Catheter-Related Bloodstream Infection

Authors: Emilio Bouza, M.D., Ph.D., Almudena Burillo, M.D., Ph.D.

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Although there is no arguing that intravascular catheters are an essential item of the intensive
care unit, catheter-related bloodstream infections (CR-BSI) increase morbidity and mortality,
prolong hospitalization and generate considerable medical costs. In this chapter, we describe the
epidemiology, pathogenesis, differential diagnosis and clinical manifestations of CR-BSI and
discuss what to do when a CR-BSI is suspected through a review of current drugs of choice for
empirical treatment, antimicrobial treatment of specific pathogens, duration of treatment,
indications for sparing or removing a catheter, endpoints of therapy, and the treatment of its
complications.

EPIDEMIOLOGY
Intravascular catheters are indispensable in modern-day medical practice particularly in intensive
care units (ICU) (99). Their use, however, puts patients at risk of local and systemic infectious
complications, including local site infection, catheter-related bloodstream infections (CR-BSI),
septic thrombophlebitis, infective endocarditis (IE), and other metastatic infections.

Some 20-30% of all nosocomial bacteremias occur in the ICU, with an incidence rate that ranges
from 2.5 to 6.7 episodes per 100 admissions (2). The majority of serious CR-BSI –up to 87%–
are associated with central venous catheters (CVC), and especially affect ICU patients
(124, 150, 151). In these patients, who may be colonized with hospital-acquired organisms,
central venous access might be needed for extended periods of time and the catheter may be
manipulated multiple times per day for the administration of fluids, drugs, and blood products.

In the United States, the number of CVC-days per ICU per year has been estimated at 15 million
(86). If the average rate of CR-BSI is close to 5 per 1,000 catheter days in the ICU (2, 95), this
means that approximately 80,000 CVC-associated BSI occur in the ICU each year in the United
States. The mortality attributed to these BSI has ranged from null, in studies that corrected for
severity of illness (16, 44, 121, 138), to up to 35% in prospective studies that did not consider
disease severity (34, 107). The cost per infection is an estimated $25,155-$127,610
(45, 76, 99).

PATHOGENESIS
CR-BSI arise from any of four major sources: skin colonization, intraluminal or hub
contamination, secondary seeding from a BSI, and, rarely, contamination of the infusate
(3, 10, 46, 133).

The most common source of CR-BSI is colonization of the intracutaneous and intravascular
portions of the catheter by microorganisms from the patient's skin and occasionally the hands of
health care workers (11, 133, 137). A number of studies have found strong correlation between
heavy skin colonization and organism growth in cultures of samples taken from the catheter
insertion site, especially when short-term intravascular devices are used (7,11, 142). Organisms
are thought to migrate from the skin along the outer surface of the catheter and into the catheter
wound at the fibrin sheath that surrounds intravascular catheters. Scanning electron micrographs
have revealed that both the outer and inner surfaces of catheters can become colonized with
microorganisms (112). Thus, it is not surprising that common skin commensals, such
as coagulase-negative staphylococci and Staphylococcus aureus, are often isolated from
colonized catheters and patients with primary CR-BSI. Host blood factors (e.g., fibrinogen,
fibronectin) interacting with inserted intravenous catheters seem to play a role in the early stages
of microbial adhesion, colonization, and infection.

Intraluminal and/or hub contamination is another important source of BSI in patients with a CVC
in place for more than two weeks or in patients with a surgically implanted device (78, 134).

Hematogenous seeding of the device can occur during a BSI originating from another focus of
infection, though this is uncommon (3) and is most likely to occur in critically ill patients or
those with long-term catheters (88, 111).

Administration of contaminated infusate or additives such as contaminated heparin flush can

result in a BSI although this is now a rare source of BSI and generally leads to epidemic
infections (29, 72, 80).

The risk of CVC infection depends on the type of catheter, the insertion technique, the site of
insertion, the sterility of the insertion procedure, the purpose of catheter use, site care, number of
manipulations and specific host factors (53, 98, 103, 131). The catheter itself is the most
significant extrinsic factor implicated in CR-BSI. The risk of CR-BSI associated with different
types of catheter was evaluated in a systematic review of 200 prospective studies that used
appropriate criteria (81). The authors concluded that all types of intravascular catheters pose
significant but often widely differing risks of BSI. A particular type of catheter may be
associated with an increased risk of infection if it is used in more severely ill or vulnerable
patients.

Other than the type of catheter and catheter location, the most important extrinsic risk factors
associated with the development of CR-BSI include: duration of catheterization, catheter
material, insertion conditions, skill of the catheter inserter and catheter-site care.

Host factors commonly associated with CR-BSI include the following: extremes of age,
increased number and severity of underlying illnesses, malnutrition, loss of skin integrity
(e.g., burns) and immune suppression, especially neutropenia.
DIFFERENTIAL DIAGNOSIS
The diagnosis of CR-BSI is always a challenge. Often, the clinician is presented with a febrile
patient with a CVC in place yet no other apparent source of infection.

