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Intravascular Catheter-Related Infections
New Horizons and Recent Advances
Issam I. Raad, MD;
Hend A. Hanna, MD, MPH
Arch Intern Med. 2002;162:871-878.
ABSTRACT
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Background Central venous catheters have become essential devices for the management
of critically and chronically ill patients; however, their use is often complicated
by catheter-related bloodstream infections (CRBSIs), many of which could be
prevented.
Methods This report is based on a literature review of more than 100 published
articles in intravascular catheter-related infections. This review focuses
on the most recent advances in the methods of diagnosis of CRBSI as they relate
to its pathogenesis and on novel preventive techniques and approaches to management.
Results Catheter-related bloodstream infections may be diagnosed by different
methods, including simultaneous quantitative blood cultures, with the central
blood culture yielding at least 5-fold colony-forming units greater than the
peripheral blood culture, and simultaneous blood cultures, whereby the catheter-drawn
blood culture becomes positive at least 2 hours before the peripheral blood
culture. Novel preventive techniques include the use of ionic silver, an anticoagulant/antimicrobial
flush solution, a new aseptic hub, and antimicrobial impregnation of catheters
and dressings. Management of CRBSIs should be based on whether the infection
is complicated or uncomplicated.
Conclusions Novel technologies that have been proved to aid in the diagnosis and
prevention of CRBSIs should be considered in clinical practice. The management
approach should be based on the type of microorganism causing the infection
and on whether the infection is complicated or uncomplicated.
INTRODUCTION
VASCULAR catheter-related infections are the leading cause of nosocomial
bloodstream infections and are associated with significant morbidity in critically
ill patients.1-4
These infections are often difficult to diagnose, prevent, and manage, adding
tremendously to the cost of health care. The cost of treating a single episode
of catheter-related bloodstream infection (CRBSI) has been estimated to be
in excess of $28 000.3 However, as we
proceed into the new millennium, new knowledge in the field has improved our
ability to diagnose, prevent, and treat CRBSIs. This review will concentrate
on the knowledge associated with catheter-related infections and the recent
advances in diagnosis, prevention, and treatment of such infections.
PATHOGENESIS: NEW FINDINGS
Catheter-related infections are often difficult to treat because they
are caused by organisms often resistant to antimicrobial agents that embed
themselves in a biofilm layer on the catheter surface and attach to the thrombin
sheath on the surfaces of intravascular devices.5-7
Our understanding of the pathogenesis of these infections during the past
decade should be the basis for appreciating new techniques and approaches
involved in the diagnosis, prevention, and management of CRBSIs. The basics
related to the pathogenesis are as follows.
Microbiological Features and Sources of Infections
The skin and catheter hub are the most common sources of colonization
of intravascular catheters.8 For short-term,
nontunneled, noncuffed catheters, the skin insertion site is the major source
of colonization, whereby organisms migrate along the external surface of the
catheter and the intercutaneous and subcutaneous segments, leading to colonization
of the intravascular catheter tip, which may lead to bloodstream infection.8-10 For long-term catheters,
such as cuffed, tunneled, silicone catheters (Hickman or Broviac), or implantable
catheters (such as ports), the lumen of the hub or the bell of the port is
the major source of colonization.10-11
These sites may become contaminated through the hands of medical personnel
during manipulation of the catheter. Because the skin of the patient or the
hands of medical personnel are the main sources for the contamination of catheters,
staphylococci, particularly coagulase-negative staphylococci, and Staphylococcus aureus are the leading causes of CRBSIs,10, 12-15
as shown in a pooled estimate derived from prospective studies published in
the 1990s that used quantitative catheter cultures (Table 1). Most of the gram-negative bacilli causing CRBSIs are nonenteric
organisms acquired from the hospital environment, such as Stenotrophomonas maltophilia, Pseudomonas
organisms, and Acinetobacter species.12-18 Candida albicans and Candida parapsilosis also colonize on the hands of medical personnel and are also associated
with glucose-containing infusions and total parenteral nutrition.18-19 These fungal organisms are, therefore,
emerging as important pathogens associated with CRBSIs.18
Gram-positive bacilli, such as Corynebacterium (especially
jeikeium strains) and Bacillus species, are rarely
introduced from the skin or the hub and may cause catheter-related infections.12-15,20-21
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Microbiological Features of Vascular Catheter-Related Colonization
and Bloodstream Infections*
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The Biofilm Factor
Staphylococci, Candida, and some other microbes
produce a slimy material rich in exopolysaccharides, resulting in the formation
of a microbial biofilm.22-23 The
biofilm helps these organisms adhere to and survive on the surfaces of foreign
bodies in the bloodstream. The organizational structure of the biofilm is
the result of communication between microbes using an elaborate system of
chemical messengers composed of acyl homoserinelactones.24
The microorganisms within the biofilm layer are resistant to the activity
of antibiotics.5, 25-26
Because the biofilm acts as a resistance factor to antibiotics, it is often
difficult to eradicate a catheter-related infection without the removal of
the catheter.
