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Tunneled catheters' outcome optimization among diabetics on dialysis through antibiotic-lock placement

2006; Elsevier BV; Volume: 70; Issue: 9 Linguagem: Inglês

10.1038/sj.ki.5001776

1523-1755

Anil Kumar Saxena, B.R. Panhotra, D.S. Sundaram, AbdulAziz Al-hafiz, Tarek Naguib, C. Venkateshappa, Bassam A. Abu‐Oun, Sultana Monira Hussain, Abdullah M Al Ghamdi,

Antibiotics Pharmacokinetics and Efficacy

Efficacy and safety of antibiotic 'locks', in prevention of thrombotic and infectious complication-related morbidity and mortality, among diabetics dialyzed through tunneled-cuffed catheters (TCCs) has not been effectively investigated. This trial was designed to investigate the outcome of TCCs (n=109), inserted among 96 diabetic end-stage renal disease patients (March 2002–February 2003), by comparing the catheter thrombosis, catheter-related bloodstream infections (CRBSI), catheter survival, and mortality rates, between the cohorts of 49 patients who had TCCs (n=51) 'locked' with cefotaxime/heparin (group I) and 47 patients with TCCs (n=58) filled with standard heparin (group II). Thrombosis was defined as the inability to use catheter at a blood flow of 200 ml/min despite intraluminal thrombolysis. Primary end points were catheter thrombosis and CRBSI; elective catheter removal and CRBSI-related death led to sensor of TCCs follow-up. Patients with intraluminal cefotaxime/heparin lock, on cumulative survival analysis, showed a superior thrombosis-free (86.3 vs 63.8%, P=0.023, log rank), infection-free (72.9 vs 27.1%, P=0.004, log rank), and thrombosis- and infection-free TCC survival (78.4 vs 37.9%, P=0.001, log rank) at 365 days, besides having significantly lower incidence of CRBSI (1.56 vs 3.68 episodes/1000 catheter days, P<0.0001) and CRBSI-related mortality (9.8 vs 23.4%, P=0.015), compared with the heparin-alone group. Deployment of cefotaxime–heparin 'lock' enhances catheter survival; reduces thrombotic and infectious complications and ensuing mortality, among diabetics on dialysis. However, further studies are needed to define the long-term implications of antibiotic locks in terms of the risk of emergence of antimicrobial resistance. Efficacy and safety of antibiotic 'locks', in prevention of thrombotic and infectious complication-related morbidity and mortality, among diabetics dialyzed through tunneled-cuffed catheters (TCCs) has not been effectively investigated. This trial was designed to investigate the outcome of TCCs (n=109), inserted among 96 diabetic end-stage renal disease patients (March 2002–February 2003), by comparing the catheter thrombosis, catheter-related bloodstream infections (CRBSI), catheter survival, and mortality rates, between the cohorts of 49 patients who had TCCs (n=51) 'locked' with cefotaxime/heparin (group I) and 47 patients with TCCs (n=58) filled with standard heparin (group II). Thrombosis was defined as the inability to use catheter at a blood flow of 200 ml/min despite intraluminal thrombolysis. Primary end points were catheter thrombosis and CRBSI; elective catheter removal and CRBSI-related death led to sensor of TCCs follow-up. Patients with intraluminal cefotaxime/heparin lock, on cumulative survival analysis, showed a superior thrombosis-free (86.3 vs 63.8%, P=0.023, log rank), infection-free (72.9 vs 27.1%, P=0.004, log rank), and thrombosis- and infection-free TCC survival (78.4 vs 37.9%, P=0.001, log rank) at 365 days, besides having significantly lower incidence of CRBSI (1.56 vs 3.68 episodes/1000 catheter days, P 65 years)31 (63.3)29 (61.2)0.885Comorbid conditions IHD9 (18.4)8 (17.0)0.854 