Infection Control & Hospital Epidemiology (2019), 1–10

doi:10.1017/ice.2019.162

Review

Advances in the prevention and management of

central-line–associated bloodstream infections: The role of
chelator-based catheter locks
Anne-Marie Chaftari MD, George M. Viola MD, Joel Rosenblatt PhD, Ray Hachem MD and Issam Raad MD
Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas

Abstract
The proper functioning of central lines is imperative for the management of patients with cancer or on hemodialysis. However, these lifelines
can become infected and can malfunction.
Chelators such as citrate and EDTA have been widely studied alone or in combination with other antimicrobial agents in catheter lock sol-
utions to prevent catheter-related bloodstream infections and to maintain catheter patency. Given their anticoagulation, antiplatelet aggre-
gation, antibiofilm, antimicrobial activity, safety profile, as well as their low cost, chelators have long been considered alternatives to heparin
and a vital component of catheter lock solutions. In this review, we present a detailed summary of the properties of chelators and in vitro and in
vivo studies of chelator-containing lock solutions.
(Received 22 October 2018; accepted 11 December 2018)

Background
Lumens of vascular catheters require hydraulic locking between
uses to prevent air emboli from entering the bloodstream. The
most common antithrombogenic lock solution to inhibit clot for-
mation is heparin saline. Heparin acts by inhibiting thrombin acti-
vation thereby preventing fibrin formation. While heparin is
effective in preventing catheter clotting, serious adverse drug
effects have been encountered. One significant issue is immune-
mediated heparin-induced thrombocytopenia and heparin has also
been shown to stimulate biofilm formation of Staphylococcus and
Candida spp in a dose-dependent manner.1–3 Chelator-based lock
solutions provide alternative antithrombogenic catheter locks
avoiding the use of heparin.
Widespread adoption of safety bundles for reducing catheter
infections have been effective in reducing contamination of exter-
nal catheter surfaces with commensal skin organisms.4,5 Catheter
lumens, however, remain vulnerable to contamination and can be
sources of catheter-bloodstream infections.6–9 Antimicrobial cath-
eters with luminal antimicrobial surface treatments also help pro-
tect catheter luminal surfaces from microbial colonization but have
important limitations such as the duration of their antimicrobial
activity diminishing while the catheter is still in use.10 Catheter lock
solutions with added antimicrobial agents present a durable bul-
wark that protects against luminally sourced infection because
the lock solution can be replenished whenever lumens are accessed.
Author for correspondence: Anne-Marie Chaftari, MD, Anderson Cancer Center,
Infectious Diseases, Infection Control and Employee Health, 1515 Holcombe Blvd.
Unit 1460 Houston, TX 77030. Email: achaftari@mdanderson.org
Cite this article: Chaftari A-M, et al. (2019). Advances in the prevention and
management of central-line–associated bloodstream infections: The role of chelator-
based catheter locks. Infection Control & Hospital Epidemiology, https://doi.org/
10.1017/ice.2019.162
© 2019 by The Society for Healthcare Epidemiology of America. All rights reserved.
Chelators
Definition, types of chelators, and anticoagulant activity of
chelators
Chelators can be defined as ligands that bind metal ions or mole-
cules at 2 or more sites in the same ligand molecule.11 Chelators
have been used intravenously to treat metal ion poisoning (eg, lead,
iron, or hypercalcemia). Calcium is critical to clot formation
through the extrinsic pathway by mediating binding between tissue
factor and factor VII.12 Citrate and EDTA are the most popular
chelators used in catheter locks. They bind calcium and inhibit
blood from clotting.
Antimicrobial/biofilm disrupting activities of chelators
Metal ions serve critical structural roles in stabilizing the extracel-
lular matrix of microbial biofilms.13,14 Furthermore, key microbial
metabolic enzymes require metal ions to function properly.15
Chelators can exhibit antimicrobial activity by depriving microbes