The Thrombin Sheath Factor
Following catheter insertion, a thrombin layer or sheath covers the
external and the internal surfaces of the intravascular segment. This sheath
is rich in host-derived proteins, such as fibrin, fibronectin, thrombospondin,
and laminin, that act as adhesins. Therefore, the thrombin layer that forms
on the intravascular surface of a catheter actually promotes adherence of
potential microbial pathogens to that surface. Staphylococcus
aureus binds strongly to fibronectin, fibrinogen, laminin, and thrombospondin.27-31
In addition, coagulase-negative staphylococci bind to fibronectin,7 while C albicans binds to
fibrin.32 Adhesins that allow coagulase-negative
staphylococci to bind to the polymer composite of catheters have also been
identified. The genes that regulate the expression of those adhesins have
also been identified.33 Therefore, the difficulties
in eradicating the organisms colonizing the catheter surface can be appreciated
because they are attached to adhesins on the surfaces of the catheter and
are covered by a protective layer of biofilm.
Quantitative Threshold
Quantitative electron microscopic studies10
suggest that most indwelling catheters become colonized after insertion, even
in the absence of symptoms. However, clinically apparent infection seems to
be a function of the number of organisms exceeding a threshold as they multiply
on the catheter surface because there is a quantitative relationship between
the number of organisms isolated from the catheter surface and the risk for
CRBSIs.34
DIAGNOSIS: NEW TECHNIQUES
The roll-plate semiquantitative culture method is the most commonly
used technique for culturing vascular catheters.35
However, this method is limited in that it cultures only the external surface
of catheters and may not retrieve organisms that are well embedded within
the biofilm layer on the catheter surface. This technique is of limited usefulness
in long-term catheters, in which the internal surface is the predominant source
of colonization and bloodstream infection.10
Several quantitative catheter culture methods are useful in establishing the
diagnosis of CRBSI, such as the use of vortex, sonication, or flushing the
catheter lumen with broth.34, 36-37
The sonication quantitative method was superior to the semiquantitative catheter
culture technique in several studies and in a recent meta-analysis.10, 38-40 The
limitation of the semiquantitative and quantitative catheter culture methods
is that they require removal of the catheter to aid in the diagnosis of CRBSIs.41 This often results in wasteful removal of noncolonized
catheters. This has led to new techniques for diagnosing CRBSIs without catheter
removal.
Novel culture techniques that suggest a catheter infection without removal
of the catheter include the following.
1. Simultaneously collected quantitative blood cultures in which the
number of microbes isolated from blood obtained through a central venous catheter
(CVC) is at least 5-fold greater than the number of microbes in a concurrent
peripheral blood culture.42
2. Simultaneous qualitative blood cultures drawn from the CVC and the
peripheral vein in which growth is detected from the blood drawn through the
CVC at least 2 hours earlier than a simultaneously drawn blood culture from
a peripheral vein.43-44 This method
is termed differential time to positivity. This is
a simple technique and, unlike quantitative blood cultures, is widely available
on an international basis because many clinical microbiology laboratories
have adopted the use of automated continuously monitored blood culture systems.
