Prevention of Bloodstream Infections in Patients

Undergoing Hemodialysis
Molly Fisher,1 Ladan Golestaneh ,1 Michael Allon,2 Kenneth Abreo,3 and Michele H. Mokrzycki 1

Abstract
Bloodstream infections are an important cause of hospitalizations, morbidity, and mortality in patients receiving
hemodialysis. Eliminating bloodstream infections in the hemodialysis setting has been the focus of the Centers for 1
Division of
Disease Control and Prevention (CDC) Making Dialysis Safer for Patients Coalition and, more recently, the CDC’s Nephrology,
partnership with the American Society of Nephrology’s Nephrologists Transforming Dialysis Safety Initiative. The Montefiore Medical
Center and Albert
majority of vascular access–associated bloodstream infections occur in patients dialyzing with central vein
Einstein College of
catheters. The CDC’s core interventions for bloodstream infection prevention are the gold standard for catheter Medicine, Bronx, New
care in the hemodialysis setting and have been proven to be effective in reducing catheter-associated bloodstream York; 2Division of
infection. However, in the United States hemodialysis catheter–associated bloodstream infections continue to Nephrology,
occur at unacceptable rates, possibly because of lapses in adherence to strict aseptic technique, or additional University of Alabama
at Birmingham,
factors not addressed by the CDC’s core interventions. There is a clear need for novel prophylactic therapies. This Birmingham,
review highlights the recent advances and includes a discussion about the potential limitations and adverse effects Alabama; and
3
associated with each option. Division of
CJASN 15: 132–151, 2020. doi: https://doi.org/10.2215/CJN.06820619 Nephrology, Louisiana
State University
Health at Shreveport,
Shreveport, Louisiana
Introduction antibiotics are administered without sending blood
In the 2018 US Renal Data Report, 80% of patients cultures in patients who become symptomatic when Correspondence:
initiated hemodialysis with a catheter and 21% are still in the hemodialysis unit. In the National Healthcare Dr. Michele H.
in use 1 year after hemodialysis initiation (1). One of Mokrzycki, Division of
Safety Network reporting system, bloodstream in- Nephrology,
the major complications of hemodialysis catheter use fection events are determined solely by a positive Montefiore Medical
is bloodstream infection, which is associated with an blood culture result and does not include intravenous Center, 3411 Wayne
increased risk of systemic infectious complications, antibiotic starts (2,13). A determination of the com- Avenue, Suite 5-H,
hospitalizations, and death (2–6). Hemodialysis cath- Bronx, NY 10467.
pleteness of capture of blood cultures for all events in Email: mmokrzyc@
eter use is associated with an eight-fold higher rate which obtaining blood cultures may have been in- montefiore.org
of vascular access-related bloodstream infections dicated is missing in this data. One proposal to
when compared with an arteriovenous fistula (2). mitigate inaccuracies in bloodstream infection report-
The definition of catheter-associated bloodstream in-
ing is to provide data about positive blood culture
fection used in various clinical trials lacks consistency
results as a percentage of all intravenous antibiotic
(7–12). In 2018, a multidisciplinary group of experts
starts in the hemodialysis facility. However, this
formed the Kidney Health Initiative’s Catheter End
assumes that intravenous antibiotics are ordered
Points Workgroup to establish a standardized defini-
solely for suspected cases of bacteremia. In addition,
tion of catheter-associated bloodstream infection in
patients on hemodialysis (12). The workgroup pro- this proposal does not account for cases of blood-
posed the following criteria for the diagnosing hemo- stream infection in which blood cultures were ob-
dialysis catheter–associated bloodstream infection: tained in the hospital and the intravenous antibiotic
(1) clinical suspicion of infection (fever/temperature course was completed during the hospitalization.
.37.5°C or rigors or altered mental status or new In the most recent National Healthcare Safety
predialysis hypotension [systolic BP ,90 mm Hg]), (2) Network Dialysis Event Surveillance report for
confirmation of bacteremia (blood cultures growing 2014, the mean rate of all bloodstream infections in
the same organism from the hemodialysis catheter catheter-dependent patients was 2.16 per 100 patient-
and a peripheral vein or dialysis bloodline), and (3) months and the mean rate for access-related blood-
exclusion of any alternate sources of infection. stream infection was 1.83 per 100 patient-months
The accurate reporting of bloodstream infection (combined permanent and temporary catheters) (2).
rates in the outpatient hemodialysis setting may be This was a marked improvement compared with the
jeopardized by methodological challenges. Patients previous report for 2006 when the rate of all blood-
who become symptomatic with fever or chills often- stream infections in catheter-dependent patients was
times present directly to the hospital, and not to the 4.2 (permanent catheters) and 27.1 (temporary cathe-
hemodialysis facility. Furthermore, on rare occasion, ters) per 100 patient-months, and access-related

