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Adjunctive Antibiotic/Anticoagulant Lock Therapy in the Treatment of Bacteremia Associated with the Use of a Subcutaneously Implanted Hemodialysis Access Device

Boorgu, R.*; Dubrow, A. J.; Levin, N. W.; My, H.; Canaud, B. J.§; Lentino, J. R.*; Wentworth, D. W.*; Hatch, D. A.*; Megerman, J.; Prosl, F. R.; Gandhi, V. C.*; Ing, T. S.*

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Abstract

Despite myriad advances in hemodialysis therapy, management of complications related to vascular access remains one of the notable challenges in the treatment of patients with end-stage renal disease (ESRD). Over the past two decades, little progress has been made in improving the performance of permanent vascular accesses. Thus, the arteriovenous fistula and arteriovenous graft continue to be the primary choices for vascular access in the ESRD patient population. 1 In 1988, Schwab et al. championed the use of a felt cuffed, subcutaneously tunneled venous catheter for the purpose of long-dwelling vascular access in dialysis patients. 2 Such venous catheters are commonly used when there are anatomic or other reasons preventing arteriovenous access placement from being carried out, or while awaiting the maturation of a newly implanted fistula or graft. Data collected by the United States Renal Data System indicate that, in 1996, 19% of all new hemodialysis patients were being dialyzed with a tunneled, cuffed venous catheter. 3 Although venous catheters have contributed substantially to the management of ESRD patients, these devices continue to exhibit high rates of failure as a result of poor flow, infection, and thrombosis. 4

To offer another option for vascular access, a novel subcutaneously implanted access device, the Dialock Hemodialysis Access System, has been developed. 5–8 In our experience with this device, patient acceptance has been satisfactory and blood flows have been adequate. 5 However, use of this device is not free from infectious complications such as bacteremia. Traditionally, management of catheter related bacteremia has often entailed the use of systemic antibiotic therapy and, in many instances, removal of the infected catheters. In an attempt to minimize the necessity of surgically removing infected Dialock devices, we investigated the feasibility of using the topical antibiotic/anticoagulant lock approach as an adjunct to systemic antibiotic therapy. 9

Materials and Methods

After having given informed consent, under a protocol approved by the institutional review board at each institution, each of the participating patients was surgically implanted with a Dialock device. 5–8 Fabricated from titanium, the device possesses two valved access ports at one end and two reinforced silicone catheters at the other. The catheters are inserted through a major upper vein into the superior vena cava or the right atrium. Before dialysis, the skin over the Dialock device is thoroughly cleaned with isopropyl alcohol and betadine. The access ports of the device are then accessed percutaneously by using two special 15-gauge needles. These needles, along with the respective catheters, functionally convert the Dialock device into twin blood channels for dialysis access (the total volume of a blood channel is on the order of 1.8 to 2.2 ml). Patency between dialysis sessions is maintained by using a heparin lock. In the present study, 26 Dialock devices have been implanted in 25 patients since May 1997. Regular dialysis sessions were performed three times a week. Patients who exhibited manifestations of bacteremia, such as fever or rigors, had cultures carried out on blood samples obtained from the Dialock device, as well as from a peripheral vein. Systemic antibiotic therapy was invariably started empirically, with the choice of antibiotic treatment being made by the patient’s physician. Initially, patients suffering from bacteremia were treated with systemic antibiotic therapy only. However, one patient treated in this manner failed to respond and continued to have manifestations of bacteremia. It was only after antibiotic/anticoagulant lock therapy had been added to the on-going, systemic antibiotic therapy that prompt resolution of the bacteremia ensued. Because of this experience, we altered our therapeutic approach to catheter related bacteremias by using both systemic antibiotics and topical antibiotic/anticoagulant lock therapy at the same time. The latter therapy consists of the instillation, after a dialysis treatment, of an antibiotic/anticoagulant mixture into both access ports and the respective catheters of a Dialock device. Before the initiation of the following dialysis session, the antibiotic/anticoagulant lock solution was withdrawn and discarded; dialysis was then performed in the usual manner. Typically, both the antibiotic/anticoagulant lock therapy and the systemic antibiotic therapy were continued for 2 to 3 weeks after the onset of bacteremia. Composition of the antibiotic/anticoagulant lock solutions and other particulars of the bacteremic episodes are presented in Table 1.

