Hm4339 235.24

British Journal of Haematology, 1999, 107, 235±241 CAN ANTIMICROBIAL CENTRAL VENOUS CATHETERS PREVENT ASSOCIATED INFECTION? Incidence of central venous catheter sepsis Teicoplanin surface coated central venous catheters Central venous catheters (CVC) are a major source of sepsis, Protein deposition onto antimicrobial polymers may reduce ranging from local infections at the site of insertion, to their ef®cacy in vivo. More recent developments have septicaemia (Maki & Mermel, 1998). The reported incidence therefore concentrated on surface coating of catheters with of CVC-related infections varies from <1% to 18% (Elliott, antimicrobials rather than chemical bonding. The loosely 1997) with a frequency of bacteraemia between <1'0 and bound antimicrobials which coat the polymer are relatively 13'0 per 1000 catheter days (Bach & BoÈhrer, 1993; Elliott easily eluted, which results in antimicrobial activity in & Faroqui, 1992). In England and Wales nearly 4000 the immediate area surrounding the catheter. Romano et al patients with catheter-related bacteraemias are noti®ed to (1993), for example, challenged a CVC coated with both the Communicable Disease Centre per annum (Elliott, 1993); hydromer and teicoplanin in a mouse model with staphylo- in the U.S.A. approximately 850 000 catheter-related infec- cocci. The antimicrobial coating prevented the formation of tions occur annually and of these more than 50 000 are abscesses which did occur around uncoated catheters.
bacteraemias (Widmer, 1997). Data from the Surveillance Jansen et al (1992a) similarly in vitro demonstrated the and Control of Pathogens of Epidemiological Importance protection offered by these teicoplanin-coated catheters when national programme has shown that 70% of all bloodstream challenged with various microorganisms. The ef®cacy of infections occurred in patients with CVC (Centers for Disease teicoplanin in hydromer-coated CVC was further evaluated Control and Prevention, 1996). A recent approach to prevent in a prospective randomized pilot study in patients under- CVC-related sepsis (CRS) has been the incorporation or going major abdominal surgery (Bach et al, 1996). Most coating of catheter polymers with antimicrobials (Elliott & of the teicoplanin coating was released during the ®rst 24 h Faroqui, 1992). A range of these catheters is now commer- of catheterization, and none was retained after 36 h. No cially available (Table I). In this review the ef®cacy and role of differences were subsequently detected in the degree of bac- antimicrobial CVC for the prevention of associated infections terial colonization between the teicoplanin-coated and uncoated catheters. Retention of antimicrobial activity was closely linked to protection from infection. These results exemplify the dif®culties in retaining antimicrobial activity One of the earliest antimicrobial polymers used for the with compounds not chemically bonded onto polymer sur- prevention of infection was gentamicin bound to polymethyl faces. Slow release of antimicrobials from catheter polymers methacrylate (PMMA). This antimicrobial polymer has been with activity retained for several weeks should be the aim.
incorporated into bone cement or used as beads for the prevention of prosthetic hip infections (Welch, 1978). Dacron Minocycline±tetracycline-coated central venous catheters with various incorporated antibiotics has also been devel- In an in vitro susceptibility study the ef®cacy of various oped in an attempt to protect vascular grafts from infection.
antimicrobial agents including vancomycin, clindamycin, However, to date these have not been widely adopted (Moore minocycline, oxacillin and rifampicin when used alone or in et al, 1981; Powell et al, 1983). Polymers bonded with anti- combination for the prevention of microbial colonization of biotics have also been produced to provide a prolonged and catheters has also been studied (Darouiche et al, 1995). The continuous delivery of prophylactic antimicrobials to pre- combination of minocycline and rifampicin had antimicro- vent CVC infection. Trooskin et al (1985), for example, used bial activity equivalent to vancomycin and other glycopep- tridodecylmethyl-ammonium chloride (TDMAC) to bind peni- tides. Similar in vitro activity was also demonstrated when cillin to polyethylene catheter segments. More than 60% of the inhibitory activity of polyurethane catheters coated with the bound penicillin remained on the catheter surface after minocycline and rifampicin was compared to catheters coated 2 weeks in plasma. The potential antimicrobial ef®cacy of with other antimicrobial agents (Raad et al, 1995). The these catheters was con®rmed in a rat model challenged with inhibitory activity of minocycline- and rifampicin-coated penicillin-sensitive Staphylococcus aureus. Solovskj et al (1993) catheters was signi®cantly greater as compared to those similarly added ampicil in and penicillin which were cova- lently bound to the polymer. These catheters inhibited the The in vivo ef®cacy of catheters coated with minocycline growth of S. aureus in in vitro experiments.
