Infection of totally implantable venous access devices: A review of the literature

Abstract

Totally implantable venous access devices, or ports, are essential in the therapeutic management of patients who require long-term intermittent intravenous therapy. Totally implantable venous access devices guarantee safe infusion of chemotherapy, blood transfusion, parenteral nutrition, as well as repeated blood samples. Minimizing the need for frequent vascular access, totally implantable venous access devices also improve the patient’s quality of life. Nonetheless, totally implantable venous access devices are not free from complications. Among those, infection is the most relevant, affecting patients’ morbidity and mortality—both in the hospital or outpatient setting—and increasing healthcare costs. Knowledge of pathogenesis and risk factors of totally implantable venous access device–related infections is crucial to prevent this condition by adopting proper insertion bundles and maintenance bundles based on the best available evidence. Early diagnosis and prompt treatment of infection are of paramount importance. As a totally implantable venous access device–related infection occurs, device removal or a conservative approach should be chosen in treating this complication. For both prevention and therapy, antimicrobial lock is a major matter of controversy and a promising field for future clinical studies. This article reviews current evidences in terms of epidemiology, pathogenesis and risk factors, diagnosis, prevention, and treatment of totally implantable venous access device–related infections.

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https://doi.org/10.1177/1129729818758999
The Journal of Vascular Access
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Vascular Access
Introduction
Long-term venous access devices (LTVADs) are essential
for reliable and safe administration of repeated intrave-
nous antineoplastic and antimicrobial therapy, total paren-
teral nutrition (PN), blood products, and blood
samplings.1–3 Guidelines strongly recommend their use
for preventing venous toxicity by chemotherapy agents
and for reducing anxiety and discomfort associated to
repeated venous access.4 First introduced in 1982,5 totally
implantable venous access devices (TIVADs) are particu-
lar types of LTVAD, which are constituted by a silicon or
polyurethane central venous catheter (CVC), usually
inserted in a vein of the supra-/infraclavicular area, and
then connected—with or without tunneling—to a reser-
voir implanted subcutaneously in the upper thoracic
region, usually over the pectoral muscle (so-called “chest
port”); as an alternative option, the catheter may be
Infection of totally implantable
venous access devices: A review
of the literature
Fulvio Pinelli1, Elena Cecero2, Dario Degl’Innocenti3,
Valentina Selmi1, Rosa Giua2, Gianluca Villa2, Cosimo Chelazzi1,
Stefano Romagnoli1 and Mauro Pittiruti4
Abstract
Totally implantable venous access devices, or ports, are essential in the therapeutic management of patients who
require long-term intermittent intravenous therapy. Totally implantable venous access devices guarantee safe infusion
of chemotherapy, blood transfusion, parenteral nutrition, as well as repeated blood samples. Minimizing the need for
frequent vascular access, totally implantable venous access devices also improve the patient’s quality of life. Nonetheless,
totally implantable venous access devices are not free from complications. Among those, infection is the most relevant,
affecting patients’ morbidity and mortality—both in the hospital or outpatient setting—and increasing healthcare costs.
Knowledge of pathogenesis and risk factors of totally implantable venous access device–related infections is crucial
to prevent this condition by adopting proper insertion bundles and maintenance bundles based on the best available
evidence. Early diagnosis and prompt treatment of infection are of paramount importance. As a totally implantable
venous access device–related infection occurs, device removal or a conservative approach should be chosen in treating
this complication. For both prevention and therapy, antimicrobial lock is a major matter of controversy and a promising
field for future clinical studies. This article reviews current evidences in terms of epidemiology, pathogenesis and risk
factors, diagnosis, prevention, and treatment of totally implantable venous access device–related infections.
Keywords
Totally implantable venous access devices, catheter-related infections, catheter-related bloodstream infections, central
line–associated bloodstream infections, port
Date received: 18 September 2017; accepted: 28 December 2017
1
Department of Anesthesia and Intensive Care, Azienda Ospedaliero-
Universitaria Careggi, Florence, Italy
2Department of Health Science, University of Florence, Florence, Italy
3 School of Human Health Sciences, University of Florence, Florence,
Italy
4Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
Corresponding author:
Fulvio Pinelli, Department of Anesthesia and Intensive Care, Azienda
Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50012 Florence,
Italy.
Email: pinellif@gmail.com
758999JVA0010.1177/1129729818758999The Journal of Vascular AccessPinelli et al.
research-article2018
Review

2 The Journal of Vascular Access 00(0)
inserted in a vein of the upper limb and connected to a
reservoir placed in the upper arm over the biceps muscle
(so-called peripherally inserted central catheter (PICC)-
port) or—though quite exceptionally—it may be inserted
in the femoral vein (so-called groin port). TIVADs mini-
mize complication rate related to central venous access if
compared to other LTVAD,6–10 provide a better cosmetic
appearance and let patients perform activities of daily liv-
ing more easily.11 Nonetheless, TIVADs are not free from
early and late complications. Infection is certainly the
most relevant and one of the most common complica-
tions, being a frequent cause of removal,2,3,7,12 thereby
reducing the cost-effectiveness of the TIVAD itself and,
more importantly, determining an increase in morbidity
and mortality.13–16 We reviewed current literature about
TIVAD-related infections, providing insight into preven-
tion and discussing the challenges associated with diagno-
sis and management of this relevant complication.
