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Prevention of uncuffed hemodialysis catheter-related bacteremia using an antibiotic lock technique: A prospective, randomized clinical trial

2005; Elsevier BV; Volume: 69; Issue: 1 Linguagem: Inglês

10.1038/sj.ki.5000012

1523-1755

Sung‐Han Kim, Kyuyung Song, Jai Won Chang, S.B. Kim, Su Ah Sung, Sung-Yoon Jo, W.Y. Cho, H.K. Kim,

Vascular Procedures and Complications

As a result of the high rate of infection, the NKF-K/DOQI guidelines recommended that an uncuffed catheter (UC) should not be used for longer than three weeks. However, the findings of the Dialysis Outcomes and Practice Patterns Study recognized that 48% of new hemodialysis patients in the US and 75% in Europe used UC for temporary access during arteriovenous fistula or graft maturation. The antibiotic lock technique (ALT) has been recommended to prevent catheter-related bacteremia (CRB). Here, we prospectively evaluated the efficacy of catheter-restricted filling using an antibiotic lock solution in preventing CRB. A total of 120 new hemodialysis patients requiring a temporary catheter while waiting for placement and maturation of an arteriovenous fistula or graft were enrolled in this study. Patients with a UC were randomly assigned to receive either an antibiotic–heparin lock solution (antibiotic group: cefazolin 10 mg/ml, gentamicin 5 mg/ml, heparin 1000 U/ml) or a heparin lock solution (no-antibiotic group: heparin 1000 U/ml) as a catheter lock solution during the interdialytic period. The end point of the trial was CRB. CRB developed in seven (11.7%) patients in the no-antibiotic group (Staphylococcus aureus, two; Staphylococcus epidermidis, five) whereas only one patient in the antibiotic group had S. aureus bacteremia. CRB rates per 1000 catheter-days were 0.44 in the antibiotic group versus 3.12 in the no-antibiotic group (P=0.031). Kaplan–Meier analysis also showed that mean CRB-free catheter survival of 59 days (95% CI, 58–61 days) in the antibiotic group was greater than that in the no-antibiotic group (55 days; 95% CI, 50–59 days). The results suggest that ALT may be a beneficial means of reducing the CRB rate in hemodialysis patients with UC. As a result of the high rate of infection, the NKF-K/DOQI guidelines recommended that an uncuffed catheter (UC) should not be used for longer than three weeks. However, the findings of the Dialysis Outcomes and Practice Patterns Study recognized that 48% of new hemodialysis patients in the US and 75% in Europe used UC for temporary access during arteriovenous fistula or graft maturation. The antibiotic lock technique (ALT) has been recommended to prevent catheter-related bacteremia (CRB). Here, we prospectively evaluated the efficacy of catheter-restricted filling using an antibiotic lock solution in preventing CRB. A total of 120 new hemodialysis patients requiring a temporary catheter while waiting for placement and maturation of an arteriovenous fistula or graft were enrolled in this study. Patients with a UC were randomly assigned to receive either an antibiotic–heparin lock solution (antibiotic group: cefazolin 10 mg/ml, gentamicin 5 mg/ml, heparin 1000 U/ml) or a heparin lock solution (no-antibiotic group: heparin 1000 U/ml) as a catheter lock solution during the interdialytic period. The end point of the trial was CRB. CRB developed in seven (11.7%) patients in the no-antibiotic group (Staphylococcus aureus, two; Staphylococcus epidermidis, five) whereas only one patient in the antibiotic group had S. aureus bacteremia. CRB rates per 1000 catheter-days were 0.44 in the antibiotic group versus 3.12 in the no-antibiotic group (P=0.031). Kaplan–Meier analysis also showed that mean CRB-free catheter survival of 59 days (95% CI, 58–61 days) in the antibiotic group was greater than that in the no-antibiotic group (55 days; 95% CI, 50–59 days). The results suggest that ALT may be a beneficial means of reducing the CRB rate in hemodialysis patients with UC. Of the various complications related to hemodialysis catheters, catheter-related infection has a significant negative impact. It increases patient morbidity and mortality, and medical costs. In particular, catheter-related bacteremia (CRB) is a severe complication that requires hospitalization, systemic antibiotic therapy, and removal, re-insertion, or replacement of catheters.1.Saad T.F. Central venous dialysis catheters: catheter-associated infection.Semin Dial. 2001; 14: 446-451Google Scholar Although the incidence of CRB is found to differ according to the investigator, the incidence of CRB was found to be higher for an uncuffed catheter (UC) at 3.8–12.8 events per 1000 catheter-days2.Kairaitis L.K. Gottlieb T. Outcome and complications of temporary haemodialysis catheters.Nephrol Dial Transplant. 