Rabih O. Darouiche
Importance of Nosocomial Bloodstream Infection
The success in using better technology and more effective medicinal agents to prolong the survival of critically ill, immunocompromised, and an older population of patients has, unfortunately, been associated with a surge in the incidence and complications of nosocomial infections. At the present time, more than 2 million cases of hospital-acquired infection occur each year in the United States, resulting in the death of about 90,000 patients.
Although bloodstream infection generally accounts for less than 15% of all cases of nosocomial infections, critically ill patients and persons with cancer have disproportionately higher rates of nosocomial bloodstream infections. This phenomenon can be explained, at least in part, by the fact that the critically ill patient is more dependent on vascular access, and the vascular catheter is the most important culprit for nosocomial bloodstream infections. For instance, not only do bloodstream infections account for 20% of all cases of nosocomial infections among ICU patients, but 87% of bacteremias originate from an infected central vascular catheter (1). Similarly, most cases of bloodstream infection among cancer patients are associated with an indwelling vascular catheter, including 70% of patients with solid tumors and 56% of those who suffer from hematologic malignancy (2).
The vast majority of the 175 million vascular catheters inserted each year in the United States are peripherally placed, and are very unlikely—less than 0.1% to 0.2%—to cause bloodstream infection (3). Most cases of catheter-related bloodstream infection (CRBSI) arise from the almost 6 million central vascular catheters inserted annually. These data include about 4.5 million short-term catheters, with a mean duration of placement of 7 to 10 days, and 1.5 million long-term catheters, over one million of which are mainly peripherally inserted central catheters (PICCs), and the rest are tunneled catheters (4).
We have witnessed over the last several years an escalating drive to prevent CRBSIs, with the intention of achieving four goals:
1. Reduce the unacceptably high incidence of catheter-related bloodstream infection. Since, on average, about 5% of the 6 million annually placed central vascular catheters result in bloodstream infection, about 300,000 cases of CRBSI occur each year in the United States, including at least 80,000 cases among ICU patients (5). The rates of CRBSI tend to be lower in the surgical care units than in medical and pediatric intensive care units; that difference is attributed, at least in part, to a relatively shorter mean duration of catheter placement in the surgical intensive care unit.
2. Avoid the serious complications of CRBSI, which can result in irreversible multiorgan damage and has an attributable mortality that can be as high as 23% (6) to 25% in critically ill patients (7,8,9).
3. Limit the economic sequelae, as the treatment of CRBSIs in a critically ill patient increases cost as much as $29,000 (7,8,9) to $56,000 (10) per case, and surviving patients are hospitalized for a mean of 6.5 (7,8,9) to 22 (10) days longer than those who do not develop such an infection. The overall annual cost of management approaches $2.3 billion.
4. Control the presence of organisms within the biofilm surrounding indwelling vascular catheters since this environment constitutes an optimal reservoir for emergence of antibiotic resistance, including vancomycin-intermediate or -resistant staphylococci (11,12).
To offer the increasingly time-constrained intensivists a scientifically based and clinically applicable assessment, this chapter will review only approaches that have been evaluated in prospective randomized clinical trials or meta-analyses that have already been reported in peer-reviewed journals. Clinical trials with less desirable designs, including nonrandomized, retrospective, and crossover studies, will not be considered because confounding variables may lead to scientifically invalid conclusions. Likewise, results of studies that have been reported in an abstract form but have not yet been subjected to the peer review process will not be addressed.
Epidemiology of Nosocomial Bloodstream Infections
In the largest and most informative assessment of the epidemiology and microbiology of nosocomial bloodstream infections, the study of Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) identified a total of 24,179 episodes of bloodstream infection in 49 U.S. hospitals from 1995 to 2002, for a rate of 60 cases per 10,000 hospital admissions (13). This study revealed that 87% of bloodstream infections were caused by a single organism, and 13% were polymicrobial. The monomicrobial episodes of nosocomial bloodstream infection were primarily caused by Gram-positive bacteria (65%, including coagulase-negative staphylococci in 31%, Staphylococcus aureus in 20%, and Enterococcus spp. in 9%), followed by Gram-negative bacteria (25%) and Candida spp. (9%). The overall crude mortality rate among patients with nosocomial bloodstream infection was 27% and was organism-specific as patients infected with Candida spp. and coagulase-negative staphylococci were the most (40%) and least (21%) likely to die, respectively. Very importantly, the percentage of hospital isolates of methicillin-resistant S. aureus (MRSA) significantly (p <0.001) increased from 22% in 1995 to 57% in 2002.
