABSI adjudication We evaluated each bloodstream infection episode according to CDC/ National Healthcare Safety Network (NHSN) CLABSI criteria and classified each episode as CLABSI or secondary bloodstream infection from another anatomical site.13
Outcome measures CVCs were removed at the discretion of each patient’s clinical care team. We recorded the duration of CVC retention following the initiation of ELT and the reasons for CVC removal. The Partners Healthcare Human Research Committee approved this study.
Results We identified 68 first bloodstream infection episodes in patients treated with adjunctive ELT for CVC salvage. Forty-five (66%) of these episodes met CDC/NHSN criteria for CLABSI.13 These patients had a median age of 53 years and most had an underlying malignancy (Table 1). Administration of chemotherapy (56%) and total parenteral nutrition (20%) were the most common CVC indications. Most patients (67%) received ELT for CLABSI associated with a tunnelled catheter. Coagulase-negative Staphylococcus (44%) was the most commonly implicated aetiological organism, followed by Gram-negative bacilli (22%) and Enterococcus faecium (7%). Patients were bacteraemic or fungaemic for a median of 3 days (IQR 2 – 4; range 0 – 7) prior to the initiation of ELT. Patients received a median of 5 days (IQR 3 – 6; range 1 – 21) of adjunctive ELT with systemic antimicrobial therapy. In 35 (78%) patients, blood cultures became sterile prior to ELT initiation; in 4 patients, blood cultures became sterile on the date of ELT initiation; and for 1 patient each, blood cultures became sterile 1, 2 and 3 days after ELT initiation. The remaining three patients were bacteraemic for 4, 6 and 7 days, respectively, after initiation of ELT, with sterilization of blood cultures after CVC removal. Two patients had recurrent bacteraemia after ELT treatment. Sixteen (36%) CLABSI patients underwent removal of their infected CVCs within 7 days of ELT treatment, 3 due to persistent bacteraemia (2 coagulase-negative Staphylococcus and 1 Bacillus cereus) and the remainder because the CVC was no longer
1666
Characteristic Patients, n
45
Age (years), median (IQR; range)
53 (41 –65; 21–90)
Female, n (%)
23 (51)
Malignancy, n (%)
34 (76)
Primary CVC indication, n (%) chemotherapy total parenteral nutrition other parenteral medications blood product transfusions haemodialysis
25 (56) 9 (20) 6 (13) 3 (7) 2 (4)
Type of CVC, n (%) tunnelled CVC (silicone) implanted port (polyurethane) PICC (polyurethane) both implanted port and PICC
30 (67) 10 (22) 4 (9) 1 (2)
Causative pathogen, n (%) coagulase-negative staphylococci Gram-negative bacillia E. faecium Streptococcus mitis S. aureus Candida spp.b B. cereus Corynebacterium jeikeium polymicrobial bacteraemiac
20 (44) 10 (22) 3 (7) 1 (2) 1 (2) 2 (4) 1 (2) 1 (2) 6 (13)
PICC, peripherally inserted central catheter. Three Escherichia coli, two S. maltophilia, two Pantoea agglomerans, one Pseudomonas aeruginosa, one Enterobacter aerogenes and one Citrobacter freundii. b One C. albicans and one C. parapsilosis. c Two S. mitis and coagulase-negative staphylococci (CoNS), two CoNS and methicillin-susceptible S. aureus, one CoNS and methicillin-resistant S. aureus and one CoNS and Enterococcus faecalis. a
clinically necessary (7), not functioning well (3) or clinician preference despite the absence of persistent CLABSI (3). One patient died of complications of an underlying malignancy 7 days after initiation of ELT without evidence of persistent CLABSI. The remaining 28 (62%) CLABSI patients retained their CVCs for a median of 71 days (IQR 34–162; range 11–569), for a total of 3274 additional patient CVC-days after ELT treatment. One patient with Stenotrophomonas maltophilia CLABSI had recurrent S. maltophilia bacteraemia 51 days after her initial CLABSI. A second patient with S. maltophilia CLABSI developed Candida parapsilosis fungaemia 115 days after the initial CLABSI and 50 colonies of S. maltophilia grew from cultures of the CVC tip. No other patients had evidence of recurrent CLABSI after ELT. Of 45 CLABSI patients, 9 (20%) had a CVC for administration of total parenteral nutrition. One patient’s CVC was removed due to persistent bacteraemia with B. cereus despite 6 days of ELT. Three
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
Demographics and details of each bloodstream infection were recorded, including the aetiological organism, duration of bacteraemia or fungaemia, concomitant systemic antibiotics and CVC type and site. The frequency and duration of repeat blood cultures after the initiation of ELT was determined at the discretion of clinical care teams. We collected details of ELT, including ELT duration and adverse events potentially related to ELT administration (CNS depression, headaches, light-headedness, dizziness, arrhythmias, fatigue, nausea, local venous irritation or flushing requiring premature cessation of ELT). Data were censored on 1 November 2011.
