Abstract
Objective:
We sought to compare the impact of antimicrobial impregnation to that of tunneling of long-term central venous catheters on the rates of catheter colonization and catheter-related bloodstream infection.
Summary Background Data:
Tunneling of catheters constitutes a standard of care for preventing infections associated with long-term vascular access. Although antimicrobial coating of short-term central venous catheters has been demonstrated to protect against catheter-related bloodstream infection, the applicability of this preventive approach to long-term vascular access has not been established.
Methods:
A prospective, randomized clinical trial in 7 university-affiliated hospitals of adult patients who required a vascular access for ≥2 weeks. Patients were randomized to receive a silicone central venous catheter that was either impregnated with minocycline and rifampin or tunneled. The occurrence of catheter colonization and catheter-related bloodstream infection was determined.
Results:
Of a total of 351 inserted catheters, 346 (186 antimicrobial-impregnated and 160 tunneled) were analyzed for catheter-related bloodstream infection. Clinical characteristics were comparable in the 2 study groups, but the antimicrobial-impregnated catheters remained in place for a shorter period of time (mean, 30.2 versus 43.8 days). Antimicrobial-impregnated catheters were as likely to be colonized as tunneled catheters (7.9 versus 6.3 per 1000 catheter-days). Bloodstream infection was 4 times less likely to originate from antimicrobial-impregnated than from tunneled catheters (0.36 versus 1.43 per 1000 catheter-days).
Conclusions:
Antimicrobial impregnation of long-term central venous catheters may help obviate the need for tunneling of catheters.
In this prospective, randomized, multicenter clinical trial, long-term central venous catheters impregnated with minocycline and rifampin were 4-fold less likely than tunneled unimpregnated catheters to result in bloodstream infection. Antimicrobial impregnation may help obviate the need for the less protective and the more expensive and cumbersome practice of tunneling catheters.
Tunneled central venous catheters commonly are used to administer prolonged courses of chemotherapy, parenteral nutrition, and antibiotics, with the assumption that tunneling protects against infection.1,2 Although prospective, randomized clinical trials have demonstrated that tunneled short-term catheters (mean duration of placement, ≤10 days) are associated with significantly lower rates of catheter colonization and catheter-related infection than nontunneled catheters,3,4 tunneling of long-term catheters (mean duration of placement, >14 days) has not been found to provide significant protection.5,6 Nevertheless, the practice of tunneling catheters is considered a standard of care for securing long-term but not short-term vascular access.1,2
Because the surgical practice of tunneling catheters canbe both cumbersome and expensive as usually it requires catheter insertion in the operating room and subsequent catheter removal by surgeons, there is a growing interest in exploring other potentially antiinfective approaches. Prospective, randomized clinical trials have demonstrated that short-term central venous catheters impregnated with chlorhexidine and silver sulfadiazine7 or with minocycline and rifampin8 significantly protect against catheter colonization and catheter-relatedbloodstream infection as compared with nonimpregnated, nontunneled catheters. The use of antimicrobial-impregnated, short-term catheters was shown to be cost-beneficial in patients at high risk for infection.9–14 The applicability of antimicrobial impregnation to long-term vascular access, however, is yet to be elucidated.15 We compared antimicrobial-impregnated, nontunneled, long-term central venous catheters with nonimpregnated, tunneled catheters in terms of the rates of colonization and bloodstream infection.
MATERIALS AND METHODS
Study Design
We conducted a prospective, randomized trial at 7 university-affiliated hospitals. The study was approved by the appropriate institutional review boards. All enrolled patients or their legal guardians gave informed consent. Men and women 18 years of age or older who required a central venous catheter for ≥2 weeks were eligible. Pregnant women and patients with a history of allergy to any of the antimicrobial agents used for impregnating the catheters were excluded.
