mini review
http://www.kidney-international.org & 2014 International Society of Nephrology
What is the evidence for intraluminal colonization of hemodialysis catheters? Leonard A. Mermel1 1
Division of Infectious Diseases, Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Hemodialysis catheter–related bloodstream infections are potentially devastating, leading to increased morbidity, mortality, and cost of care. Prospective studies published over the past 15 years shed light on the pathogenesis of these infections. The data suggest that the intraluminal microbial colonization of hemodialysis catheters often precedes bloodstream infection. This finding supports strategies aimed at preventing or eradicating intraluminal colonization. Kidney International (2014) 86, 28–33; doi:10.1038/ki.2013.527; published online 8 January 2014 KEYWORDS: catheter colonization; catheter infection; catheter-related bloodstream infection; catheter-related infection; hemodialysis catheter
Correspondence: Leonard Mermel, Division of Infectious Diseases, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903, USA. E-mail: [email protected] Received 2 August 2013; revised 13 September 2013; accepted 19 September 2013; published online 8 January 2014 28
During the initial stages of intravascular catheter colonization, a biofilm is formed that is made up of host proteins and microbes (Figure 1). Bacteria and fungi survive and proliferate within the biofilm, despite host immune defenses and therapeutic doses of antimicrobial agents.1–3 Catheter-related bloodstream infections (CRBSIs) most commonly emanate from microorganisms colonizing the catheter insertion site migrating distally along the extraluminal surface of the catheter into the bloodstream or from microorganisms that migrate intraluminally into the bloodstream from a colonized catheter hub, connector, or less often from microorganisms in contaminated infusate.4 Some investigators found that when hemodialysis catheters were routinely removed 1 month after insertion, all of the catheters had intraluminal surface biofilm and ‘ultrastructural colonization’ detected using scanning electron microscopy.5 Other investigators have identified bacteria within the biofilm on the luminal surface of hemodialysis catheters using scanning electron microscopy.6 On the other hand, another study found that the outer surface of hemodialysis catheters removed after 138±141 days in bacteremic patients had a thicker biofilm and more microbial colonization than the luminal catheter surface.7 In addition, thicker biofilm on hemodialysis catheters has been associated with positive blood cultures drawn through the catheter compared with those with negative blood cultures drawn through the catheter.8 Eventually, planktonic bacteria or fungi break off from the biofilm and seed the bloodstream, causing bacteremia or fungemia, which may lead to metastatic infection.9–11 Both intraluminal and extraluminal colonization of hemodialysis catheters are important sources of microbes leading to CRBSI. An intraluminal source may be especially important in those patients with tunneled, cuffed, long-term hemodialysis catheters. This mini review focuses on intraluminal colonization. In a seminal prospective study,12 13 patients undergoing hemodialysis through central venous catheters developed fever and rigors, 12 of whom had catheter colonization and positive percutaneously drawn blood cultures. Of these 13 patients, their infection emanated from the catheter insertion site, catheter lumen, or both sites in three, eight, and two patients, respectively, suggesting a predominant intraluminal source of infection. Studies of patients receiving hemodialysis Kidney International (2014) 86, 28–33
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LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
Double-lumen, cuffed hemodialysis catheter Catheter cuff
Adapters Microbes introduced into catheter lumen due to breach in aseptic technique Biofilm maturation
Bacteria or fungi introduced from catheter adaptor/hub Attach to hemodialysis catheter lumen
Attached cell monolayer
Detachment: planktonic bacteria or fungi, plasmids, and cell wall products enter bloodstream
Cell–cell adhesion
Catheter
Planktonic bacteria or fungi bind to host cell (for example, attachment to cell integrin) Host cell Bacterial cell wall products, DNA, and fungal cell wall products bind to Toll-like receptors and C-type lectin receptors
Production of proinflammatory cytokines and chemokines
Figure 1 | Intraluminal colonization of hemodialysis catheters.
through central venous catheters have clearly demonstrated that the catheter lumens often become colonized over time, and in many such cases the same bacteria or fungi can be isolated from percutaneously drawn blood cultures weeks later (Table 1). In another study,13 investigators performed catheter-drawn blood cultures weekly for 3 weeks just before dialysis. For 15 of 21 patients, catheter-drawn and percutaneously drawn blood cultures grew the same microorganism. All 15 patients were initially asymptomatic and afebrile during dialysis. Eight of the 15 patients subsequently developed evidence of infection manifested by Kidney International (2014) 86, 28–33
fever and rigors, and in each case the same Gram-positive or Gram-negative microorganism was grown from cultures of the hemodialysis catheter hub, and from catheter-drawn and percutaneously drawn blood cultures. This investigation suggested that patients receiving hemodialysis through catheters may develop intraluminal colonization from a colonized catheter hub, leading to bacteremia, which may occur without associated signs or symptoms. These investigators performed another study in which weekly catheter-drawn blood cultures were obtained from 28 hemodialysis patients just before dialysis.14 When a 29
30
64/51
67/43
29/26
37/33
RodriguezAranda et al.15
Nielson et al.16
Fux et al.17
Del Pozo et al.18
Abbreviations: d, days; NR, not reported.