CHF9 (18.4)10 (16.9)0.709 PVD10 (20.4)9 (19.1)0.946 CVA3 (6.4)4 (8.2)0.782Hematocrit (%, mean±s.d.)32.6±1.934.5±2.40.769Serum iron (μg/dl, mean±s.d.)76.4±8.279.4±7.60.735Serum ferritin (ng/ml, mean±s.d.)82.9±179263.4±1690.874Serum albumin (g/dl±s.d.)3.29±0.163.33±0.111.000HbA1C (%±s.d.)7.2±0.736.9±0.911.000Kt/V (mean±s.d.)1.25±0.231.31±0.191.000Type of TCCs (n (%)) SC15 (29.4)14 (24.1)0.623 IJC36 (70.6)45 (77.6)0.636CHF, congestive heart failure; CVA, cerebrovascular accidents; ESRD, end-stage renal disease; HbA1C, glycosylated hemoglobin; IHD, ischemic heart disease; IJC, internal jugular catheter; PVD, peripheral vascular disease; SC, subclavian catheter; s.d., standard deviation; TCCs, tunneled-cuffed catheters.Figures in parentheses indicate percentage. Open table in a new tab CHF, congestive heart failure; CVA, cerebrovascular accidents; ESRD, end-stage renal disease; HbA1C, glycosylated hemoglobin; IHD, ischemic heart disease; IJC, internal jugular catheter; PVD, peripheral vascular disease; SC, subclavian catheter; s.d., standard deviation; TCCs, tunneled-cuffed catheters. Figures in parentheses indicate percentage. Overall, 109 TCCs placed among 96 diabetic ESRD patients recorded 28 episodes of catheter thrombosis (25.7%), 107 episodes of CRBSI in 39 785 catheter days (2.68/1000 catheter days) and this amounts to a mean percent catheter survival at 365 days of 56.9% (62/109) and a CRBSI-related mortality of 16.7% (16/96) during the study period. Patients with cefotaxime/heparin lock (group I) had higher thrombosis-free (86.3 vs 63.8%, log rank, P=0.023), infection-free (72.9 vs 27.1%, log rank, P=0.004), and thrombosis- and infection-free TCC survival (78.4 vs 37.9%, log rank, P=0.001) at 365 days, besides having significantly lower CRBSI rate (1.56 vs 3.68 episodes/1000 catheter days, P<0.0001) and CRBSI-related mortality (9.8 vs 23.4%, P=0.015), compared with heparin-alone (group II). No statistically significant survival advantage for either IJC or SC, in any of the two groups, was observed during the study period (Tables 2 and 3, Figures 1, 2 and 3).Table 2Catheter events in diabetic ESRD patients in group-I (cefotaxime/heparin 'locked) and group-II (heparin-alone)Group IGroup IICatheter events'Locked' with cefotaxime/heparin (TCCS, n=51)Heparin alone (TCCs, n=58)RRR (%)OR95% CIP-valueDuration of catheterization (in catheter days)18 61521 170Catheter thrombosis (n (%))7 (13.7)21 (36.2)62.23.4551.639–7.368<0.001CRBSI episodes (n)2978—CRBSI/1000 catheter days1.563.6857.68.6804.373–17.388<0.0001Exit site infections (n/total (%))9/51 (17.6)9/58 (15.5)—1.1900.389–3.6440.937TCC survival at 365 days (n/total (%))40/51 (78.4)22/58 (37.9)—4.5802.444–8.626<0.0001CRBSI-associated mortality (n/total (%))5/49 (9.8)11/47 (23.4)58.22.8421.206–6.8240.01595% CI, 95% confidence interval; CRBSI, catheter-related bloodstream infection; ESRD, end-stage renal disease; OR, odds ratio; RRR, relative risk reduction; TCCs, tunneled-cuffed catheters.Figures in parentheses indicate percentage. Open table in a new tab Table 3Bacterial flora isolated from the diabetic ESRD patients with CRBSIEpisodes of CRBSIGroup IGroup IIBacterial flora isolated'Locked' with cefotaxime/heparin (TCCs, n=51)Heparin alone (TCCs, n=58)Gram-positive bacteria (n, total, %)19/107 (17.8)32/107 (29.9) Staphylococcus epidermidis713 Staphylococcus aureus1219Gram-negative bacteria (n, total, %)10/107 (9.3)46/107 (42.9) Escherichia coli39 Klebsiella pneumoniae39 Pseudomonas aeruginosa211 Acenetobactor species17 Enterococcus faecalis17 Serratia marcesens03Total29/107 (27.1)78/107 (72.8)CRBSI, catheter-related bloodstream infection; ESRD, end-stage