| Abstract|| |
Hemodialysis (HD) patients are at considerably high risk for vascular accessrelated blood stream infections (VRBSI) that result in serious complications. Such severe infections are a great deal more frequent with central venous catheters (CVCs) and polytetrafluoroethylene (PTFE) grafts than with arteriovenous fistula (AVF). Nonetheless, the CVCs, though having "undesirable" side effects, remain "unavoidable" for the patients requiring instant dialysis access, as a consequence of the unpredictable course of chronic renal disease. Although early antibiotic treatment should include the coverage for Staphylococcus aureus, the treatment of catheter-related blood stream infections (CRBSI) remains controversial. Antimicrobial- anticoagulant 'locks' have shown promising results in several recent randomized controlled trials in the treatment and prevention of CRBSI. Policy of increasing AVF prevalence beyond 50% is bound to have an enduring positive effect on HD outcomes. Standard infection control measures for hygiene and aseptic handling of CVCs cannot be overemphasized. The catheters with 'bioactive' surface with thrombo-resistant and infection-resistant properties will be available in the near future.
Keywords: Hemodialysis, Access, Infection, Management, Prevention, Strategies.
|How to cite this article:|
Saxena AK, Panhotra B R, Al-Mulhim AS. Vascular Access Related Infections in Hemodialysis Patients. Saudi J Kidney Dis Transpl 2005;16:46-71
|How to cite this URL:|
Saxena AK, Panhotra B R, Al-Mulhim AS. Vascular Access Related Infections in Hemodialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2018 Dec 11];16:46-71. Available from: http://www.sjkdt.org/text.asp?2005/16/1/46/32951
| Introduction|| |
A well functioning vascular access is the lifeline for the patients on long-term hemodialysis (HD). Dialysis access-related infections and associated hospitalization not only adversely affect the general well-being of the patients but also account for nearly a third of the cost of end-stage renal disease (ESRD) management besides being one of the major causes of morbidity and mortality second only to cardiovascular disease. ,,,
Mortality rates attributable to vascular accessrelated blood stream infections (VRBSI) among long-term HD patients vary from 12 to 25.9 %. ,, The type of vascular access determines the quality of life and the cost of dialysis treatment among ESRD patients. ,,,,, In a single center study from Oakland, the estimated cost of VRBSI-related hospitalization was demonstrated to be the lowest for arteriovenous fistula (AVF) and the highest for the tunneled cuffed catheters (TCCs), [Figure - 1].  Nevertheless, the amount of pain, frustration and human suffering leading to suboptimal quality of life of long-term HD patients as a result of these infections remain tremendous.
| Epidemiology|| |
In general, the use of central venous catheters (CVCs) for the access to circulation has been associated with much higher blood stream infection (BSI) rates compared with arteriovenous graft (AVG) and AVF.  Observational data suggests that the risk of BSI is higher for temporary untunneled catheters (UTCs) compared to permanent tunneled cuffed catheters (TCCs). The mean incidence of catheter-related blood stream infections (CRBSI) for UTCs have been reported to be 5.0 episodes/ 1000 catheter-days (range, 3.8-6.5/ 1000 catheter-days) and 3.5 /1000 catheterdays (range, 1.6-5.5/1000 catheter-days) for TCCs. ,,,,,, Among UTCs, femoral catheters (FC) have the highest infection rates (7.6 episodes/1000 catheter-days) possibly owing to their proximity to perineum, with more than 10% of the catheters becoming infected after one week of insertion. Comparatively, the mean incidence of CRBSI for internal jugular(IJ) and subclavian (SC) catheters was 5.6 episodes/ 1000 catheter-days and 2.7 episodes/1000 catheter-days, respectively; 10% infection rates were reached only after 2-3 and 4 weeks following catheter placement, respectively. ,,, On the other hand, the frequency of infections for polytetrafluoroethylene (PTFE) grafts was 0.2 / patient-year and 0.05 / patient-year for AVF, [Table - 1]. 
Likewise, a prospective study of 988 ESRD patients on HD for six months reported relative risk (RR) of BSI of 1.29 for PTFE grafts, 7.64 for CVCs and one for AVF.  A multicenter French study of the incidence and risk factors for VRBSI in long-term HD patients revealed that the patients who were dialyzed through CVCs had RR of BSI of 7. 6, while those with PTFE grafts had RR of 6.2 when compared with AVF.
At our center in the Eastern Province of Saudi Arabia, the peak incidence of VRBSI was observed among those dialyzed through FC (1.5 episodes /1000 catheter-days, RR-5.3) followed by SC (1.3/1000 catheter-days, RR4.8) and TCC group (1.15/1000 catheter-days, RR-3.29) in comparison to 1.07 episodes/ patient-year in PTFE group (RR-4.02) and 0.04/patient-year among patients with functioning AVF.  These infection rates were much lower than those reported in the French and Oakland studies. , Such variations are possibly due to differences in the patients' characteristics and vascular access management protocols practiced at different dialysis centers.