NR/55
31/28
Dittmer et al.14
Wagner et al.19
NR/21
No. of catheters/ no. of patients studied
Dittmer et al.13
Authors (reference)
P
I
B (I 93%; P 7%)
I
B (I% not specified; P% not specified) B (I 80%; P 20%)
P
Incident (I%); prevalent (P%); both (B)
T
T
B (T 17%; N 83%)
B (T 4%; N 96%)
T
B (T 35%; N 65%)
B (T 67%; N 33%)
Tunneled (T%); nontunneled (N%); both (B)
Catheter type
2 ml/10 ml/every 7d/2% and 4% at 2 and 4 weeks, respectively, after enrollment for coagulasenegative staphylococci NR/2 ml (blood leukocytes cultured)/every 14d/median 151d (range 0–452d) after enrollment
5 ml/10 ml/weekly 3/ 95%/mean 59d (range 8–233d) 5 ml/10 ml/every 7d/ 68%/mean 27d (range 5–115d) from enrollment
3 ml/every 3–4d/NR/NR
5 ml or 0.5 ml/every 15d/25%/mean 391d (±389d) from enrollment NR/every 7d/16% after catheter insertion for coagulase-negative staphylococci/NR
No; fluid culture volume/frequency/% colonized catheters/ time to colonization
Initial arterial and venous intraluminal fluid discarded Yes; discard volume/fluid culture volume/frequency/% colonized catheters/time to colonization
Table 1 | Studies involving serial intraluminal hemodialysis catheter blood cultures
NR/when suspected/50%/mean 7.5d/50%
NR/when suspected or after colonization detected/95% /median 36d (range 2–150d)/100%
NR/when suspected/no bloodstream infections
NR/when suspected/NR/NR/NR
10 ml; 20 ml/weekly after first positive intraluminal culture/52%/mean 32d (range 5–126d)/100% B3 ml; NR/when suspected or after colonization detected/unknown/median 28d (interquartile range 5–45d)/100%
Volume (catheter-drawn; percutaneously drawn)/frequency/% colonized catheters develop positive peripheral blood culture with same microorganism/time to peripheral blood culture positivity after intraluminal colonization detected/% of peripheral blood culture positivity preceded by catheter-drawn blood culture positivity with same microorganism 10 ml; 20–40 ml/weekly 3 and when suspected/76%/NR/100%
Blood cultures
mini review LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
Kidney International (2014) 86, 28–33
LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
catheter-drawn blood culture revealed growth, the investigators then obtained percutaneously drawn blood cultures. For 21 of 31 catheters, positive catheter-drawn blood cultures developed at a mean of 27 days after hemodialysis catheter insertion. In 12 of the 21 instances, concordant microbial growth of predominantly coagulasenegative staphylococci from percutaneously drawn blood cultures developed at a mean of 32 days after the first positive catheter-drawn blood cultures were noted. Percutaneously drawn blood cultures revealed growth only after at least 3000 colony forming units/ml of bacteria were detected in intraluminal fluid cultures. These findings suggest that intraluminal catheter colonization, as measured by positive blood cultures drawn through a catheter, occurs in hemodialysis catheters, and if left unchecked this can lead to CRBSI, as defined by growth from percutaneously drawn and catheter-drawn blood cultures. One group of investigators cultured the initial 5 ml of fluid drawn from hemodialysis catheter lumens every 15 days just before dialysis.15 In B10% of the instances when luminal fluid cultures were obtained, the initial 0.5 ml of the heparin catheter lock solution was cultured separately. Overall, the mean time from catheterization to the first positive intraluminal fluid-culture–growing coagulase-negative staphylococci was 378 days ±365 days, in sharp contrast to the findings of one of the above-noted studies.14 All of the patients enrolled in this study had tunneled catheters, whereas two-third of the patients in the above-noted study14 apparently had nontunneled, temporary hemodialysis catheters, which have been demonstrated to become colonized earlier than tunneled hemodialysis catheters.16 Additional factors may have contributed to this disparity, such as differences in culture methodologies, possible differences in compliance with aseptic technique when handling catheter hubs, different patient populations, and so on. Investigators15 noted that there was a prior positive luminal fluid culture documented for 14 of 19 catheters (74%) causing CRBSI, compared with 2 of 45 catheters (4%) without CRBSI (Po0.001). The median time from a positive luminal fluid culture to an episode of CRBSI was 32 days (interquartile range, 5–45 days), 32 days (interquartile range, 27–79 days), and 2 days (interquartile range, 2–23 days; P ¼ 0.03) for all CRBSI episodes, CRBSI due to Staphylococcus epidermidis, and for non S. epidermidis or polymicrobial CRBSI, respectively. Thus, the virulence of bacteria colonizing the luminal surface of hemodialysis catheters likely has an impact on the time from detection of growth in intraluminal fluid until bacteremia is detected, as measured by percutaneously drawn blood cultures (that is, CRBSI). Molecular fingerprinting confirmed that the bacteria that had grown in luminal fluid cultures were identical to each of the S. epidermidis strains causing CRBSI. In addition, the findings of this study are similar to the mean time of 27 days from a positive catheter-drawn blood culture to an episode of CRBSI in an above-noted study.14 The overall (that is, combining results of the 0.5-ml heparin lock solution Kidney International (2014) 86, 28–33
mini review