Diagnosis of Catheter-Related Infection
Since bloodstream infection is the most common serious complication of indwelling vascular catheters, early and accurate diagnosis of this infectious complication is essential. According to the Centers for Disease Control and Prevention (CDC) (14), CRBSI is defined as the isolation of the same organism (i.e., 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. Until recently, catheter colonization was almost always defined as the growth in cultures from either the tip or subcutaneous segment of the catheter of greater than or equal to 15 colony-forming units/mL by the semiquantitative roll-plate method (15), or greater than or equal to 1,000 colony-forming units/mL by the quantitative sonication method (16).
This standard manner of diagnosing CRBSI, however, is retrospective, as it requires removal and culture of the vascular catheter. Regrettably, only 15% to 25% of central venous catheters removed because of suspected catheter-related infection yield growth from cultures of the catheter tips (17). This explains the escalating interest in assessing and implementing procedures that are intended to prospectively diagnose catheter-related infection without removal of the catheter (18). The potential roles of two such microbiologic methods that could indicate whether the catheter is the source of bloodstream infection have been recently assessed. Both methods require concurrent collection of peripheral and central (i.e., through the lumen of the catheter) blood cultures. The first qualitative method—differential time to positivity (DTP)—which relies on the understanding that the culture of a blood sample that contains higher bacterial concentration would become positive, as detected by production of carbon dioxide by multiplying organisms, at least 2 hours before this would occur in a culture from peripheral blood (2). In the setting of a CRBSI, in which the catheter itself was the source of infection, the supposition is that the bacterial load of the infected catheter is higher than that seen in peripheral blood. The other quantitative method—paired quantitative blood cultures (PQBC)—is based on the anticipation that the number of colony-forming units (CFU) retrieved from a central blood culture would be greater than or equal to fivefold higher than that grown from cultured peripheral blood (19). Although a meta-analysis of 51 studies of both short- and long-term catheters published from 1996 to 2004 demonstrated that the PQBC method is the more accurate method in diagnosing intravascular device-related bloodstream infection (20), the PQBC method is less accurate than the DTP method for diagnosing bloodstream infection associated with short-term catheters (2,19). Furthermore, the PQBC method is more laborious and less implemented in hospital microbiology laboratories than the DTP method. In addition to considering the sensitivity, specificity, and the positive and negative predictive values of different diagnostic methods that do not require catheter removal, other factors—such as availability, ease of performance, cost, and clinical scenarios of individual patients—often affect the frequency of implementing various diagnostic methods in different medical facilities.
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Figure 31.1. Exit-site infection around an indwelling double-lumen left subclavian central venous catheter that clinically manifested with pain, tenderness, erythema, and swelling. |
Infections associated with vascular catheters can also present as an exit-site infection (Fig. 31.1), which manifest as erythema, tenderness, swelling, and drainage. Since inflammatory skin changes can be detected in only about one fourth of patients with bloodstream infection associated with central venous catheters, the absence of exit-site infection does not negate the existence of CRBSI. Patients with a tunneled vascular catheter can also develop tunnel infection which, like bloodstream infection but unlike exit-site infection, usually requires the removal of the infected catheter to establish cure.
Pathogenesis and Impact on Prevention
Source of Pathogens
The four potential sources of pathogens are the patient's skin around the site of catheter insertion, a contaminated catheter hub, hematogenous seeding from a distant site of infection, and infected infusate. The source of infecting organisms is not determined in about 25% of patients with CRBSI. Not only do both of the first two sources listed above originate from the skin—of the patient and health care providers—but they collectively are responsible for the vast majority of catheter-associated infections. The patient's skin around the catheter insertion site is the most common source of organisms that colonize central venous catheters with a short-term (mean duration, less than 7 to 10 days) indwelling time (21). As shown in Figure 31.2, the concentration of bacteria on the skin differs between various body sites, with the highest concentration generally present in the femoral area, which is greater than the jugular area, which itself is greater than the subclavian area. Factors that favor higher bacterial concentration on the skin where catheters are inserted include soiling by bacteria-containing bodily fluids and secretions, presence of hair follicles, high temperature, and moist environment. After colonizing the external surface of the catheter, skin-derived flora migrate along the subcutaneous segment into the distal intravascular segment to potentially result in bloodstream infection. In this clinical scenario of infection associated with long-term vascular catheters that are subjected to more extensive manipulation at the catheter hub, the catheter hub becomes contaminated by organisms that originate from the hands of medical personnel, then migrate along the internal surface of the catheter into the intravascular segment before causing bloodstream infection (22). The difference in the pathogenesis of infections associated with short-term versus long-term catheters helps explain why a surface-modified vascular catheter with antimicrobial activity only along the external surface is likely to protect against infection associated with short-term but not long-term catheters.
