Prevention of Central Venous Catheter-Related Bloodstream Infection by Use of an Antiseptic-Impregnated Catheter

A Randomized, Controlled Trial

  1. Dennis G. Maki, MD;
  2. Susan M. Stolz, MS;
  3. Susan Wheeler, RN, MSN; and
  4. Leonard A. Mermel, DO, ScM
  1. From the University of Wisconsin Hospital and Clinics and University of Wisconsin-Madison, Madison, Wisconsin. Acknowledgments: The authors thank the physicians and nurses of the University of Wisconsin Center for Trauma and Life Support for their generous cooperation and permission to study patients with central venous catheters; research nurses Mary Meisch, Elizabeth Buckley, Mary Cullera, Josephine Krueger, and Yda Pack; Donald A. Berry, PhD, for statistical assistance; and Gail Maki, Peggy Barden, and Rachael Mikkelson for secretarial support. Grant Support: In part by a grant from Arrow International, Reading, Pennsylvania. None of the authors hold any personal financial interest in the new catheter studied in this trial or have served as consultants to Arrow International. Requests for Reprints: Dennis G. Maki, MD, University of Wisconsin Hospital and Clinics-H4/574, Madison, WI 53792. Current Author Addresses: Dr. Maki: University of Wisconsin Hospital and Clinics-H4/574, Madison, WI 53792.
     
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    Abstract

    Background: Bloodstream infection related to short-term use of noncuffed central venous catheters is a common and serious problem. Technologic innovations to reduce the risk for these infections are needed.

    Objective: To determine 1) the efficacy of a novel antiseptic catheter in preventing central venous catheter-related infection, 2) patient tolerance of this catheter, and 3) the sources of bloodstream infection originating from noncuffed, multilumen central venous catheters.

    Design: Randomized, controlled clinical trial.

    Setting: Medical-surgical intensive care unit of a 450-bed university hospital.

    Participants: 158 adults scheduled to receive a central venous catheter; 403 catheters were studied.

    Intervention: Participants received either a standard triple-lumen polyurethane catheter or a catheter that was indistinguishable from the standard catheter and was impregnated with chlorhexidine and silver sulfadiazine.

    Measurements: Catheters were studied for colonization and catheter-related bloodstream infection at removal; local and systemic effects of catheters were assessed. The origin of each catheter-associated bloodstream infection was sought by culturing all potential sources (skin, catheter segments, hubs, and infusate) and confirmed by restriction-fragment DNA subtyping.

    Results: Antiseptic catheters were less likely to be colonized at removal than control catheters (13.5 compared with 24.1 colonized catheters per 100 catheters; relative risk, 0.56 [95% CI, 0.36 to 0.89]; P = 0.005) and were nearly fivefold less likely to produce bloodstream infection (1.0 compared with 4.7 infections per 100 catheters; 1.6 compared with 7.6 infections per 1000 catheter-days; relative risk, 0.21 [CI, 0.03 to 0.95]; P = 0.03). In the control group, 8 catheter-related bloodstream infections were caused by Staphylococcus aureus, gram-negative bacilli, enterococci, or Candida species; no infections with these organisms occurred in the antiseptic catheter group [P = 0.003]. No adverse effects from the antiseptic catheter were seen, and none of the 122 isolates obtained from infected catheters in either group showed in vitro resistance to chlorhexidine-silver sulfadiazine. Cost-benefit analysis indicated that the antiseptic catheter should prove cost-beneficial if an institution's rate of catheter-related bacteremia with noncuffed central venous catheters is at least 3 infections per 1000 catheter-days).

    Conclusions: The chlorhexidine-silver sulfadiazine catheter is well tolerated, reduces the incidence of catheter-related infection, extends the time that noncuffed central venous catheters can be safely left in place for the short term, and should allow cost savings.

    See related articles on pp 267-274 and 275-280 and editorial comment on pp 304-306.

    Noncuffed central venous catheters used for the short term account for 90% of all vascular catheter-related bloodstream infections. These catheters become colonized from multiple sources, most often by microorganisms that colonize the skin surrounding the insertion site [1]. Large numbers of microorganisms adhere to the surface of the implanted, colonized catheter [2]. Strategies to block microbial access to the transcutaneous tract, such as use of more potent cutaneous antiseptic agents [3], topical application of antimicrobial agents [4], or attachment of a subcutaneous silver-impregnated cuff [5], have helped prevent catheter-related infection. Technologic innovations that render the catheter surface more resistant to microbial colonization should in theory be most likely to reduce the risk for catheter-related bloodstream infection.

