Healthcare-Associated Infections Related to Use of Intravascular Devices Inserted for Long-Term Vascular Access
Anne-Marie Chaftari
Issam Raad
Long-term intravascular devices (IVDs) have become indispensable in the modern medical care of chronically ill patients such as cancer patients, patients with renal failure requiring chronic hemodialysis, or patients requiring organ or bone marrow transplantation. In the 1960s and 1970s, treatment of cancer patients through a small peripheral venous catheter was often complicated by extravasation of vesicant chemotherapeutic agents and thrombosis of peripheral veins, which limited the use of parenteral anticancer chemotherapy. Long-term silicone central venous catheters (CVCs) allowed the extended, safe use of anticancer chemotherapeutic agents as well as the potential for appropriate use of total parenteral nutrition (TPN) fluids, blood products, and other intravenous therapeutic agents. For patients with short bowel syndrome, long-term CVCs have become the only source for nutritional support through TPN. Similarly, patients requiring hemodialysis who have had prior failure of arteriovenous fistulas or shunts become totally dependent on intravascular catheter-related access for their hemodialysis. In all of these clinical situations, the long-term CVC becomes an essential device for the maintenance of life.
There is no standard agreed-upon definition for longterm catheters in terms of the duration of catheterization. Sherertz defined long-term catheters as those with a duration of placement of an average of >8 days. Rather than using an average duration, we have defined this term in a previous study to signify catheters that remain in place for >30 days. We also defined short-term catheterization by duration of placement of <10 days, and intermediate catheterization by duration of placement ranging between 10 and 30 days (1).
Long-term IVDs can be categorized into one of three groups: (a) nontunneled long-term CVCs (such as peripherally inserted central catheters [PICCs] or subclavian CVCs such as Hohn catheters); (b) cuffed and tunneled catheters (such as Hickman/Broviac, Groshong, and tunneled Uldall catheters); and (c) implanted subcutaneous central venous ports.
NONTUNNELED CATHETERS
Traditionally, it was assumed that the only method of maintaining long-term intravascular access in chronically ill patients was through surgically implantable CVCs such as the tunneled catheters and implantable ports. Over the last decades, nontunneled long-term silicone CVCs (particularly PICCs) have become more accepted as a cost-effective form of intravascular access. In addition, these catheters could be maintained for a long period, up to 400 days, without complications (2). Nontunneled long-term catheters consist of two types: long-term nontunneled subclavian catheters and PICC lines. Nontunneled subclavian catheters are inserted percutaneously via the subclavian vein into the superior vena cava, in the outpatient nonsurgical setting. The advantage of these catheters is that they are associated with low cost, because their insertion does not require the use of an operating room or a special surgical technique (3). In addition, these catheters can be exchanged over a guidewire, and the removed intravascular segment may be cultured if a catheter infection is suspected or if a new catheter needs to be inserted. These catheters are available as single-, double-, or triple-lumen cannulas.
The PICC lines are becoming widely used, particularly for outpatient long-term central venous therapy, such as patients requiring intravenous home antibiotics for osteomyelitis or endocarditis, cancer patients, or patients requiring TPN delivery. These catheters are usually inserted in the antecubital space, via the cephalic or basilic vein, and advanced into the central venous system. These catheters are very cost-effective, because they can be inserted in the outpatient clinic by a trained infusion therapy nurse and do not require a physician for their insertion. These catheters can be maintained for an average of 3 months and are associated with a low infection rate and cost (2). However, their main disadvantage is a high rate of aseptic thrombophlebitis related to mechanical contact (4). Traditionally, many of these catheters were made of silicone, although
over the last decade, most PICCs are power injectable made of polyurethane and hence allow the use of contrast material for diagnostic imaging.
over the last decade, most PICCs are power injectable made of polyurethane and hence allow the use of contrast material for diagnostic imaging.