Paradoxically, a recent Italian multicenter study evaluating hospitalization and death rates in 2836 HD patients reported that even though the patients were dialyzed via CVC, had significantly higher hospitalization and death rates than those dialyzed through AVF; the difference in the relative risk (RR) of death disappeared after correction for age, gender, malnutrition, diabetes, hemoglobin, albumin and comorbidity. The authors concluded that the use of CVC per se was not associated with increased risks of mortality and hospitalization but other factors such as female gender, old age, diabetes and other comorbidities, hypoalbuminemia, anemia, erythropoietin resistance, and less frequent use of biocompatible membranes among patients on HD via CVCs were responsible for the associated unfavorable outcomes. 
| Pathogenesis|| |
The majority of vascular access-related infections are catheter-related, suggestive of our continued dependence on CVCs to commence and carry out HD in routine practice and emergency situations. Pathogenesis of vascular catheter-related infection is a complex process that involves interaction between several factors. ,,,,,, Nonetheless, the primary event in the pathogenesis remains the entry of microorganisms with subsequent colonization, multiplication and eventually dissemination in to the blood circulation. Skin and the hubs are the most frequent sources of colonization of the percutaneous vascular catheters. ,,, The catheter hubs are most often colonized through contaminated hands of dialysis personnel, while skin borne organisms such as coagulase negative Staphylococci and Staphylococcus aureus are leading pathogens that cause CRBSI through extraluminal route. ,
For the temporary TUCs, the organisms migrate from the skin insertion site along with the intracutaneous segment, finally reaching the intravascular segment and the tip of the catheter.  On the other hand, in long-term catheters particularly those that are cuffed and/or surgically planted, the hub is a major source of colonization of catheter lumen, which ultimately leads to BSI through luminal colonization of the intravascular segment.  However, any of these types of CVCs may get colonized either through extraluminal (skin-related) or intraluminal (hub-related) routes, [Figure - 2].
The organisms that adhere to the catheter surface maintain themselves by producing "extracellular slime", a substance rich in exopolysaccharides, often referred to as fibrous glycocalyx or microbial biofilm.  The organisms embed themselves in the biofilm layer, becoming more resistant to the antimicrobial activity of glycopeptide antibiotics. , Electron microscopic studies have revealed that the colonization of CVCs is almost universal and nearly all catheters eventually become colonized shortly following insertion.  However, the risk of infection is directly related to the quantitative level of organisms multiplying on the surface of the intravascular segment of the catheter. Therefore, the factors related to immunological status of the host, the virulence of microorganism enhanced by the biofilm environment are the major determinants of the risk of CRBSI among patients on HD.  Bacteria embedded in the biofilm are less permeable to phagocytes and antibiotics as antibiotics can act only on the organisms located in the superficial regions of the biofilm. Difficulties arise in the eradication of bacteria colonizing catheter lumen and in such cases; catheter removal is often the only option to eradicate the infection.
| Risk Factors Related to the Development of VRBSI|| |
It is evident from the Untied States Renal Data System (USRDS) 1999 and United Kingdom (UK) Renal Registry 2002 annual reports that the elderly, females, blacks, diabetics and obese patients with ESRD are less likely to have native AVF; only 23% of HD patients in the United States were dialyzed through AVF in 1997. ,,,,, Forty six percent of the elderly patients started on HD has at least two comorbid conditions correlated with poor vascular frame work and/or limited life expectancy and is often considered unsuitable for placement of PTFE graft or AVF.  They are left with CVCs as a sole option for survival on HD and become exposed to an added risk of developing CRBSI and ensuing serious complications, [Table - 2]. 
The patients on long-term HD particularly the elderly and diabetic are at increased risk of S. aureus nasal carriage; the literature reports upto 60% carriage rate in these patients. ,,,,,,, Since S. aureus disseminates from the nasal reservoir to hands and skin to infect the vascular access sites, the nasal carriers are at a great high risk of developing vascular access related infections. ,, S. aureus has a unique predilection to cause fatal infections among those who have intravascular prosthetic devices such as the CVCs.  The intravascular catheters become rapidly coated with some serum constituents such as fibrinogen, fibronectin and laminins that facilitate the attachment of Staphylococci to the foreign material of the catheter through microbial surface components recognizing adhesive matrix molecule (MSCRAMM) mediated mechanisms. ,, Furthermore, S.aureus elaborates glycocalices, which promote the bacterial colonization and further spread of infection. ,, Von Eiff et al, reported that S.aureus blood isolates from HD patients with BSI were clonally identical to those obtained from their nasal specimen in 82.2% of the cases, suggesting that the organisms in the blood stream originated from the patients own nasal flora.  Evidently, CVC placement near the patient's nose and mouth, such as that occurs with subclavian or jugular vein catheters, exposes the patient's catheter exit site to the nasal drainage/discharge and infectious airborne droplets. Methicillin-resistant S. aureus (MRSA) may be transmitted in this mode. 
ESRD patients are known to suffer from impaired immune defence mechanisms, attributable to the larger proportions of elderly population with comorbid conditions such as diabetes mellitus, malignancy or malnutrition particularly related to uremia and HD treatment. ,,,,,, Uremia and inflammation induced by HD filters can cause oxidative stress activation, apoptosis and reduced numbers of T lymphocytes leading to defects in the cell mediated immunity. , In addition, MHC class II analog protein (Map) expressed by S. aureus also attenuates the host's cell-mediated immunity by reducing T cell proliferative response to gram-positive bacterial infections. 