Epidemiology
While certainly being one of the most frequent TIVAD-
related complications, infection has a huge variability in
terms of incidence rate throughout the literature. Recent
papers report infection rates ranging from 0.018
events/1000 catheter days to 0.35 events/1000 catheter
days in adult cancer patients,17–22 while a higher infec-
tion rate (1.21/1000 catheter days) was reported in a
study on pediatric oncology patients.23 These recent data
are not much different from the incidence reported in
less recent studies in cancer patients, that is, a range
from 0.11 to 0.37/1000 catheter days,2,3,24–30 but also in
patients with cystic fibrosis.31–34 Despite this variability,
which could be ascribed to various factors related, for
example, to the type of population studied or to the study
design, there is no doubt that TIVAD-related infection is
the most frequent indication to port removal.26,27,29,35–38
In a recent French study on a cohort of patients with
solid tumors, port-related infections required TIVAD
removal in 81% of the cases, while conservative treat-
ment was feasible only in a minority of patients.37
Moreover, in the same study, 48% of the TIVAD-related
infections were associated with complications, including
25% of septic shock. A high incidence rate of death at
12 weeks (46%) has been reported in patients with
TIVAD-related infection.39 All this considered, it is evi-
dent that TIVAD-related infections have a relevant
impact on morbidity and mortality, both in the hospital
or outpatient setting. Furthermore, the cost associated
with each episode of catheter-related bloodstream infec-
tion (CRBSI) is particularly relevant, being associated
with several expensive interventions (diagnostic proce-
dures, forced hospitalization, antibiotic treatment,
removal and placement of a new device, etc.).
Pathogenesis of TIVAD-related
infections
When dealing with TIVAD-related infection, it is impor-
tant to understand the mechanisms underlying the bacterial
colonization of an implantable intravascular device. First,
extra-luminal contamination (i.e. migration of organisms
along the external surface of the catheter) may occur dur-
ing TIVAD insertion, particularly if appropriate antiseptic
procedures are not adopted.40,41 Extra-luminal colonization
during port maintenance may also occur (inappropriate
disinfection of the skin before insertion of the Huber nee-
dle). Though, in TIVADs, the most frequent route of con-
tamination is intraluminal (i.e. migration of organisms into
the lumen of the catheter after contamination of the cathe-
ter hub or, less frequently, after infusion of contaminated
solutions). Another possible but infrequent route of cathe-
ter colonization is hematogenous (i.e. contamination from
blood-borne bacteria coming from a distant source42–44).
As the microorganisms interact with the catheter, bacte-
rial colonization of the device may occur by different
mechanisms. First, anytime a catheter is placed in the
bloodstream, its external surface is slowly but inevitably
wrapped by a connective tissue—the so-called fibrin sheath
or fibrin sleeve or (more appropriately) fibroblastic
sheath—which is the physiological response of the blood to
the foreign body (the venous catheter) placed into the ves-
sel.45,46 Even if the bare surface of the catheter is inhospita-
ble to colonization, this fibroblastic sheath may theoretically
host a subsequent bacterial or fungal colonization.42,47
Though, there is still no convincing evidence that the fibro-
blastic sheath may actually favor the growth of the micro-
organisms, considering that sheath formation happens in
100% of VADs, while the event of a CRBSI is fortunately
quite uncommon.
However, on the internal surface of the catheter, the
organisms which are constantly present in the lumen attach
to the walls of the catheter, forming colonies and secreting
a sticky polysaccharide matrix that forms the so-called
biofilm, which is an ideal microenvironment for bacterial
survival.42,48 The transition of microbes from the attach-
ment to the walls inside the biofilm to a free-floating form
can lead to injection of bacteria into the bloodstream, with
subsequent bacteremia and sometimes a clinically evident
bloodstream infection. This progression from catheter col-
onization (a phenomenon constantly present in any intra-
vascular device, with no exception) to CRBSI (a relatively
rare occurrence) is probably related to the virulence of the
germs, but it may also be a quantitative phenomenon, as
the number of organism present in the biofilm is propor-
tional to the risk of bacteremia, which in turn increase the
probability of developing a CRBSI.49 In addition, the bio-
film itself may increase the pathogenicity of microbes, act-
ing as a barrier toward host defense mechanisms and

Pinelli et al. 3
potentially making them less susceptible to antimicrobial
agents.50–54
The microorganisms responsible for TIVAD-related
infections are various, essentially represented by bacteria
and fungi. As regards bacteria, Coagulase-Negative
Staphylococci (CoNS) are frequently encountered, fol-
lowed by Staphylococcus aureus, while Candida species
are the most common pathogens among fungi.17,18,37,38,55
Some studies have also reported a high frequency of gram-
negative strains as responsible for port infection, like
Klebsiella species and Escherichia coli or Pseudomonas
aeruginosa.19,21,23,27,56,57 This variability is likely related to
different variables as the characteristics of the patient pop-
ulation, the type of intravenous treatment (i.e. PN vs
chemotherapy), and the nature of the environmental micro-
flora. As CoNS are part of the normal flora of the human
skin, their frequent role as pathogens is suggestive of
extra-luminal contamination due to inadequate skin disin-
fection before the insertion of the Huber needle.