of these essential metal ions, such as iron, cobalt, manganese,
nickel, copper, and zinc.15
Chelators used in catheter-lock solutions
Different chelators have been studied for use in catheter lock sol-
utions. The use of citrate and ethylene diamine tetra-acetic acid
(EDTA)–based antimicrobial lock solutions has been used most
commonly. Others that have been assessed include n-acetyl cys-
teine and antibiotics with chelating properties16 including tetracy-
clines17,18 and quinolones.19 Chemical properties of EDTA and
Citrate-based chelators, as well as studies utilizing them in catheter
lock solutions for the prevention and treatment of catheter-related
2 Anne-Marie Chaftari et al
bloodstream infections (CRBSI), are summarized in the following
sections.
EDTA-based catheter lock solutions
Each molecule of EDTA presents 6 cationic binding sites.20 The
molecular geometry provides binding for cobalt, iron, nickel, cop-
per, zinc, and other metal ions. Disodium EDTA, which has a pH
in the normal blood range, binds calcium, is well suited to be a
component of an antimicrobial catheter lock solution. Ionized
EDTA first performs its antimicrobial inhibitory functions, and
subsequently, the residual EDTA binds calcium and performs its
anticoagulant function. Significant doses of EDTA can cause hypo-
calcemia and other severe toxicities.21,22 In the Trial to Access
Chelation Therapy, 1,708 patients with prior history of myocardial
infarction were randomized to receive 40 infusions of a 500-mL
high-dose chelation solution that included 3 g of disodium
EDTA versus placebo for the reduction of cardiovascular events.23
A total of 52 chelation patients (6.2%) and 30 placebo patients
(3.5%) developed asymptomatic hypocalcemia (P = .008); only 1
patient developed hypocalcemia and muscle cramping. The pres-
ence of EDTA at safer, submicrobicidal or subinhibitory concen-
trations, or the presence of partially protonated EDTA (eg, the
diacidic, disodium EDTA salt) although not fully microbicidal,
can still provide anticoagulant activity and can synergistically
impair biofilm and microbial function in combination with other
potent antimicrobial agents.24,25 Several antimicrobial lock solu-
tion combinations have taken advantage of this synergy potential
and have combined potent antibiotics with disodium EDTA.
More potent, fully deprotonated tetrasodium EDTA has also
been studied as a combined single-agent anticoagulant-antimicro-
bial lock solution. At concentrations of 4%, it has antimicrobial
effects, and it has been able to eradicate in vitro biofilms of
Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia
coli, and Klebsiella pneumoniae following 21 hours of exposure.26,27
Several antibiotic EDTA combination catheter lock solutions have
been studied. Minocycline-EDTA (M-EDTA) has demonstrated
in vitro activity against S.epidermis, S. aureus, and CA: Candida
albicans biofilms with exposures of 24 hours.28 However, we have
found that in many cases, it is not possible to reliably remove
lumens from service for >2 hours for disinfection by locking.
Therefore, low concentrations of ethanol (25%) were added to
M-EDTA catheter lock solutions to accelerate disinfection of
catheter surfaces. This lock solution demonstrated the ability to
rapidly (within 2 hours) eradicate biofilms of MRSA, vancomycin-
resistant Enterococcus faecium (VRE), P. aeruginosa, Acinetobacter
baumanni, and Candida spp, while prescribing an ethanol concen-
tration below the 60% threshold to avoid mechanical damage to the
integrity of the catheter polymer, and below the 28% threshold
reported to cause protein precipitation in blood.29
The first successful use of the M-EDTA lock solution (Table 1)
for the prevention of central venous catheter (CVC)–related infec-
tions has been reported in 3 patients with recurrent bloodstream
infections.30 A cumulative of 40 CVC-related infections occurred
in these 3 patients during the pre–M-EDTA lock follow-up period
of 76 months, while the infection rate decreased to zero in the sub-
sequent 17 months of the M-EDTA intervention period (P = .01).
Subsequently, Chatzinkolau et al31 developed a prospective cross-
