Download Catheter-associated urinary tract infections: new aspects of novel

International Journal of Antimicrobial Agents 28 (2006) 485–490
Review
Catheter-associated urinary tract infections: new aspects
of novel urinary catheters
U-Syn Ha a , Yong-Hyun Cho b,∗
a
Department of Urology, St Vincent Hospital, The Catholic University of Korea College of Medicine,
62 Yeouido-dong, Yeongdeungpo-gu, 150-713 Seoul, Republic of Korea
b Department of Urology, St Mary’s Hospital, The Catholic University of Korea College of Medicine,
62 Yeouido-dong, Yeongdeungpo-gu, 150-713 Seoul, Republic of Korea
Abstract
Nosocomial urinary tract infection is the most common infection acquired both in hospitals and nursing homes and is usually associated with
catheterisation. These catheter-associated urinary tract infections (CAUTIs) have been reported to increase mortality and have a considerable
economic impact. To date, the sole effective preventative strategy is the use of a closed drainage system and removal of the catheter as soon as
possible. The underlying cause of CAUTI is the formation of a pathogenic biofilm on the surface of the indwelling urinary catheter. Currently,
researchers seek to alter the catheter surface in order to inhibit biofilm formation. Many substances are being studied for their potential as
biofilm-disrupting catheter coatings. Among these substances, recently developed antibiotic-coated catheters may provide promise for the
control of CAUTI. More basic research at the level of pathogenesis and catheter substance is needed to design novel strategies.
© 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Keywords: Catheter-associated urinary tract infection; Prevention; Antibiotic-coated catheter
1. Introduction
Urinary tract infection (UTI) is the most prevalent cause
of nosocomial infections, with an incidence of ca. 40%
of all cases of nosocomial infection [1], among which
80% involve catheter-associated urinary tract infection
(CAUTI) [2,3]. Although most CAUTIs are asymptomatic,
it has been reported that a close relationship exists between
symptomatic expression and increased rate of mortality
in diabetic, immunocompromised, debilitated patients
[4].
The major route of infection in CAUTI is ascending (i)
at the time of insertion of a catheter through the urethra, (ii)
via the mucosal layer between the catheter and urethra and
(iii) through the catheter lumen [2]. The risk of acquiring
CAUTI depends on the method and duration of catheterisation, the quality of catheter care and host susceptibility. The
most effective way of preventing CAUTI is to keep the sys∗
Corresponding author. Tel.: +82 2 3779 1024; fax: +82 2 761 1626.
E-mail address: [email protected] (Y.-H. Cho).
tem of urine drainage closed from the bladder to the collection
bag [2,4,5]. CAUTI is seen within several days in 100% of
cases when the system of urine drainage could not be maintained as closed [6]. However, maintaining a closed system
of urine drainage is actually difficult and, even if the system
is maintained as closed, CAUTI is reported to occur in 50%
of cases when the system is in operation for more than 5 days
[7].
Many innovations have been tried in clinical settings to
prevent CAUTI. These have included the use of antiseptic
lubricating gel at catheter insertion [8], the use of a tape seal
applied to the catheter drainage tubing junction [9], antireflux
valves, or anti-infective irrigation of the bladder or instillation of antiseptics in the collection bag [10–12]. However,
compared with the closed drainage system, all of these have
failed to show significant benefits.
In the last few years it has been reported that biofilm formation on the urinary catheter may play a key role in the
pathogenesis of CAUTI and in the resistance of CAUTI to
management. Renewed interest has therefore arisen in altering the catheter surface to inhibit biofilm formation. A recent
0924-8579/$ – see front matter © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2006.08.020
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U.-S. Ha, Y.-H. Cho / International Journal of Antimicrobial Agents 28 (2006) 485–490
approach to solve some of the problems associated with
CAUTI has been the application of a range of different coatings to the surface of the catheter. The results have been varied
but promising.
The purpose of this article is to analyse and review
up-to-date reports published on the pathogenesis of and
prevention strategies for CAUTI. Reviewed articles mainly
concern biofilms and recently developed urinary catheters
coated with various materials targeted against the pathogenesis of biofilms. Reviewed clinical studies are focused on
randomised clinical trials of currently marketed catheters
coated with novel materials; trials with inclusion of longterm catheterisation (>30 days) or insufficient data were
excluded. These reports provide a better understanding of
CAUTI and enable us to step forward in the prevention of
CAUTI.