TUNNELED CATHETERS
In 1973, Broviac et al. (5) described the first surgically implanted tunneled catheter to be used in pediatric patients requiring long-term TPN. Later, Hickman et al. (6) described another long-term tunneled catheter for cancer patients requiring bone marrow transplantation. These catheters are usually tunneled under the skin for several inches until they reach the cannulated vein. Tunneled catheters have a Dacron cuff that is located in the proximal subcutaneous segment 5 cm from the exit insertion site. After insertion, the Dacron cuff becomes enmeshed with fibrous tissue, hence anchoring the catheter and creating a tissue interface mechanical barrier against the migration of skin microorganisms along the external intracutaneous pathway. Tunneled catheters usually exit the body midway between the nipple and the sternum. Another vascular access catheter is the Groshong, which, unlike the Hickman/Broviac, is thin walled and has two slit valves adjacent to a rounded closed end that remains closed unless fluids are being infused or blood is being drawn. This decreases the risk of intraluminal blood clotting or infusion of air when the catheter is not in use. Hence, this type of catheter does not require daily heparin flushes, but rather is flushed with saline on a weekly basis.
IMPLANTABLE PORTS
To eliminate the migration of skin microorganisms from the skin insertion site in externalized catheters along the intracutaneous pathway, the surgically implanted subcutaneous central venous ports were developed where the whole catheter, including the metallic port, is placed beneath the skin (7). Hence, implantable ports consist of a metal/titanium or plastic port placed beneath the skin and connected to a catheter that enters the cannulated vein. Ports are usually placed in a subcutaneous pocket on the upper chest or, less often, in the antecubital area of the arm (peripheral port). Ports are available as single- or doublelumen catheters with or without Groshong valves and can be accessed as needed with a steel needle.
EPIDEMIOLOGY
The bloodstream infection (BSI) rates associated with longterm CVCs should be reported using catheter-days as the denominator. The Centers for Disease Control and Prevention (CDC) recommends that rates of central line-associated bloodstream infections (CLABSI) be expressed per 1,000 device-days. This recommendation takes into consideration the varying risks of CLABSI over time for the different types of CVCs. According to Crnich and Maki (8), although the rates of CLABSI per 100 CVCs used are usually higher for long-term devices, the risk per 1,000 catheter-days is usually considerably lower than that for short-term CVCs. Previous studies showed that the average infection rate for long-term CVCs in cancer patients ranged from 1 to 1.5 episodes per 1,000 catheter-days (9,10,11,12). Assuming this rate and the fact that three million long-term CVCs are inserted annually in the United States (with an average dwell time of 100 days), the estimated annual number of episodes of catheter-associated bacteremia that occur in the United States related to the use of these catheters in cancer patients is between 300,000 and 450,000.
Several studies have compared the efficacy of tunneled catheters (such as Hickman/Broviac catheters) with implantable ports. Mueller et al. (13), in a prospective, randomized study, compared the complications of the two types of long-term catheters and found no significant difference in infection rates between the two types of devices. Similarly, Keung et al. (14) conducted a retrospective study of infectious complications in 111 longterm CVCs. Multivariable analysis revealed no significant difference in infection rates between tunneled catheters and implantable ports. On the other hand, there are several studies that suggest that ports may be associated with lower infection rates. Mirro et al. (15) evaluated 266 tunneled catheters and 93 implantable ports in children with cancer, and showed that, when all causes of failure were analyzed including infectious complications, ports had a significantly longer duration of use than tunneled catheters. In a prospective observational study conducted at Memorial Sloan-Kettering on 1,630 long-term CVCs (923 tunneled catheters and 707 ports), Groeger et al. (16) found that the incidence of infection per device per day was 12 times greater with the tunneled catheter than with ports. Therefore, these data might suggest that ports are associated with a lower infection rate than tunneled catheters, even though they are not conclusive. In addition, the data should be analyzed with caution because there could be confounding variables, such as the various uses of the catheters (including the use of TPN), duration of neutropenia, and thrombotic complications that were not taken into consideration.