There are many causes, both infectious and noninfectious, of fever in the ICU patient. Although
the results of one study indicate that both occur with similar frequency, its incidence varies with
the ICU patient population and with the definition of infection employed (31). Distinguishing
between infectious and noninfectious causes of fever can be difficult and requires careful clinical
assessment. Blood cultures are the only useful test; the clinical diagnosis of septicemia is
unreliable and mortality is high. Blood cultures are therefore mandatory in all ICU patients with
new-onset fever.

Microbial Causes

In patients with a temperature of 38.9ºC to 41.0ºC, an infectious cause of their fever should be
assumed (84). A greater diagnostic challenge arises when the patient’s temperature lies between
38.3ºC (101ºF) and 38.9ºC (102ºF) for which the differential diagnosis list is the longest.
Fortunately, most noninfectious causes of fever can be excluded on the basis of a detailed history
and examination (84). On the other hand, both infectious and noninfectious causes of fever may
coexist. Common infectious causes of fever are ventilator-associated pneumonia, CR-
BSI, sepsis and surgical site infection. Other less common causes are: sinusitis,
empyema, endocarditis, suppurative thrombophlebitis, intra-abdominal abscess, cholangitis,
pseudomembranous colitis, diverticulitis, septic arthritis, cellulitis, myonecrosis, necrotizing
fascitis or meningitis. The urinary tract is unimportant in most ICU patients as a primary source
of infection (84, 141).

Noninfectious Causes

Critically ill patients frequently show single spikes of temperature which return to normal
without treatment related to intervention-induced bacteremia, endotracheal suctioning, urinary
catheter placement and transfusion of blood products. The fever related to an invasive procedure
or manipulation of an indwelling device with or without transient bacteremia frequently resolves
spontaneously, while fever due to underlying chronic diseases, the current medical illness or its
complications or reactions following drug therapy may be persistent. Systemic inflammatory
reactions after surgery that mimic clinical sepsis are frequent in post-operative patients (120).
Most noninfectious causes of fever provoke temperatures <38.9ºC (102ºF) (36). Exceptions to
this include drug fever, transfusion reactions, adrenal insufficiency, thyroid storm, neuroleptic
malignant syndrome, heat stroke and malignant hyperthermia (36, 84). A temperature ≥41.1ºC
(106ºF) is usually noninfectious in origin (37).
CLINICAL MANIFESTATIONS
Primary bloodstream infections are classified as either laboratory confirmed infections or clinical
sepsis according to CDC definitions for nosocomial infections (28). For a laboratory-confirmed
bloodstream infection, at least one of the following criteria must be fulfilled:

Criterion 1: a recognized pathogen cultured from one or more blood cultures.

Criterion 2: at least one of the following signs or symptoms: fever (>38ºC), chills or
hypotension, and at least one of the following:

a. Common skin contaminant

(e.g., diphtheroids, Bacillus spp., Propionibacterium spp., coagulase-negative staphylococci –
CNS–, or micrococci) cultured from two or more blood cultures drawn on separate occasions.

b. Common skin contaminant (e.g., diphtheroids, Bacillus spp., Propionibacterium spp., CNS, or
micrococci) cultured from at least one blood culture in a patient with an intravascular line and
antimicrobial therapy initiated by physician.

c. Positive blood antigen test (e.g., Haemophilus influenzae, Streptococcus

pneumoniae, Neisseria meningitidis, or group B Streptococcus); signs, symptoms and positive
laboratory results not related to an infection at another site.

For a diagnosis of clinical sepsis, the patient must have at least one of the following clinical signs
or symptoms with no other recognized cause: fever (>38ºC), hypotension (systolic pressure ≤90
mm Hg), or oliguria (<20 cm3/hr) and blood culture not done or no organisms or antigen
detected in blood and no apparent infection at another site, along with treatment for septicemia
prescribed.

The accuracy of these definitions has been evaluated in different studies with variable results
(sensitivity 21-85%) (49, 153). Laboratory-based surveillance alone seems to underestimate the
incidence of primary BSI (67). Whether clinical sepsis represents a primary BSI or whether it is
a systemic reaction accompanying an unrecognized infection at another site or a noninfectious
systemic inflammatory response are valid concerns (6, 85, 106). The definition of clinical sepsis
is not specific because it requires, among other criteria, only one of three clinical signs (fever,
hypotension, or oliguria). Signs and symptoms are so unspecific that a scoring system for the
clinical diagnosis of CR-BSI has even been proposed (79). Also, the CDC surveillance definition
mandates antimicrobial therapy prescribed by the physician for the suspected sepsis.