Risk factors
The knowledge of the risk factors associated with TIVAD-
related infections is important in order to adopt preventive
measures targeted to lower and ideally reduce to zero early
and late infectious complications. Several studies have
focused on the assessment of patient-related risk factors.
Among cancer patients, those with hematologic malignan-
cies suffer of higher infection rates,12,17,19,28,58–60 and both
young age and a low white blood cell count represent addi-
tional risk factors.12,23,27,28,61 The existence of an underly-
ing hematologic malignancy is more significantly
associated with late infections than with early local infec-
tions, and impaired immunity caused by both the disease
itself and an intensive chemotherapy schedule may also be
responsible of such complications.17,35,58,62 HIV-infected
cancer patients are reported to have a high incidence rate
of TIVAD-related infections, up to 3.20/1000 catheter
days,56,63–65 while diabetes does not seem to increase port
infections rate in cancer patients.66,67 However, diabetes
was found to be a risk factor for port infection in cystic
fibrosis.68 Placement of the port in hospitalized patients
was also associated with higher risk of developing a
TIVAD-related infection if compared to port placement in
outpatients; this may be easily explained by the risk sec-
ondary to a prolonged exposition to nosocomial flora.6,17,20
Indications for TIVAD placement may affect infection
rate: palliative chemotherapy was found to be associated
with a higher risk than adjuvant chemotherapy.12,17,19 The use
of port for PN also increases the risk of TIVAD-related infec-
tions, possibly because of PN itself, since both lipids and
amino-acids favor bacterial colonization and biofilm forma-
tion or also because of the more frequent manipulations of
the line associated with this kind of treatment.25,38,61,67,69 As
regards the site of port placement, insertion at the chest
(chest-port) and in the upper limb (PICC-port) share an iden-
tical risk of infectious complications,70 while ports placed
with a femoral venous access (groin ports) have a higher
infection risk.20,71 The obsolete technique of venous cannula-
tion by venous cut-down is also associated with a very high
risk of infection and is discouraged by the Centers for
Disease Control and Prevention (CDC) guidelines. Technical
difficulties at the time of insertion (for instance, repeated
attempts during “blind” cannulation of the veins with the
landmark technique) may increase bacterial colonization
because of prolonged procedural time and occurrence of
local hematomas.61 In this regard, real-time ultrasound-
guided puncture and cannulation of the vein appear to have a
role not only for the prevention of mechanical complication
but also for the prevention of infection. The most obvious
and relevant risk factor related to the technique of insertion is
nonetheless the omission of those interventions which are
recommended by the international guidelines for a proper
prevention of intra-procedural contamination during inser-
tion: choice of a dedicated ambient for performing the proce-
dure, appropriate hand hygiene before the procedure, skin
antisepsis with 2% chlorhexidine in alcohol, maximal barrier
precautions (sterile gloves, sterile gown, non-sterile mask,
non-sterile cap, and long sterile cover for the ultrasound
probe), and use of an intra-procedural checklist.
Frequent manipulation of the line, typically in hospital-
ized patients and more particularly in immunosuppressed
patients, is known to increase infection rates.63,72 The
appropriate interval between TIVAD placement and its
first use is controversial. The old-fashioned recommenda-
tion was to wait at least 24 h before the first use, but some
authors have reported shorter intervals without any
increased risk of infection;73–75 however, a few other stud-
ies suggest a reduction of infection and removal rate by
adopting longer intervals (>6 days) between placement
and first use.76,77 Finally, to our knowledge, only one study
considered the type of device as a possible risk factor for
TIVAD-related infections; as the interpretation of this
study has many concerns (one above all: the TIVADs were
inserted with the obsolete technique of venous cut-down)
and the two types of ports were different under too many
aspects (size, material and shape of the reservoir; size and
material of the catheter; etc.), it is difficult to understand
which features of the device might have an impact as
TIVAD–CRBSI prevention strategies.21 Other studies are
necessary to confirm or disprove this evidence, since dif-
ferent devices may differ in many structural features.
Diagnosis
Signs and symptoms of local and/or systemic infection
may represent a suspicion of catheter-related infection, but
its confirmation requires microbiological methods and

4 The Journal of Vascular Access 00(0)
precise criteria. Samples for culture should be obtained
before the initiation of antibiotic therapy: current Infectious
Diseases Society of America (IDSA) guidelines recom-
mend the simultaneous culture of blood from the device
and blood from a peripheral vein. Since the risk of false
positive due to contamination during peripheral blood cul-
ture is very high, skin preparation before peripheral veni-
puncture for blood culture should be done exclusively with
2% chlorhexidine in alcohol. As defined by the Guidelines
of the IDSA,78 TIVAD-infective complications can be
local, of the bloodstream—CRBSIs—or both. Local infec-
tions include infections of the tract of tunneled catheter
(tenderness, erythema, and/or induration more than 2 cm
along the subcutaneous tract of the catheter) or infections
of the pocket (tenderness, erythema, and/or induration
over the pocket; spontaneous rupture and drainage, puru-
lent collection or skin necrosis). Both can be associated
with concomitant bloodstream infection. As the same
Guidelines strongly recommend, when a local infection is
suspected, it is mandatory to obtain samples for culture
from swab of the drainage; culture of peripheral blood
should be done to rule out systemic infection.78 In case of
local skin infection, blood samples should not be taken
from the port, because of the risk of spreading the infec-
tion. In all other cases, blood cultures should always be
obtained from both the device and a peripheral vein.