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Figure 31.2. Colony-forming units of bacteria residing per square centimeter (cfu/cm2) of skin surface in different body sites. |
Type of Pathogens
The pathogenesis of infections associated with vascular catheters dictates the microbiology of this infection. Because the patient's skin around the catheter insertion site and the hands of medical personnel provide the two most common sources of pathogens, at least two thirds of cases of catheter-related infection are caused by staphylococcal organisms (coagulase-negative staphylococci and Staphylococcus aureus) (23). Less common pathogens, including Gram-negative bacteria and Candida spp., collectively cause about 25% of infection cases and are particularly prominent in infections from vascular catheters placed for long periods of time. Because of this wide array of potential pathogens, potentially preventive approaches that are active only against Gram-positive bacteria may not significantly reduce the overall rate of infection and, in some instances, may even predispose to superinfection by less common pathogens.
Milieu of Pathogens
Like other medical devices, infection of vascular catheters centers around the universal formation of a layer of biofilm surrounding the indwelling catheter (Fig. 31.3). The biofilm is composed of both bacterial products (fibroglycocalyx in the case of coagulase-negative staphylococci) and host factors—platelets and tissue ligands such as fibronectin, fibrinogen, and fibrin that variably adhere to well-described receptors on the surface of certain organisms, including staphylococcal and Candida organisms (24). Not only does the biofilm act as a protective barrier for embedded organisms against host immune defenses, including phagocytosis and opsonization (25,26), but it also can impair the activity (27) and, possibly, the penetration (28) of antibiotics against the slowly growing sessile organisms that inhabit the biofilm. This unique biofilm environment may explain why surface-modified vascular catheters containing antimicrobial agents that retain activity within the biofilm, and leach from the catheter surface to produce a zone of inhibition against deeply embedded organisms within the biofilm, tend to be clinically protective (Fig. 31.4).
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Figure 31.3. A cross-sectional image of a multilumen central venous catheter delineating the presence of a layer of biofilm around the luminal surface of the catheter. |
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Figure 31.4. Zone of inhibition around an antimicrobial-coated device placed on the surface of an agar plate that had been freshly inoculated with a biofilm-producing clinical strain of Staphylococcus aureus. This zone of inhibition was assessed 24 hours after incubating the agar plate at 37°C and resulted from the leaching of the antimicrobial agent off the coated device surface into the surrounding agar to result in killing of bacteria. |
Prevention of Vascular Catheter-Associated Infections
Bloodstream infection is the most common serious complication of indwelling vascular catheters. Although catheter colonization is a prelude to catheter-associated infection, most colonized catheters do not become clinically infected (24). Therefore, a significant reduction in the rate of catheter colonization does not, in and of itself, constitute proof of clinical efficacy. The ultimate proof of clinical efficacy is a significant reduction in the rate of CRBSI in a sufficiently powered, prospective, randomized clinical trial. As a corollary, if an inadequately powered clinical trial that fails to demonstrate a significant reduction in the rate of CRBSI despite a significantly lower rate of catheter colonization in the experimental versus control group, it is implied that the experimental strategy is either not clinically protective or needs to be examined in a larger clinical trial. In that regard, a properly conducted meta-analysis that adjusts well to confounding variables may help address the benefit of a potentially preventive approach. A critical analysis of the peer-reviewed literature allows the categorization of potentially preventive measures into three groups: (i) approaches that do not significantly reduce catheter colonization or CRBSI, (ii) approaches that significantly reduce catheter colonization but not CRBSI, and (iii) approaches that significantly reduce CRBSI. Although the most desirable impact of potentially preventive measures is a reduction in mortality associated with CRBSI, it would be impractical to conduct a several-thousand-patient clinical trial that would be sufficiently powered to assess this outcome, which has a relatively low incidence—equivalent to the incidence of catheter-related bloodstream infection times the risk of dying from catheter-related bloodstream infection.
Approaches That Do Not Significantly Reduce Catheter Colonization or CRBSI
Silver-coated Catheters
This represents the most investigated approach in this category and focuses on modification of the catheter surface with different silver-containing moieties. Not only did in vitro studies yield conflicting findings with regards to efficacy—since some showed reduced bacterial adherence to the surfaces of polyurethane silver-coated catheters (29) and others indicated that the use of silicone silver-coated catheters is ineffective (30)—but the results of animal models also yielded inconclusive results (31). Although one prospective randomized clinical trial reported that silver-coated central venous catheters were protective (32), subsequent prospective randomized clinical trials found no evidence of clinical efficacy (33,34). The most recent assessment showed that short-term, central venous catheters impregnated with silver ions bonded to an inert ceramic zeolite reduce neither catheter colonization nor CRBSI (35). Not only is the silver application to the surface of short-term catheters mostly ineffective, but its incorporation onto the surface of long-term catheters can negatively impact the incidence of infection and cause adverse events. For instance, a prospective randomized clinical trial of tunneled long-term (mean dwell time, 92 days) hemodialysis catheters demonstrated a statistically insignificant trend for higher rates of catheter colonization (2.8 versus 1.3 cases per 1,000 catheter-days) and catheter-related infection (1.8 versus 1.1 cases per 1,000 catheter-days) in patients with silver-coated versus uncoated catheters, respectively (36). In addition to being clinically ineffective, the silver-coated hemodialysis catheters were removed in 2 of 47 (4%) patients because of the chronic development of hyperpigmented skin lesions at the site of catheter insertion, thereby contributing to the decision to abandon the clinical use of that particular silver-coated catheter (36). Several factors are responsible for the poor clinical efficacy of silver-coated catheters: (a) Since incorporated silver molecules do not effectively leach off the surface of most coated catheters, they do not produce effective zones of inhibition around the catheter surface that would ensure access of the coating agents to biofilm-embedded organisms; (b) silver tends to bind to host proteins, thereby resulting in lower concentration of free active silver molecules; and (c) the antimicrobial activity of silver can be impaired in the presence of bodily fluids (37).