There are very few data in the literature comparing tunneled with nontunneled long-term CVCs in terms of infection rates. In a prospective randomized study, Andrivet et al. (17) showed that the infection rate associated with nontunneled subclavian silicone CVCs was not different from that related to tunneled silicone catheters. However, the lack of a difference could be related to the small sample size. In a prospective study evaluating nontunneled long-term CVCs at the M. D. Anderson Cancer Center, we determined that the infection rate for PICC lines and nontunneled subclavian CVCs was 1.4 per 1,000 catheter-days, which was comparable to what was described for Hickman catheters in the literature (2). At the M. D. Anderson Cancer Center, the cost of insertion of nontunneled catheters, including the chest x-ray postinsertion and other related fees, is in the range of $1,190 to $1,326 as compared with more than $6,502 for the Hickman tunneled CVC. The cost of placing an implantable port at our institution is about $7,076. Given the comparable durability of all long-term catheters, the potential marginal difference in infection rates might not justify the wide difference in cost between the tunneled catheters and ports on the one hand and the nontunneled CVC (PICC lines and nontunneled subclavian catheters) on the other.
PATHOGENESIS
Microbial adherence and colonization of long-term catheters is the by-product of the interaction of several factors: (a) host-derived proteins, (b) microbial factors, (c) catheter material, and (d) iatrogenic factors.
After insertion, a thrombin sheath covers the internal and external surfaces of the catheter, which is rich in host proteins (18,19). These proteins include fibronectin, fibrinogen, laminin, thrombospondin, and collagen (20, 21, 22, 23, 24). Staphylococcus aureus binds strongly to fibronectin and fibrinogen, whereas coagulase-negative staphylococci (CNS) bind strongly to fibronectin (20,21). In addition, Candida albicans has been shown to bind well to fibrin (25).
Biofilm formation represents the microbial factor involved in the enhancement of adherence of microorganisms to catheter surfaces. Microorganisms, such as CNS, S. aureus, and even Candida parapsilosis, have the potential of undergoing intrinsic phenotypic changes that result in the expression of several enzymes that lead to the production of an exopolysaccharide, thus causing the biofilm to form (26, 27, 28, 29, 30, 31). Microorganisms embed themselves in this layer of biofilm (or microbial slime), and hence protect themselves from antimicrobial agents such as glycopeptides (32). Other microbial factors, such as hydrophobicity and the surface charges of microorganisms, contribute to the adherence to catheter materials such as silicone (33,34). Hydrophobic staphylococcal microorganisms adhere better to silicone surfaces of which most long-term catheters are made than to the polyurethane or Teflon surfaces of short-term catheters.
The material from which the catheters are made plays a role in the adherence of microorganisms to the catheter surface. The physical characteristics of the catheter surfaces, including hydrophobicity, surface charges, irregularities, and defects on the catheter surface and the thrombogenicity of the catheter surface, contribute to the process of microbial adherence (3,35). Several investigators have shown, for example, that Staphylococcus and Candida species adhere better to polyvinyl chloride catheters than to Teflon catheters (36,37). Sherertz et al. (38) have demonstrated in a rabbit model that silicone catheters are easier to infect with S. aureus than polyurethane, Teflon, or polyvinyl chloride catheters. This was also shown by Vaudaux et al. (39), who demonstrated that indwelling silicone catheters, after being removed from patients, were more prone to S. aureus adherence than were polyurethane or polyvinyl chloride catheters. This was related to the fact that silicone catheters tend to have a direct toxic effect on neutrophils, alter neutrophil chemotaxis, and cause a localized depletion of complement (40,41).
Iatrogenic factors associated with medical interventions in high-risk patients entail a higher risk of colonization of catheter surfaces. These consist of the use of TPN fluids and lipid emulsions, interleukin-2, and long-term hemodialysis (3,35). TPN has been associated with higher rates of infection in tunneled catheters (42). The 25% dextrose and the lipid emulsions have been associated with microbial growth, particularly Candida species and Malassezia furfur (35). In addition, interleukin-2 has also been shown to predispose to catheter colonization and infection by staphylococcal microorganisms (43,44). It is postulated that interleukin alters neutrophil chemotaxis toward staphylococcal microorganisms, and hence leads to a higher degree of colonization of catheter surfaces with these microbial agents. Finally, chronic hemodialysis patients have a high rate of nasal carriage of S. aureus, ranging from 30% to 65% (45, 46, 47). Hemodialysis patients who are chronic carriers of S. aureus have a threefold higher risk of contracting catheter-related S. aureus BSI when compared with noncarriers (48). The majority (more than 90%) of S. aureus infections in carriers are caused by the same type as that carried in the nares (45).