cultures with the culture results of the 5 ml of fluid containing heparin and blood) sensitivity, specificity, and positive and negative predictive values for luminal fluid cultures to predict CRBSI were 95%, 86%, 83%, and 96%, respectively. The sensitivity and specificity of the 5-ml intraluminal fluid (that is, blood and heparin) cultures was 80% and 100%, respectively, and 100% and 100%, respectively, for 0.5-ml intraluminal heparin cultures. The predictive value of cultures from arterial and venous lumens was similar. Another study found that 16% of incident hemodialysis catheter-drawn blood cultures obtained just before dialysis had the growth of coagulase-negative staphylococci after a median of 24 and 138 days of nontunneled and tunneled catheter use, respectively.16 Most (73%) ‘catheter septicemia’ episodes were preceded by positive catheter-drawn blood cultures. In a study that performed weekly hemodialysis catheterdrawn blood cultures immediately before dialysis,17 only 4% of catheter-drawn blood cultures had growth of coagulasenegative staphylococci by 4 weeks of study. These findings are in contrast to some of the above-noted studies,10,14 which may reflect differences in the proportion of incident and prevalent catheters in the studies, or possibly for other reasons as specified above. In another study, investigators obtained blood from each incident tunneled catheter lumen every 2 weeks, centrifuged the blood to obtain the buffy-coat–containing leukocytes, and then cultured 50 ml of the fluid.18 The median time from catheterization to the first positive intraluminal buffy coat blood culture was 151 days (range 0–452 days). The median time from positive buffy coat blood cultures to CRBSI was 36 days (range 2–150 days) after excluding patients who had a CRBSI without previously positive intraluminal buffy coat blood cultures. Most CRBSI episodes were due to coagulasenegative staphylococci. The latter findings are similar to those of two of the above-noted studies (that is, 27 days14 and 32 days15). These authors noted an increased sensitivity of arterial lumen buffy coat blood cultures (data not provided). In a study in which investigators obtained blood from each prevalent tunneled catheter lumen before each hemodialysis session, blood was analyzed with the help of peptide nucleic acid fluorescence in situ hybridization and acridine-orange leucocyte cytospin testing.19 The two hemodialysis patients who developed coagulase-negative staphylococcal CRBSI had the identical microorganism identified by testing intraluminal blood samples 7 and 8 days before symptoms of CRBSI developed. The sensitivity, specificity, positive and negative predictive values for peptide nucleic acid fluorescence in situ hybridization or acridine-orange leucocyte cytospin testing were 100%, 96%, 50%, and 100%, respectively. In one study, 15 of 24 (75%) asymptomatic patients with tunneled hemodialysis catheters in place for more than 30 days had intraluminal colonization detected by cultures of intraluminal heparin or an intraluminal brush technique.20 Two-thirds of the bacteria were coagulase-negative 31
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LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
staphylococci. As with an above-noted study,18 these investigators also found that arterial lumen cultures were most sensitive. Specifically, 9 of the 11 catheters with positive intraluminal heparin cultures were detected using cultures of the arterial lumen compared with 6 of the 11 detected by venous lumen cultures. Other investigators found that all 26 patients using either temporary or permanent hemodialysis catheters dialyzed for 51±35 days had blood cultures growing predominantly coagulase-negative staphylococci drawn through catheter lumens after discarding heparinlocking solutions.21 Three of the 26 had concomitant percutaneously drawn blood cultures. A limitation of some of the above-noted studies reflects the fact that some investigators did not perform molecular fingerprinting or additional typing methods to determine whether or not additional episodes of bacteremia were relapses or new infections in those patients who had more than one such event, or to confirm that potential skin contaminants grown from percutaneously drawn and catheter-drawn cultures were truly identical.13,14,18,20,21 Finally, in one study,16 the case definition for CRBSI was met if a catheter-drawn blood culture or a percutaneously drawn blood culture was documented rather than requiring growth in the latter culture to meet the case definition. Nevertheless, data derived from the above-noted studies suggest that intraluminal hemodialysis catheter colonization often precedes CRBSI measured by concomitant growth from percutaneously drawn blood cultures. This insight should direct efforts toward minimizing catheter hub colonization and eventual luminal colonization. In addition, a better understanding of the pathogenesis of hemodialysis CRBSI afforded by these studies should focus prevention strategies on the catheter lumen, such as using antimicrobial lock solutions beginning after hemodialysis catheter insertion, or initiated once luminal colonization is detected. For example, in one study,18 investigators obtained blood cultures in patients whose intraluminal buffy coat blood cultures were found to contain at least 1000 colony forming units/ml of bacteria. Thirteen patients with 28 coagulase-negative staphylococcal catheter colonization episodes met this criterion and had positive catheter-drawn blood cultures, as well as negative percutaneously drawn blood cultures, or the ratio of quantitative blood cultures through the catheter and percutaneously was less than 4:1, respectively. For these patients’ catheters, a teichoplanin/heparin catheter lock solution was used after each dialysis session for 21 days. Quantitative blood cultures obtained 1 week later were negative in 25 of the 28 patients. However, 17 of these 28 patients had a relapse of catheter colonization with a median free interval of 70 days (range 2–101 days). In one of the above-noted studies,21 23 patients who only had growth from catheter-drawn blood cultures of coagulase-negative staphylococci or Staphylococcus aureus then had their hemodialysis catheters locked once with a combination of taurolidine, citrate, and urokinase and then locked after each dialysis session with a combination of taurolidine, citrate, 32