1999; 14: 1710-1714Google Scholar, 3.Oliver M.J. Callery S.M. Thorpe K.E. et al.Risk of bacteremia from temporary hemodialysis catheters by site of insertion and duration of use: a prospective study.Kidney Int. 2000; 58: 2543-2545Google Scholar, 4.Weijmer M.C. Vervloet M.G. ter Wee P.M. Compared to tunnelled cuffed haemodialysis catheters, temporary untunnelled catheters are associated with more complications already within 2 weeks of use.Nephrol Dial Transplant. 2004; 19: 670-677Google Scholar than a tunnelled cuffed catheter (TCC) at 0.5–5.5 events per 1000 catheter-days.5.Schwab S.J. Buller G.L. McCann R.L. et al.Prospective evaluation of a dacron cuffed hemodialysis catheter for prolonged use.Am J Kidney Dis. 1988; 11: 166-169Google Scholar, 6.Moss A.H. Vasilakis C. Holley J.L. et al.Use of a silicone dual-lumen catheter with a dacron cuff as a long term vascular access for hemodialysis patients.Am J Kidney Dis. 1990; 16: 211-215Google Scholar, 7.Dryden M.S. Samson A. Ludlam H.A. et al.Infective complications associated with the use of Quinton 'Permcath' for long-term central vascular access in hemodialysis.J Hosp Infect. 1991; 19: 257-262Google Scholar, 8.Marr K.A. Sexton D.J. Conlon P.J. et al.Catheter-related bacteremia and outcome of attempted catheter salvage in patients undergoing hemodialysis.Ann Intern Med. 1997; 127: 275-280Google Scholar, 9.Saad T.F. Bacteremia associated with tunneled, cuffed hemodialysis catheters.Am J Kidney Dis. 1999; 34: 1114-1124Google Scholar In terms of the incidence of CRB by site of catheter insertion, the incidence of bacteremia exceeded 10% One week after UC insertion into the femoral vein and after three weeks for the internal jugular vein.3.Oliver M.J. Callery S.M. Thorpe K.E. et al.Risk of bacteremia from temporary hemodialysis catheters by site of insertion and duration of use: a prospective study.Kidney Int. 2000; 58: 2543-2545Google Scholar Therefore, the NKF-K/DOQI guidelines recommended TCC as a temporary hemodialysis catheter during the arteriovenous fistula or graft maturation period.10.NKF-K/DOQI Clinical Practice Guidelines for Vascular Access The NKF Dialysis Outcomes Quality Initiative 'DOQI'.Am J Kidney Dis. 1997; 30: S150-S191Google Scholar, 11.NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: update 2000 The NKF Dialysis Outcomes Quality Initiative 'DOQI'.Am J Kidney Dis. 2001; 37: S137-S181Google Scholar However, TCC insertion is associated with disadvantages such as medical expense, post-catheter placement pain, the need for expert manpower, a fluoroscopic monitoring facility, and a protracted operation time. Thus, it is common practice to use a UC for three or more weeks despite the increased risk of infection.12.Pisoni R.L. Young E.W. Dykstra D.M. et al.Vascular access use in Europe and the United States: results from the DOPPS.Kidney Int. 2002; 61: 305-316Google Scholar A single Korean institutional study by Kim et al.13.Kim J.S. Lee E.Y. Kim M.H. et al.A study on the about timing of arteriovenous fistula for maintenance hemodialysis patients.Korean J Nephrol. 1999; 18: 959-964Google Scholar reported that 67% of new end-stage renal disease (ESRD) patients received catheter-based dialysis therapy and of them, 69% used a UC for more than 3 weeks. According to the Dialysis Outcomes and Practice Patterns Study (DOPPS), the percentage of patients with a UC among total hemodialysis catheter patients was 48% in the United States and 75% in Europe.12.Pisoni R.L. Young E.W. Dykstra D.M. et al.Vascular access use in Europe and the United States: results from the DOPPS.Kidney Int. 2002; 61: 305-316Google Scholar Vascular access for hemodialysis is easily provided by catheters, but the high risk of catheter-related infection has a significant adverse effect on the clinical course of ESRD patients. In an attempt to prevent infection, the antibiotic lock technique (ALT) was introduced to prevent intraluminal spread by microorganisms that can occur through the catheter hub. However, previous studies have focused on TCC only.1.Saad T.F. Central venous dialysis catheters: catheter-associated infection.Semin Dial. 2001; 14: 446-451Google Scholar, 14.Berrington A. Gould F.K. Use of antibiotic locks to treat colonized central venous catheters.J Antimicrob Chemother. 