renal disease; TCCs, tunneled-cuffed catheters.Figures in parentheses indicate percentage. Open table in a new tab Figure 2Kaplan–Meier cumulative survival curves demonstrating the probability of infection-free survival of TCCs (IJC and SC) group I (diabetic ESRD patients with cefotaxime–heparin 'lock') and group II (with heparin alone) on long-term HD.View Large Image Figure ViewerDownload (PPT)Figure 3Kaplan–Meier cumulative survival curves demonstrating the probability of thrombosis and infection-free survival of TCCs (IJC and SC) group I (diabetic ESRD patients with cefotaxime–heparin 'lock') and group II (with heparin-alone) on long-term HD.View Large Image Figure ViewerDownload (PPT) 95% CI, 95% confidence interval; CRBSI, catheter-related bloodstream infection; ESRD, end-stage renal disease; OR, odds ratio; RRR, relative risk reduction; TCCs, tunneled-cuffed catheters. Figures in parentheses indicate percentage. CRBSI, catheter-related bloodstream infection; ESRD, end-stage renal disease; TCCs, tunneled-cuffed catheters. Figures in parentheses indicate percentage. As catheter surface represents the real battlefield between the bacteria and host defense mechanisms, the common objective with the use of an antimicrobial – anticoagulant 'lock' had been to create an intraluminal microenvironment intimidating to invading microorganisms and to prevent biofilm formation that facilitates bacterial multiplication, platelet adhesion, coagulation activation, and, consequently, thrombogenesis.4.Raad I.I. Luna M. Khalil S.M. et al.The relationship between the thrombotic and infectious complications of central venous catheters.JAMA. 1994; 13: 1014-1016Crossref Scopus (421) Google Scholar,12.Mittleman M.W. Pelak M. Shah C. Costerton J.W. Eradication of microbial biofilms with an antimicrobial catheter-lock solution [Abstract].in: General Meeting of American Society of MicrobiologyMay 2001Google Scholar The results from recent randomized controlled studies on the use of antimicrobials (e.g. citrate taurolidine and 30% trisodium citrate) and catheter-restricted filling with antibiotic lock solutions (aminoglycosides – gentamicin/amikacin and cephalosporins – cefazolin/cefotaxime), in combination of anticoagulants (heparin/citrate), are clearly supportive of a significant role that antibiotic – anticoagulant locks could play in reducing the incidence of catheter thrombosis and CRBSI and these locks, thus, can enhance the infection- and/or thrombosis-free survival rates of TCCs.13.Saxena A.K. Panhotra B.R. Prevention of catheter-related bloodstream infections: an appraisal of developments in designing an infection-resistant 'dream dialysis-catheter'.Nephrology. 2005; 10: 240-248Crossref PubMed Scopus (12) Google Scholar Jurewitsch14.Jurewitsch B. Taurolidine 2% as an antimicrobial lock for prevention of recurrent catheter-related bloodstream infections.J Parenter Enteral Nutr. 1998; 22: 242-244Crossref PubMed Scopus (67) Google Scholar reported the efficacy of 2% taurolidine as a catheter lock in the prevention of sepsis primarily in parenteral nutrition patients with the reduction in infection rate from 8.5 to 0.5 episodes/1000 catheter days. Later, Sodermann15.Sodermann K. Polaschegg H.D. Feldmer B. Two years' experience with Dialock and CLS (a new antimicrobial lock solution).Blood Purif. 2001; 19: 251-254Crossref PubMed Scopus (56) Google Scholar evaluated 1.35% taurolidine and 4% sodium citrate combination (Neutrolin™, Biolink, Norwell, MA, USA) on 71 long-term HD patients with TCCs, treated for an average period of 16 months. Of these patients 64% had no catheter-related infections, only 11% had CRBSI at the rate of 0.3 episodes/1000 catheter days, which was significantly lower than in historical controls. Recently, Betjes and Van Agteren,16.Betjes M.G. Van Agteren M. Prevention of dialysis access-related sepsis with citrate-taurolidine containing lock solution.Nephrol Dial Transplant. 