and heparin. When these patients had repeat catheter-drawn blood cultures after removal of the locking solution 34±8 days later, none of these cultures had microbial growth. The data from these studies suggest that some locking regimens may eradicate intraluminal hemodialysis catheter colonization. However, relapses may occur depending on the lock solution used and microbial pathogen involved. In addition, growth from weekly cultures of hemodialysis catheter luminal fluid could alert nephrologists that such patients have an increased risk of CRBSI, and such information should lower the threshold for obtaining percutaneously drawn blood cultures or blood cultures collected during dialysis to detect true bacteremia or fungemia 22,23 and consider initiating antimicrobial lock therapy at that point in time. A shortcoming to this approach is extraluminal hemodialysis catheter colonization, which will not be detected by cultures of intraluminal fluid and which will not respond to lock therapy. Bacteria or fungi that infect hemodialysis catheters, similar to other intravascular devices, will form a biofilm that aids in their survival.3,24 As noted above,5–7 biofilm has been noted in several studies of ex vivo hemodialysis catheters. Biofilm development on a catheter surface begins with microbial attachment, maturation of the biofilm, and final detachment of microbes from the biofilm surface. Microbes are difficult to eradicate from a mature biofilm, but there are various approaches currently being investigated to do so, which include enzymatic dispersal or breakdown of the biofilm, blocking cell–cell signaling among bacteria or fungi in a biofilm, or use of antimicrobial peptides that have bactericidal activity against dormant microbes within a biofilm.25 In addition, recent data suggest that altering the surface of catheters can prevent the initial microbial attachment, thereby preventing biofilm formation.26 Thus, in the future, modification of hemodialysis catheter composition will inevitably occur, along with the development of novel catheter lock solutions, which will mitigate the risk of catheter infection in vulnerable hemodialysis patients. What are some take-home messages and implications for the practicing nephrologist? Hemodialysis catheters can become colonized with bacteria on the luminal and extraluminal surface. Luminal surface colonization can be detected by cultures of the luminal contents. Some nephrologists may wish to obtain such cultures, particularly in high-risk patients with a history of recurrent catheter infections, on a regular basis and initiate preventative strategies if intraluminal colonization is detected. Alternatively, a nephrologist may wish to initiate preventative strategies starting at the time of catheter insertion. Some of the above-noted studies and others27–30 demonstrate that antimicrobial lock solutions containing either antibiotics, antiseptics, anticoagulants, other novel agents, or combinations of these, can prevent biofilm formation, catheter colonization, and catheter-related bloodstream infection. Some of these studies and more rigorous animal models31 suggest that some antimicrobial lock solutions can eradicate biofilm-containing bacteria. Kidney International (2014) 86, 28–33
LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
Importantly, some lock solutions such as ethanol have been associated with adverse reactions or can adversely affect the catheter integrity.32 Some antimicrobial-coated central venous catheters have been demonstrated to reduce the risk of CRBSI in prospective, randomized trials,33 but there are few such studies involving hemodialysis catheters, and none have demonstrated a significant reduction in CRBSI.34–36 Finally, before turning to technologic advances to mitigate the risk of hemodialysis CRBSI, recent collaborative quality improvement efforts focusing on basic infection control interventions have been demonstrated to effectively reduce bloodstream infections in outpatient hemodialysis units.37,38 In the future, further adoption of such quality improvement efforts and implementation of technologic advances to this vulnerable patient population holds the greatest hope for the prevention of these life-threatening infections. DISCLOSURE
Partial, unrestricted financial support was provided by Fresenius, which had no influence on the content of this article.
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18.
19.
20.
21.
22.
23.
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Dasgupta MK. Biofilms and infection in dialysis patients. Semin Dial 2002; 15: 338–346. Marcus RJ, Post JC, Stoodley P et al. Biofilms in nephrology. Expert Opin Biol Ther 2008; 8: 1159–1166. Stewart PS, Costerton JW. Antibiotic resistance of bacteria in biofilms. Lancet 2001; 358: 135–138. Mermel LA. What is the predominant source of intravascular catheter infections? Clin Infect Dis 2011; 52: 211–212. Bosma JW, Siegert CE, Peerbooms PG et al. Reduction of biofilm formation with trisodium citrate in haemodialysis catheters: a randomized controlled trial. Nephrol Dial Transplant 2010; 25: 1213–1217. Kanaa M, Wright MJ, Sandoe JA. Examination of tunnelled haemodialysis catheters using scanning electron microscopy. Clin Microbiol Infect 2010; 16: 780–786. Ramanathan V, Riosa S, Al-Sharif AH et al. Characteristics of biofilm on tunneled cuffed hemodialysis catheters in the presence and absence of clinical infection. Am J Kidney Dis 2012; 60: 976–982. Jones SM, Ravani P, Hemmelgarn BR et al. Morphometric and biological characterization of biofilm in tunneled hemodialysis catheters. Am J Kidney Dis 2011; 57: 449–455. Olson ME, Lam K, Bodey GP et al. Evaluation of strategies for central venous catheter replacement. Crit Care Med 1992; 20: 797–804. Fux CA, Wilson S, Stoodley P. Detachment characteristics and oxacillin resistance of Staphyloccocus aureus biofilm emboli in an in vitro catheter infection model. J Bacteriol 2004; 186: 4486–4491. Lewis SL, Sexton DJ. Metastatic complications of bloodstream infections in hemodialysis patients. Semin Dial 2013; 26: 47–53. Cheesbrough JS, Finch RG, Burden RP. A prospective study of the mechanisms of infection associated with hemodialysis catheters. J Infect Dis 1986; 154: 579–589. Dittmer ID, Sharp D, McNulty CAM et al. Bacterial colonization and peripheral bacteraemia associated with central venous haemodialysis catheters: a cross-sectional study. Nephrology 1997; 4: 557–561. Dittmer ID, Sharp D, McNulty CA et al. A prospective study of central venous hemodialysis catheter colonization and peripheral bacteremia. Clin Nephrol 1999; 51: 34–39. Rodrı´guez-Aranda A, Alcazar JM, Sanz F et al. Endoluminal colonization as a risk factor for coagulase-negative staphylococcal catheter-related bloodstream infections in haemodialysis patients. Nephrol Dial Transplant 2011; 26: 948–955.