2001; 48: 597-603Google Scholar In this study, we evaluated the ability of ALT to reduce UC infection rates, because UCs are frequently used as a means of temporary vascular access despite their well-known high rate of infection. The clinical and biochemical characteristics of patients in the antibiotic group and the no-antibiotic group are shown in Table 1 . No statistically significant differences were found between the two groups in terms of age, sex, underlying diabetic nephropathy, hemoglobin, serum ferritin, serum albumin, and duration of catheterization.Table 1Characteristics of patientsCharacteristicsAntibiotic groupNo-antibiotic groupP-valueAge (years)53.68±15.20156.18±15.684NSSex (male) (n (%))33 (55.0)28 (46.7)NSDM (n (%))30 (50.0)33 (55.0)NSHemoglobin (g/dl)8.80±1.149.03±1.07NSFerritin (μg/l)392.1±48.2403.8±58.5NSAlbumin (g/dl)3.47±0.663.35±0.58NSDuration of catheterization Mean (days)37.68±6.4437.37±5.59NS Median (range) (days)36.50 (28–60)35.50 (28–61)NSThe % of catheter use >30 days88.396.7NSData are means±s.d.DM: diabetes mellitus; NS: not statistically significant. Open table in a new tab Data are means±s.d. DM: diabetes mellitus; NS: not statistically significant. The incidence of CRB was significantly lower in the antibiotic group (P=0.031); CRB rates per 1000 catheter-days were 0.44 events in the antibiotic group versus 3.12 events in the no-antibiotic group. CRB developed in seven patients (11.7%) in the no-antibiotic group but in only one patient (1.7%) in the antibiotic group. All causative organisms were Gram-positive: one case of Staphylococcus aureus in the antibiotic group, two cases of S. aureus, and five cases of Staphylococcus epidermidis in the no-antibiotic group, and all Staphylococci were methicilin-sensitive strains (Tables 2 and 3 ).Table 2Incidence of CRBTotal (n=120)Antibiotic group (n=60)No-antibiotic group (n=60)P-valueNo. of patients (n, %)8 (6.7)1 (1.7)7 (11.7)CRB rates per 1000 catheter-days0.443.120.031Mean CRB-free catheter survival (days)59 (95% CI, 58–61)55 (95% CI, 50–59)CRB: catheter-related bacteremia; CI: confidence interval. Open table in a new tab Table 3CRB patientsPatientDays to CRBOrganismAntibiotic groupM/51DM35S. aureusNo-antibiotic groupF/31Non-DM36S. epidermidisF/51Non-DM34S. epidermidisM/48Non-DM28S. aureusF/43DM31S. epidermidisM/43Non-DM42S. epidermidisF/56DM44S. epidermidisM/35Non-DM37S. aureusCRB: catheter-related bacteremia; M: male; F: female; DM: diabetes mellitus.All Staphylococci were methicilin-sensitive strains. Open table in a new tab CRB: catheter-related bacteremia; CI: confidence interval. CRB: catheter-related bacteremia; M: male; F: female; DM: diabetes mellitus. All Staphylococci were methicilin-sensitive strains. Cumulative infection-free catheter survival was significantly higher in the antibiotic group than in the no-antibiotic group (log-rank statistic, 4.66; P=0.031) (Figure 1 ). Given the current situation whereby UCs are commonly used as a means of temporary vascular access until arteriovenous fistula or graft maturation, we undertook this study to determine whether the use of ALT for hemodialysis patients with UC could provide an effective low-cost alternative means of reducing the CRB rate. Before introducing ALT in the dialysis unit, only 12 patients (4.8%) had started dialysis with arteriovenous fistula or graft, or had received a TCC insertion for temporary or permanent vascular access. Thus, most of the new hemodialysis patients in our dialysis unit used a UC and were thus exposed to a greater risk of infection. In the present study, the control group (no-antibiotic group) showed an 11.7% incidence of CRB (3.12 events per 1000 catheter-days), which was similar to the incidences of CRB in previous UC studies. However, the application of ALT resulted in a considerable reduction in CRB rate (0.44 events per 1000 catheter-days). This result is consistent with that of a comparative study by Dogra et al.,15.Dogra G.K. Herson H. Hutchison B. et al.Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling with gentamicin and citrate: a randomized controlled study.J Am Soc Nephrol. 