2004; 19: 1546-1551Crossref PubMed Scopus (187) Google Scholar in a single-center open-label clinical trial on 76 TCCs placed among 58 patients, reported four episodes of CRBSI in heparin group as opposed to none in patients with catheters locked with Neutrolin (P<0.05). Following encouraging preliminary reports by Ash et al.17.Ash S.R. Mankus R.A. Sutton J.M. et al.Concentrated sodium citrate (23%) for catheter lock.Hemodial Int. 2000; 4: 22-31Google Scholar on the use of high concentration of trisodium citrate (23% TSC), a non-antibiotic antimicrobial with local anticoagulation properties) as catheter– locking solution to prevent CRBSI, Weijmer et al.,18.Weijmer M.C. van den Dorpel M.A. Van de Ven P.J. CITRATE Study Group et al.Randomized, clinical trial comparison of trisodium citrate 30% and heparin as catheter-locking solution in hemodialysis patients.J Am Soc Nephrol. 2005; 16: 2769-2777Crossref PubMed Scopus (243) Google Scholar in their multicenter, randomized trial also observed enhanced overall patency (P=0.005) and reduced CRBSI rates (87%, P 10%) was thought to be unsafe as TSC provides local anticoagulation by binding to Ca2+; even small amounts of citrate entering the right atrium of heart could cause life-threatening depression of ionic Ca2+ levels in the cardiac muscle leading to serious pacemaker dysfunction and fatal cardiac arrhythmias. In vivo experiments suggest that the degradation of cardiac function could occur even at lower concentrations if TSC spills out of the catheter.15.Sodermann K. Polaschegg H.D. Feldmer B. Two years' experience with Dialock and CLS (a new antimicrobial lock solution).Blood Purif. 2001; 19: 251-254Crossref PubMed Scopus (56) Google Scholar For this reason, Food and Drug Administration issued a warning against the use of TSC in concentrations above 4%.18.Weijmer M.C. van den Dorpel M.A. Van de Ven P.J. CITRATE Study Group et al.Randomized, clinical trial comparison of trisodium citrate 30% and heparin as catheter-locking solution in hemodialysis patients.J Am Soc Nephrol. 2005; 16: 2769-2777Crossref PubMed Scopus (243) Google Scholar,19.FDA issues warning on Tricitrasol® Dialysis Catheter Anticoagulant. FDA Talk Paper. T00-16. 14-4-2000Google Scholar Dogra et al.7.Dogra G.K. Herson H. Hutchison B. et al.Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling of gentamicin and citrate: a randomized control study.J Am Soc Nephrol. 2002; 13: 2133-2139Crossref PubMed Scopus (234) Google Scholar demonstrated a clear decline in the incidence of CRBSI (0.03 vs 0.42/100 catheter days, P=0.003) and substantial increase in mean infection-free catheter survival rate (282 vs 181 days, P=0.002) in the gentamicin/TSC (40 mg/ml and 3.13% TSC; ratio 2:1) group compared to that of heparin group. However, predialysis gentamicin levels were found to be significantly higher in patients randomized to gentamicin group (2.8 mg/l vs <0.2 mg/l, P=0.008). Authors cautioned to establish the safety of 'locked' dose of gentamicin for ototoxicity before the adoption of the technique.7.Dogra G.K. Herson H. Hutchison B. et al.Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling of gentamicin and citrate: a randomized control study.J Am Soc Nephrol. 