The most common microorganisms causing catheterassociated infections in long-term CVCs are CNS, S. aureus, and yeasts (49). This is related to the fact that staphylococci are skin microorganisms. In addition, staphylococci and Candida adhere well to host proteins found on catheter surfaces and tend to form a microbial biofilm (25, 26, 27, 28, 29, 30, 31). This is in contrast to gram-negative microorganisms, such as Escherichia coli and Klebsiella pneumoniae, that do not adhere well to fibronectin and fibrin and are not known to produce a biofilm. Other microorganisms that have been associated with long-term CVC infections are Bacillus species, Corynebacterium species, Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, micrococcus, Achromobacter, rapidly growing mycobacteria, and various other fungal microorganisms such as M. furfur and Fusarium oxysporum (50).
For long-term catheters, the lumen seems to be the major site of colonization and source of CLABSIs. This has been shown for catheters used for long-term hemodialysis and for CVCs used for TPN and cancer treatment (51, 52, 53). Previous investigators highlighted the hub as the most common source for long-term catheter-related bloodstream infections (CR-BSIs) (51,54). However, for short-term catheters with an average duration of <8 days, the skin seems to be the major source, followed by the hub/lumen (55,56). The relative contribution of contaminated infusate, hematogenous seeding from a remote infected source, or extension from a contiguous site of infection seems to be low even in long-term catheters. Using semiquantitative scanning electron microscopy studies, we have determined that the extent of biofilm formation and colonization is greater on the external surface of short-term catheters (<10 days of catheterization) than the internal surface (1). However, for catheters that remain in place for >30 days, this phenomenon is reversed with greater biofilm formation and ultrastructural colonization in the lumen of the catheter versus the external surface.
Electron microscopy studies have shown that colonization is universal (1,57). It involves all CVCs within 24 hours of insertion (57). However, although colonization is universal, only a few catheters are associated with infection. There is a quantitative relationship between the number of microorganisms (particularly free-floating microorganisms) on the catheter and the risk of BSIs. Sherertz et al. (58) studied 1,610 CVCs and found that the greater the number of microorganisms retrieved from the catheters by sonication, the greater the risk of BSI. Therefore, infection could be a function of whether the microorganisms on the catheter surface, particularly those that are free-floating, exceed a certain quantitative threshold due to various risk factors outlined above.
MANIFESTATIONS AND DEFINITIONS
The clinical manifestations of a CLABSI for long-term catheters consist of systemic manifestations such as fever and chills, which are nonspecific, particularly in the immunocompromised patient. Clinical evidence of a local infection at an exit site, tunnel, or port pocket would be necessary to suggest the catheter as the source of the BSI. However, for PICC lines, local catheter site inflammation consisting of erythema and phlebitis could be aseptic in nature and reflect a local mechanical irritation of the vein due to the insertion of a large catheter in the relatively small basilic or cephalic veins (2). Therefore, local catheter-related infection or systemic CLABSI should be defined in terms of clinical manifestations associated with microbiologic data implicating the catheter as the source of the infection (Tables 18-1 and 18-2). The following definitions were proposed in a recent guideline by the Infectious Diseases Society of America (IDSA) (59):
Local catheter infection: Local catheter infection could exist in different forms, depending on the type of catheter (nontunneled or tunneled implantable port). However, in the presence of positive results of a blood culture, it would be classified as CLABSI (59,60).
Exit-site infection: erythema, tenderness, or induration within 2 cm of the catheter exit site, may be associated with other signs and symptoms of infection such as fever or purulent drainage emerging from the exit site.