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Nielsen J, Kolmos HJ, Rosdahl VT. Poor value of surveillance cultures for prediction of septicaemia caused by coagulase-negative staphylococci in patients undergoing haemodialysis with central venous catheters. Scand J Infect Dis 1998; 30: 569–572. Fux CA, Uehlinger D, Bodmer T et al. Dynamics of hemodialysis catheter colonization by coagulase-negative staphylococci. Infect Control Hosp Epidemiol 2005; 26: 567–574. Del Pozo JL, Aguinaga A, Garcia-Fernandez N et al. Intra-catheter leukocyte culture to monitor hemodialysis catheter colonization. A prospective study to prevent catheter-related bloodstream infections. Int J Artif Organs 2008; 31: 820–826. Wagner J, Schilcher G, Zollner-Schwetz I et al. Microbiological screening for earlier detection of central venous catheter-related bloodstream infections. Eur J Clin Invest 2013; 43: 964–969. Koch M, Coyne D, Hoppe-Bauer J et al. Bacterial colonization of chronic hemodialysis catheters: evaluation with endoluminal brushes and heparin aspirate. J Vasc Access 2002; 3: 38–42. Zwiech R, Adelt M, Chrul S. A taurolidine-citrate-heparin lock solution effectively eradicates pathogens from the catheter biofilm in hemodialysis patients. Am J Ther 2013 [Epub ahead of print]). Quittnat Pelletier F, Joarder M, Lok CE. Accuracy of blood culture results from hemodialysis circulation as compared to the gold standard for diagnosing catheter-related blood stream infections (NKF abstract 211). Am J Kidney Dis 2012; 59: B67. Quittnat Pelletier F, Joarder M, Lok CE. Challenges in obtaining peripheral blood cultures on hemodialysis patients during hemodialysis (NKF abstract 212). Am J Kidney Dis 2012; 59: B67. Dunne WM Jr.. Bacterial adhesion: seen any good biofilms lately? Clin Microbiol Rev 2002; 15: 155–166. Brooks JL, Jefferson KK. Staphylococcal biofilms: quest for the magic bullet. Adv Appl Microbiol 2012; 81: 63–87. Desrousseaux C, Sautou V, Descamps S et al. Modification of the surfaces of medical devices to prevent microbial adhesion and biofilm formation. J Hosp Infect 2013; 85: 87–93. Boyce JM. Prevention of central line-associated bloodstream infections in hemodialysis patients. Infect Control Hosp Epidemiol 2012; 33: 936–944. Hemmelgarn BR, Moist LM, Lok CE et al. Prevention of dialysis catheter malfunction with recombinant tissue plasminogen activator. N Engl J Med 2011; 364: 303–312. Maki DG, Ash SR, Winger RK et al. A novel antimicrobial and antithrombotic lock solution for hemodialysis catheters: a multi-center, controlled, randomized trial. Crit Care Med 2011; 39: 613–620. LaPlante KL, Mermel LA. In vitro activity of daptomycin and vancomycin lock solutions on staphylococcal biofilms in a central venous catheter model. Nephrol Dial Transplant 2007; 22: 2239–2246. Chauhan A, Lebeaux D, Decante B et al. A rat model of central venous catheter to study establishment of long-term bacterial biofilm and related acute and chronic infections. PLoS One 2012; 7: e37281. Slobbe L, Doorduijn JK, Lugtenburg PJ et al. Prevention of catheter-related bacteremia with a daily ethanol lock in patients with tunnelled catheters: a randomized, placebo-controlled trial. PLoS One 2010; 5: e10840. Casey AL, Mermel LA, Nightingale P et al. Antimicrobial central venous catheters in adults: a systematic review and meta-analysis. Lancet Infect Dis 2008; 8: 763–776. Trerotola SO, Johnson MS, Shah H et al. Tunneled hemodialysis catheters: use of a silver-coated catheter for prevention of infection–a randomized study. Radiology 1998; 207: 491–496. Chatzinikolaou I, Finkel K, Hanna H et al. Antibiotic-coated hemodialysis catheters for the prevention of vascular catheter-related infections: a prospective, randomized study. Am J Med 2003; 115: 352–357. Schindler R, Heemann U, Haug U et al. Bismuth coating of non-tunneled haemodialysis catheters reduces bacterial colonization: a randomized controlled trial. Nephrol Dial Transplant 2010; 25: 2651–2656. Lindberg C, Downham G, Buscell P et al. Embracing collaboration: a novel strategy for reducing bloodstream infections in outpatient hemodialysis centers. Am J Infect Control 2013; 41: 513–519. Patel PR, Yi SH, Booth S et al. Bloodstream infection rates in outpatient hemodialysis facilities participating in a collaborative prevention effort: a quality improvement report. Am J Kidney Dis 2013; 62: 322–330.
33
http://www.kidney-international.org & 2014 International Society of Nephrology
What is the evidence for intraluminal colonization of hemodialysis catheters? Leonard A. Mermel1 1
Division of Infectious Diseases, Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Hemodialysis catheter–related bloodstream infections are potentially devastating, leading to increased morbidity, mortality, and cost of care. Prospective studies published over the past 15 years shed light on the pathogenesis of these infections. The data suggest that the intraluminal microbial colonization of hemodialysis catheters often precedes bloodstream infection. This finding supports strategies aimed at preventing or eradicating intraluminal colonization. Kidney International (2014) 86, 28–33; doi:10.1038/ki.2013.527; published online 8 January 2014 KEYWORDS: catheter colonization; catheter infection; catheter-related bloodstream infection; catheter-related infection; hemodialysis catheter
Correspondence: Leonard Mermel, Division of Infectious Diseases, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903, USA. E-mail: [email protected] Received 2 August 2013; revised 13 September 2013; accepted 19 September 2013; published online 8 January 2014 28
During the initial stages of intravascular catheter colonization, a biofilm is formed that is made up of host proteins and microbes (Figure 1). Bacteria and fungi survive and proliferate within the biofilm, despite host immune defenses and therapeutic doses of antimicrobial agents.1–3 Catheter-related bloodstream infections (CRBSIs) most commonly emanate from microorganisms colonizing the catheter insertion site migrating distally along the extraluminal surface of the catheter into the bloodstream or from microorganisms that migrate intraluminally into the bloodstream from a colonized catheter hub, connector, or less often from microorganisms in contaminated infusate.4 Some investigators found that when hemodialysis catheters were routinely removed 1 month after insertion, all of the catheters had intraluminal surface biofilm and ‘ultrastructural colonization’ detected using scanning electron microscopy.5 Other investigators have identified bacteria within the biofilm on the luminal surface of hemodialysis catheters using scanning