over study in which 48 pediatric control patients with cancer who
received heparin flushes were compared to 14 children who
received M-EDTA lock solutions. All patients were followed for
6 months and had an implantable venous-access port systems.
The M-EDTA group had more predisposing risk factors for infec-
tion compared to the heparin group: higher rate of hematological
malignancies (P = .05), longer duration of neutropenic (P = .03)
and longer duration of catheter placement (P = .001). None of
the patients in the M-EDTA group had any complications, whereas
10 infectious episodes occurred in the heparin group (2.23 infec-
tions per 1,000 catheter days).
Bleyer et al32 performed the first ramdomized controlled trial
(RCT), comparing 27 patients to receive heparin versus 30 patients
to receive M-EDTA lock solution. At 90 days, the rate of newly
placed catheter survival for hemodialysis was higher in the
M-EDTA compared to the heparin group (P = .07), mainly due
to thrombosis. Only 1 patient belonging to the heparin group
developed a CVC-related infection with Entrobacter aerogenes.
Although ≤52% of the patients had a surveillance blood culture
or CVC culture at the time of removal, the rate of catheter coloni-
zation was much higher in the heparin group, with 9 of 14 cultured
catheters being colonized versus only 1 of 11 catheters in the
M-EDTA group (P = .005). Campos et al33 proceeded with another
unblinded RCT in which 95 hemodialysis tunneled or nontunneled
catheters locked with heparin was compared to 92 catheters locked
with M-EDTA. The CRBSI rates were 4.3 per 1,000 catheter days in
the heparin group (19 cases) and 1.1 per 1,000 catheter days in the
M-EDTA group (5 cases; P = .005). That is, the 90-day CRBSI-free
survival was 91.3% in the M-EDTA group and 69.3% in the hep-
arin group.
Subsequently, João Luiz et al34 led a double-blinded RCT com-
paring heparin, trisodium citrate 30%, and M-EDTA locks. All
included 68 patients on hemodialysis, had less hydraulic resistance
while on the M-EDTA locks (0.9 events per 1,000 catheter days),
than the trisodium citrate (2.0 events per 1,000 catheter days), or
with the heparin locks (9.2 events per 1,000 catheter days;
P = .001). Except for 1 case of CRBSI in the trisodium citrate group,
no other bloodstream events or adverse reactions occurred.
Notably, Kanaa et al35 compared the sole use of heparin versus
EDTA lock solutions in a population undergoing hemodialysis.
This RCT revealed a significant improvement in the catheter col-
onization rate from 0.14 per 1,000 catheter days in the EDTA
group to 1.08 per 1,000 catheter days in the heparin group (IRR,
0.13; 95% CI, 0.003–0.94; P = .02). The CRBSI rate was relatively
similar with a 0.28 incidence rate in the EDTA group, and 0.68 in
the heparin group (P = .30). Thereafter, Nori et al,36 compared
in an open label, RCT, the use of heparin, M-EDTA, and gentami-
cin plus trisodium citrate antimicrobial lock solutions. The
demographics of patients requiring tunneled hemodialysis cathe-
ters and thrombolytics were similar (P > .10); however, the rate of
CRBSI was higher in the heparin group than the other 2 groups,
which were similar: 4, 0.4, and 0 episodes per 1,000 catheter days,
respectively.
Raad et al37 developed the first therapeutic pilot trial utilizing
systemic antimicrobials plus M-EDTA in 25% ethanol lock solu-
tion, administered for only 2 hours, for the salvage of infected
CVCs. In total, 30 enrolled patients were compared to a historical
well-matched control group of 60 patients treated with systemic
antimicrobials plus CVC removal. Although the antimicrobial lock
group (median, 11 days) received a shorter duration of appropriate
systemic antimicrobial therapy than the control group (median, 16
days; P = .0001), and the time between onset of bacteremia and
starting intervention (catheter removal [median, 2 days] vs lock
therapy [median, 4 days]) was significantly different (P = .0002),
the rate of infectious and mechanical complications favored the
antimicrobial lock group (0 vs 18%; P = .014).
 Infection Control & Hospital Epidemiology
Table 1. EDTA Chelator-Based Antimicrobial Catheter Lock Solutions for the Prevention or Treatment of Catheter-Related Infections