Approximately 90% of primary BSI occurs in patients with intravascular devices, especially
central lines, and these are the most powerful risk factors for BSI (35). Both clinical sepsis and
catheter infections have the same risk factors (67). Blood cultures are performed in most cases of
BSI. In a study by Hugonnet et al., 29.2% of BSI in a medical ICU were microbiologically
confirmed, and 70.8% were clinical sepsis (67). Blood for cultures had been drawn in most of the
clinical sepsis episodes (82.5%) and proved negative. BSI causes fever and chills 1-2 h after the
presence of microorganisms can be detected in the blood, which is why blood cultures are often
negative at the time of the temperature spike (125). Further, most patients with clinical sepsis are
under treatment with broad-spectrum antimicrobials for other conditions, decreasing the
sensitivity of blood cultures (50).

In a multicenter study in which nosocomial BSI acquired in adult ICUs in 30 hospitals in Spain
were analyzed, episodes were classified according to the patient’s systemic response as sepsis,
severe sepsis and septic shock (146). Among 590 episodes of nosocomial BSI, the host reaction
was classified as sepsis in 371 patients (62.8%), severe sepsis in 109 patients (18.5%), and septic
shock in the remaining 110 patients (18.6%). The systemic response differed markedly according
to the source of BSI. Thus, episodes of CR-BSI showed the lowest rate of septic shock (12.8%),
whereas episodes of BSI secondary to lower-respiratory tract, intra-abdominal or surgical
wound and soft tissue infections accounted for the highest incidence of severe sepsis and septic
shock.

It also seems that the systemic response may differ according to the microorganism causing the
episode of BSI. Gram-negative and Candida sp. have been associated with a higher incidence of
severe sepsis and septic shock (146), whereas CNS is the microorganism causing the lowest
incidence of septic shock. A multicenter study by Brun-Buisson et al. separately examined BSI
in the ICU and it was found that episodes caused by CNS were associated with a reduced risk of
severe sepsis (OR=0.2, p=0.02) compared to those caused by other microorganisms (25).

Infrequently, CR-BSI may be associated with local catheter site signs and symptoms similar to
those of aseptic phlebitis, such as erythma, tenderness, warmth and lymphangitis. Even so, local
signs of infection lack the sensitivity and specificity to be diagnosed as a CR-BSI (132), with the
exception of gross pus visible at the catheter exit site (92).

How to Differentiate Infection and Non-infection

C-reactive protein (CRP) and procalcitonin (PCT) are the most promising objective markers to
distinguish bacterial infection from other causes of fever or systemic inflammatory response
syndrome (SIRS). CPR is an acute phase protein secreted by the liver and is a marker of
inflammation. It is a more sensitive marker of sepsis than either body temperature or white blood
cell count (WCC) but lacks specificity (108).

PCT is a propeptide of calcitonin that is produced in the C cells of the thyroid. It is a more
specific marker of bacterial infection than CRP (93). PCT levels rise earlier than CRP and
correlate more closely with severity of disease (32). However, there are conflicting data
regarding its use in helping to distinguish infection from other causes of SIRS (26, 140, 145). A
review of these trials concluded that PCT was not useful for diagnosing sepsis in patients with
SIRS (61). Temperature, WCC, neutrophil percentage or changes in these values were not found
to be clinically reliable for predicting BSI (94). In another study, increased CRP and WCC were
described as suggestive of Gram-negative BSI, while almost unchanged CRP and WCC were
observed in patients with Gram-positive BSI (147). Despite these differences, however,
antimicrobial treatment cannot be withheld, started or guided based on these biomarkers.
DIAGNOSIS
To establish a diagnosis of CR-BSI, there has to be microbiological evidence incriminating the
catheter as the source of the bloodstream infection.

Diagnostic approaches can be classified into two main groups: those that require catheter
removal and those that can be undertaken with the catheter left in place (118). It should always
be borne in mind that the positive predictive value of all tests increases greatly with high pre-test
clinical probability, and this confirms the idea that rather than performing routine cultures, tests
should only be carried out if a CR-BSI is clinically suspected.

Reported figures indicate that the removal of a catheter because of clinical suspicion of CR-BSI
is unnecessary in over 70% of cases (i.e., the catheter is sterile) (87). This may be an important
issue, in that the removal of a CVC will limit vascular access, and diagnostic methods that do not
require catheter removal are currently being assessed (130). It is also true that many cases of CR-
BSI can be empirically managed without immediate catheter withdrawal (9, 126).

Procedures Without Removal of the Catheter

The diagnosis of CR-BSI by conservative methods (i.e., without catheter-withdrawal) is highly

convenient. Conservative procedures to assess catheter-tip colonization or CR-BSI include
superficial cultures (semiquantitative cultures of skin around the portal of entry and of catheter
hubs), differential paired quantitative blood cultures (comparing colony counts in blood obtained
from peripheral veins and catheter hubs) and, more recently, differential time to positivity (DTP),
in which time to positivity is compared between blood cultures obtained simultaneously from
peripheral veins and from catheter hubs (22, 30, 54).