In patients with exhausted vascular access sites, contraindication to AVF placement for medical reasons (heart failure, severe limb ischemia) or 'late' referral, the use of CVCs becomes inevitable. ,, The frequent use of CVCs at the beginning of HD in patients with ESRD in fact has been interpreted as an 'index of late referral. In a recent study, a quarter of the Italian dialysis centers experienced the problem of late referral in more than 40% of patients admitted for renal replacement therapy.  The high risk HD environment for transmission of nosocomial infections presents a pressing demand for extra skilful nursing care and high levels of hygiene and cleanliness. Understaffing plays a key role in the development of CRBSI; the risk of infection has been reported to rise significantly, with nursing staff reduction below a critical level. ,
| Complications and Bacterial Flora Associated with VRBSI|| |
Besides sepsis with peripheral circulatory failure and disseminated intravascular coagulation, metastatic complications occur in a large proportion of patients with infected vascular access; these include endocarditis, osteomyelitis, septic arthritis, septic pulmonary emboli, and spinal epidural abscesses, [Table - 3]. ,,,
Infective endocarditis (IE) is one of the most serious and life-threatening complications, as a result of exogenous artificial material, such as PTFE grafts and CVCs. , The tip of CVC is usually positioned in the atrium, close to the cardiac valves, which carries a special risk of infective endocarditis. In Marr's original description, 22% (9/41) of patients developed complications such as osteomyelitis, septic arthritis, IE and death.  The rate of complications was nearly twofold (41%) in patients with Gram-positive bacteremia. Predominantly S. aureus has been associated with the most devastating metastatic complications among HD patients due to its predilection to adhere to heart valves and bone.
In another description by Marr's et al, 65 episodes of S. aureus bacteremia (1.2 episodes/ 100 patient-months) were identified among HD patients; 44% of the patients developed complications including IE among 12% of cases. Sixty seven percent of the patients in this study group were dialyzed through CVCs indicating that catheters were the greatest risk factor for the development of infective endocarditis, in this cohort. 
In a recent retrospective study from Taiwan  to determine IE and the mortality risk factors among 288 HD patients, the prevalence of IE was 6.9%. The most common pathogen was S. aureus (60%). Patients with cardiac pacemakers, congestive heart failure, previous heart surgery, low serum albumin at the time of admission, shorter duration of HD and those dialyzed via non-cuffed dual-lumen catheters were found to be at significantly higher risk of developing IE. The overall mortality in HD patients with IE was 60%, while it was 100% in patients with MRSA associated endocarditis. Univariate analysis of in-hospital clinical parameters for mortality revealed no significant difference in age, diabetes, duallumen catheter implantation, serum albumin, time to diagnosis, and time to antibiotic use. 
Early reports of low incidence of infective endocarditis may have underreported the incidence since transthoracic echocardiography (TTE) is relatively less sensitive compared with transesophageal echocardiography (TEE). There was evidence of infective endocarditis by TEE in 19% of patients with negative TTE and 21% in patients with indeterminate TTE findings.  Unexplained infectious problems in patients with CVCs should always prompt a careful search for access infection and endocarditis. 
Even though S. aureus is associated with the development of vascular access-related BSI in the majority of cases; the patients on long-term HD carry a significantly high risk of having BSI due to gram-negative bacilli. Data from Duke medical center, USA showed that over 60% of the VRBSI were Gram positive cocci, while 24% of them were due to the Gram negative bacilli.  In another study, 52% of the VRBSI were caused by Gram positive cocci, 26.7% by Gram negative bacilli and approximately 20% were polymicrobial, [Table - 4].  However, a study at our center revealed relative predominance of Gram negative bacilli (54%) over S. aureus (29%) among patients with VRBS, [Figure - 3]. 
Regardless of the type of microorganisms, the previous history of VRBSI has been reported to be a significant risk factor for further bacterial infection (RR-7.33). The patients who experience an episode of BSI have twice the risk of death from any cause and eight fold higher risk of death from BSI.  Moreover, the use of synthetic vascular accesses such as PTFE grafts and CVCs have been associated with relatively resistant type of anemia requiring a great deal higher recombinant human erythropoietin and intravenous iron dosing. ,
| Relationship between Thrombogenesis and HD Catheter Infections|| |
The pathogenesis of colonization of CVCs involves the formation of a thrombin sheath and/or a bacterial biofilm.  Following insertion, a thrombin sheath rich in host proteins envelops the internal and external surfaces of the intravascular segment of catheter. The proteins in the thrombin sheath such as fibrin, fibrinogen, fibronectin, laminin, thrombospondin and collagen act as adhesins. The organisms such as coagulase negative staphylococci bind to fibronectin, whereas S. aureus binds strongly to fibronectin, and fibrinogen. This intriguing process observed at the molecular level transforms into a remarkable relationship between thrombogenesis and infection, which dictates the prevention of catheter-related thrombus as an additional mechanism for reducing CRBSI. ,,
| Relationship between Vascular Access Related Infections and Cardiovascular Mortality|| |
A novel hypothesis to explain the relationship between inflammation, infection and mortality due to cardio-vascular disease (CVD) in ESRD patients, is fast emerging. Recent data shows that chronic inflammation, a non-traditional risk factor that is commonly observed in HD patients, may cause malnutrition and progressive atherosclerotic CVD by several pathogenetic mechanisms. A baseline level of systemic inflammation present in the patients with ESRD, serves as a risk factor for CV mortality. When these patients develop infection, the level of inflammation is amplified and increases the CV risk several-fold.  Although the origin of inflammation may include protein carbamylation, dialyzer bioincompatibility, impure dialysate, and back-filtration, factors such as VRBSI has been reported to play a major role in the progression of inflammation in HD patients. 