Catheters Coated with Benzalkonium Chloride
In vitro studies showed that heparin-coated catheters possess some antimicrobial activity, possibly attributable to the weak antiseptic benzalkonium chloride, which is applied to the catheter surface primarily for its surfactant activity to allow bonding with heparin (38). However, small prospective randomized clinical trials failed to show a decrease in the rate of CRBSI associated with the benzalkonium chloride–coated catheters (39,40).
Approaches That Significantly Reduce Catheter Colonization But Not CRBSI
Dipping Catheters in Antibiotic Solutions
This bedside approach relies on dipping positively charged surfactant (usually tridodecyl methyl ammonium chloride, TDMAC)-pretreated catheters in a solution of negatively charged antibiotics such as cephalosporins and glycopeptides just prior to catheter insertion. Although a prospective randomized clinical trial showed that short-term central venous and arterial catheters that were pretreated with TDMAC and dipped at the bedside in cefazolin were sevenfold less likely to be colonized than undipped catheters, there was no demonstrated impact on the occurrence of CRBSI (41). A not-so-well-designed prospective randomized clinical trial also reported that immersion of short-term central venous catheters in vancomycin just prior to insertion was associated with a 22% reduction in the rate of catheter colonization (defined in that study as any level of bacterial growth by roll-plate culture of the catheter tip) as compared with nonimmersed catheters (42). The drawbacks of dipping catheters in vancomycin are the absence of impact on the incidence of catheter-related bloodstream infection and the occurrence of Candida overgrowth.
Catheters Coated with Silver-Platinum-Carbon
A prospective randomized clinical trial showed that short-term central venous catheters coated with silver-platinum-carbon (so-called oligon) were significantly less likely to become colonized than conventional uncoated catheters (18.6% versus 29.6%, p = 0.003) (43). However, there was no significant reduction in the rate of bloodstream infection associated with coated versus uncoated catheters (3.3% versus 4.3%).
Approaches That Significantly Reduce CRBSIs
Quite understandably, the most recent CDC guidelines included new recommendations for using all of the following clinically protective measures, including cutaneous antisepsis with chlorhexidine (category IA), maximal sterile barriers (category IA), and catheters coated with the combinations of chlorhexidine plus silver sulfadiazine, or minocycline plus rifampin (category IB) (14).
Cutaneous Antisepsis with Chlorhexidine
The objective of antiseptic cleansing of the skin is to achieve a major reduction—preferably a greater than or equal to 3 log reduction—in bacterial concentration on the skin surface at the catheter insertion site. Prompted by an expanding body of supporting evidence, almost a dozen clinical guidelines issued by various scientific and regulatory organizations, both individually and in collaboration, have recommended the use of chlorhexidine-containing preparations rather than povidone-iodine or alcohol for cleansing the skin around the vascular catheter insertion site (14). A prospective randomized clinical trial showed that vascular catheters inserted when using 2% aqueous chlorhexidine were significantly less likely to become colonized than catheters placed by using either 10% povidone-iodine or 70% alcohol (3). More important, CRBSI was fourfold to fivefold less likely in the former group than in the latter two groups (0.55% versus 2.6% and 2.3%, respectively). In a meta-analysis of eight prospective randomized clinical trials that included a total of 4,143 vascular catheters, the relative risk of CRBSI was twice as high among patients who receive povidone-iodine versus chlorhexidine (44). The superiority of chlorhexdiine over iodophor and alcohol could be predicted by comparing their characteristics, as shown in Table 31.1. Unlike iodophor and alcohol, chlorhexidine provides a residual and persistent antimicrobial activity that is not impaired by exposure to organic matter such as blood, does not irritate the skin, and has minimal absorption through the skin. Although 2% chlorhexidine compounds appear to be optimal in terms of both efficacy and safety, only recently has aqueous chlorhexidine become available in the United States, where the most frequently used form of chlorhexidine is in combination with an alcohol, usually isopropyl alcohol. As Table 31.2 delineates, the combination of chlorhexidine and alcohol has many more favorable properties than the combination of iodophor and alcohol. These recognizable differences have contributed to the escalating application of antiseptic solution that contains the combination of chlorhexidine and alcohol on the skin surrounding the insertion site of vascular catheters.
