Changing patterns of antibiotic resistance—update on antibiotic management of the infected vascular access

Renaat A. Peleman1,, Dirk Vogelaers1 and Gerda Verschraegen2

1 Department of Internal Medicine, Division of Infectious Diseases and 2 Department of Microbiology, University Hospital, Ghent, Belgium

Introduction

Haemodialysis can be performed either through permanent arteriovenous (a-v) access, such as a fistula or a graft, or through temporary catheter access. Infection associated with haemodialysis catheters has emerged as one of the most prominent and most serious complications encountered in dialysis patients, and remains a significant cause of morbidity and mortality. This editorial is aimed at providing an update on changing management attitudes towards the infected vascular access as well as on changing patterns of antibiotic resistance, due to shifts of causative micro-organisms and antimicrobial susceptibilities.

Types of vascular access

Haemodialysis requires a reliable, repetitive access to the circulation, capable of providing rapid extracorporeal blood flow. Permanent vascular access should be easily accessible and suitable for undisturbed, long-term use. This is generally obtained by an a-v fistula, by a synthetic a-v fistula (a-v graft) composed of polytetrafluoroethylene (PTFE), or by a catheter, either for acute or for chronic use (double-lumen, cuffed tunnelled catheters) [1]. Primary a-v fistulae are the preferred form of vascular access for they have good long-term patency and infrequently develop infectious complications. They currently constitute less than 20% of the prevalent haemodialysis access in the US, as their creation is limited in an ageing and diabetic population with poor peripheral vasculature.

When an endogenous a-v fistula placement fails, the predominant form of vascular access currently used is the PTFE graft. Synthetic grafts have a higher long-term complication rate due primarily to the development of graft vein stenosis.

Infection of the graft usually requires its removal. Silastic, double-lumen, cuffed tunnelled catheters are central venous catheters, which are primarily used as intermediate-duration vascular access to allow maturation of endogenous fistulae [2]. However, they can also provide acceptable long-term access in patients who have exhausted all available sites [3]. Nevertheless, these catheters are a poor option for long-term access since they provide lower blood flows and have higher rates of infection or other complications. The Dialysis Outcome Quality Initiative (DOQI) guidelines recommend that, unless a-v access options have been exhausted, these catheters should not be used as permanent access [4].

Epidemiology of vascular access infection

Haemodialysis patients are known to be at increased risk of infection due to various defects in their immune function related to the underlying disease, the uraemic state, or the dialysis procedure itself.

Infection associated with haemodialysis catheters has emerged as one of the most prominent and serious complications that is encountered in dialysis patients [1] and remains a significant cause of morbidity and mortality. In a longitudinal 7-year cohort study, Powe et al. found at least one episode of septicaemia in 11.7% of haemodialysis patients [5].

The majority of bacteraemias are caused by vascular access, with indwelling catheters being responsible more often than either fistulae or synthetic grafts. The incidence of bacteraemia associated with non-cuffed, temporary haemodialysis catheters ranges from 1.6 to 7.7 bacteraemias per 1000 catheter-days; in contrast, the incidence of infection is usually lower with tunnelled, cuffed catheters (0.2–0.5 bacteraemias per 1000 catheter-days) [6]. Interestingly, a prospective study reported an incidence of bacteraemia of 3.9 per 1000 catheter-days, similar to the frequency seen with non-tunnelled catheters. The patients underwent routine, not special, catheter care, similar to that used in outpatient practice. This result suggests that in this centre many, if not most, infections are caused by contamination of the catheter lumen, as opposed to the migration of bacteria down the outer surface of the catheter [6].

Risk factors for septicaemia

Risk factors for catheter infection include conditions of catheter placement, catheter manipulation, catheter hub colonization, the foreign body effect of the cuffed, tunnelled catheter, prolonged duration of usage, skin and nasal colonization with Staphylococcus aureus, thrombosis, recent surgery, diabetes mellitus, use of a transparent dressing, and iron overload [1]. Metastatic complications (osteomyelitis, endocarditis, septic arthritis) range in frequency from 8.7 to 50%, with most studies quoting an average of 25%, depending upon the type of vascular access and the organism involved [6,7]. The increased use of cuffed catheters has led to an increasing incidence of metastatic infections, especially when S. aureus is implicated [8].