electron microscopy.6 On the other hand, another study found that the outer surface of hemodialysis catheters removed after 138±141 days in bacteremic patients had a thicker biofilm and more microbial colonization than the luminal catheter surface.7 In addition, thicker biofilm on hemodialysis catheters has been associated with positive blood cultures drawn through the catheter compared with those with negative blood cultures drawn through the catheter.8 Eventually, planktonic bacteria or fungi break off from the biofilm and seed the bloodstream, causing bacteremia or fungemia, which may lead to metastatic infection.9–11 Both intraluminal and extraluminal colonization of hemodialysis catheters are important sources of microbes leading to CRBSI. An intraluminal source may be especially important in those patients with tunneled, cuffed, long-term hemodialysis catheters. This mini review focuses on intraluminal colonization. In a seminal prospective study,12 13 patients undergoing hemodialysis through central venous catheters developed fever and rigors, 12 of whom had catheter colonization and positive percutaneously drawn blood cultures. Of these 13 patients, their infection emanated from the catheter insertion site, catheter lumen, or both sites in three, eight, and two patients, respectively, suggesting a predominant intraluminal source of infection. Studies of patients receiving hemodialysis Kidney International (2014) 86, 28–33
mini review
LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
Double-lumen, cuffed hemodialysis catheter Catheter cuff
Adapters Microbes introduced into catheter lumen due to breach in aseptic technique Biofilm maturation
Bacteria or fungi introduced from catheter adaptor/hub Attach to hemodialysis catheter lumen
Attached cell monolayer
Detachment: planktonic bacteria or fungi, plasmids, and cell wall products enter bloodstream
Cell–cell adhesion
Catheter
Planktonic bacteria or fungi bind to host cell (for example, attachment to cell integrin) Host cell Bacterial cell wall products, DNA, and fungal cell wall products bind to Toll-like receptors and C-type lectin receptors
Production of proinflammatory cytokines and chemokines
Figure 1 | Intraluminal colonization of hemodialysis catheters.
through central venous catheters have clearly demonstrated that the catheter lumens often become colonized over time, and in many such cases the same bacteria or fungi can be isolated from percutaneously drawn blood cultures weeks later (Table 1). In another study,13 investigators performed catheter-drawn blood cultures weekly for 3 weeks just before dialysis. For 15 of 21 patients, catheter-drawn and percutaneously drawn blood cultures grew the same microorganism. All 15 patients were initially asymptomatic and afebrile during dialysis. Eight of the 15 patients subsequently developed evidence of infection manifested by Kidney International (2014) 86, 28–33
fever and rigors, and in each case the same Gram-positive or Gram-negative microorganism was grown from cultures of the hemodialysis catheter hub, and from catheter-drawn and percutaneously drawn blood cultures. This investigation suggested that patients receiving hemodialysis through catheters may develop intraluminal colonization from a colonized catheter hub, leading to bacteremia, which may occur without associated signs or symptoms. These investigators performed another study in which weekly catheter-drawn blood cultures were obtained from 28 hemodialysis patients just before dialysis.14 When a 29
30
64/51
67/43
29/26
37/33
RodriguezAranda et al.15
Nielson et al.16
Fux et al.17
Del Pozo et al.18
Abbreviations: d, days; NR, not reported.
NR/55
31/28
Dittmer et al.14
Wagner et al.19
NR/21
No. of catheters/ no. of patients studied
Dittmer et al.13
Authors (reference)
P
I
B (I 93%; P 7%)
I
B (I% not specified; P% not specified) B (I 80%; P 20%)
P
Incident (I%); prevalent (P%); both (B)
T
T
B (T 17%; N 83%)
B (T 4%; N 96%)
T
B (T 35%; N 65%)
B (T 67%; N 33%)
Tunneled (T%); nontunneled (N%); both (B)
Catheter type
2 ml/10 ml/every 7d/2% and 4% at 2 and 4 weeks, respectively, after enrollment for coagulasenegative staphylococci NR/2 ml (blood leukocytes cultured)/every 14d/median 151d (range 0–452d) after enrollment
5 ml/10 ml/weekly 3/ 95%/mean 59d (range 8–233d) 5 ml/10 ml/every 7d/ 68%/mean 27d (range 5–115d) from enrollment
3 ml/every 3–4d/NR/NR
5 ml or 0.5 ml/every 15d/25%/mean 391d (±389d) from enrollment NR/every 7d/16% after catheter insertion for coagulase-negative staphylococci/NR
No; fluid culture volume/frequency/% colonized catheters/ time to colonization
Initial arterial and venous intraluminal fluid discarded Yes; discard volume/fluid culture volume/frequency/% colonized catheters/time to colonization
Table 1 | Studies involving serial intraluminal hemodialysis catheter blood cultures
NR/when suspected/50%/mean 7.5d/50%
NR/when suspected or after colonization detected/95% /median 36d (range 2–150d)/100%
NR/when suspected/no bloodstream infections
NR/when suspected/NR/NR/NR
10 ml; 20 ml/weekly after first positive intraluminal culture/52%/mean 32d (range 5–126d)/100% B3 ml; NR/when suspected or after colonization detected/unknown/median 28d (interquartile range 5–45d)/100%
Volume (catheter-drawn; percutaneously drawn)/frequency/% colonized catheters develop positive peripheral blood culture with same microorganism/time to peripheral blood culture positivity after intraluminal colonization detected/% of peripheral blood culture positivity preceded by catheter-drawn blood culture positivity with same microorganism 10 ml; 20–40 ml/weekly 3 and when suspected/76%/NR/100%
Blood cultures
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LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