Paired Quantitative Cultures (Central and Peripheral)

The sensitivity of the hub-blood culture is improved when a simultaneous peripheral blood
culture is obtained. By comparing microbial counts for hub and peripheral blood cultures,
bacterial overload in the central blood culture is observed when a CR-BSI is present. Conversely,
when the BSI is not related to a CVC, microbial counts are similar. In 1979, Wing et al. first
used differential quantitative blood cultures in a patient with suspected CR-BSI who had a
permanent indwelling hyperalimentation catheter (155). Blood drawn from the peripheral vein
had 25 colonies per ml, whereas blood drawn through the hub showed more than 10,000 colonies
per ml. When the CVC was removed, the catheter tip was found to be infected with the same
microorganisms that were present in the blood.

A significant differential colony count of > 3:1 for the CVC versus the peripheral vein culture is
indicative of CR-BSI, with a sensitivity of about 80% and a specificity of 90-100% (13).

Several ways of performing such cultures exist: the pour plate technique, the lysis-centrifugation
technique and direct inoculation of blood on agar media. The lysis-centrifugation technique
(Isolator, DuPont Co., Wilmington, Del.) is more sensitive than standard broth cultures for
detecting low levels of bacteremia, it eliminates the need to perform bedside inoculations and the
need for immediate transfer of the blood to the laboratory, although contaminants are more
frequent and it is more expensive than the simple pour plate technique (13). Blood is inoculated
into tubes with saponin, a cell-lysing agent. The contents of the tube are Vortex mixed and the
tube is centrifuged. The supernatant (lysate) is removed with a syringe, and the concentrate is
then inoculated onto agar plates. Tubes should be processed within 8 hours of inoculation (64).
After overnight incubation, plates are examined to determine the number of colony forming units
(cfu).

Differential Time to Positivity

In clinical microbiology practice, the time to blood culture positivity is measured using
automatic devices. A given cutoff value, linked to the metabolic growth and number of
microorganisms initially present in the bottle, indicates that microbial multiplication has
occurred in the bottle. The larger the bacterial inoculum, the quicker this cutoff value is reached.
In an in vitro study, a linear relationship between the initial concentration of various
microorganisms and the time to positivity of cultures was observed for all species tested (15).
Similar results have been reported using continuous-monitoring blood culture systems for the
diagnosis of CR-BSI due to CNS, with an average decrease of 1.5 h to positivity for each tenfold
increase in concentration (14). For an accurate interpretation of the DTP, a rigorous method is
mandatory. The first milliliters of blood drawn via the catheter should be used for culture and not
discarded, and only aerobic bottles are needed. For multiple lumen catheters, blood should be
drawn from the distal port, which corresponds to the portion of the device cultured (14). A DTP
of >120 minutes is highly predictive of CR-BSI (119). The performance of this test is as follows:
sensitivity, 94%; specificity, 89-91%; positive predictive value, 85-88% and negative predictive
value, 89-95%, depending on the type of catheter (short- vs. long-term) and on the type of patient
evaluated.

Superficial Cultures (Combined Exit-Site and Hub Cultures)

Exit-site cultures mainly reflect the extraluminal contamination route, which is predominant for
short-term catheters. This diagnostic technique was first proposed by Bjornson et al. in 1982 in
patients receiving total parenteral nutrition (11). In this study, the growth of more than 1,000
organisms at the catheter entry site was significantly associated with CR-BSI. Cultures of the
catheter hub mainly reflect the endoluminal contamination route, which is the main route of
infection for long-term catheters such as those used in cancer patients or patients on total
parenteral nutrition (136).

Cutaneous specimens are obtained with a dry or a moistened swab, after removal of the dressing.
No antiseptic agent is needed. The cotton swab is moistened with 0.01 M phosphate-buffered
saline (PBS) using the blister of the swab. The swab is then rubbed on the skin in two
perpendicular directions on a predefined area surrounding the insertion point of the catheter (e.g.,
in a 3 cm radius; a template may be used). To sample each of the catheter’s hubs, the catheter is
clamped to avoid any blood contamination, and the luer lock is removed aseptically. After
cleaning the outside of the hub with a disinfectant, the inner hub sample is taken using a swab
that is introduced into the hub and rubbed repeatedly against its inner surface. A different swab is
used for each hub.

All swabs are taken immediately to the laboratory, where a semiquantitative culture is performed
by streaking with each swab the entire surface of a Columbia agar plate supplemented with 5%
sheep’s blood. The threshold for positivity is 15 cfu per plate.

Gram staining of skin and hub swabs could also be helpful for the rapid diagnosis of CR-BSI
(77). Superficial cultures are indicated only when CR-BSI is suspected (“targeted” cultures).
Their high sensitivity and high negative predictive value makes them most useful for ruling out a
CR-BSI (30).