The treating physicians determined whether enrolled patients would require a 9.5-French, single-lumen, or a 9.0-French, double-lumen silicone catheters. Patients were then assigned randomly to receive either a noncuffed, nontunneled catheter impregnated with minocycline and rifampin or a cuffed, tunneled, nonimpregnated catheter (Cook Critical Care, Bloomington, IN). Minocycline and rifampin were present along both the external and luminal surfaces of the antimicrobial-impregnated catheters, but the catheter hubs were not impregnated. The 2 study catheters were identical in all respects except for the antimicrobial impregnation and the cuffs used for tunneling. All catheters were sterilized with ethylene oxide before use. We were ethically prohibited from randomizing patients to a third group of nontunneled, nonimpregnated catheters.
The antimicrobial-impregnated, nontunneled catheters were inserted at the bedside, whereas the nonimpregnated, tunneled catheters were placed in the operating room or a special procedure suite. Catheters were inserted through a new venipuncture into the subclavian vein or, in patients with thrombosed subclavian veins, into the jugular vein using maximal sterile barrier precautions. Catheter care was similar for both types of catheters. At the time of catheter insertion and at each dressing change, the insertion site was disinfected with 10% povidone-iodine. The transparent dressing (OpSite; Smith & Nephew, London, England) was changed and the insertion site was inspected 3 times a week. Decisions to remove catheters were made solely by patients’ physicians, who kept catheters in place until they were no longer needed or until an adverse event, such as catheter malfunction or catheter-related infection, necessitated removal.
Cultures
Four-centimeter segments from the tip and subcutaneous sections of the aseptically removed catheters were cultured first by the roll-plate method and then by the sonication method.16 In patients in whom catheter-related infection was suspected on clinical grounds, one or more peripheral blood samples for culture were collected before or immediately after catheter removal. Isolated organisms were identified by standard microbiologic techniques.
Molecular Fingerprinting
Extracted DNA from blood and catheter isolates in patients with catheter-related bloodstream infection was amplified by rep-PCR17 with use of DiversiLab Kits (Bacterial Barcodes, Inc., Houston, TX). Thermal cycling consisted of 3 steps: (1) initial denaturation at 94°C for 2 minutes; (2) 35 cycles of denaturation at 94°C for 30 seconds, annealing (at 45°C for Staphylococcus, 50°C for Enterococcus, 55°C for Enterobacter and Acinetobacter, and 53°C for Candida) for 30 seconds, and elongation at 70°C for 90 seconds; and (3) final extension at 70°C for 3 minutes. Amplicons were separated by microfluidics in DNA Labchips (Bacterial Barcodes) in a model 2100 Bioanalyzer (Agilent, Palo Alto, CA). Pearson correlation coefficients were generated with use of DiversiLab software (version 2.1.66). The Unweighted Pair Group Method with Arithmetic Mean (UPGMA) method was used to create dendrograms. Isolates were considered highly similar if DNA profiles shared >95% similarity.
Antimicrobial Activity of Impregnated Catheters
Two 1-cm sections were cut from the ends of each catheter after the 4-cm segment had been removed. One wasused to examine the durability of antimicrobial activity of catheters impregnated with minocycline and rifampin by using a modified Kirby-Bauer technique to assess the zone of inhibition against a biofilm-producing clinical isolate of Staphylococcus epidermidis.18 The second catheter section was assessed by high-performance liquid chromatograpy for the residual levels of minocycline and rifampin.18
Definitions of Outcomes
The investigators who assessed the outcomes of catheter colonization and bloodstream infection in each hospital relied on information contained in the completed case forms with regard to clinical findings and results of cultures, and were unaware of the type of inserted catheter. We applied the definitions of catheter colonization and bloodstream infection that had been proposed by the Centers for Disease Control and Prevention1 and used in previous clinical trials.8,19 Catheter colonization was defined as the growth in cultures from either the tip or subcutaneous segment of the catheter of ≥15 colony-forming units by the roll-plate method or ≥1000 colony-forming units by the sonication method. Catheter-related bloodstream infection was defined as the isolation of the same organism (ie, the same species with identical antimicrobial susceptibility) from the colonized catheter and from peripheral blood in a patient with clinical manifestations of sepsis and no other apparent source of bloodstream infection. Patients who had no clinical manifestations of sepsis and, therefore, did not need to have blood cultures obtained were considered not to have bloodstream infection, even if the study catheter was not cultured upon removal.