132 Copyright © 2020 by the American Society of Nephrology www.cjasn.org Vol 15 January, 2020
CJASN 15: 132–151, January, 2020
bloodstream infection rates were 3.1 (permanent catheters)
and 17.8 (temporary catheters) per 100 patient-months (13).
Similarly, from 2003 to 2013 the hospitalization rate for
vascular access infections has declined in both incident
and prevalent patients on dialysis (30% and 46% reduction,
respectively) (14). However, there was a simultaneous rise
in the rate of hospitalization for bacteremia/sepsis in
both incident (38% increase) and prevalent (40% increase)
patients (14). One explanation may be a change in the
frequency of coding from the diagnosis “vascular-access
infection” to an increase in use of the code “bacteremia.”
Further investigation into these apparent paradoxical find-
ings would be informative. In the recent US Renal Data
Systems annual report for 2018, septicemia accounted for
8% of all deaths (1). Sepsis is a potentially preventable cause
of mortality in hemodialysis population, and a significant
percentage is vascular access related. Interventions to re-
duce infections in the hemodialysis setting include protocols
for catheter reduction, new tools to improve compliance
with the existing Centers for Disease Control and Preven-
tion’s core interventions for catheter care, improving patient
and staff education, and the development of novel devices
for preventing catheter colonization (15).
Interventions for Catheter Reduction
There are several interventions that can decrease the
incidence and prevalence of catheters in patients on hemo-
dialysis. There is evidence that early referral of patients to
nephrologists, multidisciplinary teams, and vascular access
coordinators who provide education to patients; implanta-
tion of early-stick grafts; and urgent-start peritoneal dialysis
can play a role in decreasing catheter use.
Early referral of patients with CKD to the nephrologist
results in dialysis modality choice discussions and, there-
after, leads to timely referral for permanent vascular access
placement, to a transplant center for enlistment or plan-
ning for peritoneal catheter insertion. In a small study of
135 patients, early (.4 months before dialysis initiation)
referral to a nephrologist was associated with a greater
likelihood of starting hemodialysis using a permanent vascu-
lar access (48% early referral versus 4% late referral) (16).
Similarly, in study of a large cohort of 2398 incident patients
on hemodialysis, late referral to a nephrologist (,90 days of
hemodialysis initiation) was associated with a 42% higher
risk of initiating hemodialysis with a catheter compared
with those seen by a nephrologist earlier in the course of
their kidney disease (odds ratio [OR], 1.42; 95% confidence
interval [95% CI], 1.17 to 1.71) (17).
There is modest evidence that when multidisciplinary
teams (consisting of physicians, nurses, social workers,
and dietitians) provide education to patients, either pre-
hemodialysis or at initiation of hemodialysis, the preva-
lence of catheters decreases (18,19). In the Treatment
Options Program, implemented by a large dialysis orga-
nization, patients were educated on modality choice and
vascular access prehemodialysis. Patients undergoing
hemodialysis enrolled in this program (n52800) had a
lower likelihood of initiating hemodialysis with a cath-
eter compared with matched control patients (n52800)
(63.2% versus 75.8%; P,0.001) (18). Similar findings were
reported in the Incident Management of Patients Actions
Preventing Bloodstream Infections in Hemodialysis, Fisher et al. 133
Centered on Treatment program, also implemented by a
large dialysis organization. When patients received educa-
tion at the initiation of hemodialysis, using a multidisciplin-
ary team, the proportion of patients with an arteriovenous
fistula or graft versus a catheter was significantly higher for
patients in the intervention group at 6 months (0.60 versus
0.52; P,0.001) and 1 year (0.63 versus 0.48; P,0.001) (19).
Contrary to the positive results of these studies, a quality
improvement initiative using a multidisciplinary vascular
access team to educate patients initiating hemodialysis in
Canadian units did not show a decrease in catheter-free
arteriovenous fistula use at 1 year (20).
The utilization of a vascular access coordinator can
significantly decrease hemodialysis initiation with a catheter.
A quality improvement project in Australia reported that
prehemodialysis patient education and coordination by a
vascular access coordinator resulted in a significant de-
crease in catheter-initiated hemodialysis (from 39% to 25%)
(P50.007) and a reduction in the total number of catheter
days (2833 versus 4685 days) (21). Similar findings were
reported from a program in the United States, where the
implementation of a comprehensive access program led
by a vascular access coordinator resulted in a significant
reduction in prevalent catheter use at .90 days after
hemodialysis initiation (from 11% to 6%; P,0.001) (22).
The use of a vascular access coordinator in the hemodi-
alysis unit can also improve outcomes after an episode of
catheter-associated bloodstream infection. A quality im-
provement project in the Bronx and Connecticut (n5223
episodes of catheter-associated bacteremia) reported a
significant reduction in recurrent bacteremia in 3 months
(from 18% to 6%; P,0.02) and death due to sepsis (6%
versus 0%; P50.05) in hemodialysis units with a vascular
access coordinator (23).
In patients in need of urgent-start dialysis, the creation
of an early-cannulation arteriovenous graft and place-
ment of a peritoneal dialysis catheter for immediate use
are additional options available to reduce catheters. In a
randomized, controlled trial, patients in need of an urgent
vascular access for hemodialysis were randomized to
receive an early-cannulation arteriovenous graft (n560)
or a tunneled catheter (n561) (24). At 6 months of follow-
up, bloodstream infections developed more frequently in
catheter group (16.4%) compared with the arteriovenous
graft group (3.3%; P50.02). In a retrospective study from
China, 96 patients starting dialysis with a peritoneal dialysis
catheter were compared with 82 patients starting with a
hemodialysis catheter (25). A significantly higher inci-
dence of bloodstream infection occurred in the hemodi-
alysis catheter group at 30 days (11% hemodialysis
catheter versus 0 peritoneal catheter; P50.003). Although
both studies comprised a single center, with small numbers
of patients, they suggest that avoiding catheters can reduce
bloodstream infections in patients with ESKD on dialysis.
Challenges to Adherence with the Centers for Disease
Control and Prevention’s Core Interventions
Implementation of the Centers for Disease Control and
Prevention’s core interventions for hemodialysis catheter
care has been associated with a 20%–50% reduction in
bloodstream infection rates and hospitalizations due to
134 CJASN

Figure 1. | Potential strategies for the prevention of bloodstream infections in patients undergoing dialysis. Educating patients and hemo-
dialysis staff about the risks of long-term catheter use and about optimal catheter care are key components to reduce bloodstream infections.
Attention to proper catheter exit-site care and hub disinfection using recommended antiseptic agents, and the use of recommended topical
ointments during exit site dressing changes are important core interventions. Novel therapies, including chlorhexidine containing hub devices,
and chlorhexidine dressings may further reduce bloodstream infections in catheter-dependent hemodialysis patients. In select patients,
novel non-antibiotic locking solutions and Staphylococcus decolonization protocols may also be considered. CDC, Centers for Disease
Control and Prevention.
CJASN 15: 132–151, January, 2020
sepsis (Figure 1) (15,26–28). Several objective factors may
potentially interfere with optimal adherence with the
Centers for Disease Control and Prevention’s core inter-
ventions in outpatient hemodialysis units in the United
States. Until studies are completed that quantify and
account for missing blood culture results, conclusions about
the effect of specific factors remain speculative. Possible
factors present in the outpatient hemodialysis setting that
may play a role include the high patient-to-staff ratio, the
proportion of patients dependent upon dialysis catheters,
and a high staff turnover. The rate of catheter use is high
among new hemodialysis starts. The newly started patients
are typically placed on the available late dialysis shifts at the
three medical centers where the authors work. To the extent
that this holds true across the United States, the result
would be a disproportionately high number of catheter-
dependent patients on the late shifts. Additionally, in
about half of the states, only nurses but not patient care
technicians are permitted to connect and disconnect
catheter patients (29). The high burden of catheter-
dependent patients on those late shifts is compounded
by the restriction of catheter care to nurses and presents a
huge burden on nursing staff. It is not unusual for one
nurse to be responsible for five or more catheter-
dependent patients. A high dialysis patient-to-nurse ratio
has been associated with more frequent access infections
(30). It is possible that this high workload may cause lapses
in adhering to the Centers for Disease Control and Pre-
vention guidelines, thereby contributing to an increased risk
of catheter-associated bloodstream infections. In contrast, in
Canada, Europe, and Japan, hemodialysis care is provided
exclusively by nurses, and the ratio of patients to nurses is
only 3–4:1, as compared with 8–12:1 in the United States.
A recent observational study reported the counterintu-
itive finding that the frequency of catheter-associated
bloodstream infection in a given hemodialysis unit was
inversely related to the proportion of patients using a
catheter at that unit (31). In other words, the greater the
proportion of catheter-dependent patients, the lower the
frequency of catheter-associated bloodstream infection.
One possible explanation for this surprising finding may
be that in hemodialysis units where a greater proportion
(.20%) of patients use a catheter, there may be a higher
percentage of healthier patients, who are therefore less
prone to infection. One can speculate that these healthier
patients may be suitable for an arteriovenous fistula or
graft, and might not have a catheter if they were dialyzing
in units with lower catheter percentages (,10%). Catheter-
dependent patients in facilities with a lower catheter
percentages (,10%) may have more comorbidities and
unsuitable for other forms of vascular accesses, and
therefore be at higher risk for infection. Consistent with
this hypothesis is the finding that catheter-associated
bloodstream infection rates are particularly low in Alberta,
Canada (0.19 per 1000 days or 0.57 per 100 patient-months),
despite the fact that in Canada, 45% of patients on hemo-
dialysis are catheter-dependent (32,33). An alternative expla-
nation is that in high-catheter-percentage units, experienced
staff, who are frequently performing catheter care may better
adhere to core infection prevention techniques.
It is possible that lapses in adherence with the Centers
for Disease Control and Prevention core interventions is a
Preventing Bloodstream Infections in Hemodialysis, Fisher et al. 135
factor contributing to the relatively high catheter-associated
bloodstream infection rate in the United States. There is
clearly a need for studies on the use of catheter care audit
checklists to assess whether they improve adherence with
the Centers for Disease Control and Prevention guidelines.
In addition, in an effort to reduce catheter-associated blood-
stream infection, novel interventions have been developed
to reduce exit-site and catheter lumen bacterial colonization.
These measures are described in following sections.
Patient Self-Care and Showering
Frequent and consistent patient education about the
associated infectious risks of prolonged hemodialysis
catheter use and on self-care of the catheter are impor-
tant for engaging patients to be an active participant
in improving safety (34). Historically, showering was
discouraged in catheter-dependent patients on hemodi-
alysis; however, showering is important from a quality-
of-life perspective. The Centers for Disease Control and
Prevention now recommends showering be permitted,
using exit-site and hub protection with an impermeable
cover to reduce the likelihood of introducing organisms
into the hemodialysis catheter. Sheet and pouch products
have been designed to prevent water contamination of
the hemodialysis catheter during showering, but may be
cost-prohibitive. There is insufficient evidence to determine
whether showering with a protocol that includes hemodi-
alysis catheter hub protection or after-shower exit-site care
decreases catheter-associated bloodstream infection rates
(35,36). In a small study, comparable bloodstream in-
fection rates were reported in patients on hemodialysis
trained in after-shower exit-site care and a control group
for which standard catheter care was performed
by hemodialysis nurses (35). Similarly, another small
trial compared showering without an exit-site dressing
(with catheter hub protection) to a no-showering policy.
There was no difference in bloodstream infection rates
between the groups, suggesting that showering without an
exit-site dressing may be safe (36). Further investigation
with a large, randomized clinical trial is warranted.
Interventions Targeting the Catheter Exit Site
Ointments
Topical antimicrobial ointments that are applied to the
catheter exit site are recommended at time of catheter
insertion and at each hemodialysis session (Table 1) (37–42).
The Centers for Disease Control and Prevention recom-
mends using polysporin triple antibiotic ointment (bacitracin/
gramicidin/polymyxin B) or povidone iodine ointment, which
have been shown to be associated with a 75%–93% reduc-
tion in catheter-associated bloodstream infection (15,37,40).
Polysporin ointment was also associated with a signifi-
cant reduction in mortality, and long-term follow-up over
6 years was not associated with a change in microbiologic
isolates over time (40,41). Unfortunately, gramicidin is
not available in the United States, although polysporin
ointments containing bacitracin/zinc/polymyxin B are
in clinical use, but have not been rigorously studied for
catheter-associated bloodstream infection prophylaxis.
Mupirocin has also been associated with an 85% reduction
 136
Table 1. Topical ointments and dressings used for hemodialysis catheter exit-site application