catheter-drawn blood culture revealed growth, the investigators then obtained percutaneously drawn blood cultures. For 21 of 31 catheters, positive catheter-drawn blood cultures developed at a mean of 27 days after hemodialysis catheter insertion. In 12 of the 21 instances, concordant microbial growth of predominantly coagulasenegative staphylococci from percutaneously drawn blood cultures developed at a mean of 32 days after the first positive catheter-drawn blood cultures were noted. Percutaneously drawn blood cultures revealed growth only after at least 3000 colony forming units/ml of bacteria were detected in intraluminal fluid cultures. These findings suggest that intraluminal catheter colonization, as measured by positive blood cultures drawn through a catheter, occurs in hemodialysis catheters, and if left unchecked this can lead to CRBSI, as defined by growth from percutaneously drawn and catheter-drawn blood cultures. One group of investigators cultured the initial 5 ml of fluid drawn from hemodialysis catheter lumens every 15 days just before dialysis.15 In B10% of the instances when luminal fluid cultures were obtained, the initial 0.5 ml of the heparin catheter lock solution was cultured separately. Overall, the mean time from catheterization to the first positive intraluminal fluid-culture–growing coagulase-negative staphylococci was 378 days ±365 days, in sharp contrast to the findings of one of the above-noted studies.14 All of the patients enrolled in this study had tunneled catheters, whereas two-third of the patients in the above-noted study14 apparently had nontunneled, temporary hemodialysis catheters, which have been demonstrated to become colonized earlier than tunneled hemodialysis catheters.16 Additional factors may have contributed to this disparity, such as differences in culture methodologies, possible differences in compliance with aseptic technique when handling catheter hubs, different patient populations, and so on. Investigators15 noted that there was a prior positive luminal fluid culture documented for 14 of 19 catheters (74%) causing CRBSI, compared with 2 of 45 catheters (4%) without CRBSI (Po0.001). The median time from a positive luminal fluid culture to an episode of CRBSI was 32 days (interquartile range, 5–45 days), 32 days (interquartile range, 27–79 days), and 2 days (interquartile range, 2–23 days; P ¼ 0.03) for all CRBSI episodes, CRBSI due to Staphylococcus epidermidis, and for non S. epidermidis or polymicrobial CRBSI, respectively. Thus, the virulence of bacteria colonizing the luminal surface of hemodialysis catheters likely has an impact on the time from detection of growth in intraluminal fluid until bacteremia is detected, as measured by percutaneously drawn blood cultures (that is, CRBSI). Molecular fingerprinting confirmed that the bacteria that had grown in luminal fluid cultures were identical to each of the S. epidermidis strains causing CRBSI. In addition, the findings of this study are similar to the mean time of 27 days from a positive catheter-drawn blood culture to an episode of CRBSI in an above-noted study.14 The overall (that is, combining results of the 0.5-ml heparin lock solution Kidney International (2014) 86, 28–33
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cultures with the culture results of the 5 ml of fluid containing heparin and blood) sensitivity, specificity, and positive and negative predictive values for luminal fluid cultures to predict CRBSI were 95%, 86%, 83%, and 96%, respectively. The sensitivity and specificity of the 5-ml intraluminal fluid (that is, blood and heparin) cultures was 80% and 100%, respectively, and 100% and 100%, respectively, for 0.5-ml intraluminal heparin cultures. The predictive value of cultures from arterial and venous lumens was similar. Another study found that 16% of incident hemodialysis catheter-drawn blood cultures obtained just before dialysis had the growth of coagulase-negative staphylococci after a median of 24 and 138 days of nontunneled and tunneled catheter use, respectively.16 Most (73%) ‘catheter septicemia’ episodes were preceded by positive catheter-drawn blood cultures. In a study that performed weekly hemodialysis catheterdrawn blood cultures immediately before dialysis,17 only 4% of catheter-drawn blood cultures had growth of coagulasenegative staphylococci by 4 weeks of study. These findings are in contrast to some of the above-noted studies,10,14 which may reflect differences in the proportion of incident and prevalent catheters in the studies, or possibly for other reasons as specified above. In another study, investigators obtained blood from each incident tunneled catheter lumen every 2 weeks, centrifuged the blood to obtain the buffy-coat–containing leukocytes, and then cultured 50 ml of the fluid.18 The median time from catheterization to the first positive intraluminal buffy coat blood culture was 151 days (range 0–452 days). The median time from positive buffy coat blood cultures to CRBSI was 36 days (range 2–150 days) after excluding patients who had a CRBSI without previously positive intraluminal buffy coat blood cultures. Most CRBSI episodes were due to coagulasenegative staphylococci. The latter findings are similar to those of two of the above-noted studies (that is, 27 days14 and 32 days15). These authors noted an increased sensitivity of arterial lumen buffy coat blood cultures (data not provided). In a study in which investigators obtained blood from each prevalent tunneled catheter lumen before each hemodialysis session, blood was analyzed with the help of peptide nucleic acid fluorescence in situ hybridization and acridine-orange leucocyte cytospin testing.19 The two hemodialysis patients who developed coagulase-negative staphylococcal CRBSI had the identical microorganism identified by testing intraluminal blood samples 7 and 8 days before symptoms of CRBSI developed. The sensitivity, specificity, positive and negative predictive values for peptide nucleic acid fluorescence in situ hybridization or acridine-orange leucocyte cytospin testing were 100%, 96%, 50%, and 100%, respectively. In one study, 15 of 24 (75%) asymptomatic patients with tunneled hemodialysis catheters in place for more than 30 days had intraluminal colonization detected by cultures of intraluminal heparin or an intraluminal brush technique.20 Two-thirds of the bacteria were coagulase-negative 31
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LA Mermel: Evidence for intraluminal colonization of hemodialysis catheters
staphylococci. As with an above-noted study,18 these investigators also found that arterial lumen cultures were most sensitive. Specifically, 9 of the 11 catheters with positive intraluminal heparin cultures were detected using cultures of the arterial lumen compared with 6 of the 11 detected by venous lumen cultures. Other investigators found that all 26 patients using either temporary or permanent hemodialysis catheters dialyzed for 51±35 days had blood cultures growing predominantly coagulase-negative staphylococci drawn through catheter lumens after discarding heparinlocking solutions.21 Three of the 26 had concomitant percutaneously drawn blood cultures. A limitation of some of the above-noted studies reflects the fact that some investigators did not perform molecular fingerprinting or additional typing methods to determine whether or not additional episodes of bacteremia were relapses or new infections in those patients who had more than one such event, or to confirm that potential