2. Pathogenesis of CAUTI-associated biofilm
Previous studies confirmed that bacteria associated with
CAUTI grow in glycocalyx-enclosed microcolonies in a
biofilm on the catheter surface [13]. On scanning electron
micrographs, such microcolonies were easily seen to be
enveloped in a slime or glycocalyx exuded by the adherent bacteria. Beginning with only loosely bound bacteria and
their products, the biofilm of glycocalyx readily coalesces
with other bacterial exopolysaccharides and host products
to produce a thick and condensed biofilm, occluding the
inner or outer surface of the catheter [14]. Adherent bacterial
colonies within a biofilm form a functional union in which
a microenvironment is maintained. This microenvironment
is characterised by concentration of enzymes and metabolic
products and the relative exclusion of gases such as oxygen [15]. Consequently, adherent biofilm bacteria in such an
environment are metabolically inactive compared with their
planktonic counterparts and appear to be resistant to antibiotics, the potencies of which are related to bacterial growth
rates [16]. Furthermore, the biofilm might be expected to
act as a mechanical barrier, protecting the entrained bacteria
from natural host defence mechanisms and antibiotic activity [17,18]. Previous studies showed that systemic antibiotics
kill planktonic bacteria in urine and reduce the initial rate of
catheter-associated bacteriuria, but fail to eradicate the sessile
biofilm bacteria, except when a very high dose of antibiotic
was noted to kill the biofilm bacteria on a Foley catheter
[19,20].
Recently, Anderson et al. [21] suggested that this bacterial reservoir may be within the living tissue of the bladder
itself. They found that clinical isolates of uropathogenic
Escherichia coli formed tightly packed, biofilm-like pods in
mouse bladder epithelial cells. This article is the first description of biofilm formation within eukaryotic cells. If supported
by further studies, these intracellular biofilms could certainly
account for the persistence of pathogens in the damaged
mucosa of a catheterised urinary tract [15]. An intricate
understanding of the pathogenesis of CAUTI, such as biofilm
formation, may lead to novel mechanisms to prevent this disease.
3. Disrupting biofilm formation with novel catheter
coatings
3.1. Silver-coated catheters
Silver has antiseptic effects and several studies have
investigated the efficacy of silver-coated catheters, with
mixed results (Table 1) [22–26]. In 1979, Akiyama and
Okamoto [22] first described the use of a silver-coated
urinary catheter in 102 patients and found that none of those
treated with a silver-coated catheter developed bacterial
infections.
Schaeffer et al. [23] reported 74 patients with spinal cord
injury or neurological injury who were randomised to receive
either a silver oxide-coated silicone catheter or an uncoated
silicone catheter. Bacteriuria was documented in 27% of
cases in the silver-coated catheter group and in 55% of the
control group (P = 0.02). More recent research has also found
that there was a statistically significant difference in the
occurrence of bacterial infection in patients treated with a
silver alloy-coated catheter compared with those treated with
a standard device [24,25].
These trials increased interest in silver-coated catheters for
the prevention of CAUTI. However, since these trials were
too small to determine the efficacy of silver-coated catheters,
two large clinical trials were conducted.
In a clinical trial involving 1309 hospitalised patients,
Riley et al. [26] not only failed to demonstrate the efficacy
of silver-coated catheters in the prevention of CAUTI, as
suggested in prior studies, but also showed a significantly
increased incidence of bacteriuria in male patients. A second
investigation reported that silver-coated catheters reduced the
incidence of UTI only among women not receiving antimicrobial agents in a prospective clinical trial involving 482
hospitalised patients [27].
More recently, a prospective crossover study involving
3036 patients evaluated the efficacy of a silicone-based,
silver-impregnated urinary catheter [29]. This study found
that silicone-based, silver-impregnated urinary catheters
were not effective in preventing CAUTI.
The apparent superiority of silver-impregnated catheters
in earlier studies [22–25] compared with more recent clinical
studies [26–29] may be due to the fact that in earlier studies
controls were usually latex-based and in more recent studies
silicon-based catheters were used. Until now, the use of more
expensive silver-coated catheters to prevent CAUTI has not
been supported by quality data, and resistance to silver was
likely to become a problem with widespread use. However,
the concept of disrupting biofilm formation is also applicable
to other agents used to impregnate urinary catheters, including hydrogels and antibiotics.
Hydrogels, macromolecular polymers that absorb relatively large volumes of liquid within their polymeric structures [30], result in the formation of a thin water film on the
contacting surface, thus improving its smoothness and lubricity. These properties might act as potential barriers to bacterial
infection and reduce the adhesion both of Gram-positive and
Gram-negative bacteria to catheters [31] and thus may be
used to impregnate urinary catheters.