Study Size
Although tunneling and antimicrobial impregnation of catheters have not been directly compared, previous studies indicated comparable rates of colonization of central venous catheters impregnated with minocycline and rifampin (7.9%)19 and tunneled catheters (8.2%)4 that had remained in place for a mean of 8 days. Therefore, we hypothesized that the 2 catheters examined in the present study would have equivalent rates of catheter colonization of about 15% (almost double the reported rate of colonization of similarly designed short-term catheters). Randomly assigning approximately 157 evaluable catheters to each study group would have allowed us to detect with 80% power and 95% confidence that the difference between the rates of catheter colonization in the 2 groups is within ± 0.10 (ie, noninferiority with delta = 10%).
Statistical Analyses
The significance of the differences between the 2 study groups was determined with use of Student t test for continuous variables and Fisher exact test or the χ2 test for categorical variables. Yates’ correction for continuity was applied where appropriate. All P values were based on 2-tailed tests of significance. The hypothesis of noninferiority was evaluated by the method of Blackwelder20 with use of a delta of 0.10. The proportions of catheters that were free of colonization and not associated with bloodstream infection as a function of the duration of placement were compared between the 2 groups with use of a log-rank test on the Kaplan–Meier estimates. For catheters associated with bloodstream infection, the indwelling time was calculated as time from catheter placement to diagnosis of bloodstream infection. The multivariate logistic regression model was used to estimate the simultaneous effects of multiple variables on the incidence of catheter-related bloodstream infection. To avoid rejecting variables that might have influenced the outcome, variables that were significant at a P value of ≤0.25 in the univariate analysis were entered in a stepwise manner into logistic-regression analyses and tested for an independent effect. The limit for entering or removing variables in the logistic-regression models was a P value of ≤0.05. Computations were performed with use of SYSTAT 10.2 (SYSTAT Software, Inc.; Richmond, CA). Data from zones of inhibition were fit to a linear least squares regression. An independent monitoring board composed of 2 infectious disease physicians and a statistician reviewed and helped interpret thefindings of the study. Interim analysis of data was not performed.
RESULTS
Characteristics of Study Groups
A total of 351 study catheters were inserted. Because 39 catheters were not cultured (15 were removed without notification of study coordinators, 10 were grossly contaminated at the time of explantation, 10 were inserted in patients who subsequently died, and 4 were inserted in patients who were lost to follow-up), a total of 312 catheters (166 antimicrobial-impregnated and 146 tunneled) were evaluable for analysis of catheter colonization. Five catheters (4 inserted in patients who were lost to follow-up and 1 inserted in a patient whose cause of death was not investigated) were excluded from analysis of catheter-related bloodstream infection. Of the total of 346 catheters that were included in the analysis of catheter-related bloodstream infection, 186 were antimicrobial-impregnated and 160 were tunneled (Fig. 1). These 2 groups of evaluable patients were well matched with respect to most characteristics, including gender, age, type of underlying disease, risk factors for infection, receipt of systemic antibiotics, site of catheter insertion, and number of catheter lumens (Table 1). Not surprisingly, given the hesitancy by some physicians and patients to remove a surgically tunneled catheter, even when the catheter is no longer actively used, the mean duration of placement of tunneled catheters was longer than that of antimicrobial-impregnated catheters (mean, 43.7 ± 37.9 versus 30.2 ± 21.1 day, P < 0.001). Tunneled catheters were 3 times more likely than antimicrobial-impregnated catheters to be removed because of positive blood cultures (19 of 160 [11.9%] versus 7 of 186 [3.8%], P= 0.008).
FIGURE 1. Study flow. CRBSI indicates catheter-related bloodstream infection.