CJASN
Standard
Definition of
Rate Ratio
Study N Methods Bloodstream Definition Used Ointment Control Outcome P Value Concerns
(95% CI)
Infection
Used

Levin 129 Randomized, No Positive Povidone- No ointment Bloodstream 0.07 (0.06 ,0.01 Nontunneled
et al. (37) double-blind, peripheral iodine infection to 0.24) catheters
placebo- blood culture included
controlled trial without
another
demonstrable
focus
Sesso 136 Randomized, No (1) One or more Mupirocin Povidone-iodine Staphylococcus 0.14 (0.03 ,0.001 Potential for
et al. (38) prospective peripheral aureus to 0.63) resistance with
trial blood cultures bloodstream long-term use
with infection
Staphylococcus
aureus; (2)
fever .37.8°C,
with or
without other
signs of
infection
Johnson 50 Prospective, No (1) A single Mupirocin No ointment Bloodstream 0.15 (0.03 ,0.01 Potential for
et al. (39) randomized, positive infection to 0.80) resistance with
controlled, culture long-term use
open-label together with a
trial positive
culture from
the catheter tip
or exit site with
same
organism; (2)
two or more
positive
cultures with
no evidence of
other infection
source
Lok 169 Double-blind, Yes Health Canada Bacitracin- Placebo a) Bloodstream a) 0.25 (0.19 a) ,0.001 Gramicidin
et al. (40) placebo- guidelines (7) gramicidin- infection to 0.34) b) 0.004 containing
controlled, polymyxin B b) Death b) 0.22 (0.07 polysporin
randomized (polysporin to 0.74) triple ointment
trial triple is not available
ointment) in United
States
 CJASN 15: 132–151, January, 2020
Table 1. (Continued)
Standard
Definition of
Rate Ratio
Study N Methods Bloodstream Definition Used Ointment Control Outcome P Value Concerns
(95% CI)
Infection
Used

Battistella 1478 Quality Yes Health Canada Bacitracin- Historical Bloodstream ,1.0/1000 — Gramicidin
et al. (41) improvement guidelines (7) gramicidin- controls infection catheter-d containing
report polymyxin B polysporin
(polysporin triple ointment
triple is not available
ointment) in United
States
Johnson 101 Prospective, Yes Health Canada Antibacterial Mupirocin Bloodstream 0.94 (0.27 0.92 Underpowered
et al. (42) open-label, guidelines (7) honey infection to 3.24) to prove
randomized, equivalence
controlled trial
Camins 121 Prospective, Yes CDC/NNIS (9) Chlorhexidine- Transparent Bloodstream 1.22 (0.75 0.46 Lack of efficacy
et al. (46) nonblinded, impregnated dressing infection to 1.97)
crossover sponge
intervention
trial
Apata N/A Quality No Bacteremia in Chlorhexidine- Dry gauze Bloodstream 0.5 95% CI, 0.04 Local allergic
et al. (47) improvement any patient impregnated dressing plus infection N/A reaction/rash,
report with a transparent antibiotic (not ,1.0/1000 cost
tunneled dressing specified) catheter-d
catheter or ointment

Preventing Bloodstream Infections in Hemodialysis, Fisher et al.

tunnel site
infection

95% CI, 95% confidence interval; CDC, Centers for Disease Control and Prevention; NNIS, National Nosocomial Infections Surveillance System; N/A, not available.

