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

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. 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 g/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 pract