Hence, this technique, if verified further by large, prospective, clinical
studies, would constitute an easily adopted and inexpensive method for diagnosing
CRBSIs without removal of the indwelling catheter.
3. Catheter-related bloodstream infections can also be diagnosed using
an endoluminal brush technique that involves brushing the lumen of the catheter
and using an acridine orange leukocyte cytospin test on blood drawn through
colonized catheters.45 The brush method had
a sensitivity of 95% and a specificity of 84% in diagnosing CRBSIs without
catheter removal. However, this method was associated with the induction of
transient bacteremia in 6% of the patients in the study. More recently, Kite
and colleagues46 demonstrated that acridine
orange staining of blood drawn from the CVC could provide a rapid diagnosis
of CRBSI. However, further studies are required to support such a finding.
Clinical data that would suggest the catheter as the source of the bloodstream
infection include the following: (1) the absence of any other source for the
bloodstream infection except the catheter, with the isolation of an organism
often associated with CRBSIs, such as Staphylococcus epidermidis, S aureus, or C parapsilosis; and (2) local catheter infection around the catheter, such as exit
site inflammation, tunnel tract inflammation, or a port pocket abscess associated
with bloodstream infection.
PREVENTION: NOVEL TECHNOLOGY
New technologies that have been developed to prevent CRBSIs and have
been shown in clinical studies to be efficacious in decreasing the risk of
CRBSIs are the following: (1) ionic silver, (2) an anticoagulant/antimicrobial
flush, (3) a new aseptic hub model, and (4) antimicrobial impregnation of
catheters and dressings.
Silver Ions
Silver in its ionic form has broad-spectrum antimicrobial activity against
bacteria and fungi. A silver-impregnated subcutaneous collagen cuff has been
developed and is usually placed at the interface of the skin insertion site
and the proximal subcutaneous space.47 This
cuff significantly decreases the risk of colonization associated with short-term
catheters (mean duration of placement, <10 days).47-48
However, the silver cuff failed to prevent CRBSIs for long-term catheters
with a mean duration of placement of 20 days or longer.48-51
This could be attributed to the biodegradable nature of the collagen, whereby
the silver ions chelated to the cuff are released completely within 3 to 7
days. Because of its limited efficacy, the use of the attachable silver cuff
is not recommended.52 More recently, a silver
iontophoretic device has been developed, whereby silver ions are released
through a low-voltage current going through silver wires that are attached
to the intercutaneous proximal segment of the catheter connected to a small
electric power source.53 This silver iontophoretic
device has a long-lasting effect and prevents catheter infections in vitro
and in vivo.53-54 The clinical
safety and efficacy of this device have not been demonstrated.
Antimicrobial/Anticoagulant Flush Solution
Antimicrobial flush solutions, often consisting of an anticoagulant
with an antimicrobial agent, have been used to fill the lumen of the catheter
at least once daily.55-56 This
procedure has been mostly used in long-term catheters in which the hub and
luminal colonization are the leading causes of CRBSIs.55
However, this intervention could also be useful in short-term catheters. Various
antimicrobial agents have been used as part of antibiotic lock or flush solutions
and have been shown to decrease the risk of recurrence of infection and the
need for catheter removal.57-58
Vancomycin hydrochloride, in combination with heparin sodium, has been used
as a daily flush solution and has been shown to decrease the risk of catheter
infection.55 Another study56
failed to show that this combination is effective in reducing the risk of
CRBSIs caused by organisms attributable to lumen colonization.