137
138 CJASN
in the bloodstream infection rate; however, there are reports
of developing resistant microbes with the long-term routine
use of mupirocin (38,39). Medicinal honey has been shown
to be similar in efficacy to mupirocin in a small study (42).
The advantage of medicinal honey is that it has a low
likelihood for selecting resistant strains and is effective
against antibiotic-resistant microorganisms. Well designed,
adequately powered studies are needed before medicinal
honey can be recommended for catheter-associated blood-
stream infection prophylaxis. When using any ointment,
checking catheter compatibility is mandatory, and a chart is
available on the Centers for Disease Control and Prevention’s
website (15).
Antimicrobial Dressings
In the 2017 Centers for Disease Control and Prevention’s
updated guidelines, chlorhexidine-impregnated sponge dress-
ings are recognized as an alternative to ointments for
prophylactic use in short-term, nontunneled catheters
(43). These recommendations were on the basis of studies
performed in hospitalized patients not on hemodialysis.
Chlorhexidine is a nonantibiotic antimicrobial agent; there-
fore, the risk of selection for resistant organisms is minimal.
Chlorhexidine-impregnated dressings were associated
with a 70% reduction in bloodstream infection rates
(44,45). Data from studies performed in catheters used
for hemodialysis are conflicting (Table 1) (46,47). A study
comparing chlorhexidine-impregnated sponge dressing
with a transparent dressing at the catheter exit site found
no difference in bloodstream infection (46). In contrast, in a
recent quality improvement project a 50% reduction in
bloodstream infection was reported using chlorhexidine-
impregnated transparent dressings (changed weekly) com-
pared with the control group using dry gauze dressings
with antibiotic ointment applied to the catheter exit site
(changed three times weekly) (47). The weekly cost per
patient of the chlorhexidine dressing regimen was twice
that of the standard dressing, which may be offset by
overall cost-savings from a reduction in bloodstream
infections. Unfortunately, although a reduction in blood-
stream infection saves overall health care costs, the
savings are not realized by the dialysis provider.
Interventions Targeting the Catheter Hub and Lumen
Hub Devices
Data regarding catheter hub devices on bloodstream
infection outcomes are provided in Table 2 (48–51). There
are two published studies using a neutral-valve catheter
hub connector, which is changed weekly and locked with
either saline or heparin. The first was a small study in which
bloodstream infection rates did not statistically differ be-
tween neutral-valve connector with saline lock and stan-
dard catheter caps locked with citrate (concentration 46.7%)
(48). The second study was a large, retrospective trial that
reported a small reduction in the use of intravenous
antibiotics with the neutral-valve connector, but no differ-
ence in bloodstream infection rates (49).
Another novel hub device contains a chlorhexidine-
coated rod that extends into the catheter lumen (50,51). It
is changed with each hemodialysis session and used with a
heparin lock. In a prospective, cluster-randomized trial,
the use of the chlorhexidine cap was associated with a
significant reduction in the rate of positive blood culture
episodes (56%) and in hospital admissions for bloodstream
infections (40%) over a 1-year follow-up period, when
compared with standard caps (50). A recently published,
prospective, cluster-randomized trial compared blood-
stream infection rates between hemodialysis facilities using
the chlorhexidine cap to a neutral-valve connector with
disinfecting caps containing 70% isopropyl alcohol (51).
The use of the chlorhexidine cap was associated with a 63%
reduction in bloodstream infection compared with the
neutral-valve connector plus 70% isopropyl alcohol cap.
The chlorhexidine cap has been approved by the US Food
and Drug Administration for use in hemodialysis catheters,
and has recently replaced the neutral-valve connector hub
device in some units operated by large dialysis organi-
zations in the United States. The cost of chlorhexidine-
coated rod hub devices varies according to the volume
purchased, and is $6 per pair if purchased directly in
small quantities. Hymes et al. (50) argue that the upfront
cost of the chlorhexidine-coated rod hub device may be
offset by reducing the total economic effect of catheter-
associated bloodstream infections, and project that the
estimated savings to dialysis providers and Medicare
would be $2400 and $16,000 per episode, respectively.
Antimicrobial Lock Solutions
Antimicrobial lock solutions are highly concentrated
antiseptic agents that are instilled in the catheter when
the catheter is not in use, thereby targeting the intraluminal
route of entry (52–86). An antiseptic agent is needed to
prevent colonization and biofilm formation, thereby re-
ducing catheter-associated bloodstream infections. Anti-
septic catheter locking agents may consist of an antibiotic
or a nonantibiotic solution, and both types of catheter locks
have been shown to effectively reduce the incidence of
catheter-associated bloodstream infections in clinical trials
(Table 3). The routine use of an antibiotic-containing
catheter lock for prevention of bloodstream infections in
hemodialysis may result in the emergence of resistant
organisms, and has led to the development of safer, nonan-
tibiotic locks. The second component added to most antimi-
crobial locks is an anticoagulant, used to prevent catheter
dysfunction. Heparin promotes biofilm formation, whereas
citrate in concentrations in concentrations $0.2% prevents
biofilm formation, making citrate advantageous (87).
Antibiotic Locks
A variety of antibiotic-containing locking agents have
been studied for the prevention of catheter-associated
bloodstream infection in the hemodialysis setting (Table 3)
(52–70). The current Centers for Disease Control and
Prevention recommendations are for the limited use of
prophylactic antimicrobial lock solutions in catheter-
dependent patients on hemodialysis who have a history
of multiple bloodstream infections (15). The prophylactic
use of combination antibiotic-anticoagulant catheter lock
solutions is associated with a significant reduction in
bloodstream infections (range 50%–100% reduction). The
antibiotics used as a catheter locking-solution in these trials
were gentamicin, tobramycin, minocycline, cefotaxime,
vancomycin, cefazolin, and trimethoprim, with gentamicin
 CJASN 15: 132–151, January, 2020
Table 2. Hub devices used for hemodialysis catheters

Standard
Definition of Definition of
Rate Ratio
Study N Methods Bloodstream Bloodstream Hub Device Control Outcome P Value Concerns
(95% CI)
Infection Infection
Used

Bonkain 66 Prospective, No Same organism Neutral valve Standard cap1 Composite of 0.16 (0.02 0.06 No difference,
et al. (48) nonblinded, in two blood connector1 trisodium catheter to 1.38) small
randomized samples from saline lock citrate dysfunction underpowered
trial catheter with (46.7%) lock or study
clinical bloodstream
suspicion infection
Brunelli 17,145 Retrospective, No (1) IV antibiotics Neutral valve Standard cap1 a) IV Antibiotic a) 0.87 a) ,0.001; Retrospective
et al. (49) observational started; (2) connector1 heparin lock start (0.82 to b) 0.34 study
analysis receipt of saline lock b) Bloodstream 0.93);
antibiotics infection b) 0.95
course; (3) (0.88 to
positive blood 1.09)
cultures
Hymes 2470 Prospective, No Positive blood Chlorhexidine Standard cap1 a) Bloodstream a) 0.44 a) 0.01 Cost
et al. (50) cluster- cultures cap1 heparin lock infection rate (0.23 to b) 0.6
randomized, reported heparin lock b) IV Antibiotic 0.83);
comparative start b) 0.9
effectiveness (0.74 to
trial 1.19)
Brunelli 1671 Prospective, Yes NHSN (2) Chlorhexidine NVC1 Bloodstream 0.37 (0.20 0.003 Cost
et al. (51) cluster- cap1 70% infection to 0.68)

Preventing Bloodstream Infections in Hemodialysis, Fisher et al.

randomized, heparin lock isopropanol
open-label alcohol cap
trial

95% CI, 95% confidence interval; IV, intravenous; NHSN, National Healthcare Safety Network.