The diagnosis of CRBSI is based on one of the follow-
ing: (a) positive blood culture from a peripheral vein, with
either positive semi-quantitative (>15 colony-forming
units (CFUs)/catheter segment) or quantitative (>103
CFU/catheter segment) culture, with concomitant positive
culture of the same organism from a catheter segment; (b)
simultaneous positive cultures of blood samples from the
catheter and from a peripheral vein, as long as the quantita-
tive essay shows a ratio of at least ≥5:1 (TIVAD vs periph-
eral); and (c) simultaneous positive cultures of blood
samples from the catheter and from a peripheral vein, with
the catheter blood becoming positive at least 2 h before the
positivity of peripheral blood. The latter, known as delayed
time to positivity (DTP), is currently regarded as the most
accurate and most cost-effective diagnostic method.
When the TIVAD is removed, a negative culture of the
catheter tip cannot exclude the diagnosis; culture of the
material inside the reservoir may be more sensitive than
catheter tip culture for the diagnosis of CRBSI;79 there-
fore, the internal lumen of the reservoir should be cul-
tured.79 Nevertheless, simultaneous quantitative blood
cultures and the differential time to positivity of qualitative
blood cultures, which do not require port removal, are the
most frequently used methods for diagnosis.80
In terms of cost-effectiveness, DTP is today the method
to be preferred, since quantitative culture is relatively
expensive and not easily available in all labs. This implies
that in the case of suspected port-related infection, the first
intervention must be a simultaneous culture of blood from
a peripheral vein and blood from the device: (a) the diag-
nosis of port-related infection will be confirmed only if the
same germ is cultured on blood samples, as long as the
culture of the blood from the device becomes positive at
least 2 h before the peripheral culture; (b) the simultaneous
growth of germs in both blood samples at similar times of
positivity (or an early positivity in the peripheral blood) is
diagnostic for a bloodstream infection non-related to the
device; (c) the presence of germs exclusively in the blood
drawn through the device will imply a diagnosis of coloni-
zation, without bloodstream infection; (d) the presence of
germs exclusively in the peripheral blood culture will usu-
ally suggest a false positive due to contamination (typi-
cally because of inadequate skin antisepsis before blood
drawing).
Prevention
Strategies to prevent port infections should start from the
insertion. A scrupulous attention and adherence to guide-
lines is required to minimize the risk of incoming complica-
tion. The guidelines we refer to are epic3 2014 guidelines40
and Centers for Disease Control and Prevention (CDC)
2011 guidelines,81 as well as the very recent Infusion Nurses
Society (INS) 2016 guidelines.82
Prevention starts with working in a clean environment
every time a port is placed or handled. An operating room
or a radiological suite recently used for clean-contaminated
or contaminated procedures is not an appropriate environ-
ment. The ideal environment is a procedural suite strictly
dedicated only to TIVAD insertion (or more generally to
LTVAD insertion). Hand hygiene is mandatory because
hand-mediated transmission is a major contributing factor
in the acquisition and spread of infection in hospitals, and
washing hands either with water and soap or with waterless
alcohol-based hand rub is associated with a reduction in
infections.83,84 Alcohol scrub is known to be more effective
than washing with water and soap: the latter is to be pre-
ferred only in specific situations (for instance, when there is
visible dirt on the hands or when there is a risk of contami-
nation by spore-forming bacteria). Using an aseptic surgi-
cal technique during port insertion with maximal sterile
barrier precautions (i.e. cap, mask, sterile gown, sterile
gloves, a sterile full-body drape, and a long sterile cover for
the probe) lowers the rate of infection.85 It is very important
to educate healthcare staff and periodically assess knowl-
edge of and adherence to guidelines.86,87 The use of check-
lists at the time of insertion has been proven to be effective
both as an educational tool and as a tight verification of the
adherence to the guidelines during each maneuver.
Most guidelines also agree that venous cannulation by
real-time ultrasound guidance effectively reduces the risk
of intra-procedural contamination if compared to the
“blind” cannulation by landmark technique or to the
venous cutdown.54,88

Pinelli et al. 5
During insertion and usage of port, appropriate prepara-
tion of the skin also reduces the risk of catheter-related
infection. This is a crucial point. Indeed, microorganisms
that colonize the skin are the cause of most CRBSI.17
Many investigations have been performed to identify the
most effective antiseptic agent for skin preparation.89–91
Chlorhexidine gluconate in alcohol has shown to lower
rates of catheter colonization or CRBSI more than povi-
done-iodine or alcohol alone.90 A recent review and meta-
analysis by Maiwald and Chan92 showed that chlorhexidine
gluconate is more efficient than povidone-iodine, but that
the presence of alcohol provides additional benefit.