2002; 13: 2133-2139Crossref PubMed Scopus (234) Google Scholar McIntyre et al.8.McIntyre C.W. Hulme L.J. Taal M. Fluck R.J. Locking of tunneled hemodialysis catheters with gentamicin and heparin.Kidney Int. 2004; 66: 801-805Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar recently reported symptoms compatible with aminoglycoside ototoxicity in about 10% of patients when TCCs had been locked with high dosages of gentamicin (40 mg/ml) for long periods. Earlier, Saxena et al.20.Saxena A.K. Panhotra B.R. Naguib M. Sudden irreversible sensory-neural hearing loss in a diabetic on hemodialysis, receiving amikacin as antibiotic-heparin lock.Pharmacotherapy. 2002; 22: 105-108Crossref PubMed Scopus (39) Google Scholar in a case report noted manifestation of sudden irreversible ototoxicity in a diabetic ESRD patient having TCC 'locked' with amikacin, to prevent recurrent episodes of CRBSI.21.Saxena A.K. Characteristics of ototoxicity of aminoglycosides 'locked' to prevent hemodialysis catheter-related infections.Hemodial Int. 2006; 10: 94Crossref PubMed Scopus (2) Google Scholar Thus, the efficacy and safety of currently available antimicrobial/antibiotic/lock protocols using sodium citrate and/or aminoglycosides for the TCCs placed among diabetic ESRD patients, who often have underlying cardiac and/or hearing disability, clearly become questionable. The preference of cefotaxime plus heparin over other antimicrobials/anticoagulant combinations, in the present study on the diabetic ESRD patients, was primarily based on the lack of cardio/ototoxic potentials of the basic components of this TCCs 'locking' solution.9.Saxena A.K. Panhotra B.R. Locking hemodialysis-catheters with cefotaxime instead of gentamicin to avoid ototoxicity.Kidney Int. 2005; 67: 2505-2506Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Even though cefotaxime was not used earlier in catheter locks, its excellent clinical efficacy and microbiological safety profile has been demonstrated in the management of infections in critically ill patients.22.Francisco I.L. Mercedes P. Pedro O. et al.Cefotaxime, twenty years later: observational study in critically ill patients.Enferm Infecc Microbiol Clin. 2001; 19: 211-218Crossref PubMed Scopus (7) Google Scholar In the present study, the overall catheter thrombosis, CRBSI incidence, CRBSI-related mortality, were much lower than the published reports, whereas the percent catheter-survival rates were comparable to those reported elsewhere.2.Miles A.M. Friedman E.A. Dialytic therapy for diabetic patients with terminal renal failure.Curr Opin Nephrol Hypertens. 1993; 6: 869-875Google Scholar, 7.Dogra G.K. Herson H. Hutchison B. et al.Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling of gentamicin and citrate: a randomized control study.J Am Soc Nephrol. 2002; 13: 2133-2139Crossref PubMed Scopus (234) Google Scholar, 8.McIntyre C.W. Hulme L.J. Taal M. Fluck R.J. Locking of tunneled hemodialysis catheters with gentamicin and heparin.Kidney Int. 2004; 66: 801-805Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 9.Saxena A.K. Panhotra B.R. Locking hemodialysis-catheters with cefotaxime instead of gentamicin to avoid ototoxicity.Kidney Int. 2005; 67: 2505-2506Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 10.Jaar B.G. Hermann J.A. Furth S.L. et al.Septicemia in diabetic hemodialysis patients: comparison of incidence risk, factors, and mortality with nondiabetic hemodialysis patients.Am J Kidney Dis. 2000; 35: 282-292Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 11.Alain G.B. Sharon S. Frederick L.B. Diabetes and risk of infection-related mortality in the US.Diabetes Care. 2001; 24: 1044-1049Crossref PubMed Scopus (173) Google Scholar, 15.Sodermann K. Polaschegg H.D. Feldmer B. Two years' experience with Dialock and CLS (a new antimicrobial lock solution).Blood Purif. 