Table 1. Patient, CVC and bloodstream infection characteristics of patients with CLABSI who received adjuvant 70% ELT
JAC
Ethanol-lock therapy for central venous catheter salvage
of these patients had their catheters removed after 2 days of ELT, one because the CVC was no longer clinically necessary for the patient’s nutrition and two because the CVC was not functioning well despite the absence of persistent CLABSI. The remaining five patients had sterilization of blood cultures and retained their CVCs for a median of 82 days.
Safety and adverse events
Discussion The use of 70% ELT for adjunctive therapy of CLABSI appeared to be well tolerated and potentially effective in a cohort comprised predominantly of cancer patients requiring long-term indwelling CVCs for chemotherapy and supportive care. Only five (11%) patients had persistent or recurrent bacteraemia triggering CVC removal after ELT: three patients had persistent bacteraemia with coagulase-negative Staphylococcus or B. cereus during the initial CLABSI episode, while two patients had evidence of recurrent S. maltophilia infection several weeks after the initial CLABSI episode. While 36% of CVCs were removed within 1 week of ELT initiation, mostly in patients whose CVCs were no longer clinically necessary, 28 of 45 (62%) patients retained their CVCs for a median of 71 additional CVC-days without recrudescent bloodstream infection. While this study is relatively small in size and retrospective in nature, with substantial heterogeneity in the length of bacteraemia prior to ELT, the duration of ELT exposure and each clinician’s threshold for CVC removal, it is the largest and most comprehensive assessment of the clinical safety and efficacy of ELT in adult CLABSI patients to date, with a relatively long duration of follow-up after ELT exposure. Our findings should be interpreted cautiously: prior to initiation of this ELT protocol, the majority of patients with CLABSI at our institution had prompt removal of their CVCs, so it was not possible to define a comparable control group where CVC salvage was attempted with systemic antimicrobial therapy alone, making it challenging to draw definitive conclusions about the efficacy and safety of exposure to adjunctive ELT. Also, due to the retrospective nature of this analysis, the assessment of adverse events associated with ELT depended on the quality of physician and nursing clinical documentation, which was variable. However, no patients in this cohort were reported to have any symptoms theoretically associated with ethanol toxicity, namely CNS depression, arrhythmias, fatigue, headaches, dizziness, nausea, lightheadedness, local venous irritation or flushing, that triggered discontinuation of ELT. Additionally, there were no documented reports of CVC malfunction or diminished integrity attributed to ELT. Ethanol is comparable or superior to antibiotic agents in sterilizing catheter-associated biofilms in vitro. Sherertz et al.14
Acknowledgements Results from this study were presented in part at the Forty-ninth Annual Meeting of the Infectious Diseases Society of America, Boston, MA, USA, 2011 (Abstract 670).
1667
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
There were no documented adverse events potentially associated with ELT in the 45 CLABSI patients. Two of the 23 patients treated with ELT for secondary bloodstream infection discontinued ELT therapy after 3 and 5 days, respectively, because of recurrent CVC lumen occlusion. No patients were reported to have experienced CNS depression, arrhythmias, fatigue, headaches, dizziness, nausea, light-headedness, local venous irritation or flushing, attributed clinically to ELT.