TABLE 1. Characteristics of Evaluable Patients
Colonization of Catheters
Forty-one of 166 (24.7%) antimicrobial-impregnated catheters and 41 of 146 (28.1%) tunneled catheters were colonized according to at least 1 method of assessment (relative risk, 1.14; 95% confidence interval [CI] 0.78–1.65; P = 0.58). Additionally, no significant differences were detected in the rates of colonization between the 2 groups of catheters when assessed by each of the 4 segment-culture methods (tip-roll plate, tip-sonication, subcutaneous segment-roll plate, and subcutaneous segment-sonication) or by any combination of these assessment methods. The Blackwelder test for noninferiority with a delta of 0.10 demonstrated that, in terms of rates of catheter colonization, antimicrobial-impregnated catheters were equivalent to tunneled catheters (P = 0.005) with a power of 80%. The rates of catheter colonization per 1000 catheter-days were 7.9 (95% CI 5.5–10.4) for antimicrobial-impregnated catheters and 6.3 (95% CI 4.4–8.2) for tunneled catheters (P = 0.46). Analysis of the Kaplan–Meier estimates of the risk of catheter colonization according to the length of time the catheters were in place in each group showed no significant differences between the 2 study groups (P = 0.20 by the log-rank test).
Gram-positive organisms accounted for almost half of all cases of catheter colonization in both study groups (Table 2). A statistically insignificant trend was noted for higher likelihood of fungal colonization of antimicrobial-impregnated versus tunneled catheters (relative risk, 2.94; 95% CI 0.82–10; P = 0.09), whereas gram-negative bacteria (relative risk, 2.56; 95% CI 0.80–8.13; P = 0.15) and polymicrobes (relative risk, 2.27; 95% CI 0.80–6.50; P = 0.19) tended to colonize tunneled catheters more than antimicrobial-impregnated catheters.
TABLE 2. Microbiologic Causes of Catheter Colonization
Catheter-Related Bloodstream Infection
Twelve cases of bloodstream infection were attributed to catheters that had been in place for a median of 19 days (mean, 49 days; range, 9 to 275 days). Ten cases (6.3%) of bloodstream infection were related to tunneled catheters, as compared with 2 cases (1.1%) associated with antimicrobial-impregnated catheters (relative risk, 5.81; 95% CI 1.29–26.1; P = 0.015). Two patients developed bloodstream infection associated with tunneled catheters that had been kept in place after no longer actively used. A single patient died as a result of bloodstream infection due to Enterobacter aerogenes associated with a tunneled catheter. The rates of catheter-related bloodstream infection per 1000 catheter-days were 0.36 (95% CI 0–0.85) for antimicrobial-impregnated catheters and 1.43 (95% CI 0.54–2.32) for tunneled catheters (P = 0.13). Figure 2 shows the Kaplan-Meier estimates of the risk of catheter-related bloodstream infection according to the duration of catheterization in each group and illustrates that antimicrobial-impregnated catheters were protective against infection (P = 0.03 by the log-rank test). Antimicrobial-impregnated catheters also provided significant (P = 0.02 by the log-rank test) protection against the occurrence of catheter-related bloodstream infection when assessing only catheters that had remained in place for ≤30 days (which represents the mean and median duration of placement of antimicrobial-impregnated catheters).
FIGURE 2. Kaplan–Meier survival curves for bloodstream infection in association with catheters impregnated with minocycline and rifampin versus tunneled catheters. The number of study catheters in each group that were at risk for developing infection at various time points is shown below the figure. The risk of bloodstream infection was significantly lower in association with the catheters impregnated with minocycline and rifampin versus tunneled catheters (P = 0.03 by the log-rank test).
We identified 3 factors that may have increased the likelihood of catheter-related bloodstream infection in the univariate analysis (with P ≤ 0.25 as the criterion), including duration of catheterization (P < 0.001), use of a tunneled catheter (P = 0.015), and reason for catheter removal (P = 0.05). However, upon entering these 3 factors into a multivariate logistic-regression model, only the use of a tunneled catheter was identified as a significant predisposing factor (odds ratio, 6.25; 95% CI 1.32–25; P = 0.02).
Although double-lumen catheters were twice as likely as single-lumen catheters to result in bloodstream infection, this difference was not significant in the univariate analysis (9/207 = 4.4% versus 3/139 = 2.2%; P = 0.37). Furthermore, multivariate logistic-regression analysis indicated that the number of catheter lumens was not a predictor of catheter-related bloodstream infection (P = 0.28).