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Table 31.1 Comparison of Individual Antiseptic Agents |
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Maximal Sterile Barriers
In contrast to traditional sterile precautions that include the use of gloves and a small drape, maximal sterile precautions comprise the use of gloves, a large drape, a cap, a mask, and a gown. When compared in a prospective randomized fashion, the use of maximal sterile barriers versus traditional sterile precautions when inserting long-term (mean duration of placement, 70 days), noncuffed silicone vascular catheters was associated with a significantly lower incidence of catheter colonization (0.3 versus 1 per 1,000 catheter-days; p = 0.007) and CRBSI (0.08 versus 0.5 per 1,000 catheter-days, p = 0.02) (45,46). Although this protective measure is intended to be used for insertion of all central venous catheters, it is currently used less frequently outside the intensive care units and specialty care areas in which reside patients with a high risk of infection, including those with bone marrow transplant or leukemia.
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Table 31.2 Comparison of Solutions that Contain Combinations of Antimicrobial Agents |
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Catheters Coated with Chlorhexidine and Silver Sulfadiazine
There exist two catheters coated with the combination of chlorhexidine and silver sulfadiazine. The first-generation, and most studied, catheter (47,48,49,50,51,52,53,54,55,56) has antimicrobial agent incorporated only along the external surface of the catheter. The second-generation catheter differs in two ways from the first-generation catheter: Both antimicrobial agents are incorporated onto the external and internal surfaces, and it contains three times the amount of chlorhexidine (57).
The largest prospective randomized clinical trial of the first-generation devices coated with chlorhexidine/silver sulfadiazine in 403 short-term (mean duration of placement, 6 days), polyurethane central venous catheters demonstrated a significant reduction in the rate of catheter colonization (13.5% versus 24.1%; p = 0.005) and CRBSI (1.0% versus 4.6%; p = 0.03) as compared with uncoated catheters (50). Although most other clinical trials (47,51,52,53,54,55,56) showed that chlorhexidine/silver sulfadiazine–coated catheters were significantly less likely to be colonized than uncoated catheters, they could not demonstrate a significant reduction in the rate of CRBSI; these studies were not sufficiently powered to detect significant differences in the rates of CRBSI. Additionally, however, a meta-analysis of 12 clinical trials showed that these antimicrobial-coated catheters resulted in a significant reduction in the rates of both catheter colonization (odds ratio = 0.44; p <0.001) and CRBSI (odds ratio = 0.56; p = 0.005) (58).
Since this first-generation chlorhexidine/silver sulfadiazine–coated catheter provided only short-lived (about 1 week) antimicrobial activity, and only along the external surface of the catheter (53), it was not likely to protect against infection of long-term catheters that frequently become contaminated with bacteria migrating from the contaminated hub along the internal surface of the catheter. Not unexpectedly, a large (680 catheters) prospective randomized clinical trial showed that placement of chlorhexidine/silver sulfadiazine–coated central venous catheters for a mean of 20 days in patients with hematologic malignancy did not reduce the rate of CRBSI as compared with uncoated catheters (5% versus 4.4%) (59).
The second-generation chlorhexidine/silver sulfadiazine–coated catheters have a longer durability of antimicrobial activity than the first-generation catheters (60). A recent report of a large (842 catheters) prospective randomized clinical trial demonstrated that second-generation chlorhexidine/silver sulfadiazine–coated polyurethane short-term central venous catheters are less likely to become colonized than uncoated catheters (9% versus 16%, p <0.01) but had a statistically insignificant trend for a lower rate of CRBSIs (0.3% versus 0.8%) (57). Since the incidence of CRBSI in the uncoated catheter group was lower than usual, this study may not have had sufficient power to assess the desired outcome. Because both the first-generation and second-generation chlorhexidine/silver sulfadiazine–coated catheters generally reduce catheter colonization to a similar degree, it is reasonable to regard these two catheters as being equally protective against infection.
Catheters Coated with Minocycline and Rifampin
This unique combination of antibiotics was selected for the following reasons: (a) Both agents are active against the vast majority of staphylococcal isolates, including MRSA and MRSE (61); (b) the combination of agents provides broad-spectrum antimicrobial activity against most pathogens that can cause CRBSI, thereby reducing the likelihood of developing superinfection by Gram-negative bacteria or Candida spp. (62,63); (c) since minocycline and rifampin have different mechanisms of activity, with minocycline retarding protein synthesis and rifampin inhibiting DNA-dependent RNA polymerase, it is unlikely that a bacterial strain will become concomitantly resistant to both agents; and (d) unlike many antibiotics–including vancomycin, ciprofloxacin, and the aminoglycosides–that are much less active against biofilm bacteria than planktonic bacteria, rifampin (64) and minocycline (65) are particularly active against biofilm-embedded bacteria.