skin contaminants grown from percutaneously drawn and catheter-drawn cultures were truly identical.13,14,18,20,21 Finally, in one study,16 the case definition for CRBSI was met if a catheter-drawn blood culture or a percutaneously drawn blood culture was documented rather than requiring growth in the latter culture to meet the case definition. Nevertheless, data derived from the above-noted studies suggest that intraluminal hemodialysis catheter colonization often precedes CRBSI measured by concomitant growth from percutaneously drawn blood cultures. This insight should direct efforts toward minimizing catheter hub colonization and eventual luminal colonization. In addition, a better understanding of the pathogenesis of hemodialysis CRBSI afforded by these studies should focus prevention strategies on the catheter lumen, such as using antimicrobial lock solutions beginning after hemodialysis catheter insertion, or initiated once luminal colonization is detected. For example, in one study,18 investigators obtained blood cultures in patients whose intraluminal buffy coat blood cultures were found to contain at least 1000 colony forming units/ml of bacteria. Thirteen patients with 28 coagulase-negative staphylococcal catheter colonization episodes met this criterion and had positive catheter-drawn blood cultures, as well as negative percutaneously drawn blood cultures, or the ratio of quantitative blood cultures through the catheter and percutaneously was less than 4:1, respectively. For these patients’ catheters, a teichoplanin/heparin catheter lock solution was used after each dialysis session for 21 days. Quantitative blood cultures obtained 1 week later were negative in 25 of the 28 patients. However, 17 of these 28 patients had a relapse of catheter colonization with a median free interval of 70 days (range 2–101 days). In one of the above-noted studies,21 23 patients who only had growth from catheter-drawn blood cultures of coagulase-negative staphylococci or Staphylococcus aureus then had their hemodialysis catheters locked once with a combination of taurolidine, citrate, and urokinase and then locked after each dialysis session with a combination of taurolidine, citrate, 32
and heparin. When these patients had repeat catheter-drawn blood cultures after removal of the locking solution 34±8 days later, none of these cultures had microbial growth. The data from these studies suggest that some locking regimens may eradicate intraluminal hemodialysis catheter colonization. However, relapses may occur depending on the lock solution used and microbial pathogen involved. In addition, growth from weekly cultures of hemodialysis catheter luminal fluid could alert nephrologists that such patients have an increased risk of CRBSI, and such information should lower the threshold for obtaining percutaneously drawn blood cultures or blood cultures collected during dialysis to detect true bacteremia or fungemia 22,23 and consider initiating antimicrobial lock therapy at that point in time. A shortcoming to this approach is extraluminal hemodialysis catheter colonization, which will not be detected by cultures of intraluminal fluid and which will not respond to lock therapy. Bacteria or fungi that infect hemodialysis catheters, similar to other intravascular devices, will form a biofilm that aids in their survival.3,24 As noted above,5–7 biofilm has been noted in several studies of ex vivo hemodialysis catheters. Biofilm development on a catheter surface begins with microbial attachment, maturation of the biofilm, and final detachment of microbes from the biofilm surface. Microbes are difficult to eradicate from a mature biofilm, but there are various approaches currently being investigated to do so, which include enzymatic dispersal or breakdown of the biofilm, blocking cell–cell signaling among bacteria or fungi in a biofilm, or use of antimicrobial peptides that have bactericidal activity against dormant microbes within a biofilm.25 In addition, recent data suggest that altering the surface of catheters can prevent the initial microbial attachment, thereby preventing biofilm formation.26 Thus, in the future, modification of hemodialysis catheter composition will inevitably occur, along with the development of novel catheter lock solutions, which will mitigate the risk of catheter infection in vulnerable hemodialysis patients. What are some take-home messages and implications for the practicing nephrologist? Hemodialysis catheters can become colonized with bacteria on the luminal and extraluminal surface. Luminal surface colonization can be detected by cultures of the luminal contents. Some nephrologists may wish to obtain such cultures, particularly in high-risk patients with a history of recurrent catheter infections, on a regular basis and initiate preventative strategies if intraluminal colonization is detected. Alternatively, a nephrologist may wish to initiate preventative strategies starting at the time of catheter insertion. Some of the above-noted studies and others27–30 demonstrate that antimicrobial lock solutions containing either antibiotics, antiseptics, anticoagulants, other novel agents, or combinations of these, can prevent biofilm formation, catheter colonization, and catheter-related bloodstream infection. Some of these studies and more rigorous animal models31 suggest that some antimicrobial lock solutions can eradicate biofilm-containing bacteria. Kidney International (2014) 86, 28–33
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Importantly, some lock solutions such as ethanol have been associated with adverse reactions or can adversely affect the catheter integrity.32 Some antimicrobial-coated central venous catheters have been demonstrated to reduce the risk of CRBSI in prospective, randomized trials,33 but there are few such studies involving hemodialysis catheters, and none have demonstrated a significant reduction in CRBSI.34–36 Finally, before turning to technologic advances to mitigate the risk of hemodialysis CRBSI, recent collaborative quality improvement efforts focusing on basic infection control interventions have been demonstrated to effectively reduce bloodstream infections in outpatient hemodialysis units.37,38 In the future, further adoption of such quality improvement efforts and implementation of technologic advances to this vulnerable patient population holds the greatest hope for the prevention of these life-threatening infections. DISCLOSURE
Partial, unrestricted financial support was provided by Fresenius, which had no influence on the content of this article.
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