and rifampicin has subsequently been determined. In a rabbit model, catheters coated with minocycline and rifampicin Correspondence: Dr T. S. J. Elliott, Department of Clinical Micro- were signi®cantly more ef®cacious than those coated with biology, Queen Elizabeth Hospital, University Hospital Birmingham chlorhexidine gluconate and silver sulphadiazine (CH-SS) in NHS Trust, Edgbaston, Birmingham B15 2TH.
preventing colonization and infection when challenged with Table I. Antimicrobial catheters available for clinical use.
* Only available as a PICC (peripherally inserted central catheter).
S. aureus (Raad et al, 1996a). The antimicrobials were not Cefazolin-bonded central venous catheters permanently bonded to the catheter surface and, following Cefazolin bonded onto CVC with a cationic surfactant has implantation, were released over several weeks. The mino- also been evaluated (Kamal et al, 1991) on surgical intensive cycline and rifampicin catheter (Bio-guard SpectrumTM, care (ICU) patients. A signi®cant reduction in the number of Cook, Bloomington, Ind., U.S.A.) has been further evaluated infections associated with this cephalosporin-coated CVC as in a double-blind randomized clinical trial (Raad et al, 1997).
compared to uncoated catheters was reported (2% v 14%). In In this study 281 hospitalized patients received either coated a more extensive study, also on ICU patients, cefazolin-coated antimicrobial catheters (147) or uncoated catheters (151).
catheters were compared to a standard non-antimicrobial Microbial colonization occurred in 36 (26%) of uncoated catheter. The antibiotic-coated CVC resulted in a signi®cant catheters and 11 (8%) of coated catheters (P < 0'001).
reduction in catheter-associated bacteraemia and the cumu- Catheter-related bloodstream infections developed in seven lative risk of infection was signi®cantly reduced (Kamal et al, patients with uncoated catheters and none with coated 1998). Other b-lactam antibiotics have also been used to catheters. Multivariate logistic regression analysis of the coat catheters, including dicloxacillin (Sheretz et al, 1989) results demonstrated that the coated catheter was an inde- which reduced colonization and catheter infections in a pendent protective factor against catheter-related coloniza- tion. No adverse effects were related to the coated catheters.
In a further multi-centre clinical trial (Darouiche et al, 1997, 1999) the minocycline- and rifampicin-coated catheter was Concern has been raised about the possible emergence of compared to CVC coated with CH-SS. A total of 738 evalu- antimicrobial resistance with the widespread use of anti- able catheters were studied and 356 were impregnated with biotics in catheter materials. Antibiotic combinations such as minocycline and rifampicin and 382 with CH-SS. The CVC minocycline and rifampicin used to prevent catheter-related impregnated with minocycline and rifampicin were threefold sepsis may, however, reduce the likelihood of the emergence less likely to be colonized and 12-fold less likely to produce of resistance (Yourassowsky et al, 1981; Darouiche et al, catheter-related bloodstream infections than those with 1991). The protective action of minocycline has been related CH-SS. The CVC coated with minocycline and rifampicin to its lipophilic nature and ability to penetrate into tissues retained antimicrobial activity for at least 2 weeks (Darouiche and bio®lms accessed by rifampicin. However, as has been et al, 1999; Raad et al, 1998), thereby offering protection shown with many topically applied antimicrobials, emer- from initial colonization and subsequent infection during gence of resistance may be stimulated by the use of catheters, this period. It is unclear why the catheters impregnated with particularly those coated with only a single antibiotic.
minocycline and rifampicin compared so favourably with the Research to reduce catheter-related sepsis has therefore CH-SS. This may have been due to the minocycline and also been focused on the application of antiseptics rather rifampicin catheter being coated on both the internal and than antimicrobials. The more recent emergence of vanco- external surfaces whereas the CH-SS is coated only on the mycin-resistant Staphylococcus aureus in both Japan and the external surface. Alternatively minocycline and rifampicin United States has highlighted the need to restrict the use of may exhibit enhanced antimicrobial activity as compared to antibiotics such as the glycopeptides (Smith et al, 1999), and CH-SS, particularly against microorganisms in a bio®lm.