According to guidelines,40 skin at the insertion site must be
decontaminated with a single-use application of 2% chlo-
rhexidine gluconate in 70% isopropyl alcohol and it must
be allowed to dry 30 s prior to start the procedure. Povidone
iodine should be used only in patients with known allergy
to chlorhexidine. Application of antimicrobial ointments
to the port wound at the time of insertion is not recom-
mended because the efficacy of this practice for infection
prevention is uncertain and it even might promote fungal
infections and antimicrobial resistance.40 However, the
risk of local wound infection after port implantation may
be reduced by proper choice of the site of the pocket (ide-
ally: just below the clavicle for chest ports; at the upper
arm for PICC ports) and avoidance of transcutaneous
sutures which are inevitably associated with bacterial con-
tamination of the subcutaneous tissue which host the reser-
voir (this implies skin closure of the pocket wound with
intradermal stitches and/or cyanoacrylate glue).
Systemic antibiotic prophylaxis before or during port
insertion is not recommended—and even overtly discour-
aged—by international guidelines.78 A recent meta-analy-
sis from Johnson et al., including four studies and 2154
patients undergoing port placement, demonstrated no sta-
tistically significant effect of antibiotic prophylaxis on
rates of infection. Unnecessary administration of antibiot-
ics results in a higher risk of allergic reactions, may help
the development of multidrug-resistant organisms, and
increases the costs of healthcare.93
There is no convincing evidence that antibiotic lock
solutions should be used routinely to prevent CRBSIs.
Most of the studies available are conducted in hemodialy-
sis patients. Prophylactic antibiotic lock therapy (ALT) has
shown only marginal benefit in oncologic patient.94 In
addition, concerns exist about the potential side effects
(toxicity, allergic reactions, and emergence of bacterial
resistance) associated with the antibiotic drug. Therefore,
the CDC guidelines suggest to consider prophylactic anti-
biotic lock only in patients with long-term catheters who
have a history of multiple CRBSI despite optimal maximal
adherence to aseptic technique.8
A possible prevention of strategies in patients with
LTVAD at high risk of infection may also be represented
not by the prophylactic antibiotic lock but by the
prophylactic lock with non-antibiotic antimicrobial agents
such as taurolidine, citrate, or ethylenediaminetetraacetic
acid (EDTA), possibly in association.82,95 The interest in
testing these agents is high, since they are safe, inexpen-
sive, and effective against all germs and are not associated
with the risk of eliciting allergic reactions or bacterial
resistance.
Lock prophylaxis
Let us analyze more closely the pros and cons of the pro-
phylactic lock. Antibiotic lock prophylaxis, the periodic
loading of the dead space of the device with a highly con-
centrated antibiotic solution, is a technique proposed for
prevention of CRBSI. The solution of antibiotic is allowed
to dwell—or is “locked”—inside the catheter while the
CVC is not in use, so to reduce the degree of colonization
and decrease the risk of infection. Prophylactic antibacte-
rial lock is expected to reduce the bacterial colonization of
the device, but data available are still not conclusive for
scarcity of strong evidence from high-quality scientific
studies.8 Furthermore, there are concerns about the risk of
non-infective complications96 and the possible emergence
of resistances.97 Clinical practice guidelines recommend to
consider a prophylactic lock not routinely, but just for
patients with a history of multiple CRBSI in spite of adher-
ence to strict aseptic measures and in cases where the event
of infection would be particularly hard to manage, such as
in the case of patient with limited venous resources.8,78,82
Lots of antibiotic lock solutions have also been evaluated,
mostly on hemodialysis catheters, either alone or in com-
bination, including vancomycin, gentamicin, cefazolin,
cefotaxime, minocycline, ciprofloxacin, and linezolid.97
Though, despite their efficacy, antibiotic agents may not
be the best choice for a prophylactic lock.
As a matter of fact, in this setting, non-antibiotic sub-
stances with antimicrobial proprieties are an interesting
area of development. Prophylactic locks with ethanol, tau-
rolidine, citrate, or EDTA have been studied in the last
years. Several studies on the effect of ethanol in preventing
CRBSI, both in children and adults, have been publis
hed98–105 and suggest that prophylactic ethanol lock (EL)
decreases the rates of infection and catheter removal. In
those studies, the most effective ethanol concentration was
70%.106 Despite good results with ethanol prophylaxis,
there are concerns about safety. In fact, the use of ethanol
could be associated with structural changes in catheters
and it may affect catheter integrity (mostly, first-genera-
tion polyurethane, but also silicone and carbothane cathe-
ters).107 Concerns exist also about the possible systemic
toxicity of ethanol, such as tiredness, headaches, dizziness,
nausea, light-headedness, and abnormalities of liver func-
tion test.108,109 Moreover, a placebo randomized controlled
trial (RCT) of daily EL to prevent CRBSI in patients with
tunneled catheters found that the reduction in the incidence

6 The Journal of Vascular Access 00(0)
of infections using preventive EL was non-significant,
although the low incidence of CRBSI due to intraluminal
contamination may preclude definite conclusions; also, the
low incidence of CRBSI in the placebo group suggests that
the study was underpowered.110 Furthermore, ethanol is
known to interact with serum proteins and other proteins,
inducing their precipitation and subsequent lumen occlu-
sion. Finally, no study with EL in ports is currently
available.