More recently, Henrickson et al59 demonstrated
in a prospective randomized study that either vancomycin and heparin or vancomycin,
ciprofloxacin hydrochloride, and heparin flush solutions are efficacious in
reducing the risk of CRBSIs. However, the Centers for Disease Control and
Prevention guidelines recommend against the use of vancomycin as a prophylactic
agent in the prevention of CRBSIs because it is an independent risk factor
for the acquisition of vancomycin-resistant enterococci.60
In addition, prolonged use of vancomycin could lead to the emergence of staphylococci
with intermediate resistance to vancomycin.61-65
A novel flush solution consisting of a combination of minocycline hydrochloride
(a tetracycline active against gram-positive organisms) and EDTA has been
developed.66 This combination is synergistic
against resistant gram-positive and gram-negative bacteria and C albicans. It has also been shown in a clinical study66
to be highly efficacious in preventing the recurrence of staphylococcal infections
in short- and long-term catheters. A more recent prospective randomized study
demonstrated the efficacy of this combination in preventing CRBSIs in patients
undergoing hemodialysis with a long-term indwelling CVC. The combination of
minocycline and EDTA had an equivalent anticoagulant activity to heparin.67 Like EDTA, citrate has been shown to have comparable
anticoagulant activity to heparin in a prospective randomized study68 involving patients undergoing hemodialysis.
Aseptic Hub Model
A new antiseptic hub attachment has been developed to protect the contamination
of the hub and the lumen. This model is used by attaching to the hub of the
catheter and has been shown in an animal study69
to prevent catheter colonization. In addition, a clinical study70
in patients with long-term catheters showed that they decreased the rate of
CRBSIs by 4-fold. This model will be most useful in long-term catheters with
a high risk of hub and lumen colonization. However, a recent clinical trial71 failed to show any benefit from using the new aseptic
hub in reducing the risk of catheter infection. Hence, further prospective
randomized studies are necessary to evaluate whether this new technology does
prevent CRBSIs and whether it is cost-effective.
Antimicrobial Impregnation of Catheters and Dressings
The impregnation of catheters with antimicrobial agents, as predicted
by Maki and colleagues in 1988, has proved to be "the most effective technologic
innovation in reducing the risk of device-related infection."47(p313)
During the past decade, several studies8, 15, 72-74
have shown that vascular catheters impregnated with antimicrobial agents decreased
the risk of catheter colonization and CRBSIs. The best-studied antimicrobial
catheters are those that are impregnated with a combination of either chlorhexidine
gluconate and silver sulfadiazine or minocycline and rifampin.74-75
The indications for using antimicrobial catheters are as follows: (1) units
with a risk of catheter infections exceeding 3% or 3.3 per 1000 catheter days,
(2) femoral or internal jugular vein insertion (which is associated with a
greater risk of infection than subclavian vein catheterization9, 74, 76),
(3) central catheters are expected to remain in place for longer than 4 days,
(4) patients with burns, (5) patients with neutropenia or patients undergoing
transplantation, (6) patients undergoing hemodialysis, (7) patients with short-bowel
syndrome, (8) patients who would receive total parenteral nutrition, (9) patients
colonized with methicillin-resistant S aureus, (10)
patients with an open wound in the proximity of the insertion site, (11) insertion
or exchange in a patient with a known infection or bacteremia, and (12) emergency
insertion of the catheter. Maki and colleagues8
demonstrated that catheters coated on the external surface with chlorhexidinesilver
sulfadiazine decrease the risk of colonization 2-fold and the risk of CRBSIs
by at least 4-fold compared with uncoated catheters. Several studies77-80 failed
to show any benefit from the use of catheters coated on the external surface
with chlorhexidinesilver sulfadiazine (first-generation aseptic catheters),
particularly when used for longer than 2 weeks. A recent meta-analysis75 of 12 studies showed that these catheters coated
with chlorhexidinesilver sulfadiazine do decrease the risk of CRBSIs
associated with short-term CVCs. In most of these studies, the semiquantitative
roll-plate culture technique, which cultures only the external surface, was
used without any attempt to culture the internal surface. Using the Mantel-Haenszel