In a recent article by Bouza et al. the authors compared three procedures for the diagnosis of CR-
BSI without catheter removal (superficial cultures, paired quantitative blood cultures and DTP
(20). The DTP procedure displayed a higher sensitivity and negative predictive value for
predicting catheter tip colonization than quantitative blood cultures (96.4% and 99.4% vs. 71.4%
and 95.6%, respectively) (Table 1). Nevertheless, differential quantitative blood cultures with a
ratio >5 offered the best specificity for the diagnosis of CR-BSI (97.7%). The negative predictive
value of the three tests considered was high, and if a negative result was obtained in any of the
tests, catheter colonization and CR-BSI could reasonably be ruled out. The DTP method was less
specific than differential quantitative blood cultures and has the shortcoming of promoting the
indiscriminate use of catheter hubs to draw blood for cultures, with the consequent risk of
reporting false-positive results for bacteremia and CR-BSI. In addition, the requirements of
inoculating the same amount of blood in each culture bottle and the need to alert the
microbiology department to incubate the bottles as soon as they arrive at the laboratory are
further drawbacks of this technique. The authors conclude that owing to their ease of
performance, low cost and wide availability, semiquantitative superficial cultures (both catheter
exit-site and hubs) and peripheral-vein blood cultures combined could be used to screen for CR-
BSI, and the use of differential quantitative blood cultures reserved as a more specific
confirmatory technique.

Procedures with Catheter Removal

Once the CVC is removed, there are several diagnostic methods to demonstrate catheter
colonization: catheter tip cultures, quantitative catheter segment cultures and microscopy of
stained catheters. The semiquantitative roll-plate catheter culture (Maki’s technique) has proved
as effective as quantitative methods for diagnosing catheter colonization (21, 130). Due to the
simplicity and effectiveness of Maki’s technique, it should be the procedure of choice for
culturing catheter tips (21).

This method, nevertheless, still requires at least 24 h of incubation. Rapid information to

clinicians within 24 h of suspecting an episode of BSI is critical for intervention and modifying
therapeutic strategies (23). Acridine orange slide staining of catheter tips (confirmed by Gram
staining ) is a reliable instant procedure that may help physicians rule out the catheter as the
cause of sepsis immediately after withdrawal, and thus to make the decision to initiate or
withhold antimicrobial treatment, before the results of Maki’s technique are available (19).

The CDC Hospital Infection Control Policy Advisory Committee recommends vascular catheter
tip cultures only when there is local inflammation at the catheter insertion site or clinical signs
of bacteremia or candidemia, but not under routine conditions (99).

Strategy Used by the Authors

As already mentioned, in a patient with a CVC (short- or long-term) diagnosed with clinical
sepsis, who is mildly or moderately ill (no hypotension or organ failure), empiric antibiotic
treatment may be administered without immediate catheter removal. The management protocol
pursued at our institution is as follows: To confirm or rule out the catheter as the cause of the
bacteremia (BSI), BEFORE starting empirical antibiotic treatment, we undertake superficial
cultures (combined exit-site and hub cultures), to determine if the catheter tip is colonized, and
two peripheral vein blood cultures, to determine the etiology of the BSI.

Skin specimens are obtained with a moistened swab, after removal of the dressing. No antiseptic
agent is needed. The swab is rubbed over a predefined skin area around the insertion point of the
catheter (e.g., covering a 3 cm radius; a template may be used).

To sample each of the catheter’s hubs, the catheter is clamped to avoid blood contamination, and
the luer lock removed aseptically. After cleaning the outside of the hub with a disinfectant, the
inner hub sample is taken using an alginate swab (small bore that fits in) that is introduced into
the hub and rubbed repeatedly against its inner surface. A different swab is used for each hub.

All swabs are taken immediately to the laboratory, where a semiquantitative culture is performed
by streaking with each swab the entire surface of a Columbia agar plate supplemented with 5%
sheep’s blood. A rapid presumptive diagnosis can be reached by Gram staining of the swabs.

Superficial cultures are scored positive when the same microorganism (≥15 cfu per plate) is
isolated from any of them (skin or hub/s) and from peripheral blood. In this case, the catheter is
incriminated as the possible source of the BSI, and the consequent actions taken.

If superficial cultures (both skin and hubs) are negative, the catheter is ruled out as the origin of
BSI. We then recommend looking for a source of infection other than the CVC.

Upon catheter removal, we perform a semiquantitative count on the tip (Maki’s technique).
Colonization of the catheter tip to the amount of ≥15 cfu of the same microorganism per plate is
defined as a positive semiquantitative culture result. In highly compromised patients with proven
BSI, the isolation of 5-14 cfu/plate may be considered of value, especially if the microorganism
in question is the same as that causing the bacteremia.
ANTIBIOTIC THERAPY
Empiric Antibiotic Therapy Prior to Definitive Diagnosis

Vancomycin or teicoplanin are recommended for the empirical therapy of CR-BSI,

since CNS are the most common causative microorganisms and over 80% of these pathogens are
methicillin resistant (95).