Trials of hydrogel-coated catheters have yielded mixed
results. Some reports have indicated that there is promising
potential for these catheters, whilst other reports conflict this
positive result [28,32–34].
Bologna et al. [32] reported a trend towards a reduction in nosocomial UTI in an experimental group. However,
several other reports that conflicted this result showed no
significant differences between the incidence of bacterial
infection in hydrogel or silver and hydrogel-coated and standard catheters [28,33]. A study conducted to test for migration
of microorganisms found that hydrogel coatings facilitate the
migration of urinary tract pathogens over hydrogel-coated
catheters [34]. As a result, it was concluded that there was
insufficient evidence to support or recommend the use of
hydrogel-modified catheters.
3.3. Antibiotic-coated catheters
Reid et al. [35] reported that pre-treatment of urinary silicone latex catheters in vitro with ciprofloxacin significantly
reduced the adhesion and survival of the clinical isolate Pseudomonas aeruginosa. Results of these in vitro studies suggest
that there could be a clinical role for antibiotics in preventing CAUTI associated with bacterial adherence to prosthetic
devices. Further research has continued into the use of various
antibiotics, including gentamicin, norfloxacin, nitrofurazone
and minocycline with rifampicin for impregnated material.
Some of these devices might hold promise for reducing
CAUTI.
N.S., not significant.
16.15/1000
catheter-days
Silver (silicone)
Srinivasan et al. [29]
14.29/1000
catheter-days
N.S.
N.S.
Randomised, double-blind,
multicentre study
Randomised with
cross-over
13/109 (11.9)
9/90 (10)
Silver hydrogel (latex)
Thibon et al. [28]
487
3.2. Hydrogel-coated catheters
A total of 3036 patients evaluated; study groups
were not identical (more men, shorter duration of catheterisation in test group)
Increased incidence of bacteriuria in men
Effective only in women not receiving
antibiotics
N.S.
N.S.
Randomised, controlled
Randomised, controlled
Clinical trials suggesting that catheters coated with silver or silver hydrogel do not have a protective effect
Riley et al. [26]
Silver oxide (silicone)
85/745 (11)
73/564 (13)
Johnson et al. [27]
Silver oxide (silicone)
19/207 (9)
28/275 (10)
Liedberg and Lundeberg [24]
Liedberg and Lundeberg [25]
Silver hydrogel (latex)
Silver hydrogel (latex)
6/60 (10)
8/75 (11)
22/60 (37)
23/96 (24)
<0.01
0.02
Uncontrolled
Catheter and tube collector junction coated with
silver, small samples
Small samples
Incidence on Day 5 of catheterisation
Effective
0.02
Clinical trials suggesting that catheters coated with silver or silver hydrogel have a protective effect
Akiyama and Okamoto [22]
Silver
0/102 (0)
20/20 (100)
Schaeffer et al. [23]
Silver oxide
11/41 (27)
18/33 (55)
Control group
Test group
Results, n (%)
Test catheter coating (base)
Reference
Table 1
Results of clinical trials of silver-coated catheters
Randomised, controlled
Randomised, controlled
Comments
Study design
P-value
U.-S. Ha, Y.-H. Cho / International Journal of Antimicrobial Agents 28 (2006) 485–490
3.3.1. Gentamicin
As mentioned above, the antimicrobial coating method
has received increasing attention as a method of inhibiting
CAUTI during catheterisation. Local and sustained delivery
of an antibiotic within a therapeutic range is required. Cho
et al. [36] attempted to prepare catheters that can effectively
inhibit infections by releasing an antibiotic in a sustained
manner. Drug release studies demonstrated that the coated
catheter with gentamicin-containing poly(ethylene-co-vinyl
acetate) (EVA) and EVA/poly(ethylene oxide) (PEO) exhibited sustained release and antibacterial activity for 7 days
against Proteus vulgaris, Staphylococcus aureus and Staphylococcus epidermidis in vitro. These results imply that
catheters coated with EVA/PEO have a potential for shortterm catheterisation.
N.S.
Randomised, controlled,
multicentre study
Nitrofurazone (silicone)
Lee et al. [42]
N.S., not significant; CAUTI, catheter-associated urinary tract infection.