A promising non-antibiotic lock solution is taurolidine,
which has a large spectrum of activity against bacteria and
fungi.111 Commonly used taurolidine concentrations111
(1.35%–2%) are at least 10 times higher of the minimal
inhibitory concentration (MIC) 50 of the majority of
Gram-positive and Gram-negative microorganisms.
Several studies on the effect of taurolidine in preventing
CRBSI found that its use was associated with a reduced
CRBSI rate compared to other control lock solutions also
in high-risk patients.17,112–114
A recent report from Liu et al.,115 evaluating three stud-
ies involving 236 patients with a total of 34,984 catheter
day, indicated that catheter locking with taurolidine-citrate
reduced the incidence of CRBSI and Gram-negative bacte-
rial infection, whereas it was associated with an increased
risk of catheter obstruction. Moreover, no adverse effects or
development of resistance have ever been reported with the
use of taurolidine.111 The association with citrate appears to
be particularly promising,95 considering that the two sub-
stances may have a synergic effect against the biofilm.
Indeed, citrate—apart from its anticoagulant properties—
has well-defined antibacterial effects, but not exclusively
due to its capacity of demolishing the biofilm. The antibac-
terial effect of citrate is already present at concentration of
4%, and it increases progressively up to 40%; although
very high concentrations are potentially harmful if acciden-
tally infused into the circulation, they are not generally
recommended.
Finally, a new promising drug with very high anti-bio-
film and antibacterial effects is tetra-sodium EDTA; in
spite of a lot of experimental evidence, clinical studies are
still insufficient.116
Last but not least, it is noteworthy that no randomized
clinical study has specifically assessed the effectiveness
and safety of such non-antibiotic antimicrobial substances
(ethanol, taurolidine, citrate, and EDTA) in preventing
TIVAD-related infections.
Treatment
When a port-related BSI is diagnosed, specific therapy with
standard antimicrobial agents should be initiated as soon as
possible. These infections are most commonly caused by
CoNS, S. aureus, and Candida species and less commonly
by Bacillus species, Corynebacterium jeikeium, Enterococci,
rapidly growing Mycobacteria, and Gram-negative bacilli.28
The treatment usually includes the removal of the device
and a systemic antimicrobial therapy.117 Nevertheless, in
some situations (expected risks during the removal of the
device or expected difficulties in placing a new access due
to exploitation of the venous patrimony), the salvage of the
device may be taken into consideration.78
The removal of the device is obviously mandatory in
the presence of a tunnel or of a pocket infection or in the
presence of a complicated BSI (BSI with severe sepsis or
septic shock, endocarditis, septic thrombophlebitis, osteo-
myelitis, or other hematogenous seeding).78 A non-compli-
cated CRBSI due to S. aureus and Candida spp. is also an
indication for port removal.
If a non-conservative strategy is decided, the TIVAD is
promptly removed. The time between the clinician’s decision
to remove the port and its actual removal is a variable signifi-
cantly associated with the occurrence of complications.37
If a conservative strategy is decided, in cases of uncom-
plicated CRBSI not caused by S. aureus or Candida spp., a
therapy with systemic antibiotics in combination with ALT
should be considered.78 The TIVAD should also be
removed if blood cultures are persistently positive 72 h
after antibiotics are started (when no other site of infection
has been identified) or if bacteremia recurs shortly after
completion of a course of antibiotics.118
In case of a tunnel infection or a pocket infection, cul-
tures of local discharge and blood cultures should be
obtained. These infections usually require prompt catheter
removal, incision, and drainage if indicated and 7–10 days
of antibiotic therapy with modification of empiric antibiot-
ics based on cultures and the antibiotic susceptibilities of
the recovered pathogens.78
Once a CRBSI is diagnosed, specific therapy with
standard antibiotic agents should be initiated as soon as
possible. ALT is indicated when catheter salvage is the
goal for patients with uncomplicated CRBSI involving
long-term catheters.78 The duration of antimicrobial ther-
apy depends on several factors including type of microor-
ganism implicated, catheter removal or retention, clinical
response to antimicrobial therapy within the first 48–72 h,
and the possible development of other complications.
According to the IDSA,78 strategies for managing CRBSI
vary by pathogen.