    A novel antiseptic central venous catheter, made of polyurethane and impregnated with chlorhexidine and silver sulfadiazine, was recently developed (Arrow International, Reading, Pennsylvania). Chlorhexidine, a potent antiseptic, has been used widely throughout the world for more than three decades for cutaneous disinfection [3, 6]; for handwashing [7, 8]; for oral care [9]; for irrigation of surgical wounds [10], the peritoneum [11], the urinary bladder [12], and the vagina [13]; for topical treatment of burn wounds [14, 15]; and as part of most water-soluble medical lubricants. Silver sulfadiazine, a stable combination of the antiseptic silver and sulfadiazine, also exhibits potent bactericidal and fungicidal activity [16] and has been used worldwide for more than 20 years in a topical formulation for preventing burn wound infection [17-19].

    We did a randomized trial to determine the efficacy of the antiseptic catheter for prevention of central venous catheter-related infection and patient tolerance of the catheter. The origin of each catheter-related bloodstream infection was confirmed using restriction-fragment DNA subtyping to show concordance between isolates obtained from the catheter and those obtained from blood cultures.

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    Methods

    Patients

    Our study was conducted at the Center for Trauma and Life Support, a 24-bed medical-surgical intensive care unit in the University of Wisconsin Hospital and Clinics [20]. All adult patients who were not known to be allergic to chlorhexidine, silver, or sulfonamides and were scheduled to receive a central venous catheter for short-term use were eligible to participate. All patients were informed of the nature of the study before written consent to participate was requested.

    Procedures for Insertion and Care of Catheters

    Catheters were inserted by house officers who wore masks, sterile gloves, and surgical gowns and used large sterile drapes [20]. After the intended insertion site was quantitatively cultured, the site was disinfected with 10% povidone-iodine, applied with scrubbing for at least 30 seconds. The catheter was then inserted percutaneously using the Seldinger technique. Before a second catheter was inserted over a guidewire into an old site, the hub of the first catheter and the guidewire were disinfected using gauze saturated with povidone-iodine. Sites were dressed with sterile gauze and tape. Every 48 hours, the dressing was removed, the site was inspected and recleansed with povidone-iodine, and a new dressing was applied.

    Study Design

    Each time a catheter was scheduled to be inserted in a study patient, it was randomly assigned from a blinded preset randomization schedule to be a control catheter or an antiseptic catheter. The patients' physicians and nurses, the principal investigator, and the research microbiologist who processed all cultures were blinded to each study catheter's group.

    Measurements

    Each study catheter was evaluated daily by a team of research nurses. The patient was asked about discomfort at the insertion site and was evaluated for systemic effects that may have been caused by the catheter. When the dressings were changed and when the catheter was removed, the site was visually inspected and scored quantitatively for inflammation [21]. Decisions to remove catheters were made independently by the patients' physicians. At removal, the site was again cultured by a research nurse, the hub and infusate from each lumen were cultured, and the catheter was removed and cultured [3, 20]. Peripheral blood cultures were done for patients who had any signs of infection.

    Data obtained for each catheter included the patient's medical diagnoses and Acute Physiology and Chronic Health Evaluation II (APACHE II) score [22] on the first catheter day, the use of other invasive devices, clinical and laboratory data pertaining to infection, the anatomical location of the catheter, the experience of the physician inserting the catheter, the difficulty of insertion (insertion was considered difficult if >2 attempts were required), the condition of the insertion site [21], and the number of hours the catheter had been in place.

    Blood specimens were drawn from 20 randomly selected patients (12 with an antiseptic catheter and 8 with a control catheter) immediately before catheter insertion, 1 day after insertion, every 5 days thereafter, and upon catheter removal. Specimens were tested for the presence of chlorhexidine by use of high-performance liquid chromatography (HPLC) (limit of detection, 16 ng/mL), for the presence of silver by use of absorption spectrophotometry (limit, 5 ng/mL), and for the presence of sulfadiazine by use of HPLC (limit, 0.2 µg/mL).

    Features of the Catheters

    Two noncuffed, triple-lumen central venous catheters manufactured by Arrow International were studied: a standard 30.5-cm, 16-G catheter made of polyurethane (model C514703-A) and the test catheter (ARROWgard, Model C514703-A). The test catheter is identical to the control catheter except that the external surface of the former is impregnated with minute quantities of chlorhexidine gluconate (0.75 mg) and silver sulfadiazine (0.70 mg). The two catheters were indistinguishable to users.