Rate of No. of Catheter

CLABSI/1000 Mechanical Failure
catheter days (Thrombosis or
Study Type of No. of Catheter or No. of Decrease Blood
Author/Year Type of Study Population Cathetera Intervention Patients Days patients P Value Flow) P Value
Raad 199730 Case report Recurrent CVC 1=2 patients 3 mg M þ 30 mg EDTA/mL 3 510 0 N/A 0 N/A
infections 2=1 patient
Chatzainikolaou Crossover Cancer 4 Heparin 48 4,481 2.23 .05 2 thrombosis >.99
200331 prospective
3 mg M þ 30 mg EDTA/mL 14 2,073 0 0
study
32
Bleyer 2005 RCT HD with new 1=9 patients Heparin 27 2,118 1 patient (RR, .35 At 90 days, 8 NS
CVC placements 2=48 patients 8.3%;) patients were
thrombosis free
(40%).
3 mg M þ30 mg EDTA/mL 30 2,336 0 At 90 days, 6
patients were
thrombosis free
(60%).
Nori 200636 RCT, HD 2=(new and Heparin 5,000 IU/mL 20 1,734 4 Heparin vs Thrombolytic use= 3 >.10
unblinded vintage HD gentamicin,
Gentamicin 4 mg/mL þ 3.13% 20 2,002 0 Thrombolytic use= 2
catheters) .008, heparin
Trisoidium citrate
vs M, .020
3 mg M þ 30 mg EDTA/mL 21 2,453 0.4 Thrombolytic use= 1
Feely 200777 Retrospective HD with 2 3 mg M þ 30 mg EDTA/mL (3 patients 4 1,697 1.18 .001 N/A N/A
chart review recurrent had received gentamicin 56 mg/mL/ (compared
bacteremia heparin 5,000 IU/mL flushes due to to historical
(incidence=6.61- discontinuation of minocycline) baseline
15.38) data).
Campos 201133 RCT, HD 1=135 patients Heparin 5,000 IU/mL 95 4,376 Overall 4.3. .005 Catheter dysfunction .31
unblinded 2=52 patients Nontunneled removed due to low
4.1. Tunneled flow 14 (3.2/1,000
4.8. days)
3 mg M þ 30 mg EDTA/mL 92 4,371 Overall 1.1. Catheter dysfunction
Nontunneled removed due to low
4.1. Tunneled flow 20 (4.6/1,000
4.8. days; p=0.31)
Kanaa 201535 RCT, part- HD 2=Subclavian Heparin 5,000 IU/mL 56 7,387 0.68 IRR, 0.40; Achieved adequate Achieved
blinded or internal 95% CI, 0.08– blood flow=75.3%. adequate blood
jugular 2.09; P=.30 Thrombolytic use=9 flow (P=.001).
patients Thrombolytic use
(P=.01)
4% tetra-sodium EDTA 59 7,306 0.28 Achieved adequate
blood flow, 66.8%
Thrombolytics, 22
patients (P=.01).
(Continued)

3
 4
Table 1. (Continued )