The clinical efficacy of this catheter surface modification was initially confirmed in a prospective randomized clinical trial that showed that polyurethane short-term (mean duration of placement, 6 days) central venous catheters coated with minocycline and rifampin were significantly less likely than uncoated catheters to become colonized (8% versus 26%; p <0.001) and cause bloodstream infection (0% versus 5%; p <0.01) (66). In a large (738 catheters) prospective randomized clinical trial, polyurethane short-term (mean duration of placement, 8 days) central venous catheters coated with minocycline and rifampin were more protective than the first-generation chlorhexidine/silver sulfadiazine–coated catheters, with a threefold lower rate of catheter colonization (7.9% versus 22.8%; p <0.001) and a 12-fold lower rate of CRBSI (0.3% versus 3.4%; p <0.002) (67).
The superior clinical protection afforded by minocycline/rifampin–coated catheters was predictable, since these catheters were shown in an animal study to prevent S. aureus infection of percutaneously placed catheter segments better than first-generation chlorhexidine/silver sulfadiazine-coated catheters (63); and since they have a longer in vivo durability of antimicrobial activity than first-generation chlorhexidine/silver sulfadiazine–coated catheters, as determined by the residual zones of inhibition generated by catheters removed from patients (68). The production of an effective zone of inhibition by an antimicrobial-coated catheter surface may serve to inhibit adherence of organisms not only to the catheter surface, but also to various host-derived adhesins such as fibronectin, fibrinogen, fibrin, and laminin that exist within the biofilm layer surrounding the indwelling prosthesis (69,70). The size of the in vitro zone of inhibition against S. aureus around a coated vascular catheter is likely to predict the clinical efficacy, or lack thereof, in preventing catheter colonization and CRBSI (71). The optimal characteristics of antimicrobial-coated vascular catheters are listed in Table 31.3.
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Table 31.3 Comparison of Antibiotic Dipped versus Antimicrobial Coating of Vascular Catheters |
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The clinical benefit achieved by incorporating the combination of minocycline and rifampin onto the surfaces of short-term polyurethane central venous catheters prompted the assessment of this approach in long-term silicone catheters. Indeed, a prospective randomized clinical trial demonstrated that similarly coated long-term silicone central venous catheters were fourfold less likely than uncoated catheters to result in bloodstream infection (2% versus 8%, p = 0.002) (72). Even more important, in a prospective randomized multicenter clinical trial conducted to determine whether antimicrobial coating can obviate the need for the not-so-practical, time-consuming, and expensive practice of tunneling long-term central venous catheters, nontunneled minocycline/rifampin–coated catheters were significantly less likely than tunneled uncoated catheters to result in bloodstream infection (73). In general, clinical trials have shown no evidence of developing antimicrobial resistance when using either short-term (67,68) or long-term (74) central venous catheters coated with minocycline and rifampin and short-term chlorhexidine/silver sulfadiazine-coated catheters (50).
Table 31.4 summarizes the advantages of using antimicrobial-coated versus antibiotic-dipped catheters. Both patient-specific and institution-based factors should guide the use of antimicrobial-coated catheters. In general, the clinical protection afforded by antimicrobial-coated catheters has been documented only in populations of patients at high risk for infection—including critically ill patients, immunocompromised subjects, recipients of total parenteral nutrition, and so forth—and are not intended to be used in patients at low risk of infection, such as persons embarking on an elective surgical procedure and expected to have the central venous catheter in place for only 1 to 2 days. An institutional incidence of catheter-related bloodstream infection of more than 3.3 per 1,000 catheter-days (equivalent to about 2%) is felt by some authorities high enough to consider the use of antimicrobial-coated vascular catheters (50,75,76). Although clinically protective antimicrobial-coated catheters generally cost about 20% more than uncoated prototypes, tremendous savings can be incurred when using chlorhexidine/silver sulfadiazine (77) and, even more so, the more clinically protective minocycline/rifampin-coated catheters (78).
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Table 31.4 Optimal Characteristics of Antimicrobial-Coated Vascular Catheters that would Predict Clinical Efficacy |
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Controversial Practices
Unlike the above described measures that have attracted almost unanimous evidence-based agreement regarding their efficacy or lack thereof, the following practices continue to stir some controversy.