    Microbiological Methods

    Antimicrobial Activity on the Catheter Surface

    We used an in vitro assay [23] to measure antimicrobial activity on the surfaces of the control and antiseptic catheters against clinical isolates of Staphylococcus aureus, S. epidermidis, Enterococcus faecium, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, and Candida albicans. These species account for more than 95% of catheter-related bloodstream infections [1]. Residual surface activity on each study catheter removed from patients in both groups was also measured using the same assay; the segment was first washed for 1 minute in sterile 0.9% saline.

    Skin at the Insertion Site

    Approximately 20 cm2 of skin was cultured quantitatively with a premoistened, sterile, cotton-tipped applicator (Culturette, Marion Laboratories, Inc., Kansas City, Missouri), as described elsewhere [3, 21].

    Catheters and Catheter Hubs

    For each catheter, two 5-cm segments-a proximal intracutaneous segment and the tip (both transported in a sterile container)-were cultured semiquantitatively (Culturette) [24]. Each of the three hubs was cultured with small cotton-tipped applicators (Medix, Inc., Van Nuys, California) [3, 21].

    Infusate and Subtyping of Isolates

    Three mL of fluid was aspirated from the most distal injection port of each lumen and was cultured quantitatively [3, 21]. Microorganisms were identified according to standard criteria [25]. When catheter-associated bloodstream infection occurred, we determined whether the bacteremia or candidemia originated from the catheter using pulsed-field electrophoresis after digestion of genomic DNA with restriction endonucleases [26] on the blood isolates and all isolates of the same genus that were recovered from the insertion site, catheter segments, infusate, or hubs.

    Tests for Resistance to Chlorhexidine-Silver Sulfadiazine

    Isolates from infected catheters in both groups were tested for susceptibility to chlorhexidine-silver sulfadiazine by using the in vitro assay for surface activity [23]. In this assay, segments of a sterile, unused antiseptic catheter were imbedded in agar that contained the isolate and zones of inhibition were measured.

    Definitions

    Catheter-tip colonization was defined as a positive semiquantitative culture of an intravascular catheter segment (>15 colony-forming units) and was synonymous with local colonization of the catheter [24]. Catheter-related bloodstream infection was defined as isolation of the same strain from the catheter segment, a hub, or infusate and from one or more peripheral blood cultures, as proven by restriction-fragment subtyping.

    Unit of Analysis and Statistical Analyses

    In this trial, the experimental unit was central venous catheters rather than individual patients. If a patient needed continued central venous access after the first study catheter was removed, subsequent catheters were also studied; at the time of insertion, each subsequent catheter was randomly assigned to be a control or an antiseptic catheter. Risk for nosocomial infection of all types, including vascular catheter-related bloodstream infection, increases with the time during which a patient requires intensive care [27]. In practice, many patients require more than one central venous catheter, and subsequent catheters are commonly inserted into an old site over a guidewire [28-34]. Subsequent catheters present a higher risk for infection than do first catheters [1], especially if inserted into an old site over a guidewire [34]. Limiting entry into a clinical trial of a new technology aimed at preventing catheter-related infection to first catheters precludes study of subsequent, higher-risk catheters (especially those inserted over a guidewire into old sites), compromises assessment of the technology, and limits application of study results to clinical practice.

    We determined at the outset of the trial that the analysis of outcome would be restricted to catheters that had been in place for at least 8 hours and that could be cultured at removal. The significance of differences between the two study groups was determined by using a chi-square test or Fisher exact test for categorical data and the Student t-test for continuous data. The cumulative risk for developing catheter-related infection in each group was compared using a log-rank test on the Kaplan-Meier estimates [35]. All P values reported are based on two-tailed tests of significance. All 95% CIs are asymptotic approximations computed by using Epi Info, version 5.0 (USD, Inc., Stone Mountain, Georgia).

    According to the study design, many patients received more than one catheter, and an analysis with catheters as the experimental unit makes an assumption of independence that may or may not be justified. Thus, the potential benefit of the antiseptic catheter was also analyzed with the patient as the experimental unit. To measure the benefit of the antiseptic catheter in terms of catheter-related infection, a score was assigned to each catheter as follows. For control catheters: new site with infection, +K; new site with no infection, −1;old site over guidewire with infection, +K; old site over guidewire with no infection, −2.For antiseptic catheters: new site with infection: -K; new site with no infection, +1; old site over guidewire with infection, -K; old site over guidewire with no infection, +2.