method, it was demonstrated that the short-term use (<2 weeks) of these
catheters is associated with a decrease in CRBSIs.52
The lack of efficacy of chlorhexidinesilver sulfadiazineimpregnated
catheters in situations requiring long-term catheterization of longer than
3 weeks was attributed to the reduced antimicrobial activity of the catheter
over time and lack of luminal protection.52, 81-82
The advantage of these catheters is that they are precoated and, hence, do
not need to be treated at the bedside. However, there are several limitations
to these catheters: (1) Only the external surface is coated.8
(2) The catheters have a short antimicrobial durability and lack efficacy
with long-term use (>2 weeks).80-82
(3) There is concern about the potential anaphylaxis associated with these
catheters, probably related to chlorhexidine.83-85
The risk of such a complication is low and could be genetically related because
it has appeared only in Japan (which led to the banning of these catheters
in that country), not in the United States.83
The US Food and Drug Administration recently approved the use of an improved
version of this catheter (second-generation catheters) with added intraluminal
chlorhexidine impregnation and slightly more prolonged antimicrobial activity.86
Catheters impregnated with minocycline and rifampin have the advantage
of coating the internal and external surface of the catheter. These catheters
were significantly superior in vitro and in an animal model to catheters impregnated
with chlorhexidinesilver sulfadiazine.80
In a large, prospective, randomized, multicenter, double-blind trial,73 these catheters significantly decreased the risk
of CRBSIs by more than 5-fold. In addition, they were highly cost-effective,
resulting in an annual cost savings of more than $500 000 in a hospital
that uses 850 CVCs per year.73 In a more recent
prospective, randomized, multicenter, clinical trial,87
these catheters were shown to be 12-fold less likely to be associated with
CRBSIs when compared with catheters externally impregnated with chlorhexidinesilver
sulfadiazine. Concerns related to the potential for emergence of antibiotic
resistance (especially to rifampin) with the use of this catheter were raised.
Two large, prospective, randomized trials74, 87
failed to demonstrate the emergence of antibiotic resistance. In addition,
the use of such catheters in the intensive care unit of a cancer center resulted
in a significant decrease in the frequency of nosocomial vancomycin-resistant
enterococcirelated bacteremia.88 However,
a thorough investigation is required to determine the risk of emergence of
resistance to rifampin and minocycline associated with long-term use of these
catheters. A recent in vitro study89 suggested
that the susceptibility of S epidermidis to rifampin
may decrease after repeated exposure of the organism to catheters impregnated
with minocycline and rifampin. A novel dressing impregnated with chlorhexidine
and placed around the catheter insertion site has recently been shown to reduce
the risk of CRBSIs 3-fold in a prospective, randomized, multicenter study.90
MANAGEMENT: NEW APPROACH
The most crucial question related to the management of CRBSIs is to
determine whether the catheter should be removed. A new approach is to decide
on catheter removal based on whether there is a low, moderate, or high risk
of CRBSIs. Risk depends on the type of the organism (low or high virulence)
and whether the CRBSI is complicated or uncomplicated. Hence, the following
novel approach is suggested (Figure 1).
1. A low-risk CRBSI consists of an uncomplicated CRBSI caused by an
organism of low virulence, which is not usually associated with deep-seated
infections, such as coagulase-negative staphylococci.91-92
2. A moderate-risk CRBSI consists of an uncomplicated CRBSI that is
caused by organisms of a moderate to high virulence associated with the tendency
for deep-seated infections, such as S aureus and Candida species.93-95
3. A high-risk CRBSI is a complicated CRBSI, often occurring in a critically
ill or immunocompromised patient.96-99
A complicated CRBSI consists of the following: (1) a CRBSI associated
with hypotension or organ hyperfusion; (2) the persistence of the fever or
positive blood culture results for more than 48 hours after the initiation
of appropriate antimicrobial therapy; (3) a CRBSI associated with septic thrombosis
of the great vein, septic emboli, or deep-seated infections, such as endocarditis93, 96; and (4) the presence of a tunnel
or port pocket infection.