139
 140
Table 3. Antimicrobial locking solutions used for hemodialysis catheters

CJASN
Standard
Definition of Definition of
Rate/1000
Study N Methods Bloodstream Bloodstream Antimicrobial Locking Solution Control Outcome P Value Concerns
Catheter-Days
Infection Infection
Used

Pervez 36 Prospective, No Fever or chills Gentamicin 20 mg/ml1 Heparin 1000 U/ml Bloodstream 0.62 versus 2.11 N/A Resistance not
et al. (52) randomized without an citrate 4.67% infection measured
study alternate source
of infection
Dogra et al. 83 Double-blind, Yes CDC/IDSA (10) Gentamicin 27 mg/ml1 Heparin 5000 U/ml Bloodstream 0 0.3 versus 4.2 ,0.001 Vestibular toxicity,
(53) randomized trial citrate 1% infection resistance not
measured
McIntyre 50 Prospective, Yes CDC/IDSA (10) Gentamicin 5 mg/ml1heparin Heparin 5000 U/ml Bloodstream 0.3 versus 4 0.02 Resistance not
et al. (54) randomized, 5000 U/ml infection measured
controlled trial
Nori 30 Prospective, open- Yes CDC/IDSA (10) Gentamicin 4 mg/ml1 Heparin 5000 U/ml Bloodstream 0 versus 4 0.008 Resistance not
et al. (55) label, citrate 3.13% infection measured
randomized,
controlled trial
Venditto 265 Prospective, No Two positive Gentamicin (N/A) Heparin (units N/A) Bloodstream 0.4 versus 2.9 0.06 Resistance not
et al. (56) observational trial blood cultures 1heparin infection measured
from peripheral
or catheter in a
symptomatic
patient with
fever .38°C
with no other
apparent source
of infection
Landry 1410 Retrospective chart Yes CDC/IDSA (12) Gentamicin 4 mg/ml1 Historical controls Bloodstream 0.83–1.2 versus 17.0 N/A 4 yr study, gentamicin
et al. (57) review after heparin 5000 U/ml before introduction infection resistance observed
initiation of a unit of locks in 32%. Bloodstream
protocol infection (coagulase-
negative
staphylococci n513,
Enterococcus n57,
Streptococcus n52,
Staphylococcus
aureus n51)
Fernández- 101 Prospective, No Clinical Gentamicin 5 mg/lumen None Bloodstream 0.11 N/A 7 yr study, no
Gallego observational improvement (approximately 1.5 mg/ml) infection and resistance for
et al. (58) study after antibiotics 1heparin 100 U bacterial pathogens
in patients with resistance to “normally sensitive
a fever and with gentamicin to gentamicin”, two
positive blood cases of MRSA
cultures taken resistant to
from the circuit, gentamicin
excluding other
possible
infection sites
Moran 303 Randomized, No Presence of a Gentamicin 0.32 mg/ml1 Heparin 1000 U/ml Bloodstream 0.28 versus 0.91 0.003 4.5 yr study, no change
et al. (59) prospective, positive blood citrate 4% infection in gentamicin
single-blinded, culture resistance
multicenter trial obtained from
catheter,
associated with
fever or chills or
hypotension
Moore 555 Prospective, Yes CDC/IDSA (12) Gentamicin 0.32 mg/ml1 Heparin 1000 U/ml a) Bloodstream a) 0.45 versus 1.68 a) 0.001 3 yr study, reduction
et al. (60) multicenter, citrate 4% infection b) 10% versus 18% b) 0.001 in gentamicin
observational b) Mortality HR 0.32 (0.14–0.75) resistance by
cohort study approximately 50%
(P50.01)
 CJASN 15: 132–151, January, 2020
Table 3. (Continued)
Standard
Definition of Definition of
Rate/1000
Study N Methods Bloodstream Bloodstream Antimicrobial Locking Solution Control Outcome P Value Concerns
Catheter-Days
Infection Infection
Used

Goh 64 Single-center, Yes NHSN (2) a) Gentamicin 5 mg/lumen a) Heparin 1000 U/ml Bloodstream a) 0.66 versus 1.42 0.001 Resistance not
et al. (61) retrospective (approximately 1.5 mg/ml) b) Heparin 1000 U/ml infection RR 0.46 (0.30 to 0.72) measured
cohort study 1 Heparin 1000 U/ml b) 0.16 versus 1.42
b) Gentamicin 1Citrate RR 0.11 (0.05 to 0.22)
Onder 43 Single-center, No Positive blood Tobramycin 5 mg/dl1 Heparin 5000 U/ml Bloodstream 6.2 versus 16.8 0.2 Resistance not
et al. (62) retrospective culture from the tissue plasminogen activator infection measured
cohort study catheter with or 1 mg/ml
without
positive
peripheral
blood culture
with systemic
symptoms
(fever, chills,
vomiting,
hypotension)
and no other
identified
source of
infection
Bleyer 60 Single-center, No Catheter Minocycline 3 mg/ml1 Heparin (dose N/A) Bloodstream 0 versus 0.47 0.35 Resistance not
et al. (63) double-blind, colonization EDTA 30 mg/ml infection measured
randomized, plus a
controlled trial peripheral
blood culture
growing the
same organism
Campos 204 Multicenter, open- Yes KDOQI and CDC Minocycline 3 mg/ml1 Heparin 5000 U/ml Bloodstream 1.1 versus 4.3 0.005 Resistance not
et al. (64) label, (8,10) EDTA 30 mg/ml infection measured

Preventing Bloodstream Infections in Hemodialysis, Fisher et al.

randomized,
controlled trial
Saxena and 96 Prospective, case- Yes CDC (9) Cefotaxime 10 mg/ml1 Heparin 5000 U/ml Bloodstream 1.65 versus 3.13 N/A Resistance not
Panhotra control study heparin 5000 U/ml infection measured
(65)
Saxena 113 Single-center, Yes CDC (9) Cefotaxime 10 mg/ml1 Heparin 5000 U/ml Bloodstream 1.44 versus 3.15 ,0.001 Resistance not
et al. (66) double-blind, heparin 5000 U/ml infection measured
randomized,
controlled trial
Al-Hwiesh 63 Single-center, Yes CDC (9) Vancomycin 25 mg/ml1 Heparin 5000 U/ml Bloodstream 4.54 versus 13.11 0.05 Resistance not
and Abdul- randomized, gentamicin 40 mg/ml1 infection measured
Rahman controlled trial heparin5000 U/ml
(67)
Kim 120 Single-center, Yes CDC (10) Cefazolin 10 mg/ml1 Heparin 1000 U/ml Bloodstream 0.44 versus 3.12 0.03 Resistance not
et al. (68) double-blind, gentamicin 5 mg/ml1 infection measured
randomized, heparin 1000 U/ml
controlled trial

141
 142
Table 3. (Continued)

CJASN
Standard
Definition of Definition of
Rate/1000
Study N Methods Bloodstream Bloodstream Antimicrobial Locking Solution Control Outcome P Value Concerns
Catheter-Days
Infection Infection
Used

Rijnders 270 Multicenter, open- No Clinical signs or Trimethoprim 5 mg/ Heparin 5000 U/ml Bloodstream 0.09 versus 0.41 ,0.03 Catheter dysfunction
et al. (69) label, evaluator- symptoms of ml1ethanol 25%1EDTA 3% infection
blinded, systemic
randomized, infection and
controlled trial one of the
following:
positive blood
culture in
combination
with
temperature
.38°C,
temperature
.37.5°C
(during
dialysis), rigors,
chills, malaise,
altered mental
status, or
hypotension
unresponsive to
fluids on
dialysis
Bueloni 145 Multicenter, No Presence of at least Cefazolin 12 mg/ml1 Taurolidine 1.35% a) Bloodstream a) 0.79 versus 1.1 0.01 Significantly higher
et al. (70) open-label, one of the signs gentamicin 7 mg/ml1 1citrate 4%1heparin infection rate of MRSA exit-
nonrandomized or symptoms of heparin 500 U/ml 500 U/ml b) Catheter b) 49% versus 53% 0.85 site infections with
trial infection, such removal cefazolin1gentamin
as fever, lock
tremors or
hypotension
without
another
apparent focus
of infection,
with a positive
culture if one is
performed
Allon (71) 50 Prospective, case- No Positive Taurolidine 1.35%1 citrate 4% Heparin 5000 U/ml Bloodstream 0.6 versus 5.9 ,0.001 Catheter dysfunction
control study peripheral infection
blood cultures
in a febrile
patient
Betjes and 58 Single-center, No Symptomatic Taurolidine 1.35%1 citrate 4% Heparin 5000 U/ml Bloodstream 0 versus 2.1 0.05 Catheter dysfunction
van randomized, patient with a infection
Agteren controlled trial positive
(72) bacterial blood
culture drawn
from the
dialysis
catheter with no
other apparent
source of
infection
Solomon 110 Multicenter, double- No A single positive Taurolidine 1.35%1 citrate 4% Heparin 5000 U/ml Bloodstream 1.4 versus 2.4 0.1 Catheter dysfunction
et al. (73) blind, blood culture infection
randomized,
controlled trial
 CJASN 15: 132–151, January, 2020
Table 3. (Continued)
Standard
Definition of Definition of
Rate/1000
Study N Methods Bloodstream Bloodstream Antimicrobial Locking Solution Control Outcome P Value Concerns
Catheter-Days
Infection Infection
Used