No randomized trials for the treatment of coagulase-negative CR-BSI have been performed.
Such infections may resolve with removal of the catheter and no antibiotic therapy, and some
experts recommend no antibiotic therapy in patients without a prosthetic heart valve or
pacemaker unless fever and/or BSI persist after catheter removal. Others recommend that such
infections should be treated with antibiotics for a short period of time (3-5 days).

Indications for Empiric Gram-Negative or Antifungal Coverage

Extra coverage for Gram-negative bacilli (Enterobacteriaceae and Pseudomonas spp.) should be
administered in severely ill or immunocompromised patients with suspected CR-BSI, and in
patients with a femoral CVC (89). Added coverage may take the form of a third- or fourth-
generation cephalosporin, such as ceftazidime or cefepime, or other drugs (e.g., carbapenem ±
aminoglycoside) depending on local epidemiology. The superior performance of any given
specific class of antibiotics in the treatment of a device-related Gram-negative BSI has not been
demonstrated.

The choice of an antifungal agent in patients in whom a CR-BSI due to Candida is suspected,
should depend on local epidemiology and patient factors. Three landmarks have to be
considered: whether the patient is hemodynamically stable, if azoles have been previously
administered and local epidemiology. If the patient is stable and has not received azoles,
empirical therapy should be started with fluconazole unless local epidemiology proves otherwise.
If the patient is not stable or has been given azoles, then empirical therapy should be initiated
with an echinocandin or alternatively with amphotericin B (102). The new guidelines being
prepared for the treatment of candidemia were discussed at the last International Conference on
Antimicrobial Agents and Chemotherapy held in Chicago in September (by Dr. Peter G.
Pappas); amphotericin B is no longer recommended for critically ill patients as first-line
treatment for candidemia.

Antibiotic Therapy for Specific Microbes

Confirmation of a CR-BSI, including identification of the microorganism and antimicrobial

susceptibility test results, is generally available within 48-72 hours of blood withdrawal for
culture. This information, along with the clinical condition of the patient, will be the basis for
modifying empirical treatment if necessary and initiating guided antimicrobial treatment.
To select the best antimicrobial treatment, five basic principles need to be considered: the
antimicrobial agent used should be the most efficient; it should be the safest; it should have the
most reduced spectrum; it should be the easiest to administer; and finally, it should be the most
economical. International guidelines exist with recommendations on the best antibiotic treatment
for the different bacteria (52, 87).

The intravenous antimicrobial treatment of CR-BSI in adults according to specific pathogen

isolated, is summarized in Table 2.

Duration of Therapy

The appropriate duration of antibiotic therapy for uncomplicated bacteremia (e.g., due to CNS)
caused by a non-tunneled CVC is an unresolved issue. Several aspects help to make proper
decisions: withdrawal of the catheter, clinical situation of the patient after withdrawal,
underlying conditions, persistence of positive blood cultures after 3-5 days of treatment, nature
of the microorganism causing the infection and presence of metastatic infections like
endocarditis, pulmonary septic emboli or osteomyelitis. After catheter removal, patients with no
exit site infection, tunnel infection, or port abscess caused by CNS in whom clinical progress is
good, bacteremia clears in less that 3-5 days and if there is no evidence of metastatic infection, 3
to 7 days of treatment may be sufficient.

On the contrary, patients with more virulent microorganisms such as S. aureus, Gram-negative
bacilli and other, probably require a minimum of 10-14 days of treatment even in the setting of a
proper clinical response and absence of metastatic infection (65, 110).

Patients must be carefully assessed for the development of symptoms or signs of metastatic
infection (e.g., persistent positive blood cultures, endocarditis, suppurative thrombophlebitis,
etc.), which requires four to six weeks of therapy. Other conditions that may warrant a longer
duration of therapy include immuncompromised hosts and the presence of osteomyelitis (6-8
weeks of therapy) (91).

The appropriate therapy length for non-tunneled CVC-associated S. aureus bacteremia is

controversial. Conventional practice dictates that all patients receive prolonged courses of
intravenous antibiotics. Some clinicians recommend abbreviated therapeutic courses (83, 157),
but an alternative approach involves prospectively identifying patients for whom abbreviated
therapy is appropriate. In 1999, Rosen et al. undertook a study to determine the cost-
effectiveness of transesophageal echocardiography (TEE) in establishing duration of therapy for
these infections (129). These authors compared antibiotic treatment based on TEE results with 2-
or 4-weeks of empirical therapy. The TEE strategy results ranged from savings, to costs of
$155,624 per quality-adjusted life-year. The authors concluded that for patients with clinically
uncomplicated catheter-associated S. aureus bacteremia, the use of TEE to determine therapy
duration is a cost-effective alternative to 2- or 4-weeks of empirical therapy. We perform TEE
systematically in all patients with S. aureus bacteremia unless formally contraindicated.