For low-risk CRBSIs, the infections can be treated without removal of
the catheter.91, 100 At least 80%
of CRBSIs caused by coagulase-negative staphylococci respond to antibiotic
therapy without the removal of the catheter.100
However, in patients with a prosthetic heart valve, the catheters should be
removed. For moderate-risk CRBSIs, which consist of uncomplicated infection
caused by S aureus and Candida species, the short-term catheters should be removed.93-95
In this case, transesophageal echocardiography may aid in the decision to
remove the catheters in patients with CRBSIs and guide the decision of therapy.101 However, in stable patients with long-term tunneled
catheters responding to antimicrobial therapy, consideration can be given
to the use of antibiotic lock solution without the removal of the catheter.102-103 Several studies104-106
have shown that long-term tunneled dialysis catheters may be exchanged with
guidewire in a patient with an uncomplicated suspected CRBSI and no signs
of exit or tunnel tract infection. For patients with high-risk complicated
CRBSIs (including those with tunnel tract infections), it is necessary to
remove the involved catheter.93, 97-99
The factors favoring the removal of the catheter include CRBSIs with associated
hypotension or organ hypoperfusion, the persistence of fever or positive blood
culture results after antimicrobial therapy, associated septic thrombosis
or emboli, associated tunnel or port pocket infections, and the short-term
nontunneled catheter as the culprit of bloodstream infection caused by either S aureus or Candida species.
Vancomycin is the drug of choice for the treatment of CRBSIs caused
by methicillin-resistant staphylococci. However, novel antimicrobial agents,
such as linezolid or the combination of quinupristin and dalfopristin, with
activity against methicillin-resistant staphylococci, may serve as alternative
agents to vancomycin in the treatment of CRBSIs caused by methicillin-resistant
staphylococci, particularly in patients who are either allergic to vancomycin
or colonized with vancomycin-resistant enterococci.107-111
For CRBSIs caused by methicillin-sensitive staphylococcal organisms, an antistaphylococcal
penicillin or a first-generation cephalosporin may be used if the patient
is not allergic to -lactam antibiotics. The treatment duration for coagulase-negative
staphylococcirelated CRBSIs is usually 5 to 10 days; for uncomplicated S aureusrelated CRBSIs, it should range from 10
to 14 days.94, 112 However, patients
with deep-seated infections (endocarditis or septic thrombosis) associated
with the CRBSI should receive 4 to 6 weeks of treatment with antimicrobial
therapy.93 Catheter-related bloodstream infections
caused by C albicans or C parapsilosis can be treated with fluconazole.113-114
However, resistant organisms, such as Candida krusei,
should be treated with high-dose amphotericin B, 1.0 mg/kg per day.115-117 A prospective
randomized study113 of patients, most of whom
had suspected catheter-related candidemia, showed that fluconazole given for
at least 14 days after catheter removal was as effective as amphotericin B.
Extensive guidelines for the management of catheter-related infections have
been recently published.118 These guidelines
outline the management approach regarding accurate diagnosis, catheter removal,
identification of complicated CRBSIs, duration of therapy, and type of antimicrobial
agents to be used according to microbial cause.
AUTHOR INFORMATION
Accepted for publication September 6, 2001.
We thank Leonard A. Mermel, DO, ScM, for his significant contribution
in editing the manuscript.
Corresponding author and reprints: Issam I. Raad, MD, Infectious
Diseases, Infection Control, and Employee Health, The University of Texas
M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: iraad{at}mdanderson.org).
From the Department of Infectious Diseases, Infection Control, and
Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston.
Dr Raad is a coinventor on 2 patents related to antibiotic-coated catheters.
These patents are licensed to Cook Critical Care, Bloomington, Ind, with royalty
rights to 2 institutions (The University of Texas M. D. Anderson Cancer Center
and Baylor College of Medicine, Houston). A percentage of the royalties goes
to the inventors according to the royalty policies of each institution.
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