Solomon 174 Prospective, cohort No A single positive Taurolidine 1.35%1citrate 4% a) Heparin 5000 U/ml a1) Bloodstream a1) 1.33 versus 3.25 a1) ,0.001 Cost
et al. (74) study compared blood culture 1heparin 5000 U/ml b) Taurolidine infection a2) RR 1.4 (0.5 to 3.9) a2) 0.5
with historical 1.35%1 Citrate 4% a2) First use of b1) 1.33 versus 1.22 b1) ,0.001
controls thrombolytic b2) RR 0.2 (0.06 to 0.5) b2) ,0.001
b1) Blood stream
infection
b2) First use of
thrombolytic
Winnicki 106 Multicenter, No A positive Taurolidine 1.35%1citrate 4% Citrate 4% a) Bloodstream a) 0.67 versus 2.7 0.003 Cost
et al. (75) randomized, bacterial blood 1heparin 5000 U/ml twice a infection
controlled trial culture drawn wk with taurolidine 1.35% b) Catheter b) 18.7 versus 44.3 0.001
from the 1citrate 4%1urokinase dysfunction
dialysis 25,000 U once a wk
catheter in a
symptomatic
patient with
fever or chills
associated with
dialysis and no
apparent other
source of
infection
Al-Ali 164 Multicenter, single- No Same organism Taurolidine 1.35%1citrate 4% Taurolidine 1.35% a) Catheter a) 0 versus 3 0.08 Cost
et al. (76) blinded, obtained from 1heparin 5000 U/ml twice a 1citrate 4%1heparin removal
randomized, blood aspirated wk with taurolidine 1.35% 5000 U/ml three for bloodstream
controlled trial through the 1citrate 4%1urokinase times a wk infection b) 1 versus 4 0.17
catheter hub 25,000 U once a wk b) Catheter
and from blood removal c) 5 versus 12 0.61
sample for dysfunction

Preventing Bloodstream Infections in Hemodialysis, Fisher et al.

obtained from c) Need for tissue
peripheral vein plasminogen
with no other activator use
identifiable
cause of
infection
Weijmer 291 Multicenter, double- No Fever or cold chills Trisodium citrate 30% Heparin 5000 U/ml Bloodstream 1.1 versus 4.1 ,0.001 —-
et al. (77) blind, not during a infection
randomized, dialysis
controlled trial treatment and
at least one
positive blood
culture and no
other obvious
cause of
infection
Winnett 413 Multicenter, case- No Fever and one Trisodium citrate 46.7% Heparin 5000 U/ml Bloodstream 0.81 versus 2.13 ,0.001 Not FDA approved,
et al. (78) control study positive blood infection excessive overfill
culture result may result in death
with no other
obvious source
of infection
Power 232 Single-center, No Symptomatic Trisodium citrate 46.7% Heparin 5000 U/ml Bloodstream 0.7 versus 0.7 0.9 Lack of efficacy
et al. (79) randomized, febrile patient infection
controlled trial with positive
blood cultures

143
 144
Table 3. (Continued)

CJASN
Standard
Definition of Definition of
Rate/1000
Study N Methods Bloodstream Bloodstream Antimicrobial Locking Solution Control Outcome P Value Concerns
Catheter-Days
Infection Infection
Used

Venditto 265 Single-center, Yes CDC (10) Trisodium citrate 46% Heparin (n/a) Bloodstream 3.4 versus 2.9 0.6 Lack of efficacy
et al. (56) prospective, infection
cohort study
compared with
historical controls
Correa 464 Single-center, Yes CDC (10) Trisodium citrate 30% Heparin 5000 U/ml Bloodstream Rate ratio 1.53 — Lack of efficacy
Barcellos double-blind, infection (95% CI,
et al. (80) randomized, 0.9–2.58)
controlled trial
Hemmelgarn 225 Multicenter, double- Yes Health Canadian Recombinant tissue Heparin 5000 U/ml Bloodstream 0.4 versus 1.37 0.02 Cost
et al. (81) blind, 1997 Guidelines plasminogen activator once a infection
randomized, (7) wk 1heparin 5000 U/ml
controlled trial twice a wk
Maki 407 Multicenter, No Definite catheter- Citrate 7%1methylene Heparin 5000 U/ml Bloodstream 0.24 versus 0.82 0.005 Not FDA approved
et al. (82) open-label, related: fever blue1methylparabens/ infection
randomized, with propylparaben
controlled trial concordant
positive blood
cultures drawn
from the
catheter and a
peripheral vein
or a peripheral
blood culture
and a
concordant
exit-site culture;
concordant
catheter-related
bloodstream
infection: two
concordant
positive blood
cultures but
with
temperature
not exceeding
38.0°C;
probable
catheter-related
bloodstream
infection: fever
with one
positive blood
culture
Broom et al. 49 Multicenter, Yes KDOQI (8) Ethanol 70% once a Heparin 1000 U/ml Bloodstream 0.28 versus 0.85 0.12 Small proof-of-concept
(83) open-label, wk1heparin 1000 U/ml infection study. potential
randomized, twice a wk symptoms,
controlled trial hepatotoxicity and
mechanical changes
in catheter polymer
using high-dose
ethanol
 CJASN 15: 132–151, January, 2020
Table 3. (Continued)
Standard
Definition of Definition of
Rate/1000
Study N Methods Bloodstream Bloodstream Antimicrobial Locking Solution Control Outcome P Value Concerns
Catheter-Days
Infection Infection
Used

Sofroniadou 103 Single-center, Yes CDC/IDSA (11) Ethanol 70%1heparin 2000 U/ Heparin 2000 U/ml Bloodstream 2.53 versus 6.7 0.04 Short-term study,
et al. (84) randomized, ml infection potential symptoms,
controlled trial hepatotoxicity and
mechanical changes
in catheter polymer
using high-dose
ethanol
Vercaigne 40 Multicenter, No Two or more Ethanol 30%1citrate 4% Heparin 1000 U/ml Bloodstream 0 versus 0.75 0.12 Small pilot study
et al. (85) randomized, positive blood infection
controlled trial cultures of the
same organism
from any source
(peripheral or
intravascular
device cultures)
from a patient
with no other
source of

Preventing Bloodstream Infections in Hemodialysis, Fisher et al.

infection
El-Hennawy 452 Single-center, Yes CDC/IDSA (10) Sodium bicarbonate (7.5% or Normal saline 0.9% a) Bloodstream a) 0.17 versus 2.6 0.01
et al. (86) open-label, 8.4%) infection
randomized, b) Catheter loss b) 0.4% versus 0.6% ,0.001
controlled trial due to
thrombosis c) 0.4% versus 6.6% ,0.001
c) Catheter loss
due to
bloodstream
infection

N/A, not available; CDC, Centers for Disease Control and Prevention; IDSA, Infectious Disease Society of America; MRSA, methicillin resistant Staphylococcus aureus; NHSN, National
Healthcare Safety Network; KDOQI, Kidney Disease Outcomes Quality Initiative; FDA, Food and Drug Administration.