    Each patient's score is the sum of all of the study catheters that he or she received. Confirmation of the null hypothesis (that is, no difference between the two types of catheters) would correspond to a mean score of zero for the entire study sample of 157 patients, as analyzed using the Student t-test. Because catheter-related infection was more frequent with catheters inserted in old sites over a guidewire, successful prevention of infection in that circumstance was weighted twice as heavily (2 compared with 1). K was arbitrarily assigned a value of 20, which indicates that the occurrence of infection was 10 or 20 times as bad as successful prevention of infection (1 or 2); the analysis, however, was undertaken over a broad range of values for K.

    Industry Role

    The principal investigator independently wrote the original study protocol in its entirety. Arrow International reviewed and concurred with the protocol, but the conduction of the study, analysis of the data, and reporting of the results are entirely independent of Arrow International.

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    Results

    Patient and Catheter Characteristics

    More than 90% of the patients who were invited to enroll in our study agreed to participate. A total of 442 study catheters were originally included for study; 20 control catheters and 19 antiseptic catheters were considered to be unevaluable because they were removed within 8 hours or because they could not be cultured. Complete data were obtained for 403 catheters (195 control catheters and 208 antiseptic catheters) in 158 patients.

    Patients and catheters in the two groups were similar for risk factors predisposing to nosocomial infection [27], including the physician's experience with inserting catheters and the difficulty of insertion (Table 1). Most catheters in each group were used in patients who were highly vulnerable to nosocomial infection, as shown by high APACHE II scores (median, 14 in each group), multiple invasive medical devices, and frequent hyperglycemia or hypoalbuminemia. Cutaneous colonization of the insertion site before catheter insertion, a powerful risk factor for catheter-related infection [1], was also similar in the two groups.

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    Table 1. Characteristics of Patients and Catheters*

    Most of the catheters in each group had been inserted into a subclavian vein or internal jugular vein. More catheters in the antiseptic group had been placed in an old site over a guidewire (53% compared with 42%; P = 0.03). Catheters remained in place for an average of 6 days in each group.

    Antimicrobial Activity on Catheter Surface

    No surface antimicrobial activity was detectable on unused control catheters, whereas unused antiseptic catheters showed activity against all seven species tested, including P. aeruginosa and C. albicans (zones of inhibition, 4.5 to 8.5 mm).

    Control catheters removed from patients who were receiving systemic antibiotic therapy occasionally showed low-level surface activity that was unrelated to the length of time that the catheters had been in place (mean zone of inhibition ±SD, 1.7 ± 2.8 mm); in contrast, antiseptic catheters uniformly showed residual surface activity (mean zone of inhibition, 5.4 ± 2.2 mm; P < 0.002) that declined after prolonged periods in situ. Antimicrobial activity was seen with antiseptic catheters that had been in place for as long as 15 days.

    Tolerance

    Although erythema at the insertion site occurred more frequently in the antiseptic catheter group than in the control group (54% compared with 35%; P < 0.01) (Table 2), most cases of erythema were mild (score of 1 on a scale of 0 to 2 [21]). In contrast, tenderness was more frequent with control catheters (49% compared with 34% in the antiseptic catheter group; P < 0.01). When insertion sites were scored for all inflammatory markers [21], no clinically meaningful differences were seen between the two groups. No patient in either group experienced local or systemic hypersensitivity or toxicity ascribed to a study catheter.

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    Table 2. Condition of Catheter Insertion Sites at Catheter Removal

    Very low concentrations of chlorhexidine (60 to 215 ng/mL) and silver (45 to 73 ng/mL) were detected in the blood of 1 patient each among the 12 patients who were tested with an antiseptic catheter; 6 patients showed very low concentrations of sulfadiazine (0.3 to 8.9 µg/mL).

    Microbiological Findings

    Cutaneous Colonization of Insertion Sites

    Baseline skin cultures performed before catheter insertion showed approximately 102.2 colony-forming units per site in each group (Table 1). Most colonization was with coagulase-negative staphylococci; however, site colonization by S. aureus, enterococci, gram-negative bacilli, or Candida species was found with approximately 10% of catheters in each group. At the time of catheter removal, cutaneous colonization was lower in the antiseptic catheter group (101.2 ± 1.4 colony-forming units compared with 102.0 ± 1.2 colony-forming units; P < 0.001).