2001; 19: 251-254Crossref PubMed Scopus (56) Google Scholar, 16.Betjes M.G. Van Agteren M. Prevention of dialysis access-related sepsis with citrate-taurolidine containing lock solution.Nephrol Dial Transplant. 2004; 19: 1546-1551Crossref PubMed Scopus (187) Google Scholar, 17.Ash S.R. Mankus R.A. Sutton J.M. et al.Concentrated sodium citrate (23%) for catheter lock.Hemodial Int. 2000; 4: 22-31Google Scholar, 18.Weijmer M.C. van den Dorpel M.A. Van de Ven P.J. CITRATE Study Group et al.Randomized, clinical trial comparison of trisodium citrate 30% and heparin as catheter-locking solution in hemodialysis patients.J Am Soc Nephrol. 2005; 16: 2769-2777Crossref PubMed Scopus (243) Google Scholar, 23.Pervez A. Ahmad M. Ram S. et al.Antibiotic lock technique for prevention of cuffed tunnel catheter associated with bacteremia.J Vasc Access. 2002; 3: 108-113PubMed Google Scholar, 24.Saad T.F. Bacteremia associated with tunnelled-cuffed hemodialysis catheters.Am J Kidney Dis. 1999; 34: 1114-1124Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 25.Allon M. Prophylaxis against dialysis catheter-related bacteremia with a novel antimicrobial lock solution.Clin Infect Dis. 2003; 36: 1539-1544Crossref PubMed Scopus (133) Google Scholar Additionally, the diabetic ESRD patients in cefotaxime/heparin group recorded significantly higher thrombosis-free (log rank, P=0.023), infection-free (log rank, P=0.004), and thrombosis- and infection-free TCC survival (log rank, P=0.001) at 365 days, besides having significantly lower CRBSI rate (1.56 vs 3.68 episodes/1000 catheter days, P<0.0001) and CRBSI-related mortality (9.8 vs 23.4%, P=0.015), compared with heparin-alone group. There is no experience of any adverse reaction to the components of lock solution. The CRBSI episodes were mainly caused by Gram-positive cocci – Staphylococcus aureus, S. epidermidis and Gram-negative bacilli in both groups. Cefotaxime appeared significantly more effective against Gram-negative bacilli than the Gram-positive organisms. Of over all CRBSI reduction rate of 59.5%; 78.4% reduction was observed in the infections owing to Gram-negative bacilli against that of 40.5% in Gram-positive organisms (odds ratio=5.12, 95% confidence interval, 2.635–9.948; P<0.0001), in cefotaxime group compared with heparin group. No resistance to cefotaxime was observed among the bacterial strains isolated from CRBSI episodes that occurred during 1 year of study period. This was perhaps attributable to the reasonably higher intraluminal concentrations of cefotaxime and heparin in the 'lock' that was applied since the time of catheter placement, permits little chance for bacteria to enter, colonize, and form biofilm in the catheter lumen while the 'lock' solution is kept locally restricted by making even volumes of locking solution pass to the catheter lumen to prevent the systemic spill-out of the antibiotic. Nonetheless, there remains a concern of long-term development of antimicrobial resistance with the use of antibiotic in catheter locks. Thus, catheter-restricted interdialytic filling of cefotaxime/heparin seems to be a safe and effective approach towards prevention of thrombotic and infectious complications and related mortality with enhancement of TCC lifespan, among diabetics on dialysis who are also vulnerable to comorbidities related to heart and hearing. However, long-term studies would be necessary to address the issue of potential emergence of resistant bacterial infections before antibiotic locks could clearly become the part of standard care for diabetics on dialysis.