145
 146
Table 4. Intranasal mupirocin Staphylococcus decolonization protocols used for the prevention of blood stream infections in the hemodialysis setting

CJASN
Standard
Definition of Definition of Staphylococcus
Treatment
Study N Methods Bloodstream Bloodstream Protocol Outcome aureus Infection P Value Concerns
Group
Infection Infection Rate/Patient yr
Used

Kang 19 Open, No Not reported Mupirocin twice MRSA nasal Bloodstream 1 Bloodstream N/A Potential for
et al. (95) prospective per d for 5 d for carriers infection infection resistance
cohort study 6 mo
Lederer 16 Open, No Not reported Mupirocin three MRSA nasal Bloodstream 0 N/A Potential for
et al. (96) prospective times per d for carriers infection resistance
cohort study 5 d for 12 mo
Kluytmans 226 Open, No Not reported Mupirocin twice Staphylococcus Bloodstream 0.25 versus 0.04 ,0.001 No resistance
et al. (97) prospective per d for 5 d, aureus nasal infection observed
cohort study then weekly carriers
compared for 6 mo
with historical
controls
Boelaert 80 Open, No Positive blood Mupirocin three Staphylococcus Bloodstream 0.097 versus 0.008 One mupirocin-
et al. (98) prospective cultures (two times per d for aureus nasal infection 0.024 resistant
cohort study out of six 5 d, then three carriers organism
compared bottles) times per wk identified
with historical for 6 mo, then
controls weekly for 18
mo
Boelaert 35 Single-center, No Not reported Mupirocin All Bloodstream 0.489 versus ,0.05 No resistance
et al. (99) randomized, versus placebo Staphylococcus infection 0.115; 1 observed
double-blind, three times per aureus nasal bloodstream
placebo- d for 14 d, then carriers infection in
controlled trial three times per mupirocin-
wk for 9 mo treated group

MRSA, Methicillin resistant Staphylococcus aureus; N/A, not available.