Currently, the type of vascular access has also been linked to mortality. CVCs and PTFE have significantly higher incidence of BSI and mortality both, directly as an outcome of infectious disease process and indirectly as a risk factor for the CVD.  A single episode of vascular access-related BSI increases mortality rate seven folds at six months after initiation of dialysis. Subsequently, mortality rate decreased but remained at least two folds at 5 years.  Likewise, the patients who had single episode of BSI , CV events such as - acute myocardial infarction, congestive heart failure and cerebrovascular accidents, occurred more frequently at six months after commencement of dialysis and remained elevated for up to five years.  Although inflammation may reflect underlying CVD, an acute-phase reaction may also be a direct cause of vascular injury. Available data suggest that proinflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. The elevation of markers of inflammation up to 8-10 folds has been observed among HD patients compared to healthy controls. 
Thus, it could be inferred that inhibition of the vicious cycle of malnutrition, inflammation, and atherosclerosis (MIA syndrome) would improve the survival in HD patients. 
| Diagnosis of the Vascular Access-Related Infections|| |
Various clinical and microbiological features may be suggestive of the vascular access being the source of the BSI. Clinical suspicion may be raised by the visible signs of inflammation (erythema, tenderness, warmth and swelling) at the vascular access puncture/placement or exit site with or without systemic manifestations of bacteremia such as malaise, fever, rigors, backache, altered consciousness, unexplained hypotension during HD and leucocytosis, and absence of evidence of other sources of BSI such as pneumonia, urinary tract infection and surgical wound infections. Furthermore, the blood culture may be positive for an organism recognized to be a frequent cause of VRBSI such as S. epidermidis, S. aureus or Gram-negative bacilli etc.  Isolation of these microorganisms from the blood culture obtained from peripheral vein and the swab cultures taken from the site of the inflamed vascular access should generally be sufficient to make a working diagnosis of VRBSI. Nevertheless, the onset of fever and chills, particularly during a HD session, should be considered to be a catheter infection unless proven otherwise.
Definite microbiological findings in CRBSI may include positive simultaneous blood cultures drawn through CVC and peripheral vein; the colonies isolated from the blood culture obtained through catheter should be > 30 cfu/mL or at least five folds greater than that quantified from the concurrent peripheral blood culture.  In case of non-quantitative blood cultures, the blood culture obtained through the catheter should become positive at-least two hours earlier than the simultaneous blood cultures drawn from the peripheral vein in order to suggest higher inoculums and imply the CVC as the source of BSI.  Finally, a catheter tip yielding > 15 cfu per segment with roll plate semiquantitative blood culture technique subsequent to catheter removal or exchange over a guide wire - is an indicator of CVC being the source of BSI provided that the same microorganism is isolated from the catheter tip and peripheral blood culture. ,
| Management of Vascular Access-Related Infections|| |
Local infections confined to the access puncture and cannulation sites can be treated with appropriate antibiotics based on culture results. Native AVF infections are although rare and respond well to antibiotic therapy in most instances; infections of AVF with BSI should be treated as bacterial endocarditis with 4-6 weeks of systemic antibiotic therapy. In general, elimination of AVF is only required when it becomes a source of recurrent septic emboli.
Despite current Dialysis Outcomes Quality Initiative (DOQI) guidelines recommending placement of autogenous AVF in more than 50% of patients, the great majority of HD access is still through CVCs or PTFE grafts in hospitals worldwide.  Furthermore, among permanent vascular accesses, AVG infections pose potentially life-threatening septic and bleeding complications, as well as loss of dialysis access. The management of VRBSI includes total graft excision when patients present with whole graft infection or subtotal graft excision. , Partial excision minimizes the need for extensive dissection of wellincorporated uninfected graft segments that permits continual dialysis access at the infection free portion of the graft. 
Powe et al found that CVCs raised the risk of BSI by 50% and PTFE grafts increased the risk by 33% when compared to native AVF.  The risk increased more than two folds if the catheters were used in the first six months of the HD therapy. Although the standard treatment for infected CVCs remains the removal of the device in regular clinical practice, however, the optimal management of CRBSI continues to be controversial. Raad et al suggested some clinical situations for obligatory removal of infected intravascular catheters, [Table - 5]. 
I. Antibiotic Access Salvage and Duration of Antibiotic Therapy
Marr et al proposed antibiotic salvage of the vascular catheters as an alternative to CVCs removal. Their study included 38 patients in whom bacteremia was medically treated, while the catheter remained in place. Using this approach successfully salvaged approximately 32% of the catheters.  In a study of 85 patients, the vascular the access salvage at our center through empirical amikacin-vancomycin therapy was successful in 56.4% patients with VRBSI.  Therapy with empirical antibiotics was continued post-HD for five successive dialysis sessions in patients with temporary vascular accesses (UTCs) and for 7-10 consecutive dialysis sessions in patients with permanent vascular accesses (TCCs, PTFE grafts and AVFs). A cure was defined as a 45 days symptom free interval after antibiotic therapy.  The higher success rate compared to that of Marr's et al could be due to the inclusion of AVF and PTFE grafts in our study; the success of the antibiotic therapy alone has been reported to be much higher for AVFs and PTFE grafts, whereas the yield was relatively low in case of infected CVCs. , However, another group from the same institute reported a clustering of epidural abscesses that occurred in patients undergoing dialysis during the study period, suggesting that antibiotic treatment alone may not be effective in eradicating the infection or entirely risk free; generally, it can not be considered as a substitute for catheter removal. 