Rate of No. of Catheter

CLABSI/1000 Mechanical Failure
catheter days (Thrombosis or
Study Type of No. of Catheter or No. of Decrease Blood
Author/Year Type of Study Population Cathetera Intervention Patients Days patients P Value Flow) P Value
37
Raad 2016 Prospective, Patients with 1=27 patients Control: Systemic antimicrobial plus 60 N/A 7 patients 0.09 0 N/A
open-label, cancer (55/90 2=4 patients CVC exchanged developed an
salvage pilot patients with 3=41 patients infectious
study neutropenia). 4=18 patients complication
(12%)
Intervention: Systemic antimicrobials, 30 N/A 0 0
plus 1 mg/mL minocycline and 30 mg/
mL EDTA in 25% ethanol
Luiz 201734 RCT, blinded HD 2=Subclavian Heparin 1,000 IU/mL 23 N/A 0 .32 Hydraulic resistance: <.001
2.0 events/1,000
catheter days
Trisodium citrate 30% 22 N/A 0.46 Hydraulic resistance:
2.0 events/1,000
catheter days
3 mg M þ30 mg EDTA/mL 23 N/A 0 Hydraulic resistance:
0.9 events/1,000
catheter days

Note. EDTA, ethylene diamine tetraacetic acid; CLABSI, central-line–associated bloodstream infection; CVC, central venous cathether; HD, hemodialysis; RR, rate ratio; IRR, incidence rate ratio; M, Minocycline; N/A, not applicable; NS, nonsignificant.
a
1, nontunneled; 2, tunneled; 3, peripherally inserted central catheters; 4, port.