Table 1
Table 1:
Composition of Four Varieties of Antibiotic Plus Heparin Lock Solutions for the Treatment of 14 Episodes of Dialock Device Related Bacteremic Episodes in Eight Patients*

Results

The 26 implanted Dialock devices have been used for up to 20 months (a total of 329 patient months), with a mean implantation time of 11 ± 6 (SD) months. Three thousand six hundred dialysis treatments have been performed with these devices. The cumulative incidence of catheter related bacteremia in our patients amounted to 2.9 episodes per 1,000 catheter-days. All 14 episodes of bacteremia were treated with combined systemic antibiotics and adjunctive antibiotic/anticoagulant lock therapy. One patient had five episodes of bacteremia with the same organism, viz., Staphylococcus epidermidis. The organisms associated with the bacteremic episodes in all the patients are listed in Table 1. Since embracing the combination of systemic antibiotics and lock therapy, we have been able to successfully treat all the Dialock device related bacteremic episodes. No Dialock device had to be removed because of intractable bacteremia. There have also been no metastatic infectious complications such as endocarditis, osteomyelitis, or septic arthritis.

Discussion

Catheter related bacteremia continues to be a major cause of substantial morbidity and mortality among dialysis patients. 10 Although the optimal therapy for device related bacteremia is still controversial, many clinicians advocate prompt device removal in addition to systemic antibiotic therapy. 11 Conventionally, catheter related bacteremia has been attributed to infections occurring around the exit site and on the external surface of a catheter. However, recent evidence suggests that intraluminal contamination may be equally or more important. 12 Noteworthy is the fact that, within a vascular access device, bacteria may be encased in a layer of biofilm. 13 When special circumstances (such as weakening of a patient’s defenses) permit those microorganisms to be free from the confines of a biofilm, device infection and/or bacteremia may ensue. Use of antibiotic lock therapy should help to defend against these liberated organisms.

The inability of systemically administered antibiotics to reach the lumen and internal surface of a catheter and, therefore, to engage the responsible microbes may explain the poor success rates for catheter salvage with the use of systemic antibiotic therapy alone. In a recent prospective evaluation of the use of systemic antibiotic therapy alone for catheter salvage, Marr et al. reported only a 20% salvage rate for infected tunneled catheters. 14 These authors suggested that the definitive treatment for patients with infected catheters centered on catheter removal and that attempts at catheter salvage were often futile. The antibiotic/anticoagulant lock technique seems to be an ideal method by which the lumen and inner surface of a vascular access device can be adequately sterilized. 15–24 The therapy has been in clinical use for a decade. In the initial description of the technique, a 91% salvage rate for catheters involved in catheter related bacteremia among patients receiving total parenteral nutrition therapy was reported;15 other investigators have also been able to reduce the need for catheter replacement with the antibiotic/anticoagulant technique. 23 In a recent 4 year prospective trial, an antibiotic lock mixture consisting of gentamicin and trisodium citrate was used prophylactically to prevent infections occurring in tunneled catheters used for dialysis. No episodes of catheter related bacteremia were encountered during the study period. 21 (As an aside, it should be noted that gentamicin is not compatible with heparin 25 or low molecular weight heparin [personal observation] as evidenced by the occurrence of precipitation upon mixing. It has been suggested that trisodium citrate be used as the anticoagulant instead when one wishes to use gentamicin in lock therapy.) 21 In another trial, a 100% catheter salvage rate for catheter related bacteremia was achieved with the combined use of intravenous antibiotic therapy and the adjunctive antibiotic lock method. 23 With the use of the combined therapy, all of our patients also recovered from their bacteremic episodes, and none of the Dialock devices had to be removed because of intractable bacteremia. With more than 70% of the responsible organisms being gram-positive in nature, our patients’ spectrum of bacterial flora is similar to that of patients reported by Marr et al.14 However, these latter authors reported a catheter salvage rate of only 20%, as well as a significant incidence of infectious complications. Despite a spectrum of organisms comparable to that encountered by Marr et al., by using the combined systemic and topical antibiotic therapy approach we were able to achieve a 100% device salvage rate without the undesirable occurrence of infectious complications or death. Our incidence of bacteremia of 2.9 episodes/1,000 catheter-days also compares favorably with that of 3.9 episodes/1,000 catheter-days recently reported for tunneled catheters. 14 In our study, the antibiotic/anticoagulant lock technique was often used for the same duration as the concomitant systemic antibiotic therapy. Of the eight patients who were treated with the combined technique, reinfection with the same organism occurred in only one patient. In this patient, the interval between infections was greater than 3 months in four of five bacteremic episodes. Because Marr et al. have proposed that catheters can be considered salvaged if they are in place for more than 3 months after the initial infection, 14 the four episodes of bacteremia in this particular patient can be viewed as new infections rather than recurrences.