Guidewire Exchange of Vascular Catheters
The clinical practice of exchanging central venous catheters over a guidewire has been plagued by two controversies. The first one focuses on routine guidewire exchange of noninfected catheters, and the other controversy centers around guidewire exchange of infected catheters. Although suboptimally designed studies initially encouraged routine guidewire exchange of central venous catheters, well-designed prospective randomized clinical trials yielded different results (79,80,81). For instance, a prospective randomized clinical trial found that scheduled catheter replacement over a guidewire every 3 days is associated with a higher rate of infection but a lower incidence of mechanical complications, primarily pneumothorax, than replacement of catheters when clinically indicated (mean duration of catheter placement of 7 days) (79). Since the risk of catheter-related infection increases as the duration of catheter placement extends, the results of this study (79) may not necessarily apply to clinical scenarios where catheters are clinically used for much longer periods.
The prevailing (82,83), but not universal (84,85,86), clinical practice dictates that if catheters are removed because of suspicion of infection in patients who require another vascular access, a new catheter is placed at a different site. In such patients, there is a concern that guidewire-assisted exchange of the infected catheter may result in contamination of the newly placed catheter by organisms present in the subcutaneous tract and/or the lumen of the removed catheter that may transfer onto the guidewire. The potential drawback of catheter replacement at a different site is vascular thrombosis and, hence, compromise of future intravenous access, particularly in children with cancer and patients dependent on hemodialysis (84). In hemodynamically stable patients with limited vascular access and in whom catheter-related infection is possible but not very likely, it is reasonable to insert the new catheter over a guidewire as long as the removed catheter is cultured; should culture of the removed catheter yield growth, it is recommended to remove the catheter that was newly inserted over a guidewire and place yet another catheter at a different site. Although it is theoretically plausible that insertion at the same site of a vascular catheter with effective antimicrobial coating along both the external and internal catheter surfaces may obviate the need to manipulate another vascular site, this approach requires clinical investigation.
Antimicrobial Catheter Hub
It is important to mention that the definitions of outcomes used in clinical trials examining this approach were less rigorous than those adopted in most studies of other types of potentially preventive measures. A prospective randomized clinical trial initially showed that attachment of an antimicrobial hub containing iodinated alcohol to central venous catheters, with a mean duration of placement of 2 weeks, significantly reduced the rate of colonization of the catheter hub (1% versus 11%; p <0.01) and CRBSI (4% versus 16%; p <0.01) (87). However, a subsequent prospective randomized clinical trial of 130 central venous catheters with this antimicrobial hub versus standard catheters in critically ill patients showed no differences between the two groups in the rates of colonization of the catheter tip and hub and, more important, revealed a trend for a higher rate of catheter-related sepsis in association with the use of this technology (24% versus 15%) (88). Because this antimicrobial catheter hub protects only against organisms that migrate through the hub along the internal surface of the catheter, but not against skin organisms that advance along the external surface of the catheter, the potential clinical benefit of using this preventive approach in the context of vascular catheters that remain in place for less than or equal to 7 to 10 days is doubtful.
Flushing or Locking the Catheter Lumen with Antibiotic-Anticoagulant Solutions
The relationship between infection and thrombosis of vascular catheters prompted numerous investigations of the clinical efficacy of flushing or locking the catheter lumen with various antibiotic-anticoagulant combinations that do not result in systemic levels of the antibiotic. Because this approach provides antimicrobial activity against only organisms that exist in the catheter lumen, clinical investigations have generally focused on long-term vascular catheters that are frequently infected by such a route. Prospective randomized clinical trials in immunocompromised children (89) and adults (90) revealed that flushing the lumen of long-term central venous catheters with a solution that contains vancomycin and heparin significantly reduces the rate of CRBSI due to luminal colonization by vancomycin-susceptible organisms, as compared with flushing catheters with heparin alone (0% versus 21%, p = 0.04; and 0% versus 7%, p = 0.05, respectively). One of these two studies (89) also showed that the use of vancomycin-heparin catheter flush was associated with a statistically insignificant fourfold reduction (5% versus 21%) in the rate of CRBSI due to luminal colonization by vancomycin-resistant organisms. Another prospective randomized clinical trial in children with long-term central venous catheters showed significantly lower rates of CRBSI when catheters were flushed with either vancomycin-ciprofloxacin-heparin (0.55/1,000 versus 1.72/1,000 catheter-days, p = 0.005) or vancomycin-heparin solutions (0.37/1,000 versus 1.72/1,000 catheter-days, p = 0.004) than when flushed with heparin alone (91). Other clinical trials, however, yielded discrepant results. For instance, a prospective randomized clinical trial in pediatric patients who had cancer and/or were receiving total parenteral nutrition revealed that flushing the lumen of long-term central venous catheters with a solution that also consisted of vancomycin and heparin did not reduce the rate of CRBSI due to luminal colonization by vancomycin-susceptible organisms, as compared with flushing catheters with heparin alone (1.4/1,000 versus 0.6/1,000 catheter-days, p = 0.25) (92). Moreover, catheters flushed with the combination of vancomycin and heparin were associated with a significant fourfold increase in the rate of CRBSI due to luminal colonization by vancomycin-resistant organisms (2.3/1,000 versus 0.53/1,000 catheter-days, p = 0.03) (92). In a recent meta-analysis of four prospective randomized clinical trials in high-risk children or adults, the risk ratio of developing CRBSI was 0.34 (p = 0.04) among patients who receive vancomycin-containing catheter lock solution versus those who receive only heparin (93). Although there were no observed cases of infection of vancomycin-locked catheters by vancomycin-resistant organisms (93), the potential emergence of resistance to vancomycin, a drug that is still used to treat most cases of catheter infections, continues to underscore the equivocal role of this strategy.