The 2 cases of bloodstream infection associated with antimicrobial-impregnated catheters were caused by a coagulase-negative Staphylococcus and Enterococcus faecalis. Organisms implicated in the 10 cases of bloodstream infection associated with the tunneled catheters included coagulase-negativestaphylococci (3 cases), S. aureus, Enterobacter aerogenes, Acinetobacter baumanii, Candida albicans C. parapsilosis, Saccharomyces cerevisiae (1 case each) and, in a single case, both C. parapsilosis and a coagulase-negative Staphylococcus. Antimicrobial-impregnated catheters protected against catheter-related bloodstream infection by fungi, as compared with tunneled catheters (0 of 186 [0%] versus 4 of 160 [2.5%]; P = 0.04). Roll-plate cultures of the tip and/or subcutaneous segment of the catheters yielded all 7 g-positive bacterial isolates and 4 fungal strains responsible for bloodstream infection, but both bacteremic gram-negative isolates grew only from sonication cultures of the catheter. In 8 of 9 (89%) cases in which paired catheter and blood isolates were available, molecular typing confirmed that the paired isolates were highly similar (Fig. 3).
FIGURE 3. DNA cluster analysis of paired catheter and blood isolates from 8 patients with catheter-related bloodstream infection. The x-axis indicates percent similarity. Paired catheter and blood isolates from each of the 8 patients were highly similar (ie, DNA profiles shared greater than 95% similarity). Except for patients C and D who were infected by C. parapsilosis, isolates from different patients were clearly distinguishable.
Although there was a trend toward a lower risk of nosocomial bacteremia in patients who received antimicrobial-impregnated versus tunneled catheters (26% versus 37%), the difference was not significant (P = 0.26). There were no significant differences between the 2 groups in the proportions receiving therapy with vancomycin (47% versus 56%) or antibiotics in general (95% versus 96%).
Antimicrobial Activity
The size of the zone of inhibition against a reference S.epidermidis was inversely related to the duration of catheter placement (correlation coefficient, −0.88; Fig. 4). A linear fit of the data (r2 = 0.77) indicated that the mean zone of inhibition was ≥10 mm through 60 days. The concentrations of minocycline and rifampin on the surface of catheters decreased with increasing duration of catheter placement and both agents were detectable through 60 days of dwell time.
FIGURE 4. Relationship between zone of inhibition and duration of catheterization. The size of the zone of inhibition (expressed as mean ± SD) was inversely related to the duration of catheter placement (correlation coefficient, −0.88).
Adverse Effects of the Catheters
There were no local or systemic hypersensitivity reactions associated with the use of antimicrobial-impregnated catheters.
DISCUSSION
The findings of the present trial support our hypothesis that antimicrobial-impregnated catheters are as likely as tunneled catheters to become colonized. More importantly, the antimicrobial-impregnated catheters were less likely than tunneled catheters to be associated with bloodstream infection, the most common serious complication of indwelling central venous catheters and the only clinically relevant outcome in this study. Bloodstream infection in association with tunneled long-term catheters occurred in the present study at a rate comparable to that in a recent report.21
Studies of short-term, antimicrobial-impregnated catheters have shown that clinically protective catheters (ie, reduce the rate of catheter-related bloodstream infection) also are less likely than control catheters to be colonized.7,8 However, the present trial indicates that long-term, antimicrobial-impregnated catheters can protect against catheter-related bloodstream albeit a reduction in the rate of catheter colonization is not observed when using traditional microbiology techniques. In that regard, microbial cultures are less sensitive than scanning electron or confocal laser microscopy in detecting microbial presence on the catheter surface.22 Furthermore, it is possible that the long-term presence of antimicrobial agents on the impregnated catheter surface can alter the structure of the surrounding biofilm, thereby reducing the likelihood of detachment of biofilm-embedded organisms from the surface of the long-term catheter and ultimate evolution of bloodstream infection. Therefore, we plan in future trials to assess by scanning confocal laser microscopy the impact of antimicrobial impregnation of long-term catheters on both microbial colonization and biofilm ultrastructure.