    Contamination of Catheter Hubs and Infusates

    Microbial contamination of one or more catheter hubs with more than 10 colony-forming units/mL occurred with 23.1% of control catheters and 26.4% of antiseptic catheters. Coagulase-negative staphylococci were the most frequent pathogens. Infusate contaminated with more than 10 colony-forming units/mL at the time of catheter removal, again primarily with coagulase-negative staphylococci, was found with 11.3% of control catheters and 5.8% of antiseptic catheters (P = 0.03).

    Catheter-Related Infection

    On removal, 75 catheters were found to be colonized with more than 15 colony-forming units; 11 catheters used in nine patients (seven with control catheters, two with antiseptic catheters) caused catheter-related bacteremia or candidemia (Table 3). Coagulase-negative staphylococci accounted for the largest proportion of colonized catheters in each group and the bacteremia caused by three catheters. Candida species were implicated in four blood-stream infections; gram-negative bacilli, in two; and S. aureus and enterococci, in one each.

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    Table 3. Outcomes of Catheter-Related Infection

    Antiseptic catheters were less likely to be colonized at removal than control catheters (13.5 compared with 24.1 colonized catheters per 100 catheters; relative risk, 0.56 [95% CI, 0.36 to 0.89]; P = 0.005). Nine cases of catheter-related bacteremia or candidemia occurred in the control group (4.6 infections per 100 catheters; 7.6 infections per 1000 catheter-days) compared with two cases in the antiseptic catheter group (1.0 infection per 100 catheters; 1.6 infections per 1000 catheter-days; relative risk, 0.21 [CI, 0.03 to 0.95]; P = 0.03). In the control group, eight catheter-related bloodstream infections were caused by S. aureus, gram-negative bacilli, enterococci, or Candida species; no infections with these organisms occurred in the antiseptic catheter group (P = 0.003). Both cases of bacteremia that originated from an antiseptic catheter were caused by coagulase-negative staphylococci.

    Antiseptic catheters were associated with a trend toward a reduced rate of catheter-related bloodstream infection with a patient's first study catheter (1.4 compared with 4.6 infections per 100 catheters; P = 0.14) as well as with subsequent catheters (0.8 compared with 4.6 infections per 100 catheters; P = 0.12). Antiseptic catheters also showed a similar trend toward prevention of bloodstream infection with first catheters in a site (0 compared with 3.5 infections per 100 catheters; P = 0.12) as well as with second catheters placed in an old site over a guidewire (2.0 compared with 6.1 infections per 100 catheters; P = 0.14).

    When the patient was used as the unit of analysis, the antiseptic catheter was found to confer substantial benefit in terms of prevention of catheter colonization (mean score, 2.185; P = 0.032) and prevention of catheter-related bloodstream infection (mean score, 0.975; P = 0.019). The comparison remained significant for K values ranging from 1 to 35 for catheter colonization and from 5 to 65 for catheter-related bloodstream infection. This indicates that the conclusions of the analysis are robust.

    None of the isolates from infected catheters in either group showed resistance to chlorhexidine-silver sulfadiazine in the in vitro assay. Mean zones of inhibition for strains of the same species isolated from colonized and infected catheters in the two groups differed by less than 25%. Figure 1 shows the Kaplan-Meier estimates of the cumulative risk for catheter-related bloodstream infection according to day of catheter placement in each group and shows that the catheters impregnated with chlorhexidine-silver sulfadiazine were protective (P = 0.01 by log-rank test).

    Figure 1. The differences between groups are highly significant ( = 0.01, log-rank test).
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      Figure 1. The differences between groups are highly significant ( = 0.01, log-rank test). Kaplan-Meier estimate of the cumulative risk for catheter-related bloodstream infection.P

      Sources of Organisms Causing Device-related Bacteremia

      Each of the 11 catheter-related bloodstream infections identified during the study was associated with colonization of the intravascular portion of the catheter. Efforts to identify all possible sources of organisms that colonized the catheters and produced bloodstream infection (Table 4, Figure 2) show that the skin around the insertion site and contamination of a catheter hub each seem to have been the sole identifiable source of infecting organisms in two catheter-related bloodstream infections and a potential source in four more. Contaminated infusate and hematogenous colonization of the catheter were each the sole identifiable source in one case each and a potential source in two more. Both cases of catheter-related bacteremia in the antiseptic catheter group were associated with concordant contamination of a catheter hub and a catheter that had been placed in an old site over a guidewire.