examined the efficacy of ethanol and various antibiotic agents (vancomycin, ciprofloxacin, minocycline and rifampicin) in sterilizing S. aureus biofilms incubated on silicone CVCs. At concentrations of ≥30%, ethanol was superior to all other agents tested, with 3.6 – 3.9 log units of killing at 2, 4 and 24 h.14 At concentrations of ≥35%, ethanol has been shown to reduce the metabolic activity of mature Candida albicans biofilms by .99%.15 Despite these in vitro studies demonstrating the effectiveness of ethanol in sterilizing biofilms, clinical data on the efficacy of ELT for CVC salvage are sparse and most analyses have included patients who did not clearly meet CLABSI criteria. In a retrospective analysis of 28 children with 39 discrete bloodstream infections, 16 of 24 (67%) patients treated with adjunctive ELT and only 7 of 15 (47%) treated with systemic antibiotics alone were free of recurrent bloodstream infection at 4 weeks.11 Another study of 70% ELT in 51 bloodstream infection episodes in 40 children found no recurrent bloodstream infection at 30 days in 45 of 51 (88%) episodes.10 Another study prospectively examined the effects of ELT in conjunction with systemic antibiotics in 19 paediatric and adult patients with bloodstream infection, predominantly due to Gram-negative pathogens. Of 17 patients who completed 5 days of ELT, all had sterile blood cultures 6 days after completion of ELT and 12 (71%) retained their CVCs for .14 days without recrudescent bacteraemia.12 One patient in our study had persistent B. cereus CLABSI and two patients developed late recrudescent S. maltophilia infections associated with their salvaged catheters despite appropriate antimicrobial therapy and ≥5 days of adjunctive ELT. B. cereus and S. maltophilia are known to form highly tenacious biofilms in vitro that may be refractory to sterilization by even relatively high concentrations of ethanol.16,17 CLABSI due to these organisms should probably not be considered for 70% ELT. It is difficult to assess and capture all potential adverse events associated with ELT in a retrospective analysis. The amount of ethanol that may reach the systemic circulation with our ELT protocol is miniscule, as it is mostly aspirated after the dwell period, and generally well-tolerated by our study population. Whenever possible, the ethanol-lock solution instilled in the CVC should be aspirated and not flushed into the systemic circulation. Although unlikely, clinicians should monitor patients receiving ELT closely for adverse effects that may be associated with ELT, including CNS depression, cardiac arrhythmias, excessive fatigue, prolonged headaches, dizziness, severe nausea, light-headedness, local venous irritation or flushing. The development of these or other symptoms potentially attributable to ELT should warrant reconsideration of ELT therapy for CVC salvage. The removal and replacement of long-term CVCs is burdensome and costly. Further controlled studies into the effects of adjunctive ELT, an inexpensive, well-tolerated and potentially effective method for CVC salvage in CLABSI, are warranted.
Kubiak et al.
Funding The work was carried out in part with support from the National Institutes of Health (AI097225 to S. K.).
Transparency declarations None to declare.
Supplementary data Our institutional ELT protocol is available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).
1 CDC. Vital signs: central line-associated blood stream infections— United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep 2011; 60: 243–8. 2 Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clinic Proc 2006; 81: 1159–71. 3 Mermel LA, Allon M, Bouza E et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49: 1– 45.
8 Crnich CJ, Halfmann JA, Crone WC et al. The effects of prolonged ethanol exposure on the mechanical properties of polyurethane and silicone catheters used for intravascular access. Infect Control Hosp Epidemiol 2005; 26: 708–14. 9 Oliveira C, Nasr A, Brindle M et al. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012; 129: 318– 29. 10 Onland W, Shin CE, Fustar S et al. Ethanol-lock technique for persistent bacteremia of long-term intravascular devices in pediatric patients. Arch Pediatr Adolesc Med 2006; 160: 1049– 53. 11 Dannenberg C, Bierbach U, Rothe A et al. Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheter. J Pediatr Hematol Oncol 2003; 25: 616– 21. 12 Broom J, Woods M, Allworth A et al. Ethanol lock therapy to treat tunnelled central venous catheter-associated blood stream infections: results from a prospective trial. Scand J Infect Dis 2008; 40: 399– 406. 13 Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008; 36: 309–32. 14 Sherertz RJ, Boger MS, Collins CA et al. Comparative in vitro efficacies of various catheter lock solutions. Antimicrob Agents Chemother 2006; 50: 1865– 8. 15 Rane HS, Bernardo SM, Walraven CJ et al. In vitro analyses of ethanol activity against Candida albicans biofilms. Antimicrob Agents Chemother 2012; 56: 4487– 9.
4 Yahav D, Rozen-Zvi B, Gafter-Gvili A et al. Antimicrobial lock solutions for the prevention of infections associated with intravascular catheters in patients undergoing hemodialysis: systematic review and meta-analysis of randomized, controlled trials. Clin Infect Dis 2008; 47: 83– 93.
16 Karunakaran E, Biggs CA. Mechanisms of Bacillus cereus biofilm formation: an investigation of the physicochemical characteristics of cell surfaces and extracellular proteins. Appl Microbiol Biotechnol 2011; 89: 1161– 75.
5 Davies D. Understanding biofilm resistance to antibacterial agents. Nat Rev Drug Discov 2003; 2: 114– 22.
17 Passerini de Rossi B, Feldman L, Pineda MS et al. Comparative in vitro efficacies of ethanol-, EDTA- and levofloxacin-based catheter lock solutions on eradication of Stenotrophomonas maltophilia biofilms. J Med Microbiol 2012; 61: 1248 –53.
6 Maiefski M, Rupp ME, Hermsen ED. Ethanol lock technique: review of the literature. Infect Control Hosp Epidemiol 2009; 30: 1096– 108.
1668
Downloaded from http://jac.oxfordjournals.org/ at Gebze Yük.Tek.Ens. on May 16, 2014
References
7 Peters BM, Ward RM, Rane HS et al. Efficacy of ethanol against Candida albicans and Staphylococcus aureus polymicrobial biofilms. Antimicrob Agents Chemother 2013; 57: 74– 82.