the use of antiseptic coated catheters may facilitate such an q 1999 Blackwell Science Ltd, British Journal of Haematology 107: 235±241 approach. In an early study IrgasanÒ (Ciba-Geigy, U.K.) was explanation for the reduced ef®cacy noted by Logghe et al incorporated into plastic made of ethylvinyl acetate (EVA), (1997). Further studies are required to evaluate the role of polyethylene or polypropylene. It was shown that Irgasan CH-SS in preventing CVC infection, particularly in patients inhibited a wide range of microorganisms (Kingston et al, 1986). When polymers containing this antimicrobial were Hypersensitive reactions occasionally occur when patients challenged with S. aureus in a rabbit model, protection from are exposed to chlorhexidine or silver sulphadiazine. The colonization and subsequent infection was demonstrated.
possibility that such reactions may occur through the use However, the Irgasan was eluted relatively rapidly, resulting of a catheter with a relatively small amount of CH-SS is in only short-term antimicrobial protection (Kingston et al, unlikely. In clinical trials of CH-SS catheters, and from 1992). Another antiseptic-containing polymer which has extensive use in the United States, this has been borne out.
been developed is iodine complexed with polyvinylpyrrolidone However, anaphylactic reactions have been reported with ( Jansen et al, 1992b). When challenged with microorgan- chlorhexidine (Ohtoshi et al, 1986; Cheung & O'Leary, isms, colonization was inhibited by the iodine-complexed 1985), and more recently with CH-SS-coated catheters in polymers ( Jansen et al, 1992b). However, these antiseptic Japan (World Health Organization, 1997). Possible explana- catheters remain to be clinically evaluated.
tions for these reactions include genetic predisposition or previous exposure to chlorhexidine-containing products, Chlorhexidine±silver-sulphadiazine-coated central venous resulting in increased sensitivity. Awareness of this, albeit The use of CH-SS, referred to earlier in comparative studies, A CVC coated with metallic silver (PellethaneÒ, Fresenius has been extensively studied. These catheters are coated only AG, Germany) has also been developed. This anti-infective on the external surface and the antimicrobials are released polyurethane catheter prevented microbial colonization of slowly over at least 15 d (Arrowguard BlueÒ, Arrow Inter- the device in in vitro tests ( Jansen et al, 1994) and in national Inc., Reading Pa., U.S.A.). A synergistic effect of oncology patients (Goldschmidt et al, 1995). There was a chlorhexidine gluconate and silver sulphadiazine was demon- signi®cant reduction in catheter-related infections. These strated by Modak & Sampath (1992). The chlorhexidine catheters do not contain chlorhexidine, reducing the likeli- affects the bacterial cytoplasmic membrane and enables hood of anaphylactic reactions. This catheter, however, uptake of silver ions by the cell. The silver binds to the bacterial DNA and inhibits replication. In a clinical investi- gation on 40 post-operative cardiac surgical patients a Benzalkonium-chloride-coated central venous catheters signi®cant reduction in the incidence of microbial coloniza- The hub, the distal tip of the catheter on insertion via the tion of catheter distal tips with the CH-SS-bonded catheters skin (Elliott et al, 1997), the internal lumen and external was recorded (Bach et al, 1993). Clemence et al (1993) also surface of a catheter are primary sources of microorganisms demonstrated a reduction in catheter-related septicaemia causing colonization and infection (Sitges-Serra et al, 1984; with these catheters in a crossover study of patients being Linares et al, 1985; Tebbs et al, 1995). Coating both catheter treated on intensive care units; there was a 60% reduction in surfaces is therefore important for the prevention of CVC the rate of bacteraemias. Maki et al (1997) have also carried infection as exhibited by the minocycline and rifampicin out a large comparative clinical study with the CH-SS catheter evaluations. More recently a triple lumen polyur- catheters as compared to control non-antimicrobial devices.