Patients with complicated S. aureus bacteremia should be carefully evaluated for metastatic signs
of infection and should probably not receive short-course antibiotic therapy (109). The reason for
this is that infectious complications generally occur in at least 25% of patients with CR-BSI
caused by S. aureus (68, 104). The most important complication to consider is endocarditis
owing to a frequent lack of specific signs and because short-course therapy for bacteremia
consisting of up to 2 weeks of antibiotics will often fail if there is endocarditis. A TEE should
therefore be performed in all patients with CR-BSI caused by S. aureus.

In patients with non-tunneled CVC-related Gram-negative bacteremia, the device should be

removed and treatment should be given over 10-14 days (87). There are no data from prospective
studies to date, however, to support this approach.

Empirical antifungal treatment for candidemia should be continued for 14 days after blood
cultures have turned negative and signs and symptoms of infection have resolved (87). Timing of
CVC removal may best be determined after carefully considering the risks and benefits for
individual patients (128).

NON-ANTIBIOTIC MANAGEMENT
Catheter Removal

Whether to treat a CR-BSI and the type of treatment is determined by a multitude of factors,
including the pathogen, type of catheter, severity of illness, clinical and radiographic
manifestations suggesting a complicated course, the difficulty of replacing the catheter, and
patient characteristics such as their concurrent condition (valvular heart
disease, neutropenia, thrombocytopenia) and the presence of intravascular prosthetic devices
(118).

We mentioned earlier in the Diagnosis section, that several techniques have a high negative
predictive value and can be used to rule out the involvement of the catheter (without catheter
removal) in many episodes of sepsis.

Basically, catheters should be removed in critically ill patients or when they are easy to replace.
The indications for catheter removal in CR-BSI are (fulfillment of one or more of the following):

1. Catheter easily replaceable (e.g., short-term catheter with suspicion of infection)

2. Bacteremia/sepsis persisting >48-72 h

3. Local complications (e.g., signs of tunnel or port infection)

4. Metastatic complications (e.g., IE, pulmonary embolism or peripheral embolism in arterial

catheters)

5. Patients with CR-BSI with a prosthetic intravascular device in place (e.g., prosthetic valve,
pacemaker, defibrillator, etc.)
6. Microorganisms difficult to eradicate (e.g., Staphylococcus
aureus, Bacillus spp., Corynebacterium JK, Pseudomonas spp., mycobacteria, fungi)

7. CVC replaced over a guidewire and catheter tip culture results indicating significant
colonization of the original catheter

8. Infection recurrence after antibiotics have been discontinued

On the contrary, a decision to maintain the catheter may be made when all the following criteria
are fulfilled or when rapid microbiological techniques exclude the catheter as a potential source
of the sepsis:

1. The catheter is difficult to replace

2. Blood is sterile over 48-72 h

3. There are no signs of tunnel or port infection

4. There are no signs of metastatic complications

5. CR-BSI is caused by microorganisms medically treatable

6. The patient is hemodynamically stable

Although patients with CR-BSI caused by coagulase-negative staphylococci can be treated

successfully with the catheter in place, most remaining free of recurrence, catheter retention
results in a significantly higher risk (3x or 20%) of recurrence of the bacteremia (114).
Notwithstanding, not removing the catheter in these cases has not been linked to an increased
risk of death.

In cases of CR-BSI due to S. aureus, Gram-negative bacilli or Candida spp., the consequence of
leaving the catheter in-situ is very different. For S. aureus, there is a 4-6.5 times higher risk of
death if the catheter is left in place (57, 83). In another study, it was found that up to 52% of
patients with MRSA CR-BSI in whom the catheter was not removed died (41).

In a study by Hanna et al. in which assessment was made of the outcome of CVC removal in
preventing relapse in patients with CR-BSI due to Gram-negative bacilli, infection recurrence
due to the same organism was observed only in 1 patient (1%), whereas all 5 patients with
retained CVCs relapsed after having responded to treatment (p<0.001). Catheter removal within
72 hours of the onset of the CR-BSI was the only independent protective factor against infection
relapse (odds ratio, 0.13; 95% confidence interval, 0.02-0.75; p=0.02) (66). This also holds for
glucose non-fermenting Gram-negative bacilli (17).

For Candida CR-BSI, there is a 2-10 times higher independent risk of death when the catheter is
left in-situ after the first positive blood culture (96,97). In our opinion, the only catheters that
should be preserved in patients with candidemia are those in which there is an alternative source
of candidemia. Raad et al. reported that the clinical characteristics that suggest a non-catheter
source of candidemia are disseminated infection (p<0.01), previous chemotherapy (p<0.01),
previous steroid therapy (p=0.02) and a poor response to antifungal therapy (p<0.03); in such
cases candidemia might be managed without catheter removal (116). In addition, we suggest the
use of superficial cultures (skin and hubs) to help rule out the catheter as the source of fungemia.