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      Table 4. Sources of Catheter-Related Bloodstream Infection Determined Using DNA Subtyping
      Figure 2. The strains cultured from the proximal catheter segment and catheter tip and percutaneously drawn blood show restriction-fragment patterns identica to those in strains cultured from skip of the insertion site before disinfection and catheter insertion (Skin: Before) and at the time of catheter removal (Skin: Final). The strains differ from the unrelated control strain. Presumed pathocenesis of infection is from skin to catheter to blood.
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        Figure 2. The strains cultured from the proximal catheter segment and catheter tip and percutaneously drawn blood show restriction-fragment patterns identica to those in strains cultured from skip of the insertion site before disinfection and catheter insertion (Skin: Before) and at the time of catheter removal (Skin: Final). The strains differ from the unrelated control strain. Presumed pathocenesis of infection is from skin to catheter to blood. Pulsed-field electrophoresis of genomic DNA of isolates of Staphylococcus aureus from potential sources of infection with an infected catheter, subjected to Smal digestion.

        Overall Rates of Nosocomial Bloodstream Infection

        A total of 12 nosocomial bloodstream infections occurred in study patients during exposure to a control catheter; 9 of these infections were caused by the control study catheter. Seven bloodstream infections occurred in patients exposed to an antiseptic study catheter, 2 of which were caused by the antiseptic study catheter (Table 5). The antiseptic catheter reduced the overall risk for nosocomial bloodstream infection by 45%.

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        Table 5. Effect of the Antiseptic Central Venous Catheter on the Overall Risk for Nosocomial Bloodstream Infection

        Cost-Benefit Considerations

        Beyond the 10% to 25% case-fatality rate associated with catheter-related bacteremia [36-41], a nosocomial bloodstream infection prolongs hospitalization by 7 to 14 days [36, 40, 41] and adds approximately $29 000 to the cost of hospitalization [41]. The new antiseptic catheter costs approximately $25 more than a nonmedicated triple-lumen catheter. A simple analysis of direct hospital costs suggests that if an institution's rate of catheter-related bloodstream infection with noncuffed multilumen central venous catheters is at least 2% (approximately 3 infections per 1000 catheter-days) and if the antiseptic catheter reduces the risk for catheter-related bloodstream infection by at least 50%, the use of such catheters should prove to be cost-beneficial (Table 6).

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        Table 6. Simple Cost-Benefit Evaluation of the Antiseptic Catheter, Restricted to Direct Hospital Costs
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        Discussion

        In the past two decades, central venous catheters have come into wide use throughout the world. More than 5 million central venous catheters are sold in the United States annually. Catheter-related bloodstream infection is the most frequent serious complication seen with these catheters; according to published experiences from numerous centers, infection occurs with 3% to 7% of catheters [1]. We estimate that a vascular catheter-related bloodstream infection develops in more than 250 000 patients in U.S. hospitals each year.

        Strategies for preventing central venous catheter-related bloodstream infection should be guided by an understanding of the pathogenesis of infection [1], particularly the major sources of microorganisms that colonize percutaneously inserted catheters. In our study, as many as 6 of the 11 cases of catheter-related bacteremia and candidemia may have originated from the skin around the insertion site (Table 4, Figure 2). However, 2 to 6 cases may have resulted from contamination of a catheter hub, and 1 to 3 cases may have resulted from contaminated infusate or hematogenous seeding from a remote source of infection. These findings indicate that for maximum benefit, preventive strategies must be designed to block microbial invasion from all possible sources.

        As said elsewhere [27], “the development and application of novel technology may hold the greatest promise for a quantum reduction in the incidence of infection caused by intravascular devices.” Innovations that implicitly prevent microorganisms from colonizing the implanted catheter can help reduce the effect of poor aseptic technique. Given the multiple potential sources for infection of intravascular devices and the importance of microbial adherence to the catheter surface in the pathogenesis of infection [42, 43], the most promising strategy seems to be to render the catheter surface intrinsically more resistant to colonization. Studies in animal models of vascular catheter-related infection suggest that coating or impregnating a catheter with an antibiotic or antiseptic should be of benefit [44, 45].