19/85 (22)
<0.01
0.002
Randomised, controlled
Randomised, controlled
14/174 (8)
6/50 (12)
Control group
Test group
Nitrofurazone (silicone)
Nitrofurazone (silicone)
Maki et al. [40]
Al-Habdan et al. [41]
8/170 (5)
0/50 (0)
Study design
Results, n (%)
Test catheter coating
(base)
Table 2
Results of clinical trials of nitrofurazone-coated catheters
3.3.3. Nitrofurazone
Nitrofurazone is active in vitro against a broad range
of Gram-positive and Gram-negative bacilli isolated from
patients with indwelling urinary catheters [38]. The in vitro
inhibitory activity of a nitrofurazone-coated urinary catheter
against species implicated in CAUTI was determined using
an agar diffusion assay [39]. The activity of the nitrofurazonecoated catheter was compared with that of a silver hydrogel
urinary catheter. Results showed that the nitrofurazonecoated catheter was broadly active in vitro against species
characteristic of CAUTI. There are a few randomised clinical
trials that have evaluated the efficacy of nitrofurazone-coated
catheters (Table 2) [40–42].
Recently, a multicentre study including 177 patients was
conducted to determine the CAUTI inhibition effect by
nitrofurazone-coated catheters [42]. In this study, the incidence rate of CAUTI was lower in the nitrofurazone-coated
catheter group compared with the control group. When the
catheters were maintained for >5 days but <7 days, the incidence rate of CAUTI was statistically significantly lower
in the experimental group compared with that in the control group. Considering that the incidence rate of CAUTI is
P-value
3.3.2. Norfloxacin
Gentamicin-releasing catheters have a limited role
for short-term catheterisation because gentamicin is a
hydrophilic antibiotic, thus with rapid release from the surface of coated catheters to aqueous media. Norfloxacin, a
fluoroquinolone antibiotic of hydrophobic nature, was investigated as an anti-infectious substance for use in long-term
catheterisation [37]. The norfloxacin-releasing catheters,
coated with EVA and PEO (the same matrix that previous
gentamicin-releasing catheters were coated with), showed
continuous delivery of norfloxacin for up to 30 days owing
to the hydrophobic nature of norfloxacin and EVA/PEO
incorporated in a coating layer. The coated catheters created considerable inhibition zones for 10 days against E. coli,
Klebsiella pneumoniae and P. vulgaris and have a promising
potential for clinical use in patients undergoing long-term
catheterisation.
14/92 (15)
Comments
In in vivo studies using rabbits to determine the efficacy of
gentamicin-releasing urethral catheters against microorganisms causing catheter-associated bacteriuria, the incidence
of bacteriuria between two groups after 3 days and 5 days
of catheterisation (8 and 10 rabbits for the control catheter
vs. 2 and 4 rabbits for the gentamicin-releasing catheter,
respectively) was significantly different [14]. Scanning electron microscopy showed the formation of bacterial biofilm
throughout the 3-day and 5-day catheterisation for control
catheters, but deterioration of the bacterial biofilm was visible on the surface of the gentamicin-releasing catheters. The
authors concluded that the gentamicin-releasing catheter produced an antibacterial barrier that inhibited CAUTI for 5 days
and may be useful for controlling infection in patients undergoing short-term urethral catheterisation.
Relatively low incidence rate of CAUTI in the control group
Different base catheter between two groups (latex catheter
used in the control group)
Duration of catheterisation ≤7 days; significant reduction in
CAUTI only in the 5–7 days group (13% vs. 19%)
U.-S. Ha, Y.-H. Cho / International Journal of Antimicrobial Agents 28 (2006) 485–490
Reference
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very low within 5 days of catheter insertion provided the
catheter was inserted aseptically and a closed drainage system is maintained [43], this result is clinically important since
the effect of inhibiting CAUTI was proven during the clinically important period of CAUTI expression between 5–7
days of catheterisation.
Maki and Tambyah [44] also reported that novel urinary
catheters impregnated with nitrofurazone or minocycline and
rifampicin significantly reduced the risk of CAUTI for shortterm catheterisation not exceeding 2–3 weeks. It is necessary
to confirm further the effectiveness of nitrofurazone-coated
catheters over long-term periods.
4. Conclusion
Numerous strategies have been tried to reduce the incidence of CAUTI, but few have proven effective. Recently, the
role of biofilms in the pathogenesis of CAUTI was discovered and new strategies including novel urinary catheters to
disrupt the biofilm have been investigated. Antibiotic-coated
catheters could prevent or delay the onset of CAUTI during
short-term catheterisation and hold promise for the possibility of suppression of CAUTI.
However, greater understanding of the pathogenesis of
CAUTI as well as well designed, randomised clinical studies
are required to produce ideal urinary catheters for control of
CAUTI.
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