2002; 13: 2133-2139Google Scholar who showed the preventive effect of a gentamicin–citrate mixture on the incidence of CRB in patients with TCC, and also with that of a study by McIntyre et al.,16.McIntyre C.W. Hulme L.J. Taal M. et al.Locking of tunneled hemodialysis catheters with gentamicin and heparin.Kidney Int. 2004; 66: 801-805Google Scholar who compared the use of a gentamicin–heparin mixture with heparin only. Many investigators have selected gentamicin as an antibiotic for preventive purposes, but available data of gentamicin lock solutions are relatively limited, and cannot be easily compared because of the different concentrations of gentamicin and citrate used in various studies. Andris et al.17.Andris D.A. Krzywda E.A. Edmiston C.E. et al.Elimination of intraluminal colonization by antibiotic lock in silicone vascular catheters.Nutrition. 1998; 14: 427-432Google Scholar suggested the possibility of using various types of antibiotics in ALT in the total parenteral nutrition catheter model, but there have been no studies comparing the effect of various types of antibiotic on reducing CRB. Therefore, the optimal drug regimen and concentrations for ALT need to be defined.14.Berrington A. Gould F.K. Use of antibiotic locks to treat colonized central venous catheters.J Antimicrob Chemother. 2001; 48: 597-603Google Scholar Currently, vancomycin-resistant enterococcus has become a problem, especially in hemodialysis patients owing to the widespread use of vancomycin as empiric or first-line therapy,18.Tokars J.I. Vancomycin use and antimicrobial resistance in hemodialysis centers.Am J Kidney Dis. 1998; 32: 521-523Google Scholar but the single use of cefazolin or concurrent cefazolin–gentamicin administration is found to be the empiric antibiotic of choice in a dialysis unit with a low methicillin-resistant S. aureus infection rate.19.Fogel M.A. Nussbaum P.B. Feintzeig I.D. et al.Cefazolin in chronic hemodialysis patients: a safe, effective alternative to vancomycin.Am J Kidney Dis. 1998; 32: 401-409Google Scholar, 20.Marx M.A. Frye R.F. Matzke G.R. et al.Cefazolin as empiric therapy in hemodialysis-related infections: efficacy and blood concentrations.Am J Kidney Dis. 1998; 32: 410-414Google Scholar Based on these study results, we selected cefazoline as an antibiotic for ALT. In an in vitro hemodialysis catheter study by Vercaigne et al.,21.Vercaigne L.M. Zelenitsky S.A. Findlay I. et al.An in vitro evaluation of the antibiotic/heparin lock to sterilize central venous haemodialysis catheters.J Antimicrob Chemother. 2002; 49: 693-696Google Scholar it was found that a combination antibiotic–heparin lock had a higher sterilization effect on methicillin-resistant S. epidermidis than a single antibiotic–heparin lock. They also found that a vancomycin–gentamicin–heparin lock solution (VGH lock) and a cefazolin–gentamicin–heparin lock solution (CGH lock) showed similar bactericidal effects. Accordingly, in the present study, a combination antibiotic lock was adopted by combining cefazolin (empiric antibiotic to Gram-positive organisms) and gentamicin (empiric antibiotic to Gram-negative organisms). Citrate, which has been used as an anticoagulant in catheter lock solutions in ALT, has little antimicrobial effect at concentrations of 2% or lower, and has an antimicrobial effect at concentrations of 30% or higher owing to hyperosmolality. However, it is known to show an antimicrobial effect in its mid-concentration (2.2–15%) range to Gram-positive microorganisms. Thus, there is a possibility that citrate has an additive antimicrobial effect in ALT.22.Renvent S. Dahlen G. Snyder B. Clinical and microbiological effects of subgingival antimicrobial irrigation with citric acid as evaluated by an enzyme immunoassay and culture analysis.J Periodontol. 1997; 68: 346-352Google Scholar, 23.Ajjarapu S. Shelef L.A. Fate of pGFP-bearing Escherichia coli O157:H7 in ground beef at 2 and 10 degree C and effects of lactate, diacetate, and citrate.Appl Environ Microbiol. 1999; 65: 5394-5397Google Scholar But citrate is also known to induce cardiac dysfunction24.Quarello F. Forneris G. Prevention of hemodialysis catheter-related bloodstream infection using an antimicrobial lock.Blood Purif. 2002; 20: 87-92Google Scholar and is relatively expensive compared to heparin, which has been reported to be stable in an antibiotic–heparin mixture form for a prolonged period (72 h);21.Vercaigne L.M. Zelenitsky S.A. Findlay I. et al.An in vitro evaluation of the antibiotic/heparin lock to sterilize central venous haemodialysis catheters.J Antimicrob Chemother. 