ethane catheter coated with hydromer and benzalkonium The presence of the antimicrobial signi®cantly decreased the chloride (BZC) has been developed. Unlike the CH-SS catheter, number of colonized catheters and CVC-related bacteraemias the BZC catheter is coated on both the internal and external in ICU patients. Conversely, Logghe et al (1997) have reported surfaces (Becton Dickinson Ltd, Swindon). Benzalkonium that the CH-SS catheters in patients with various underlying chloride is a quaternary ammonium compound which haematological malignancies did not reduce the risk of inhibits microbial membrane activity and DNA replication bacteraemias or septicaemias. In a further clinical study (Elliott & Tebbs, 1993). In an in vitro assessment of this Heard et al (1998) demonstrated a decrease in bacterial antimicrobial catheter, microbial colonization was signi®- growth on the CH-SS catheters, but there was no signi®cant cantly reduced both on the internal and external surfaces effect on the incidence of catheter-related bacteraemias. Two when challenged by a wide range of microorganisms (Elliott further studies have also not shown a protective effect of the & Tebbs, 1993, 1998; Tebbs & Elliott, 1994). Microbial CH-SS catheter against infection (Pemberton et al, 1996; colonization is considered to be a prerequisite of infection, Criesi et al, 1996). The disparity in the results may be due to and these ®ndings suggest that the BZC-coated catheter may several factors including differences in the types of patients offer protection from subsequent infection on both surfaces studied, the skin preparations used, post-operative wound of the device. In a clinical trial comparing the BZC catheter care, and bandages selected. In Maki et al (1997) the patients with a non-antimicrobial device, reduced colonization was had an average duration of catheterization of only 6 d. In demonstrated (Elliott & Faroqui, 1992; Elliott et al, 1998).
comparison, in the study by Logghe et al (1997) the average The use of the catheter has not been associated with any time of catheterization was 20 d and the catheter-related adverse effects in 150 patients studied to date. This is infections did not occur until the CVC had been in place for consistent with the wide applications of BZC in medicine, in >5 d. The increased loss of CH-SS by elution during the 20 d particular as a preservative, where it is well tolerated. The as compared to the 6 d therefore offers a further possible BZC catheter should be distinguished from BZC-heparin q 1999 Blackwell Science Ltd, British Journal of Haematology 107: 235±241 238 Reviewbonded catheters (AMC ThromboshieldTM, Baxter, Irvine, CVC sepsis, not requiring ITU treatment, is nearly £2000 in Calif., U.S.A.) (Mermel et al, 1993) in which the antimicrobial the U.K. (Moss & Elliott, 1997). Raad et al (1997), in a study is bound to heparin, unlike the device studied by Elliott et al on ITU patients with CVC sepsis, further demonstrated (1998) which is coated unbound. The anti-infective compo- potential hospital savings of $500 000 per annum in a U.S.
nent of the BZC-heparin-bound-catheter, which is also applied teaching hospital. However, more studies are required to to both the external and internal surfaces, has been shown fully evaluate the cost bene®t of these devices. The current in rat models to offer limited long-term protection from data on ef®cacy of these antimicrobial CVC is also still microbial colonization (Sampath et al, 1995). The presence limited, with some unexplained differences in ®ndings. These of heparin to reduce thrombus formation on this catheter differences most likely re¯ect the multitude of factors which may further reduce microbial colonization. However, full can in¯uence the risk of CRS, including catheter care, clinical evaluation is awaited on this device.
insertion protocols and antiseptic policies. Even the results of the extensive well-controlled trials such as those by Maki et al (1997) and Raad et al (1997) are dif®cult to translate to other Low amperage electrical current applied to carbon-impreg- clinical situations (Pearson & Abrutyn, 1997). These two nated catheters has also been developed to prevent CVC- studies were carried out in teaching hospitals which had related sepsis. In in vitro studies the electrical negatively relatively high rates of CRS as compared to other published charged catheters repelled microorganisms when current levels (Centers for Disease Control and Surveillance, 1996).
was applied at levels which are cardiovascularly safe (Elliott The ef®cacy and value of antimicrobial catheters in units et al, 1990; Liu et al, 1993). The bactericidal activity of the with lower rates of sepsis is therefore unclear.