II. Technique of Catheter Exchange Over a Guide Wire
Nephrologists are usually reluctant to remove infected catheters because the majority of patients with cuffed tunneled catheter have already exhausted other options for dialysis access.  Exchange of the catheter over a guide wire, during or after parenteral broad spectrum antibiotic treatment (which hopefully sterilizes the access site), was thought to be a logical extension of antibiotic access salvage technique. Shaffer et al  observed encouraging preliminary results with this approach in 10 patients; three patients needed a second exchange to eliminate the infection. Robinson et al  reported similar findings in 23 patients with bacteremia that was treated with catheter exchange and three weeks of treatment with antibiotics. Catheter tunnel infections were excluded. This protocol yielded eradication of the infection in 82% of access sites at 90day follow-up. 
Beathard et al  in their large prospective observational study of two years demonstrated equal outcomes with guidewire exchange compared with delayed catheter placement. They categorized HD patients (n =114) with infected catheters into three groups: first, those with bacteremia and minimal symptoms, second, those with tunnel or exit-site involvement and bacteremia and, third, those with severe clinical symptoms. In the first group (n = 49), the catheters were exchanged over a wire, and antibiotic therapy was instituted for three weeks; the success rate was 88% at 45 days. The second group (n = 28) was treated with catheter exchange, creation of a new tunnel and antibiotics with a 75% success rate. In the third group (n = 37) the antibiotic therapy was instituted awaiting clearance of bacteremia, and then a new catheter was placed-the success rate was 86.5% at 45 days. The authors concluded that guidewire exchange of catheter had the advantage of removing the infected catheter and the adherent biofilm, while preserving the vascular access site.
Tanriover et al  in a more recent study, compared the two strategies of catheter removal with delayed replacement and catheter exchange over a guide wire with creation of new tunnel in a total of 69 catheters and followed the infection-free survival of the new catheter; patients in both groups received three weeks of intravenous antibiotics. Although infectionfree survival of the new catheters was comparable, serious complications occurred in 19% of patients that included sepsis syndrome, endocarditis, septic arthritis, and septic emboli in both groups. Thus, despite promising results, the procedure remains controversial. 
Severe catheter sepsis remains an indication for immediate catheter removal, whereas mildly symptomatic bacteremia may be treated with catheter exchange and systemic antibiotics. Moreover, bacteremia with tunnel tract involvement should prompt catheter removal. The NKF-DOQI Work Group, (guideline 23) cautions that three weeks of systemic antibiotic therapy is needed to treat CRBSI and that a new permanent access should not be placed until cultures have been negative for at least 48 hours after cessation of antibiotic therapy. 
III. Antimicrobial-anticoagulants 'lock' Technique
Despite their adequate plasma therapeutic levels, the systemic antibiotics have low access salvage rates since they fail to diffuse in sufficient concentration inside the catheter lumen where the actual bacterial seeding occurs.  The antibiotic lock technique permits the intraluminal sterilization and reduction of the antibiotic side effects. This technique in combination with the concurrent administration of systemic antibiotics brought about the eradication of CRBSI in 90% of patients receiving home parenteral nutrition without catheter removal.  In the1997 meeting of the American Society of Nephrology (ASN), Sodermann et al  reported that a mixture of gentamicin and Tricitrasol (trisodium citrate) 'locked' into the HD catheter weekly was a superior approach to catheter salvage; it virtually reduced the incidence of CRBSI to zero than the routine locking of heparin alone in the CVCs after each HD session. In a small observational trial, continuous antibiotic infusion followed by antibiotic-heparin lock using vancomycin or ciprofloxacin successfully eradicated BSI in 100% of the 13 HD patients within 48 hours without need for CVC removal. 
In several recent studies, ,, antibiotic heparin/citrate locks have been reported to reduce risk of bacterial colonization of CVCs and consequent decrease in septicemia. A number of third generation cephalosporins, ciprofloxacin, vancomycin and gentamicin have been found to be appropriate for antibiotic-heparin lock. A fairly lower concentration of antibiotics (10 mg/ml for each of cephazolin, ceftazadime and vancomycin, and 5mg/ml for gentamicin) as compared to their systemic dosage is required to fill the lumina of the CVCs to sterilize and prevent further bacterial colonization during interdialytic period.  The theoretical advantages of this technique over systemic antibiotic administration alone include relatively higher concentrations delivered directly to the site of infection enhancing the likelihood of sterilizing the catheter luminal surfaces, lower incidence of antibiotic toxicity, less risk of promoting drug resistance (as there is no spill out of drug into the circulation) and greater practicality in out-patients setting. However, regardless of the reasonably lower regional doses of antibiotics in the catheter 'lock' solutions, aminoglycoside-associated ototoxicity has recently been reported. , Ototoxicity occurs when a critical amount of drug accumulates in the cochlear fluids by an essentially unidirectional diffusion process, at a slow rate that is linearly related to extracellular drug concentration.  Yet, antibiotic locks appear to be a plausible and attractive option to conventional modes of treatment of colonized CVCs. ,, Large multicenter randomized placebo controlled trials are necessary to provide the substantial evidence for the efficacy of antibiotic lock technique in the management of CRBSI.
| Guiding Principles, Policies and Practices for the Prevention of Vascular Access-Related Infections|| |
I. Maximal Sterile Barrier Precautions, Asepsis and Catheter Dressing.
Full barrier precautions during the vascular access placement that include sterile gloves, long-sleeved sterile gowns, masks, caps and large sterile sheet drapes may reduce the incidence of VRBSI.  Hence, comprehensive strictly enforced hygienic safety measures should be an essential part of the CVCs placement and handling in order to prevent intraluminal colonization.