Though there is no data from randomized trials with
adequate sample size to determine the optimal duration for
the treatment, patients with S. aureus CRBSI should have
the infected catheter removed, and they should receive
4–6 weeks of antimicrobial therapy because of the risk of
infective endocarditis.119 There are some exceptions to this
rule: in selected patients with uncomplicated CRBSI (as
long as they are not diabetic, not immunosuppressed, and
not bearer of prosthetic intravascular device), a shorter
duration of antibiotic therapy (i.e. a minimum of 14 days of
therapy) should be considered. If fever and bacteremia
persist for >72 h, the treatment should be extended to

Pinelli et al. 7
4–6 weeks.78 Early removal of the catheter within the first
3 days is associated with better outcome with a more rapid
response to therapy and/or a higher cure rate.120–122 Patients
with S. aureus CRBSI should perform a transesophageal
echocardiography (TEE) to rule out the presence of vege-
tations on the cardiac valves, suggestive for infective
endocarditis. TEE should be done at least 5–7 days after
the onset of bacteremia to minimize the possibility of
false-negative results, and it should be repeated in patients
with persistent fever or positive blood cultures 72 h after
catheter removal and start of the antibiotic therapy.123,124 In
extreme circumstances (e.g. no alternative catheter inser-
tion site), a combination of ALT and systemic therapy can
been used to salvage infected ports with S. aureus CRBSI,
and the patient should receive systemic and ALT for
4 weeks.125,126
CoNS are the most common cause of CRBSI but they
are also the most common contaminant; therefore, the
diagnostic criteria for CRBSI should be carefully respected
before initiating a specific therapy.28,127 Usually, in uncom-
plicated infections, a benign clinical course has to be
expected. After catheter removal, a systemic antibiotic
therapy for 5–7 days is the treatment of choice; otherwise,
if the catheter is retained, systemic antibiotic therapy for
10–14 days in combination with ALT is the most appropri-
ate strategy.78
In case of uncomplicated infections due to Enterococcus
species, a 7–14 day course of therapy is recommended
when the long-term catheter is retained and antibiotic lock
is used. Those infection are associated with a low risk of
endocarditis.128 In cases of CRBSI due to vancomycin-
resistant Enterococci, linezolid or daptomycin may be
used.78
The Gram-negative bacilli most commonly involved in
CRBSI are those that form biofilms and include
Enterobacter, Stenotrophomonas, Klebsiella, Pseudomonas,
and Acinetobacter species.129 Those can be multidrug-
resistant (MDR) microorganisms; therefore, in case of per-
sistent bacteremia or severe sepsis, the device should be
removed. Recent studies in which antibiotic lock and sys-
temic antibiotics were used to treat gram-negative rod
CRBSI have found high success rates.126,130,131 Treatment
over a 7-day period appears to resolve the infection. If this
approach fails (i.e. if bacteremia persists or severe sepsis
occurs despite systemic antibiotic therapy and ALT), the
device should be removed, and the duration of antibiotic
treatment should be extended beyond 7–14 days.78
According to guidelines,78 catheters should be removed
in all cases of CRBSI due to Candida species, and systemic
specific therapy should be promptly initiated. In the treat-
ment of candidemia caused by Candida albicans and azole-
susceptible strains, fluconazole should be administered for
14 days after the first negative blood culture. For Candida
species with resistance to azoles (e.g. Candida glabrata
and Candida krusei), echinocandins or lipid formulations
of amphotericin B are highly effective.132,133 Catheter sal-
vage by antifungal lock therapy is still investigational at the
present time and it is still not indicated.134,135
In patients with persistent bacteremia, a thrombophlebi-
tis should be suspected, that is, the concomitant occurrence
of a catheter-related thrombosis (diagnosed by ultrasound)
and catheter-related BSI (documented by DTP). The most
common microorganism implicated in this complication is
S. aureus.136 In thrombophlebitis due to CVCs, the optimal
management in terms of duration of treatment, anticoagu-
lants, thrombolytic agents, and so on is still to be defined.
For the management of endocarditis due to CRBSI, we
remand to specific papers on this issue.
ALT
According to guidelines of the IDSA, in cases of uncom-
plicated port-related bloodstream infection not involving
S. aureus or Candida spp., conservative treatment with
systemic antimicrobial and ALT can be considered.78
Being most catheter-related infections (CRI) associated
with intraluminal colonization and biofilm formation,
administration of high concentrations of antimicrobial
solution that dwells in the lumen for an extended period of
time might sterilize the device.