low amperage current resulted from hydrogen peroxide and In which clinical scenarios should these antimicrobial free chlorine produced by electrolysis at the catheter surface catheters therefore be used? The currently available anti- (Liu et al, 1997). Raad et al (1996b) have also demonstrated microbial catheters offer protection from infection for only in an in vitro study that silver iontophoretic catheters, when approximately 2 weeks. Their clinical use is therefore limited challenged with S. aureus, prevented colonization. It is to situations where short-term CVC are required, including claimed that electrolytes in body ¯uids interact with the silver stem cell transplantation, replacement for failed Hickman and platinum particles in the polymer resulting in release line insertions, and for acute septic episodes. It is important of silver ions. This technology, which has been applied to a that existing recommendations for good practice are imple- peripherally implanted central catheter (OlimpiccTM, Vygon mented and audited (Elliott et al, 1994), with appropriate (UK) Ltd) awaits clinical evaluation. Costerton et al (1994), aseptic techniques (Mass et al, 1998). For example, the have also shown enhancement of the bactericidal activity correct choice and use of cutaneous antiseptics is essential as of antibiotics against bio®lm embedded bacteria by the these can in¯uence the subsequent incidence of infection.
use of an electric ®eld. The application of low amperage The use of chlorhexidine rather than povidone±iodine for electrical current, perhaps in combination with antimicro- skin disinfection prior to insertion of an intravascular device bials, may provide a novel method for prostheses to be and post-insertion site care can reduce the incidence of protected from microbial colonization and subsequent intravascular catheter-related sepsis (Maki & Mermel, 1998; sepsis. Further developments of the application of electricity Garland et al, 1995; Mimoz et al, 1996). Other facts of catheter care which should be considered include choice of appropriate dressings and the aseptic techniques used when Clinical application of antimicrobial catheters connectors are opened. New techniques associated with the Several antimicrobial catheters appear, from the available use of catheters, for example the application of needleless clinical data, to reduce the incidence of microbial coloniza- connectors (Brown et al, 1997), should always be fully tion and infections associated with CVC. The increasing evaluated before use on patients. Antimicrobial catheters number of multiple antibiotic resistant bacteria and fungi should be considered as an addition to these approaches may, however, limit the use of antibiotics incorporated into rather than attempting to overcome poor practice with a CVC. In comparison, the widespread emergence of antiseptic- related high incidence of CRS. The antimicrobial catheters resistant microorganisms is less likely to occur, because their should be reserved, until more data becomes available, for action is via basic chemical reactions, unlike antibiotics high-risk patients such as those on intensive care units with which are generally under genetic and hence mutable and short-term catheters, particularly in situations where the transmissible control (Russell et al, 1986; Ascenzi, 1996).
background rates of CRS are high. In clinical situations Low-level plasmid-mediated resistance to cationic biocides where the CRS is already low, or when the catheters are such as chlorhexidine and quaternary ammonium com- being used for patients undergoing long-duration treatment, pounds has, however, been reported in antibiotic-resistant for example in haematological malignancy, a reduction of strains of staphylococci (Leelnporn et al, 1994). A link the incidence of bacteraemia may not ensue from the use between antibiotic and biocide resistance has also been of currently available antimicrobial catheters including the highlighted (Russell et al, 1998) and this should be taken CH-SS (D'Hoore, 1998). If antimicrobial catheters are not into account in the selection and application of antimicro- used selectively the advantages offered by them may be negated by the further emergence of microbial resistance and Antiseptic-impregnated CVC also appear to offer a cost the escalating costs of these infections will continue (Moss & bene®t (Civetta, 1996). The cost of treating a patient with q 1999 Blackwell Science Ltd, British Journal of Haematology 107: 235±241 Darouiche, R., Raad, I., Heard, S., Rand, K., Khardori, N., Harris, R., Wenker, O. & Mayhall, G. (1997) A prospective, randomized, I thank Mary McDermott for skilful secretarial support, and multicenter clinical trial comparing central venous catheters Dr Peter Lambert and Mrs Helen Moss for useful comments.
impregnated with minocycline and rifampin vs. chlorhexidine gluconate and silver sulfadiazine. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, Darouriche, R.O., Raad, I.I., Heard, S.O., Thornby, J.I., Wenker, O.C., Gabrielli, A., Berg, J., Khardori, N., Hanna, H., Hachem, R., Harris, R.L. & Mayhall, G. (1999) A comparison of two antimicrobial- impregnated central venous catheters. New England Journal of Ascenzi, J.M. (1996) Antiseptics and their role in infection control.
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