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
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( Concerning Lyme Disease ) Les Roberts, Author – The Poison Plum In 1990 I was 51 years of age and living with my wife and three daughters on lakefront property in rural South Alabama. I was president of an investment brokerage firm based in Pensacola, Florida, which I had founded 13 years earlier. I did not take good health for granted but exercised regularly with weightlifting, r
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