Povidone-iodine and alcohol are the most widely used antiseptics for cleansing catheter insertion sites; studies failed to show any statistically significant difference in the incidence of CRBSI when chlorhexidine was used as a cleansing agent. , In patients with an allergy to povidone-iodine, alternate agents such as tripple antibiotic ointment (polymyxin, bacitracin and neomycin) were used as a substitute. However, prophylactic efficacy of the polyantimicrobial gel remains to be established; due to increased catheter colonization with Candida species following the use of tripple antibiotic ointment, its application is currently not recommended. 
Dry gauze dressings rather than transparent film dressings are recommended because the latter poses a greater threat of exit site colonization.  The use of dry gauze dressing and povidone iodine and mupirocin ointment at the catheter exit site can reduce the incidence of exit site infections, especially in patients who have nasal carriage S. aureus (relative risk, RR, 0.1, 95% CI, 0.0-0.7). , In a randomized controlled trial, the Australian investigators found that the thrice-weekly application of 2% mupirocin ointment to cuffed hemodialysis exit sites markedly reduced sepsis and prolonged catheter survival. No adverse effects were noted, and antimicrobial resistance was not induced.  However, mupirocin ointment may adversely affect the integrity of polyurethane catheters. ,,
II. Nasal Decolonization of Bacterial Flora
A number of studies have shown that nasal decolonization of S. aureus effectively reduced the incidence of VRBSI in dialysis patients. , Nonetheless, the efforts to realize long-term elimination of S. aureus from the anterior nares through decolonizing agents such as oral rifampicin and mupirocin nasal applications had been associated with the development of side effects, emergence of resistance and recolonization of S. aureus, once the drug was discontinued. , Of the two types of resistance, the low-level type (MIC 8-256 mg/l) results from modification of the target enzyme and the high-level type (MIC > 500mg/l) is the product of plasmid encoded mupirocin resistant enzyme.  It is the transmissible mechanism of the high-level resistance that remains the cause of concern about the potential spread of mupirocin resistance once the drug is used on a large scale and on the long-term basis as in the chronic HD patients. Additionally, these decolonizing agents lack standardized schedules for application and their optimal duration of use is also not known.
However, short-term decolonization prior to placement of permanent vascular accesses (AVF/ PTFE graft/ TCC) may have the potential to reduce the dialysis access infections perhaps without side effects and emergence of resistance.
III. Site of Placement of CVCs
Several prospective, observational studies using multivariate analysis found that the risk of infection was significantly increased with insertion into the internal jugular vein compared with insertion into the subclavianvein ,, Therefore; catheter placement into the subclavian vein is preferable to reduce the risk of infection. However, the risk must always be weighed against non-infectious complications (subclavian stenosis) associated with the subclavian vein insertion. The risk of bacterial colonization (Hazard ratio, 4.2, 95% CI, 2.0-8.8) and deep vein thrombosis is much higher with insertion of catheter into femoral vein than with subclavian or internal jugular vein insertion. , For that reason, femoral venous catheterization should be limited to circumstances that prevent the use of alternative access sites.
IV. Use of Antiseptic / Antimicrobial Coated or Impregnated Catheters
The strategy of coating catheters with antimicrobial/ antiseptic agents to prevent CRBSI finds its basis in the fact that catheter surface represents the real battlefield between microorganisms and the body defence mechanisms. Various antiseptic/antimicrobials have been used to coat the surfaces of the catheters to prevent bacterial colonization, including chlorhexidine, silver sulphadiazine, minocycline, rifampicin and vancomycin.
Maki et al  incorporated chlorhexidine gluconate and silver sulphadiazine (CH/SS) to the external surface of catheters and compared their efficacy with uncoated catheters. The antiseptic catheters were less likely to be colonized at removal than control catheters) and were nearly five folds less likely to produce BSI. The result of this study could not be confirmed through further prospective randomized studies. ,, Heard et al  found no significant difference between the rates of CRBSI in the catheters coated with CH/SS and the uncoated ones. The disadvantage of these catheters was that they were coated only on the external surface while the lumens of the catheters remained uncoated. The antimicrobial durability of these catheters was less than one week. Also of concern were the reports of anaphylaxis and mortality associated with the use of CH/SS catheters, which led to the banning of these devices in Japan. ,
Raad et al found the synergistic combination of minocycline and rifampicin (M/R) to be efficacious in preventing bacterial colonization of slime-producing strains of S. epidermidis and S. aureus on the catheter surfaces., This group also found that the catheters coated with M/R had significantly better in vitro inhibitory activity against S. epidermidis, S. aureus and Enterococcus faecalis trains than did catheters coated with vancomycin (P <0.05).