Anne-Marie Chaftari et al
Infection Control & Hospital Epidemiology
Citrate-based catheter lock solutions
Citrate is naturally present in human blood at levels of ~0.1 mM.38
Like EDTA, citrate has the ability to chelate a range of metal ions
including calcium, iron, magnesium, nickel, cobalt, and zinc.38–40
Citrate has been reported to form both bidentate chelation com-
plexes (with iron, nickel, and zinc ions) and tridentate chelation
complexes (with cadmium and copper ions).41 At a concentration
of 4%, it sequesters the calcium ions needed to activate clotting.
Citrate binds calcium more weakly than EDTA (pK, 3.3)42 and
binds iron more strongly than it binds calcium (pK, 7.7) but more
weakly than EDTA binds iron.43 Citrate has concentration-depen-
dent antimicrobial activity. At a concentration >0.5%, citrate has
been reported to inhibit staphylococcal biofilm formation; how-
ever, at concentrations <0.5%, it has been reported to stimulate
SA biofilm formation.1 A concentration of 4% sodium citrate is
able to fulfill the anticoagulant function of a catheter lock solution,
but it requires concentrations >15% to be able to also provide anti-
microbial activity.44
Catheter lock solutions comprising citrate have been widely
studied with concentrations up to 46%.34,45–50 Antibiotics that have
been tested in combination with citrate as catheter lock solutions
include gentamicin, ciprofloxacin, tobramycin, vancomycin, and
telavancin.36,51–55 Citrate has also been combined with other non-
antibiotic antimicrobial agents in catheter lock solutions including
ethanol, ethanol and glyceryl trinitrate, taurolidine, and methylene
blue plus methyl and propyl parabens.52,56–68
The literature search on clinical trials using citrate-based cath-
eter lock solution revealed a total of 79 studies, of which 21 con-
sisted of clinical trials with 17 randomized studies. Several
prospective RCTs comparing citrate containing lock solutions in
combination with antimicrobials to either heparin or saline locks
are summarized in Table 2. We only included studies that reported
the incidence of CRBSI with a clear definition of the infection.
Several concentrations of citrate have been used as a component
of lock solutions. The use of high citrate concentrations (up to
30%–46.7%) have been used with promising results.34,45–50 A mul-
ticenter, double-blind, RCT comparing high citrate concentration
(30%) to heparin (5,000 IU/mL) in the Netherlands and Belgium
showed that citrate may reduce the risk of catheter-related infec-
tions by 75%, may prevent premature CVC removal, and may
decrease the risk of heparin-related bleeding complications.50
Another double-blinded RCT in Brazil comparing heparin 1,000
IU/mL to trisodium citrate 30% or minocycline 3 mg/mL in
EDTA 30 mg/mL showed that citrate and EDTA were safe and
effective for catheter patency compared to heparin.34 Similarly,
there was less catheter malfunction when hemodialyis CVC were
locked with high concentrations of citrate (46.7%) compared to
saline.45 In contrast, Power et al47 showed a significant higher rate
of catheter thrombosis with the use of 46.7% citrate compared to
heparin 5,000 IU/mL (8 per 1,000 catheter days vs 4.3 per 1,000
catheter days; P < .0001).47 The most commonly reported adverse
events with the use of high concentrations of citrate include met-
allic taste during lock instillation.46,47,50 as well as facial and periph-
eral paresthesia.47,50 High concentration of citrate may cause fatal
heart rhythm disruption, seizures, or bleeding due to hypocalce-
mia. Sodium citrate in a concentration of 46.7% has been related
to unexpected death, which led the US Food and Drug
Administration (FDA) to mandate the recall of the high 46.7%
concentration of citrate from the market.69
Citrate in 4% solution is safe and available in the United States;
it is noninferior to heparin 10,000 IU/mL in maintaining catheter
5
patency.70 Citrate 4%, when used in combination with tauroli-
dine, decreases the rate of catheter-related infections in hemodi-
alysis60–62,64 as well as in cancer patients.57,58 Few studies have
reported an increase in the rate of catheter dysfunction and an
increase in the rate of thrombolytic use to maintain CVC patency
when citrate is used in combination with taurolidine.60,62
Citrate in combination with low-dose gentamicin was shown to
be safe and effective for the prevention of CRI in hemodialysis
patients.36,51,53 However, concerns exist for the emergence of antimi-
crobial resistance with the prolonged use of antimicrobials.71,72 A
nonantibiotic lock solution containing sodium citrate 0.24 M
(7.0%) in combination with methylene blue 0.15%, methylparaben
0.15%, and propylparaben 0.015% (C-MB-P) was also shown to be
safe in hemodialysis patients. It had similar intraluminal thrombosis
prevention and significantly decreased the risk of CRI compared
with heparin.59
A novel, nonantibiotic, nonheparin, lock consisting of 15 or 30
μg/mL of nitroglycerin in combination with 4% sodium citrate and
22% ethanol was used in 60 patients with hematologic malignan-
cies who had peripherally inserted central catheters (PICCs) and
showed promising results for the prevention of CRBSI. This lock
solution was flushed after 2 hours and was well tolerated. No seri-
ous related adverse events or episodes of hypotension was reported.
Two patients experienced mild possibly related adverse events
(1 headache and 1 rash) that were both transient and reversible.73
Furthermore, several systematic review and meta-analysis of pro-
spective RCTs found a significant reduction in the rate of CRBSI. A
meta-analysis showed that prophylactic use of antimicrobial lock
solutions led to a significant reduction in the rate of CRBSI
(69%) compared to heparin.74 Another meta-analysis of RCTs
showed that the combination of citrate with antimicrobials in a lock
solution was superior to heparin for the prevention of CRBSI,
whereas citrate alone was similar to heparin.75 The same study
showed that citrate used in small (1.04%–4%) and moderate concen-
trations (4.6%–7%) was superior to heparin for CRBSI prevention
whereas higher citrate concentration (30%–46.7%) was not.75
Although the use of these lock solutions seems to be promising
for the prevention of CRBSI, studies have shown conflicting results
for catheter dysfunction and catheter patency.47,62,76 In a prospective
nonrandomized study in hemodialysis patients, the rate of catheter-
related bacteremia decreased from 5.7 per 1,000 catheter days with
heparin to 0.59 per 1,000 catheter days with a catheter lock solution
containing 1.35% taurolidine with 4% citrate. However, the catheter
patency decreased from 76% to 32% (P > .001).62
Other chelator-based catheter lock solutions, such as n-acetyl-
cysteine and chelating antibiotics (tigecycline, quinolone), have
been used in combination for their synergistic activity in biofilms
with limited safety and efficacy results.16 Therefore, given the
heterogeneity across the studies regarding the patient population
(patients characteristics), the selection of the drug, the specific drug
combination, the dose, the duration, and the type of catheter, there
is a need to conduct more uniformly designed, large, prospective
RCTs to draw robust evidence-based conclusions.
In conclusion, antimicrobial catheter lock solutions are
expected to play an increasingly significant role in combatting
luminally sourced CRBSIs, and they are expected to continue to
be actively tested in clinical settings. Chelators have emerged as
a valuable component of antimicrobial catheter lock solutions
because of their dual benefits of anticoagulation as well as biofilm
disruption and antimicrobial activity. Additionally, chelators can
potentiate antimicrobial activity of other antimicrobial agents in
catheter lock solutions by stressing microbes through deprivation
 6
Table 2. Citrate Chelator-Based (up to 7%) Antimicrobial Catheter Lock Solutions for the Prevention of Catheter-Related Infections