TABLE 18-1 Definitions of Colonization, Phlebitis, and Local Central Line-Associated Infections
Type of Central Line-Related Infection
Definitions
Catheter colonization
Significant growth of one microorganism by quantitative or semiquantitative culture of the catheter tip, subcutaneous catheter segment, or catheter hub, in the absence of simultaneous clinical symptoms
Phlebitis
Induration or erythema, warmth, and pain or tenderness along the tract of a catheterized or recently catheterized vein
Exit-site infection
Purulent drainage from the catheter exit site, or erythema, tenderness, and induration within 2 cm of the catheter exit site
Tunnel infection
Erythema, tenderness, and induration of the tissues overlying the catheter and more than 2 cm from the exit site
Pocket infection
Purulent exudate in the subcutaneous pocket containing the device or erythema, tenderness, induration, and necrosis of the skin over the pocket
Pocket infection: purulent exudate in the subcutaneous pocket containing the reservoir of the port or erythema and necrosis of the skin over the reservoir of a totally implantable device.
Tunnel infection: erythema, tenderness, and induration in the tissues overlying the catheter and >2 cm from the exit site.
Systemic catheter infection: BSI could either be
Infusate-related: with the concordant growth of a microorganism from infusate and from percutaneously obtained blood cultures with no other identifiable source of infection.
Central line-related:
Bacteremia or fungemia in a patient who has an IVD and >1 positive blood culture result obtained from the peripheral vein, clinical manifestations of infection (e.g., fever, chills, and/or hypotension), and no apparent source for BSI (with the exception of the catheter).
For the definitive diagnosis of CLABSI or CR-BSI as defined by the IDSA (59), one of the following should be present:
the isolation of the same microorganisms (species) from a semiquantitative (>15 colonyforming units (CFU)/catheter segment) or quantitative (>102 CFU/catheter segment) catheter tip culture and from at least one percutaneous blood culture
simultaneous quantitative cultures of blood drawn, one from a catheter hub and the other from a peripheral vein with a ratio of >3:1 CFU/mL (catheter vs. peripheral blood)
differential time to positivity (DTP) of 2 hours (growth in a culture of blood obtained through a catheter hub is detected by an automated blood culture system at least 2 hours earlier than a culture of simultaneously drawn peripheral blood of equal volume).
However, quantitative blood cultures are not widely available for a definite diagnosis of CR-BSI. According to the CDC, a CLABSI can be diagnosed in a patient who has a central line that was in place at the time of, or within 48 hours before, onset of bacteremia in the presence of any one of the following:
A recognized pathogen cultured from one or more blood cultures and organism cultured from blood is not related to an infection at another site.
A common skin contaminant cultured from two or more blood cultures drawn on separate occasions within two days of each other and at least one of the following clinical signs or symptoms: fever (>38°C), chills, or hypotension and signs and symptoms and positive laboratory results are not related to an infection at another site.
Most CR-BSIs are uncomplicated. However, with virulent microorganisms such as S. aureus, C. albicans, and P. aeruginosa, deep-seated infections can occur, particularly catheter-related septic thrombosis, which consists of
CR-BSI with an infected thrombus (61, 62, 63). The clinical course of septic thrombosis is characterized by occasional swelling above the site of the thrombotic vein and persistent BSI on antimicrobial therapy even after the removal of the catheter. Other deep-seated infections associated with complicated catheter-related bacteremias and fungemias consist of endocarditis, osteomyelitis, and retinitis in the case of candidemia (61,62).
CR-BSI with an infected thrombus (61, 62, 63). The clinical course of septic thrombosis is characterized by occasional swelling above the site of the thrombotic vein and persistent BSI on antimicrobial therapy even after the removal of the catheter. Other deep-seated infections associated with complicated catheter-related bacteremias and fungemias consist of endocarditis, osteomyelitis, and retinitis in the case of candidemia (61,62).
TABLE 18-2 Diagnosis of Intravascular Catheter-Related Bloodstream Infectiona | ||||||
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