Emerging resistance

Gram-positive organisms are responsible for most catheter-related infections, with staphylococci (especially coagulase-negative staphylococci) accounting for 40–77%. Of these strains, 40–75% are methicillin resistant. The remainder is due predominantly to enterococci and Gram-negative rods (mainly Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter sp., Enterobacter cloacae, and Klebsiella pneumoniae) [8,9]. The emergence of glycopeptide-resistant enterococci (GRE) is alarming in the USA but is still a minor problem in Europe. From 1989 to 1993, 3.8% of the blood isolates from blood-stream infections reported to National Nosocomial Infections Surveillance (NNIS) were vancomycin resistant. Risk factors associated with GRE include treatment with antimicrobials, gastrointestinal colonization, severity of the underlying disease, abdominal or cardiac surgery, use of indwelling devices, and prolonged hospital stay [10]. Also, methicillin-resistant S. aureus strains with decreased susceptibility to glycopeptides have been reported and may pose a future problem [8,9].

Management of the infected vascular access (diagnosis, management) Diagnosis

It is important to distinguish between catheter exit site, tunnel tract infections, and bacteremia. The definitive diagnosis of catheter-related sepsis has historically required systematic withdrawal of the catheter with culture of the catheter tip for confirmation. The utility of the roll-plate method for diagnosis of infection associated with long-term vascular access devices has not been evaluated, but recovery of >=15 colony-forming units on semiquantitative culture of the catheter tips may be diagnostic of colonization of the intravascular segment. Diagnosis of catheter-related sepsis by an endoluminal brush method can be achieved without line sacrifice and is more sensitive (95%) and specific (84%) than extraluminal sampling of the catheter tip by the Maki roll technique (82 and 66% respectively) [10]. Blood-stream infection resulting from a colonized intravascular segment also may be suspected if the concentration of the micro-organisms is >=10-fold higher on quantitative culture of blood obtained through the catheter compared with the concentration of micro-organisms in blood obtained from a peripheral venous site [11]. The diagnosis of catheter-related sepsis without removing the catheter can also be made by measuring the differential positivity times of cultures of blood drawn simultaneously from central venous catheter and peripheral sites [12].

Management

When discussing the treatment of an infection associated with a dialysis catheter, two issues must be addressed: the infection itself and the handling of the catheter.

Antibiotic therapy

When a patient with an indwelling catheter presents with a positive blood culture, immediate and prolonged antibiotic treatment is essential. Initial therapy with a glycopeptide and an aminoglycoside antibiotic is prudent until culture results are available. The advantages of this regimen include a broad spectrum of coverage for Gram-positive and Gram-negative pathogens and convenient dosing schedules in patients with end-stage renal disease [1].

Intravenous vancomycin, in a dose of 20 mg/kg, should be given weekly, while gentamicin, in a dose of 1–2 mg/kg, should be given after each haemodialysis session. The use of high-flux and/or large surface area dialysers may also require vancomycin to be given after each haemodialysis session to maintain effective blood levels. In this setting, one dosing schedule recommends that vancomycin in a dose of 500 mg be administered at the end of each haemodialysis session [8].

Rapid conversion to appropriate antibiotics, based on culture sensitivities, is needed to prevent the selection of resistant organisms as well as the development of significant ototoxicity.

Treatment should be continued for a minimum of 3 weeks [1].

Blood cultures should be repeated a week following the end of therapy to ensure that the infection has been eradicated. Routine evaluation for valvular vegetations by echocardiography should be considered [1].

Catheter management

There are several choices in the management of the catheter: leave the catheter in, change the catheter over a guide-wire with a new tunnel and new exit site, or remove the catheter and delay replacement until the infection has been treated.