Darouiche et al  evaluated 738 catheters by catheter culture in a large multicenter prospective randomized clinical study comparing the efficacy and safety of catheters impregnated with M/R with those of catheter coated with CH/SS. They found that catheters impregnated with M/R were three times less likely to be colonized than were those impregnated with CH/SS (7.9% vs. 22. 8%, P<0.001). The catheters coated with M/R were also 12 folds less likely to be associated with CRBSI than were the catheters coated with CH/SS (0.3% vs. 3.4%, P<0.001). These catheters had more durable antimicrobial activity of four weeks compared to less than three weeks for the CH/SS catheters. 
Although the antimicrobial-coated catheters have a shorter antimicrobial durability and fairly higher cost, they are important novel additions to the group of CRBSI preventive strategies. However, their use for vascular access awaits further studies because only limited data to support their efficacy among long-term HD patients, is available at present. ,
V. Dialysis Ports
The recent introduction of dialysis ports represents another move towards controlling the problem of infection in patients with longterm catheters. Two devices are in clinical trials in the USA and elsewhere, using the idea borrowed from the treatment of patients with cancer in whom subcutaneous ports had infection rates lower than those of the tunneled catheters with external hubs.  The devices consist of one or two subcutaneous ports connected to one or two silicone catheters that are placed via the internal jugular vein and accessed percutaneously.
Clinical experience with these devices is limited to small series. One device, Dialock (Biolink, Middleboro, Mass), consists of a titanium port with two individual needle passages that are connected to two 11-F catheters with spiral side holes at their tips, [Figure - 4]. The device is percutaneously accessed by using a proprietary needle-sheath combination and has a valve that holds the sheaths in place during dialysis. Published reports of two small clinical series (10 patients each) describe good results with this device, with mean flow rates of just over 300 mL/min. The early reported infection rates; however, did not demonstrate a significant reduction; Levin et al  reported 0.23 bacteremic episode per 100 catheter days, and Canaud et al  reported 0.17 episode per 100 catheter days.
The other device, LifeSite (Vasca, Tewksbury, Mass), consists of two individual titanium ports attached to 12-F silicone catheters with circumferential side holes at the tip, [Figure - 5]. The ports are accessed with a standard 14gauge dialysis needle; when turned, the ports lock the needle in place. Preliminary data have indicated rates of infection that require catheter removal of 0.13 episodes per 100 catheter days.  Neither of these devices has received U.S. Food and Drug Administration approval yet.
VI. Antibiotic-Heparin/ Citrate 'Locks'
Recently, antibiotic-heparin/ citrate locks, investigated for the prevention of gram-positive CVC-related bacteremia among neutropenic cancer patients, have shown encouraging results; none of the 60 patients receiving vancomycinheparin lock developed CRBSI over an average of ten days of observation period. 
Dogra et al  conducted a double-blind randomized study of 112 TCCs in 83 patients to compare heparin (5000 U/ml) with catheterrestricted filling of gentamicin/citrate (40 mg/ml and 3.13% citrate; ratio 2:1) as catheterlock solutions. The primary end point was CRBSI. Significantly lower incidence of CRBSI (0.03 vs. 0.42 per 100 catheter-days, P = 0.003) and considerably higher mean infection-free catheter survival (282 days vs. 181 days, P = 0.002) were observed in the gentamicin group compared to that of the heparin group. However, the predialysis gentamicin levels were found to be significantly higher in patients randomized to the gentamicin group compared to those of the heparin group (2.8 mg/L vs. <0.2 mg/L, respectively, P = 0.008)). The authors cautioned that the safety of the' locked' dose of gentamicin for ototoxicity is yet to be established.
In a prospective randomized controlled study  carried out at Louisiana State University Health Services Center in Shreveport, USA, 14 patients with TCC locked with 40 mg/ml gentamicin plus 4.6% trisodium citrate were evaluated for the CRBSI, thrombosis episodes and catheter-survival rates against 19 patients locked with heparin, alone. The group with gentamicin-citrate lock had reasonably lower incidence of CRBSI (0.62 vs. 2.11/1000 patient-days, respectively) catheter thrombosis episodes (2.5 vs.3.2/1000 patient-days, respectively) and significantly longer mean cathetersurvival percentage at 60 days following placement (74.0 ± 12 vs. 59.0 ± 11, respectively) than the control group. However, the study was prematurely terminated following FDA's ban on the use of Tricitrasol (46.7%) as catheter lock despite the fact that much lower concentration of trisodium citrate (4.6%) was used in this study and weekly predialysis gentamicin levels were measured to assess the systemic toxicity. 
McIntyre et al  in a recent randomized controlled study of 50 patients comparing gentamicin and heparin (5 mg/mL) locked tunneled CVC group with that of catheterfilled with standard heparin (5000 IU/mL) alone. They compared the number of BSI episodes, hemoglobin levels and Epoetin requirement. The gentamicin-locked group recorded just one BSI episode (0.3/1000 catheter days) compared to 10 episodes in six patients in the heparin group (4/1000 catheter days, P= 0.02). The use of antibiotic locking was also associated with significantly higher mean hemoglobin levels (P= 0.003) and a lower mean Epoetin requirement (P= 0.04).