        The chlorhexidine and silver sulfadiazine incorporated into the external surface of the antiseptic catheter that we studied are slowly released into the surrounding tissues and skin and exert inhibitory activity against the wide range of nosocomially transmitted microorganisms encountered in vascular catheter-related infection. This accounts for the sevenfold reduction in cutaneous colonization of the insertion site seen at catheter removal (Table 1). The catheter reduced the risk for complicating bloodstream infection nearly fivefold (relative risk, 0.21; P = 0.03); the greatest benefit was seen for prevention of bloodstream infections caused by S. aureus, gram-negative bacilli, enterococci, and Candida species (Table 3). None of the clinical isolates from infected catheters showed in vitro resistance to chlorhexidine-silver sulfadiazine. Persistent surface antimicrobial activity could be shown after 15 days in situ. We believe that for optimal prophylactic benefit, antimicrobial agents bound onto or incorporated into prosthetic materials must be released and achieve therapeutic levels in host tissues contiguous to the surface (Maki DG. Unpublished observations).

        Chlorhexidine, a cationic biguanide, is a potent broad-spectrum germicide with minimal inhibitory concentrations less than 50 µg/mL against nearly all nosocomially transmitted bacteria and yeasts, such as Candida species [46, 47]. Primary bacterial resistance to chlorhexidine is uncommon, and acquired nosocomial resistance, which is also rare, has been detected in clinical practice primarily when dilute aqueous solutions have been used ([48-50]). When chlorhexidine is used in concentrations of at least 2% (20 000 µg/mL) for cutaneous disinfection, nosocomial infection from extrinsic contamination by resistant organisms has been very rare. Colonization by resistant bacteria or yeasts has not been reported when chlorhexidine is used repeatedly on the skin of hospitalized patients [47, 51]. Moreover, toxicity or sensitivity has been reported [52, 53] but is exceedingly rare, and the safety of chlorhexidine seems well established [3, 6-15]. Even when chlorhexidine has been applied repeatedly to the skin of adults [54] or used for total-body bathing of newborns [55-57], no discernible organ toxicity has been seen.

        Silver sulfadiazine has also been used topically throughout the world for many years, primarily on burn wounds, where it delays colonization and substantially reduces the incidence of major infection [17-19]. Whereas bacterial resistance has occurred [18], silver sulfadiazine has retained effectiveness despite prolonged use in burn centers throughout the world [17-19]. Moreover, although silver and sulfadiazine are absorbed through the burn wound into the bloodstream [58, 59], silver sulfadiazine has been associated with little hypersensitivity (even in patients with putative allergy to sulfamonides [17-19, 59-61] or toxicity other than rare transient leukopenia [62].

        The quantities of chlorhexidine and silver sulfadiazine in an antiseptic catheter are far less than the amount to which a patient would be exposed if silver sulfadiazine cream was applied to a large burn or if chlorhexidine were used as a mouthwash or to irrigate a surgical wound or the vagina. In our study, chlorhexidine and silver were not detected in the blood of 10 of the 12 tested patients exposed to an antiseptic catheter. When chlorhexidine and silver were detected, their levels were several orders of magnitude lower than the levels known to be cytotoxic to human cells in vitro and far lower than levels seen when these compounds are used topically [54-57]. The concentrations of sulfadiazine detected in half of the tested patients who were exposed to an antiseptic catheter were far below those seen when silver sulfadiazine is used topically [58, 59]. Although the study catheter was associated with slightly more erythema around the insertion site (Table 2), possibly reflecting chemical irritation, the differences between groups were small. No patient had severe inflammation or showed evidence of hypersensitivity or toxicity; the reduced tenderness around the site of insertion of the antiseptic catheters may have been due to less catheter-related infection. Antiseptic catheters were inserted in three patients who were later found to have putatively experienced a rash after previous exposure to sulfonamides; none of these patients showed signs of hypersensitivity.

        Recent randomized clinical trials showed that coating vascular catheters with cefazolin [63] or minocycline and rifampin [64, 65] reduced the incidence of catheter-related infection, a finding that reaffirms the strategy of coating catheters and other implanted medical devices with an anti-infective agent. Potential drawbacks of using antibiotics to treat the surface of vascular catheters, however, are the ineffectiveness of these agents against antibiotic-resistant, nosocomial bacteria and fungi; the risk for the emergence of bacterial resistance during long-term use; and the potential for patient hypersensitization.