A highly concentrated antibiotic (100–1000 times MIC)
used as lock solution should have a low risk of toxicity and
adverse events, a low potential for resistance, a spectrum
of activity that include common or targeted pathogens, and
the ability to penetrate or disrupt a biofilm.137–139
Many antibiotics have been tested as lock solutions in
both in vitro models and in clinical studies, including
beta-lactams, aminoglycosides, fluoroquinolones, glyco-
peptides, oxazolidinones, polymyxins, lipopeptides, and
tetracyclines.140
CRBSI due to coagulase-negative staphylococci or
Gram-negative rods131 showed high cure rates in many
clinical trials when systemic antibiotic administration is
associated with LT. In fact, the use of vancomycin or teico-
planin locks in the treatment of coagulase-negative staphy-
lococci CRBSI had an effectiveness of 88.6% in the
treatment of port-related BSI.131 Teicoplanin locks seem to
deeply reduce the failure rate compared with vancomycin
locks.141 LT with daptomycin also seems to be very prom-
ising in those patients who had failed standard therapy
with vancomycin or cefazolin.13,142 Despite guidelines
suggest port removal if P. aeruginosa infection is identi-
fied,78 ALT with flouroquinolones and aminoglycosides
has shown good outcomes for Pseudomonas spp., similar
as for Enterobacteriaceae spp.143
As we said earlier, when CRBSI is associated with
S. aureus, the catheter should be removed because of the
high failure rates of ALT (45%–60%) and risk of death,131
but in exceptional circumstances (as, for example, no other
possible site for a VADs), when complications are

8 The Journal of Vascular Access 00(0)
excluded, cefazolin and vancomycin can be used in the
attempt of catheter rescue.78
Regarding LT for Candida infections, propensity of
this fungus to form biofilms on catheters makes these
infections difficult to treat due to multiple factors,
including increased resistance to antifungal agents.144
Thus, the cure of CRBSI due to Candida spp. still
requires catheter removal in addition to systemic anti-
fungal therapy.78 Nevertheless, promising antifungal
lock therapy strategies, including use of amphotericin,
ethanol, or echinocandins, have been tested.145,146
Clinical trials are needed to further define the safety and
efficacy of this therapy.
In addition, non-antibiotic drugs have been proposed
for lock therapy (LT). The most promising is EL therapy in
combination with systemic antibiotics. In a recent review,
Tan et al. showed rates of clinical cure ranged from 67% to
100% across all studies, with an overall clinical cure rate
of 90% and overall line salvage of 84%.106 However, none
of this study was specifically carried out on TIVADs.
Clinicians have to be aware that when using LT, a solu-
tion dwell in a catheter lumen; therefore, the potential for
occlusion exists. This risk is expected to decrease if the
solution also contains an anticoagulant. The most com-
monly used anticoagulant drugs are heparin and citrate.
Flushing of the lock solution may lead to unnecessary sys-
temic concentrations of antibiotics and anticoagulants. The
risk of toxicity is limited if the lock is aspirated instead of
flushed.109
When a CRBSI is suspected, if catheter salvage is
decided, ALT should be initiated within the first 48–72
h. In fact, this is associated with enhanced outcomes and
improved salvage of the catheter.147 Duration of ALT is
often consistent with that of concurrent systemic ther-
apy. Current guideline recommendations of targeting
10–14 days of ALT are based on limited comparative
clinical data.78 Some authors have proposed an abbrevi-
ated courses of therapy of 72 h that may offer a more
convenient, cost-effective option and reduce the risk of
resistance.140
One of the main problems related to the lock therapy is
its cost in terms of time, human resources, and drug
expense. Considering that removal and insertion of
TIVADs is nowadays carried out with minimal risk of
complications (thanks to ultrasound guidance, advanced
aseptic technique, etc.), in many situations, ALT may
prove to be time-consuming and not cost-effective.
In summary, lock therapy (LT) is not yet fully standard-
ized and may not be easy to plan and to carry out in non-
expert hands: due to many concerns related to its safety, its
effectiveness, and its cost—LT is to be considered as a
strategy for port savage only in selected cases. Nevertheless,
some of these concerns may be overcome in the future by
the introduction in clinical practice of antibacterial lock
with non-antibiotic substances.
Conclusion
Infection is one of the most frequent and certainly the most
severe complications associated with the use of TIVADs,
being associated with an increased risk of morbidity and mor-
tality, delay in treatment, prolonged hospitalization, and ele-
vated healthcare costs. Therefore, preventive measures are of
paramount importance. Clinical guidelines strongly support
and recommend the use of specific bundles for infection pre-
vention, both at the time of insertion and during maintenance.
An ideal insertion bundle should include adoption of a dedi-
cated ambient for the procedure, proper hand hygiene, skin
antisepsis with 2% chlorhexidine, maximal barrier precau-
tions, ultrasound-guided venipuncture, appropriate choice of
the site for the reservoir, and skin closure with glue. An ideal
maintenance bundle should include hand hygiene, sterile
gloves, and skin antisepsis with 2% chlorhexidine before
placing the Huber needle; securement of the Huber needle
with transparent semipermeable dressing; aseptic manage-
ment of the infusion line, including a policy of proper scrub-
bing of the hub and/or use of disinfecting caps over the hubs;
and removal/replacement of the Huber needle within 1 week.
The cornerstone for an early, accurate, and cost-effective
diagnosis is the adoption of the method of the DTP. Prompt
treatment of the TIVAD-related infection is also mandatory:
this includes systemic antibiotic treatment and removal of the
TIVAD; early removal of the device is recommended in case
of S. aureus, Gram-Negative, or Candida infections, whereas
in non-complicated infections caused by other microorgan-
isms, a conservative strategy with a systemic antibiotic treat-
ment and ALT may be considered.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
This work was supported by “Philip and Irene Toll Gage
Foundation”. This funder has provided a grant to the Department
of Health Science of the University of Florence to economically
support the feasibility, management, coordination, statistical
analysis and recruitment of investigators for this study. The
funder had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
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