No. of Rate of CRBSI/ No. of Catheter

Study Patients 1,000 catheter Mechanical Failure
Author/ Type of (no. of Catheter days or No. of (Thrombosis or
Year Type of Study Population Cathetersa Intervention CVCs) Days patients P Value or RR Decrease Blood Flow) P Value
2 mL gentamicin (40 mg/mL), 1 mL 42 (53 3,280 0 30% malfunction
Dogra Prospective, Hemodialysis Tunneled P=.003 .208
citrate 3.13% CVCs)
200253 randomized
3 mL heparin (5000 U/mL) 37 (55 2,643 2.6 42% malfunction
CVCs)
Betjes Single center, Hemodialysis Tunneled Taurolidine 1.35% and sodium citrate 37 1,519 0 P<.50 Persistent Flow .59
200461 Propsective (58 patients) and 4% dysfunction: 2.7%
randomized nontunneled
Heparin (5,000 U/mL) 39 1,885 2.1 Persistent flow
dysfunction: 5.1%
Nori 200636 Multicenter, Hemodialysis Tunneled Gentamicin/trisodium citrate 20 2,002 0*,** * NS **P=.008
Prospective, (4 mg/mL and 3.13%) ***P=.02
open-label,
Minocycline/EDTA (3 mg/mL and 21 2,453 0.4*, ***
randomized,
30 mg/mL)
controlled trial
Heparin (5,000 U/mL) 20 1,734 4**, ***
Solomon Multicenter Hemodialysis Tunneled 1.35% taurolidine þ 4% citrate 53 8,129 1.4 .10 28 needed Hazard ratio,
201060 prospective thrombolytics/ 8 CVCs 2.5; 95% CI
randomized, removed 1.3–5.2;
double blind P=.008
Heparin (5,000 U/mL) 54 9,642 2.4 14 needed
thrombolytics/3 CVCs
removed
Maki 201159 Multicenter, 0.24 M (7.0%) sodium citrate, 0.15% 201 25,274 0.24 Relative risk, 0.29; Patency failure: 0 .04
prospective, methylene blue, 0.15% 95% confidence
randomized, methylparaben, and 0.015% interval, 0.12–0.70;
open label propylparaben (C-MB-P), P=.005.
Heparin (5,000 U) 206 24,395 0.82 Patency failure: 4
Filiopoulos Single center, Adult Nontunneled 4% citrate- 1.35% taurolidine 59 N/A 3.67* **
,
*NS **P=.01 Thrombosis: 9 (11.84%) NS
201152 prospective, hemodialysis ***P=.03
Gentamicin 40 mg/mL heparin 60 2.74*, *** 11 (14.84%)
randomized
5,000 IU/mL
Heparin 5,000 IU/mL 58 9.92**, *** 6 (8.95%)
Moran Multicenter Hemodialysis Tunneled Gentamicin 320 μg/mL in 4% sodium 155 39,827 0.28 P=.003 42 CVC removed for .20
201251 prospective citrate poor flow/ 2.36 TPA
randomized use/1,000 catheter days
Heparin (1000 U/mL) 148 32,933 0.91 35 CVC removed for