CJASN 15: 132–151, January, 2020
being the most commonly studied. Early trials, which used
a relatively high-dose gentamicin (4–27 mg/ml) lock,
reported that gentamicin alone was as effective as other
antibiotic combinations and had a broad spectrum of activ-
ity against both Gram-positive (including Staphylococcus
aureus) and Gram-negative bacteria at drug levels achieved
in the catheter lumen. The emergence of gentamicin re-
sistant strains of Enterococcus and Staphylococcus have been
associated with serious episodes of bloodstream infection,
and one death has been reported using a gentamicin (4 mg/ml)
lock (57). In more recent studies, using a lower concentra-
tion of gentamicin lock (range 0.32–1.7 mg/ml), no genta-
micin resistance has been observed over long follow-up
periods, and in one study the rate of resistance declined,
although an explanation for this finding is unclear (58–60).
In one study, a low-dose gentamicin (0.32 mg/ml)-citrate
(4%) lock was associated with significant reduction in
bloodstream infections, infection-related hospitaliza-
tions, and patient mortality (60). If a gentamicin lock is
used, a low-dose formulation (0.32 mg/ml) is recommended.
In a recent, retrospective, cost-effectiveness analysis from
New Zealand, the routine use of a gentamicin-containing
catheter lock was associated with significantly lower rates of
catheter-associated bloodstream infection, which translated
to significant cost-savings (61). Inpatient costs associated
with the management of catheter-associated bloodstream
infection were NZ$27,792 per 1000 catheter-days (heparin-
only lock) versus NZ$10,608 (gentamicin-heparin) and
NZ$1898 (gentamicin-citrate). Concerns about antibiotic
resistance associated with prophylactic use of antibiotic
catheter lock solutions have prevented their adoption by
consensus guidelines.
Nonantibiotic Locks
In an attempt to avoid the development of antimicrobial
resistance, more recent focus has been on the development
of nonantibiotic catheter lock solutions (Table 3) (56,70–86).
Taurolidine is a broad spectrum, antimicrobial agent that
reduces biofilm formation and has a low-risk bacterial
resistance. Although taurolidine-citrate 4% antimicrobial
lock is associated with a reduction in bloodstream infec-
tions, when compared with heparin lock, the need for
thrombolytic therapy is increased (71–73). Newer prepara-
tions, which have added heparin or a thrombolytic agent to
taurolidine-citrate 4%, are associated with improved rates of
catheter dysfunction and bloodstream infections (70,74–76)
A taurolidine-based, nonantibiotic lock (taurolidine-
citrate-heparin) has been shown to be as efficacious as
an antibiotic-containing lock (containing cefazolin-gentamicin-
heparin) for preventing catheter-associated bloodstream
infections (70). In this study, a higher rate of resistant
strains of methicillin-resistant organisms was reported
in the antibiotic lock group. At present, taurolidine con-
taining catheter locks are widely used in Europe, but have
not yet been approved for use in the United States. A large,
multicenter, randomized trial of a taurolidine-citrate-heparin
catheter lock was recently completed and results are available
in abstract form, however publication of the manuscript is
pending (89).
Citrate 4% locks, when used alone, are not associated
with reduction in bloodstream infection rates. The efficacy
of catheter-associated bloodstream infection reduction
Preventing Bloodstream Infections in Hemodialysis, Fisher et al. 147
using medium- and high-dose citrate (30%–47%) antimicro-
bial locks are conflicting: two studies reported a reduction in
bloodstream infection, and three studies reported no advan-
tage of citrate over heparin (Table 3) (56,77–80). Trisodium
citrate antimicrobial locks, in concentrations of between
30% and 47%, were withdrawn by the US Food and Drug
Administration after one patient death, presumably because
of overfill of the catheter (88). There are additional reports of
symptomatic paresthesia and cardiac and embolic compli-
cations due to precipitation of trisodium citrate (30%–47%) in
the catheter, and an increase in thrombolytic requirements
for catheter dysfunction (90).
Recombinant tissue plasminogen activator used weekly
as a catheter locking solution, with heparin twice weekly,
has been shown to be associated with a significant reduction
in bloodstream infection (approximately 67%) and catheter
dysfunction (approximately 50%) (Table 3) (81). Tissue
plasminogen activator is not in routine use for bloodstream
infection prophylaxis because of excessive immediate costs;
however, when counterbalanced by the anticipated reduced
cost of bloodstream infection–associated hospitalizations, a
decision analysis model calculated that there would be no
significant difference in the mean overall cost (91). Again,
under the United States health care model, prophylactic
tissue plasminogen activator would increase the cost of
providing hemodialysis, but the expected savings in re-
ducing catheter-associated bloodstream infection would
not be shared with the hemodialysis provider.
A novel, chelator-based, nonantibiotic antimicrobial
lock containing citrate 7%-methylene blue-methylparabens-
propylparaben was associated with a significant reduction
(approximately 70%) in bloodstream infections and in
catheter removal for dysfunction (Table 3) (82). This chelator-
based antimicrobial locking solution was not approved
by the US Food and Drug Administration.
Ethanol antimicrobial lock has also been studied for use
in hemodialysis catheters (Table 3) (83–85). The potential
advantages of ethanol include its low cost, reduction of
biofilm, lack of resistance, and its broad antimicrobial
and antifungal properties. In a small study, ethanol lock
70% used once weekly (heparin 1000 U twice weekly)
was associated with a reduction in bloodstream infections
when compared with heparin lock alone (83). A larger,
prospective, randomized study of ethanol 70% plus heparin
2000 U/ml lock instilled three times a week compared with
heparin alone reported a significant reduction in catheter-
associated bloodstream infections in the ethanol lock group
(84). Ethanol lock in high concentrations (70%–100%) has
been associated with catheter dysfunction, reports of head-
aches, nausea, dizziness, fatigue, hepatotoxicity, and struc-
tural changes in the catheter integrity, including elution of
molecules from the catheter polymers (92). Ethanol lock
in a concentration of 30% is not associated with alterations
in carbothane catheter integrity (93). In a small study, a lock
containing ethanol 30%-citrate 4% was associated with a
reduction in the rate of catheters removed for dysfunction
compared with heparin (85). The only catheter-associated
bloodstream infection episode occurred in the heparin
lock group. One silicone catheter was found to have a crack
in the ethanol 30% group. Ethanol locks (30%) should only be
used with compatible catheters, and the ethanol should be
withdrawn before initiation of hemodialysis (92,93). Larger,
148 CJASN
well powered clinical trials using low concentrations of ethanol
30% locks are needed.
Finally, there was a recently published prospective trial
comparing the use of a sodium bicarbonate lock solution
(8.4% or 7.5%) with a control group using saline (0.9%) for
use in hemodialysis catheters (Table 3) (86). Sodium bi-
carbonate lock was associated with a significant reduction
in catheter-associated bloodstream infections, and was
shown to prevent catheter loss caused by bloodstream
infections and thrombosis. Bicarbonate exerts antimicro-
bial activity against various bacteria, including S. aureus,
Pseudomonas aeruginosa, and Escherichia coli, by potentiating
the antimicrobial properties of mammalian antimicrobial
peptides (cathelicidins and defensins), components of in-
nate immunity. The mechanism appears to be bicarbonate’s
ability to stimulate global changes in bacterial cell walls,
gene expression, and membrane permeability. Alkaline
solutions interfere with Staphylococcus adherence and
impede biofilm formation (94). Sodium bicarbonate has
been shown to have anticoagulant properties in small in
vitro studies. By chelating calcium ions, similar to citrate,
sodium bicarbonate impairs conversion of fibrin to fibrin
clot, and prolongs prothrombin and thrombin clotting times
(95). Sodium bicarbonate lock appears to be a safe and
cost-effective intervention to reduced catheter-associated
bloodstream infections in this single study. The potential
advantage of a sodium bicarbonate lock is its anticipated
low cost and safety profile. The findings of this study
are promising, and larger, well powered studies further
evaluating the efficacy of sodium bicarbonate (8.4%) lock
in hemodialysis catheters are needed.
In summary, nonantibiotic antimicrobial lock solutions may
have an important future role as novel, low-risk approaches to
catheter-associated bloodstream infection prevention. Studies
combining nonantibiotic antimicrobial locks with chlorhex-
idine antimicrobial hub devices have not been performed,
and so it is unclear if this combination offers additional
efficacy.
Interventions Utilizing S. Aureus Decolonization
Protocols
Intranasal Mupirocin Ointment
S. aureus nasal carriage is associated with increased
risk of hemodialysis catheter–associated bloodstream infec-
tions. Decolonization protocols performed in the hemodi-
alysis setting are described in Table 4 (96–100). Intranasal
mupirocin prophylaxis was associated with a 94%–100%
efficacy for nasal decolonization and a significant reduc-
tion in the incidence of S. aureus catheter-associated blood-
stream infections. S. aureus decolonization protocols are
efficacious and cost-effective (101). Bloom et al. (101)
performed a decision analysis evaluating clinical out-
comes and cost-effectiveness of three possible manage-
ment strategies in patients on hemodialysis (1): screen
for S. aureus nasal carriage every 3 months and treat
those with a positive test result with mupirocin; (2) treat
all patients weekly with mupirocin; or (3) no preven-
tion strategy, treat infection only. Eliminating S. aureus
nasal carriage with mupirocin markedly reduced the
number of infections (approximately 50% reduction) and
reduced health care expenditures relative to treating
infections when they occur. The potential annual savings
to Medicare (in 1996 US dollars) were projected to be
$784,000–$1,117,000 per 1000 patients on hemodialysis,
depending on which prevention protocol was used. Mupirocin
has not been widely adopted in the hemodialysis setting
because of concerns of emerging resistance, although reports
of mupirocin resistance have largely been conducted in
hospitalized patients and with long term mupirocin use.
The use of S. aureus decolonization protocols in catheter-
dependent patients on hemodialysis should be revisited.
Conclusion
Catheter avoidance is the obvious best strategy for re-
ducing bloodstream infection episodes. Interventions such
as early referral of patients to nephrologists, multidisciplin-
ary teams, and vascular access coordinators who provide
education to patients; implantation of early-cannulation
arteriovenous grafts for hemodialysis; and urgent-start
peritoneal dialysis have been shown to be effective at
decreasing catheter use. However, in those patients where
the use of a catheter is unavoidable, implementation of a
multitargeted approach to prevent infections is imperative.
Active patient engagement and staff education about
appropriate catheter care, and improved adherence to the
recommended Centers for Disease Control and Prevention’s
core interventions is essential. The development of elec-
tronic chair-side checklists/audit tools for catheter care may
also improve staff antiseptic technique and patient education
in the hemodialysis unit. Novel interventions for catheter-
associated bloodstream infection prophylaxis include the
following: (1) a chlorhexidine-impregnated transparent exit-
site dressing; (2) a chlorhexidine-coated rod hub device; and
(3) an antimicrobial lock, preferably one without an anti-
biotic. There may be an important, underutilized role for
S. aureus nasal decolonization protocols using mupirocin
for patients on hemodialysis. A combination of these inter-
ventions may be optimal. Additional factors to consider when
selecting a prophylactic strategy include efficacy, cost, poten-
tial for adverse effects such as catheter dysfunction, and local
availability/device approval by regulatory agencies. Finally,
identifying barriers to safe practices in the hemodialysis
setting, using human factors systems engineering, will no
doubt be invaluable for reducing infections in the future.
Disclosures
Dr. Allon reports receiving personal fees as a consultant for
CorMedix. Dr. Allon is also the Editor-in-Chief of American Society
of Nephrology open-access journal Kidney360. Dr. Golestaneh
reports grant support from the Cardiorenal Society of America,
Horizon Pharmaceuticals, and Montefiore Care Management
Organization outside of the submitted work. Dr. Mokrzycki reports
stock ownership in Abbott Laboratories. Dr. Golestaneh and
Dr. Mokrzycki report positions as Clinical Events Committee
Members for Spyral Pivotal Hypertension On-Medications and
Spyral Pivotal Hypertension Off-Medications, sponsored by Med-
tronic. Dr. Abreo and Dr. Fisher have nothing to disclose.
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