Perspective on Future Work
Although institutional implementation of quality improvement programs to educate health care providers and improve their compliance with hand hygiene and basic infection control measures when inserting or maintaining a vascular catheter are generally beneficial, the level of adherence and duration of benefit are not optimal (94,95). Moreover, some preventive measures have probably reached a point of limited return as they have reduced but did not eliminate the occurrence of CRBSI (96). That is why it is essential that we strive to explore the potential benefit of either new innovative approaches or the application of already established technology in other clinical scenarios, which will be discussed.
Instilling a Catheter Lock Solution That Contains an Antibiofilm Plus an Antimicrobial Agent
This inclusion of an antibiofilm agent in a catheter lock combination solution would help enhance the access and activity of the antimicrobial agent against biofilm-embedded organisms.
Although numerous antibiofilm agents could theoretically be used, the use of N-acetyl cysteine is quite intriguing because of its well-established safety—FDA approved for both systemic and inhalational administration in doses that far exceed the amount that would be included in a catheter lock solution—and recent preliminary reports of in vitro efficacy (97,98).
Assessing the Clinical Value of Quorum-Sensing Inhibitors
This intriguing approach, which disrupts bacterial cell-to-cell communication, can impair the formation of biofilm in vitro and in animal models (99). However, there are no peer-reviewed clinical reports that have assessed this potentially protective approach, and the activity of different quorum-sensing inhibitors tends to be largely genus-specific; for example, the RNAIII-inhibiting peptide is active against only S. aureus and S. epidermidis (99), and yet another quorum-sensing inhibitor attenuates the virulence of Pseudomonas aeruginosa (100). It is prudent to clinically assess the safety, efficacy, and practicality of this approach.
Inserting Clinically Protective Antimicrobial-Coated Catheters to Safely Prolong the Duration of Catheter Placement
Since there is a direct relationship between the duration of catheter placement and risk of catheter-related infection (101), most clinical practitioners leave short-term central venous catheters in place for less than 10 days. Although not comprehensively investigated as of yet, it is likely that clinically protective antimicrobial-coated catheters with durable antimicrobial activity could be safely left in place for a longer period of time, perhaps for 2 to 3 weeks, without sacrificing anti-infective efficacy (102).
Applying Clinically Protective Antimicrobial Coating on Hemodialysis Catheters
Not only are hemodialysis catheters more likely to become infected than regular central venous catheters, but they are also associated with more serious clinical (including paucity of other body sites that would be amenable to placing a new hemodialysis access) and economic consequences once infection evolves (103).
Assessing the True Value of Bundled Preventive Interventions
A recent prospective cohort study of a bundle of five evidence-based measures—including hand washing, maximal sterile barriers, cleansing skin with chlorhexidine, avoiding femoral sites if possible, and removing catheters when no longer needed—reported a significant reduction in the rate of CRBSI in critically ill patients: The risk of infection compared to preintervention was 0.62 at 0 to 3 months and 0.36 at 18 months (104). These promising findings, however, were limited by the fact that the study was not randomized, potential underreporting of infection could have occurred after initiating the study, and the effect of the bundled interventions on different microbial pathogens was not investigated. Therefore, it is imperative that bundled interventions be assessed in a prospective randomized fashion.
Pearls
· The infection-prone vascular catheter, an indispensable component of modern health care, is a vice in disguise.
· Although catheter colonization is a prelude to infection, most colonized catheters do not result in catheter-related infection.
· Proof of clinical protection against infection afforded by a potentially preventative approach is defined as significant reduction in catheter-related bloodstream infection.
· Adherence to optimal infection control measures is the mainstay for preventing infection, but consistent adherence to guidelines usually drops within months of institutional implementation of educational programs.
· Although optimal infection control measures save lives, more lives can be saved by combining infection control measures and clinically protective technology.
· Antimicrobial modification of the surface of vascular catheters is not necessarily indicative of clinical protection against catheter-related infection.
· A clinically protective anti-infective approach can also incur cost savings and reduce the reservoir of antimicrobial-resistant pathogens that exist within the biofilm surrounding indwelling catheters.
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