In view of the recent reports on aminoglycoside 'lock' ototoxicity, , a prospective observational study of 67 patients was carried out at our center to evaluate the efficacy and safety of cefotaxime (10 mg/ml) and heparin (5000 U/ml) lock in the prevention of CRBSI.  A significant reduction in the incidence of CRBSI was observed compared with that of historical controls (0.55 vs. 1.19 episodes/1000 catheter-days).  Cefotaxime was selected on account of its broad spectrum and reported high clinical and microbiological safety profile. 
Although antibiotic-heparin locks are not in routine use in patients undergoing HD, yet, it appears that these 'locks' have potential to effectively prevent the episodes of CRBSI among HD patients. , ,,,,,,,,,,
VII. Nonantibiotic Locks
The hypertonic saline has been safely used to treat dialysis-induced hypotension. In addition, it has bactericidal properties enhanced by acidification, Moore et al  developed a novel non-antibiotic locking method that retained undiluted anticoagulant (heparin, 5000 U/mL) at the catheter tip and undiluted bactericidal solution (acidified concentrated saline - ACS solution) at the catheter hub using a very small air bubble (0.1 mL) in between to prevent the mixing of the two solutions through diffusion. In an in vitro study,  the ACS solution (0.9 mL of 27% saline solution with a pH of 2.0), demonstrated significantly superior bactericidal properties compared to other non-antibiotic antibacterial agents such as povidone iodine, sodium hypochlorite, and chlorhexidine, which destroyed the bacteria immediately (at the zero hour) in 89% Vs 70, 66, and 59% of the samples, respectively. At the 6th hour, 100% of the samples from the ACS, povidone iodine and chlorhexidine demonstrated zero bacterial growth. The ability to kill most of the common organisms responsible for access infections can make ACS a potentially attractive option to reduce incidence of CRBSI in HD patients.
In another recent study, Dannenberg et al  assessed the ethanol-lock technique as a means of treating the CVC infections in 28 pediatric cancer patients with Broviac catheter. Sixty seven percent of the children treated with ethanol locks had no infectious relapse within four weeks of treatment, compared with 47% treated with systemic antibiotics alone. No severe clinical side effects of ethanol flush were observed except for mild symptoms such as tiredness, headaches, dizziness, nausea, and light-headedness.
However, further confirmation of the efficacy of ACS solution and air-bubble method of locking HD catheters and ethanol-lock technique awaits full-scale well-designed prospective randomized studies.
VIII. Policy of AV Fistula Optimization; Limiting the Use of CVCs
Timely placement of a reliable permanent vascular access is crucial for the quality HD care; NKF-DOQI guidelines emphasize the native AVF as the preferred access for incident patients. However, recent data from the Dialysis Outcome and Practice Patterns Study (DOPPS) revealed that just 24% of the prevalent patients in US used AVF for HD; prevalence of AVF was significantly associated with younger age, male gender, lower body mass index, nondiabetic status, and absence of peripheral and cardiovascular disease. Among incident patients, only15% used AVF, 60% used CVC and 24% had PTFE graft. In addition, 46% of the US incident patients did not have a permanent access placed prior to starting HD. 
Several studies have shown that that exceeding the NKF-DOQI goal of more than 50% fistula placement is achievable in the USA and elsewhere. ,,, Optimized AVF placement is associated with improved patient outcomes in terms of reduction in the incidence of VRBSI and the costs of ESRD even among high-risk groups such as diabetics, the elderly and those with nasal carriage of S aureus . ,,, .
IX. Initiation and Implementation of Nationwide Pre-ESRD Programs; Limiting the Late Referrals
Patients who start chronic dialysis within one month of referral to the nephrologist (late referral) have poor HD outcomes. It is now well known that formal pre-dialysis educational and follow-up programs are more beneficial concerning early dialysis outcomes and resource utilization than the unstructured specialist follow-up. A primary barrier to native AVF creation is lack of timely referral. In Europe, 84% of new HD patients had seen a nephrologist for more than 30 days prior to ESRD compared with 74% in the US (P < 0.0001).  Strategies to increase AV fistula creation require early referral to nephrology and early placement of AVF. Pre-ESRD care has been associated with increased chances of AVF placement versus graft use (OR=1.9, P=0.01); incident HD patients have 1.8 folds greater odds ratio of initiating HD with a permanent access if the facility's usual time from referral to access placement was two weeks or less. ,, Nonetheless, a carefully established and prudently planned pre-dialysis program is more than just the timely referral. 
| Conclusion|| |
Optimization of AVF prevalence to at least 50% and minimization of the use of CVCs, which is primarily dependent upon the timely referrals and realistic countrywide implementation of a carefully crafted pre-ESRD policy, would certainly have a buoyant long-lasting effect on HD outcomes. Nonetheless, the CVCs remain unavoidable and irreplaceable tools for the patients who as a consequence of unpredictable course of progressive chronic renal disease develop an emergency situation, requiring instant dialysis access.
The innovative technology of catheters might present a novel generation of catheters with 'bioactive' surface conferring thrombo-resistant and infection-resistant properties. Nevertheless, the rigorous implementation of standard infection control measures for hygiene and aseptic handling of the vascular accesses at all times would remain a key to minimize the BSI episodes and significantly improve the long-term HD outcomes.
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Anil K Saxena
Division of Nephrology, Department of Medicine, King Fahad Hospital & Tertiary Care Center, Hofuf, Al-Hasa-31982
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]