Salvage of the catheter
Several reports of clinical series now indicate that a significant number of catheters can be salvaged, assuming that the catheter is functioning properly and that the exit site and tunnel tract are not infected. One study prospectively evaluated the use of antibiotics given both systemically and ‘locked’ into the catheter in 13 episodes of catheter-related sepsis, due predominantly to S. epidermidis and Ps. aeruginosa [13]. The patients were successfully treated with vancomycin or ciprofloxacin. Fever subsided within 48 h, there were no complications, and no patient required catheter removal. Prospective trials locking antibiotics and urokinase into the catheter between treatments both to prevent and to treat catheter-mediated bacteraemia are under way. Still, a trial of antibiotic therapy alone may be warranted in patients who are haemodynamically stable and do not have tunnel infection, particularly if vascular access is difficult [8].

Catheter exchange
The low success rate of the antibiotic salvage trial and the observation of no increased risk of metastatic infection with attempted salvage prompted the initiation of several recent studies evaluating the effectiveness of guide-wire catheter exchange [1416]. These studies included patients with no evidence of tunnel tract involvement and who had defervesced within 48 h of beginning empirical antibiotic therapy. Antibiotic therapy was continued for 3 weeks. A success rate over 80% was reported. In addition, there was no increase in the frequency of complications. Guide-wire catheter exchange therefore appears to be efficacious in the majority of this selected patient population.

Catheter removal
In patients who have exit-site or tunnel infections, the catheter must be removed and a new tunnel and exit site must be created when it is replaced. Replacing the catheter at a new site 24–48 h after the patient has become afebrile is successful in the vast majority of patients. Treatment with intravenous antibiotics for 3 weeks following an episode of catheter-elated bacteraemia is recommended. Blood cultures should be done after 1 week to ensure complete cure. But still, the risk of delaying catheter removal must always be balanced against the risk associated with re-establishing vascular access.

Prevention of catheter infection

Prevention of catheter-associated infection involves three areas: maximal barrier precautions when the catheter is placed, adherence to strict aseptic techniques at each catheter contact, and daily care of the catheter exit site and catheter management in the haemodialysis facility [1]. Meticulous aseptic technique is critical to prevent hub contamination and bacterial infection.

The use of dry gauze dressing and povidone iodine ointment at the catheter exit site is recommended whenever possible to reduce the incidence of exit-site infections, especially in patients who are nasal carriers of S. aureus [4]. Haemodialysis patients receiving anti-staphylococcal antimicrobials at the time of catheter placement have been shown to have a lower incidence of catheter-related infection. However, the role of prophylactic antimicrobials has not been studied directly, and neither has the risk for the emergence of antibiotic resistance with the adoption of this technique [11].

Recent efforts have focused on designing catheters with a lower infection rate. These include antibiotic- or antiseptic-bonded catheters and silver-coated catheters. The antibiotic-bonded catheters, although showing reduced incidence of colonization, have not yet been studied in the haemodialysis population, nor have they been studied as cuffed silastic catheters. Silver coating does not confer benefit against clinical infection or colonization [1720].

Practical guidelines

The efficacy and safety of catheter ‘salvage’ and the optimal duration of antibiotic therapy have yet to be defined. Nevertheless, the following approach can be recommended [1,4,8,11]:

When catheter-associated bacteraemia is recognized, catheters should be removed whenever possible

In case of accompanying exit-site or tunnel infection (erythema or pus at exit site), the site should be cultured, and the catheter should be subsequently removed and cultured as well.

If an alternate site for vascular access is not available, a trial of catheter salvage can be attempted, using the following guidelines:

If all of the above conditions are met, the catheter can be exchanged over a guide-wire,with 3 weeks of appropriate antibiotic therapy [15,16].

Patients who remain febrile or have positive cultures after the catheter is removed should undergo a thorough examination for metastatic complications (such as endocarditis, vertebral abscess, and osteomyelitis). As clinical signs of metastatic infection may also occur in patients without protracted fever or persistent bacteraemia, all patients with catheter-associated bacteraemia should be carefully assessed by serial clinical examinations.

Notes

Correspondence and offprint requests to: Renaat A. Peleman, Department of Internal Medicine, Division of Infectious Diseases, University Hospital, 185 De Pintelaan, B-9000 Ghent, Belgium. Back

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