Previous reports have indicated that in vitro zones of inhibition of ≥10–15 mm can accurately predict the antistaphylococcal efficacy in vivo of antimicrobial-impregnated catheters.18,22,23 The present trial indicated that long-term silicone catheters impregnated with minocycline and rifampin can provide such zones of inhibition through 60 days, approximately twice the mean and median duration of placement of such catheters. This helps explain the clinical efficacy of antimicrobial-impregnated catheters in the present study in which 70% of episodes of bloodstream infection associated with tunneled catheters were diagnosed within a month of catheter insertion.
About 6% of the 250,000 annually inserted tunneled catheters are associated with bloodstream infection, resulting in approximately 15,000 cases of infection each year, with an attributable cost per infection of $10,000 to $56,000.1,9,14,24,25 The long-term use of antimicrobial-impregnated, nontunneled catheters as an alternative to nonimpregnated, tunneled catheters can reduce the overall costs of catheter insertion and treatment of infectious complications. The $10–16 additional expense of sets of antimicrobial-impregnated versus tunneled catheters (retail price of $104 versus $94 for single-lumen catheters, and $135 versus $119 for double-lumen catheters) is more than offset by the high savings incurred by avoiding surgical implantation in the operating room. A recent analysis indicated that a tertiary care cancer center charged in 2003 an additional $5176 to insert a tunneled versus nontunneled long-term subclavian catheter (reported charges of $6502 versus $1326),26 and this center-specific additional charge had doubled during a period of 10 years.27 Because Medicare reimburses inpatient facilities according to diagnosis-based DRG system, the overall Medicare reimbursement (including both facility and physician fees) for insertion of catheters is variable. Although the overall Medicare reimbursement for catheter insertion is generally lower than the corresponding private charges, the difference in Medicare reimbursement for insertion of a tunneled versus nontunneled catheter is still sizable. For instance, Medicare reimburses physicians an average of $775 for implanting a tunneled catheter (CPT code 36558) versus $349 for inserting a nontunneled catheter (CPT code 36556) at a “nonfacility” (Medicare Physician Fee Schedule at http://www.cms.hhs.gov/physicians/mpfsapp/step1.asp).
The use of catheters impregnated with antibiotics has raised some concern regarding the potential for development of antimicrobial resistance. Some studies in vitro and in experimental animals had reported that catheters impregnated with minocycline and rifampin may be at a higher risk of being colonized by antibiotic-resistant bacteria,28,29 but these studies have varying relevance for the usual clinical situation. In contrast, prospective, randomized clinical trials of similarly impregnated short-term central venous8,19 and hemodialysis30 catheters have failed to show evidence of resistance developing to either agent. The repeated use of short-term central venous catheters impregnated with minocycline and rifampin in bone marrow transplant patients for periods exceeding 4 years did not appear to result in antibiotic resistance.31 However, continued surveillance of antimicrobial susceptibility is required, particularly when using long-term, antimicrobial-impregnated catheters.
In conclusion, long-term catheters impregnated with minocycline and rifampin prevent bloodstream infection more effectively than do tunneled catheters and do so at a lower cost. Because nontunneled catheters generally are less cumbersome to insert and remove than tunneled catheters, they are also less likely to cause bloodstream infection in association with idle catheters.32 The findings of this trial may constitute the basis to reconsider the practice of surgical tunneling of long-term catheters, which is still regarded as standard of care despite the lack of significant protection against bloodstream infection.5,6
ACKNOWLEDGMENTS
The authors are indebted to Daniel M. Musher, MD, Richard H. Hamill, MD, and John I. Thornby, PhD, for serving on the study monitoring board and for their critical review of the manuscript. The authors also thank Ruth Ann Luna and Shaunte Jones for their assistance with molecular fingerprinting.
Footnotes
Supported in part by the Department of Veterans Affairs, Washington, DC, and Cook Critical Care, Bloomington, Indiana. The Department of Veterans Affairs provided personnel and laboratory support. Cook Critical Care provided a grant and supplied both types of study catheters. The study was designed and conducted by the investigators who prepared and submitted the manuscript without review or approval of the manuscript by Cook Critical Care.
Reprints: Rabih O. Darouiche, MD, Center for Prostheses Infection, Baylor College of Medicine, 1333 Moursund Avenue, Suite A221, Houston, TX 77030. E-mail: rdarouiche@aol.com.
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