2002; 49: 693-696Google Scholar hence, we chose heparin as an anticoagulant. No catheter malfunction was found in the present study in relation to the application of ALT and this may be due to the relatively short-term use of less than two months. McIntyre et al.16.McIntyre C.W. Hulme L.J. Taal M. et al.Locking of tunneled hemodialysis catheters with gentamicin and heparin.Kidney Int. 2004; 66: 801-805Google Scholar also reported no difference in catheter functions between the ALT group and heparin groups. There was no experience of adverse reaction due to aminoglycoside ototoxicity or cephalosporin CNS toxicity in all patients of the ALT group. As no adverse events associated with ALT may be due to the short-term use of ALT, lower antibiotic concentrations, and small number of patients in our dialysis unit, further studies are needed in this area. This study has several limitations. Although there was no adverse reaction due to aminoglycoside ototoxicity or cephalosporin CNS toxicity, drug level monitoring to identify systemic exposure to antibiotics such as cefazolin and gentamicin was not carried out in this study. Cefazolin is known not to have adverse CNS effects when administered three times a week,20.Marx M.A. Frye R.F. Matzke G.R. et al.Cefazolin as empiric therapy in hemodialysis-related infections: efficacy and blood concentrations.Am J Kidney Dis. 1998; 32: 410-414Google Scholar and is not considered to cause a problem because antibiotics act in the lumen of catheters and, even in the case of leakage, antibiotics were present at low dose. In the case of gentamicin, about 10% of patients complained of symptoms compatible with aminoglycoside ototoxicity when TCC had been used for long periods at high dosages (ca. 40 mg/ml).15.Dogra G.K. Herson H. Hutchison B. et al.Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling with gentamicin and citrate: a randomized controlled study.J Am Soc Nephrol. 2002; 13: 2133-2139Google Scholar This warrants the study of the efficacy of lower gentamicin concentrations. Because plasma levels of both antibiotics were not measured and this study was conducted at a single medical center, these may limit the generalization of the results from this study, preventing CRB. Additional studies are needed to confirm the suitability of antibiotic mixture of this study protocol. Also, ALT was applied to patients using UCs for longer than 1 month in this study. Therefore, the data suggest that ALT is only needed when catheters are in place for a period longer than 1 month. This means a clear restriction for the usefulness of this approach. Additional studies are needed to evaluate the usefulness of short-term application of ALT to UCs used for less than 1 month. ALT in patients using UC may be a low-cost means of reducing the incidence of CRB in patients in whom it is practically difficult to place a TCC for temporary vascular access during arteriovenous fistula or graft maturation. But widespread use of ALT may not be ideal because of the selection for antibiotic-resistant organisms. A recent study comparing taurolidine lock with standard heparin lock reported effective reduction of CRB.25.Allon M. Prophylaxis against dialysis catheter-related bacteremia with a novel antimicrobial lock solution.Clin Infect Dis. 2003; 36: 1539-1544Google Scholar, 26.Betjes M.G. van Agteren M. Prevention of dialysis catheter-related sepsis with a citrate–taurolidine-containing lock solution.Nephrol Dial Transplant. 2004; 19: 1546-1551Google Scholar Taurolidine is not an antibiotic but has a broad range of antimicrobial activity, and bacterial resistance has not been observed.27.Torres-Viera C. Thauvin-Eliopoulos C. Souli M. et al.Activities of taurolidine in vitro and in experimental enterococcal endocarditis.Antimicrob Agents Chemother. 2000; 44: 1720-1724Google Scholar, 28.Shah C.B. Mittelman M.W. Costerton J.W. et al.Antimicrobial activity of a novel catheter lock solution.Antimicrob Agents Chemother. 2002; 46: 1674-1679Google Scholar Thus, taurolidine-containing catheter lock solution may be an alternative strategy for preventing emergence of antibiotic-resistant bacteria. This study suggests that ALT may be a beneficial means of reducing CRB in UC for temporary vascular access during arteriovenous fistula or graft maturation. Further studies are required to determine the optimal drug regimen and concentrations for ALT.