Anne-Marie Chaftari et al
poor flow/ 3.42 TPA use
/1,000 catheter days
(Continued)
 Infection Control & Hospital Epidemiology
Table 2. (Continued )

No. of Rate of CRBSI/ No. of Catheter

Study Patients 1,000 catheter Mechanical Failure
Author/ Type of (no. of Catheter days or No. of (Thrombosis or
Year Type of Study Population Cathetersa Intervention CVCs) Days patients P Value or RR Decrease Blood Flow) P Value
Dumichen Single center, Pediatric Tunneled 1.35% taurolidine þ 4% citrate 35 6,576 0.3 P=.03 3 .61
201258 randomized cancer
Heparin (5,000 IU) 36 7,233 1.3 2
Handrup Single center, Pediatric Tunneled 2.5 mL taurolidine 1.35%/sodium 58 (64 39,127 0.4 Incidence rate ratio, 4 .98
201357 prospective, cancer and ports citrate 4%/heparin 100 IE/mL CVCs) 0.26 (95% CI= 0.09–
randomized, 0.61); P=.0005.
250 IE heparin in 2.5 mL sterile 54 (65 1.4 4
open label
normal saline 0.9% CVCs)
Klek 201556 Single center, Home 6.6 Fr 2% taurolidine lock 10 3,658 0 P=1.0 10% 1.0
prospective, parenteral Broviac
randomized nutrition 1.35% taurolidine þ citrate lock 10 3,650 0.273 0
Saline flush 10 3,660 0 0

Note. EDTA, ethylene diamine tetraacetic acid; CI, confidence interval; CRBSI, catheter-related bloodstream infection; CVC, central venous cathether; NA, not available; NS, not significant.
a
1, nontunneled; 2, tunneled; 3, peripherally inserted central catheter; 4, port.

7
8 Anne-Marie Chaftari et al
of key metal ions. As a result of these properties, as well as their
record of safety when used at modest concentrations, chelators
should play an increasingly role in the development of antimicro-
bial catheter lock solutions used for the prevention as well as the
management of CRBSI. Citrate concentrations <10% appear quite
safe and capable of performing the anticoagulant function of cath-
eter lock solutions, but concentrations >10% require further robust
studies to establish their safety. The low-cost and wide availability
of trisodium citrate and EDTA are expected to continue their use as
the predominant chelators in antimicrobial catheter lock solutions.
However, safety considerations and regulatory precedents will
likely limit their concentrations and will necessitate inclusion of
other antimicrobial agents to provide broad-spectrum antimicro-
bial activity. We expect more novel chelators to continue to be sub-
jects of research as components of antimicrobial catheter lock
solutions for the prevention of CRBSI, as well as the part of thera-
peutic arsenal for salvaging the infected vascular catheters. Large,
multicenter, clinical RCTs evaluating the efficacy and safety of che-
lators used as components of the lock are underway. The develop-
ment of new FDA-approved cathether lock solutions will have a
major impact in the prevention and management of these serious
life-threatening healthcare-associated infections.
Acknowledgments. We thank Ms. Salli Saxton at The University of Texas MD
Anderson Cancer Center, for helping with the submission of the manuscript.
Financial support. No financial support was provided relevant to this article.
Conflicts of interest. I. Raad and J. Rosenblatt, University of Texas MD
Anderson Cancer Center, are coinventors of the minocycline-EDTA-ethanol
lock solution technology and the nitroglycerin-based catheter lock solution
technology licensed by Novel Anti-Infective Technologies, LLC, in which they
and the UTMDACC are shareholders. All other authors report no conflicts of
interest relevant to this article.
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