The basic premise of the antibiotic lock technique is based on the high antibiotic concentrations that can be achieved in the lumen and on the internal surface of an access device. In the present study, the levels of antibiotics used ranged from hundreds to thousands of times higher than the minimum inhibitory concentrations required for inhibition of the responsible organisms. With regard to the heparin used in the lock solution, we favor the use of concentrations as high as 2,500 units/ml to minimize the chances of clotting within a device.

The issue of emergence of antibiotic resistant organisms with prolonged use of antibiotic therapy has been raised. In our patients, the duration of antibiotic lock therapy was of the same duration as conventional systemic antibiotic therapy. Because the chances of complete eradication of the responsible organisms are higher with the combined therapy than with conventional systemic antibiotic therapy alone, the probability of promoting selective growth of antibiotic resistant organisms should be less with the former than the latter therapy.

It has been suggested previously that, at high concentrations, vancomycin and heparin are incompatible when the mixture is constituted in 5% dextrose in water. 26,27 Physiologic saline is preferable to dextrose in water as a diluent for many antibiotic/heparin mixtures because of the propensity of the latter diluent to inactivate heparin. 26–28 We found that solutions containing vancomycin at a final concentrations of 1 to 3 mg/ml and heparin at a final concentration of 2,500 units/ml did not generate any precipitates if physiologic saline was used as the diluent. We noted that precipitation began to occur when the final vancomycin concentration was raised to 4 mg/ml in the presence of a final heparin level of 2,500 units/ml. Should precipitation occur when one uses the concentrations of vancomycin and heparin used in the present study (precipitation occurring, perhaps, because of variations in the manufacturing processes used by different manufacturers to produce vancomycin and heparin), one can reduce the dose of vancomycin instilled to a lower but still highly efficacious level. In light of the possible occurrence of precipitation, it is suggested that all antibiotic/heparin lock solutions be prepared in physiologic saline 27 and be closely inspected for turbidity after preparation, as well as immediately before actual administration. Furthermore, antibiotic/heparin mixtures should be used promptly once they are prepared, lest instability of the mixtures should take place.

The antibacterial activity of vancomycin in a vancomycin/heparin lock solution containing 0.5 mg/ml of vancomycin and 100 units/ml of heparin (in saline) has been discovered to be relatively intact after incubation at 37°C for a period of 10 days. 29 Because of the favorable results encountered in our patients, it is likely that the antibacterial activities of the various antibiotics used were reasonably sustained after their admixture with heparin and during their dwell within the Dialock devices. However, future definitive stability studies are required to ensure that the potency of the antibiotics selected for use in antibiotic locks in the present study is indeed adequately preserved.

The fate of the antibiotic in the antibiotic/anticoagulant lock solution once it is introduced into the Dialock device should be taken into consideration. On one occasion, after a dialysis session, we placed a lock containing vancomycin 2 mg/ml and heparin 2,500 units/ml into a patient’s Dialock device and allowed the mixture to dwell for 44 hours. At the 45th hour, we aspirated the contents of the Dialock device and found that about 10% (200 μg/ml) of the instilled vancomycin had remained. The latter vancomycin level is well above the usual minimum inhibitory concentration for, for example, Staphylococcus aureus (namely, 1 to 5 μg/ml), 30 and suggests that the antibiotic lock technique is more than adequate to maintain therapeutically effective antibiotic levels within the device.

Recently, Sodemann et al. have reported the successful use of a prophylactic taurolidine (an antimicrobial) lock in reducing the incidence of infections related to the use of tunneled catheters and the Dialock device. 24 These favorable results are reminiscent of those obtained from a study in which a minocycline/ethylenediamine tetraacetate lock mixture, was used. 18

In summary, our experience with the use of adjunctive antibiotic/anticoagulant lock therapy in the management of bacteremia related to the use of a vascular access device has been satisfactory. The combination of systemic antibiotic therapy and the antibiotic/anticoagulant lock approach may be the treatment of choice in vascular access related infections in general.

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