        Although bacteria also become resistant to antiseptic agents, this occurs far less frequently than resistance to antibiotics. Moreover, the combination of the antiseptic chlorhexidine with the antiseptic-antibiotic combination of silver sulfadiazine, which is synergistic in vitro [65], is more likely to be active against nosocomially transmitted pathogens. When used topically on burn wounds, the combination is more effective in preventing colonization than is the use of silver sulfadiazine alone [14, 15]. The combination also seems less likely to select for resistance in clinical practice, particularly given the relatively small population of organisms that colonize catheters.

        To avoid mechanical complications, central venous catheters are often inserted over a guidewire into the site of an old catheter [28-34]. In a prospective study of a silver-impregnated cuff (Vitacuff, Integra Life Sciences, Plainsboro, New Jersey), the cuff did not protect against infection with catheters inserted over a guidewire into an old site [5], presumably because the tract below the cuff was already colonized at the time the second catheter was inserted over the guidewire. In our study, the antiseptic catheter showed comparable benefit with catheters placed into a new site (0 compared with 3.5 bloodstream infections per 100 catheters) and catheters placed into an old site over a guidewire (2.1 compared with 6.1 bloodstream infections per 100 catheters).

        The cumulative risk for central venous catheter-related infection increases the longer the catheter is in place [1]. In many intensive care units, the length of time that catheters are allowed to remain in place in patients who require prolonged central access is arbitrarily limited to 3 to 7 days, after which a new catheter is inserted percutaneously into a new site (which increases the risk for pneumothorax and other mechanical complications) or a new (second) catheter is placed into the same site over a guidewire [3, 5, 28-34]. Randomized trials have not been able to show conclusively that routine site rotations or periodic catheter exchange over a guidewire are beneficial [31-34]; however, each of these studies had limited statistical power. In our study, 8 of the 11 catheter-related bloodstream infections originated from catheters placed over a guidewire into an old site. The use of novel technologies that prevent surface colonization and, in the process, catheter-related bloodstream infection can allow central venous catheters to remain safely in place for prolonged periods and obviate the need for guidewire exchanges. Actuarial analysis of the cumulative risk for catheter-related bloodstream infection (Figure 1) suggests that an antiseptic central venous catheter inserted into a new site can remain in place for at least 10 days with a low risk for development of a complicating bloodstream infection.

        Although the antiseptic catheter reduces the incidence of catheter-related infection, it is appropriate to question whether use of this catheter is cost-beneficial, at least in terms of the direct costs of hospitalization. If an institution's baseline rate of central venous catheter-related bloodstream infection is at least 2% (approximately 3 infections per 1000 catheter-days) and the new catheter reduces the risk for bloodstream infection by 50%, the use of an antiseptic catheter should be cost-beneficial (Table 5). If the antiseptic catheter further reduces the risk (as suggested by our study [Table 3]), use of the catheter should be even more cost-beneficial. Depending on the institution's baseline rate, the cost of preventing a catheter-related bloodstream infection with the antiseptic catheter should not exceed $2500 (if the baseline rate is 3 to 5 infections per 1000 catheter-days) and could be as low as $500 (baseline rate >8 infections per 1000 catheter-days). Permitting central venous catheters to be left safely in situ for longer periods should lead to even greater economic benefit. Whether combining a silver-impregnated cuff [5] with the antiseptic catheter produces added benefit is unknown.

        Although the antiseptic catheter seems to substantially reduce the risk for central venous catheter-related bloodstream infection, it should not be considered the final answer in the quest for novel technology designed for prevention. Other antimicrobial agents or novel biomaterials that confer resistance to microbial colonization should be vigorously pursued. However, it is essential that promising new technologies be evaluated in large randomized clinical trials. These trials should use rates of catheter-related bloodstream infection, rather than levels of catheter colonization, as the arbiter of preventive efficacy and should examine the relation between cost and benefit. Moreover, use of a novel technology must never compromise striving for the best aseptic technique-including the use of full sterile barriers during catheter insertion [20, 66] -and compliance with other preventive strategies known to be effective [1, 67].

        Presented in part at the 20th Annual Scientific Symposium of the Society for Critical Care Medicine, May 1992, Washington, D.C.; published in abstract form (Critical Care Medicine. 1991; 19:59); and presented in part at the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy, October 1992, Anaheim, California.

        Ms. Stolz: Microbiology Laboratory, University of Wisconsin Hospital and Clinics-CS/250, Madison, WI 53704.

        Ms. Wheeler: 2103 Ryanwood Avenue, Schofield, WI 54476.

        Dr. Mermel: Division of Infectious Diseases, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903.

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