Several other miscellaneous microorganisms can cause CR-BSI but at present, no general advice
can be given regarding whether the contaminated device should be removed, or the best
treatment to instill.

Lock Therapy

Lock therapy consists of replenishing the lumens of catheters with solutions containing high
doses of antimicrobial agents or other antimicrobial substances at concentrations able to
penetrate biofilms and to eliminate bacteria during variable periods in which the selected lumen
may be locked and maintained without flow of intravenous solutions. The use of an antibiotic
lock does not avoid the need for systemic antimicrobial therapy.

Lock-therapy is designed to treat catheter infections in which a conservative approach is both

possible and desirable or to prevent infections in particular circumstances. The sequential
administration of antibiotics through each lumen of a multi-lumen catheter is a reasonable
approach, although the evidence to support this practice in different situations is still weak.

Lock therapy should complement and not substitute systemic treatment in patients with CR-BSI
(39, 74, 117). Lock-therapy has proved to be effective in sterilizing the lumen of CVC in several
studies, which have reported on the use of several antimicrobial agents
(5, 8, 18, 27, 38, 43, 47, 48, 59, 62,63, 127, 135, 148, 156) and ethanol (42,100). Antimicrobials
that have been used for lock therapy and their recommended concentrations are provided
in Table 3.

Antimicrobial solutions with the desired agent are mixed with 1% sodium heparin to achieve a
final concentration of 100 U/ml of heparin in a volume sufficient to fill the catheter lumen/s.
Once the solution has been prepared, it should be protected from light using aluminum foil and
kept refrigerated for up to 7 days. The solution should be labeled detailing: the antimicrobial
agent and its concentration; the sodium heparin concentration; the date of preparation and the
starting volume of solution. The solution should always be handled aseptically.

Each lumen is filled with 2 to 5 ml of the prepared solution. In the case of a surgically implanted
CVC (e.g., Hickman, Broviac, Groshong or Quinton catheter), 5 ml of solution should be used to
lock each lumen. The duration of the lock depends on the use given to the catheter but should be
at least 12 hours a day. The solution is replenished every 24 hours after aspirating the existing
solution in the catheter. In patients on hemodialysis, the lock solution is replaced between
sessions. The CVC should be handled following the general care instructions for central lines.
Other promising but still experimental lock solutions include minocycline, EDTA
(12, 40, 113, 115), ethanol (24, 33, 39, 42, 75, 90, 100, 101, 105, 117, 154) and taurolidine
(69, 70, 73). Table 3 also provides information on ethanol dosages.

ENDPOINTS FOR MONITORING THERAPY

True bacteremia can be transient, persistent or breakthrough. Transient bacteremia spontaneously
subsides in less than 8-12 hours. A persistent bacteremia is one that continues beyond an
appropriate length of treatment, which for bacteremia due to methicillin-resistant S. aureus has
been established at ≥ 7 days (56) and for bacteremia caused by methicillin-susceptible S.
aureus at ≥ 2-4 days (55). A breakthrough infection is one arising during appropriate
antimicrobial therapy when previous blood cultures have been negative.

It is generally accepted that patients with bacteremia should show improvement within 48-72
hours of adequate treatment. Continued fever or its reappearance or other inflammatory response
signs or symptoms beyond 72 hours should alert the physician of a possible complicated course
of infection. Similarly, the new-onset of fever or signs of sepsis after treatment of a bacteremia
determines a need to reassess the patient to rule out relapse or a suppurating complication.

The benefits of conducting “control” blood cultures to establish the microbiological cure of a
bacteremia have not been demonstrated except in the case of S. aureus bacteremia (55) or
a Candida spp. BSI (122, 123) in which the course is likely to be complicated. In both cases,
blood cultures at 48-96 hours from the start of treatment are recommended. It is also
recommended that repeat blood cultures be undertaken in patients with continued fever or who
do not show clinical improvement within 48-96 hours of appropriate treatment, in patients in
whom fever reappears or in those in whom endocarditis is suspected.

For patients with CR-BSI in whom catheter salvage is attempted, repeat blood cultures should be
obtained (i.e., two sets of blood cultures daily) and the catheter should be removed if cultures
remain positive when drawn 72 hours after initiation of appropriate therapy. After catheters have
been removed from patients with CR-BSI, short-term CVCs may be reinserted after appropriate
systemic antimicrobial therapy is started and repeat blood cultures are negative.

COMPLICATIONS
Persistent Bloodstream Infection and Infective Endocarditis

For short-term and long-term catheters, persistent bacteremia or fungemia warrants their removal
(57, 83, 96). Patients with repeatedly positive blood cultures and/or an unchanged clinical status
persisting for 3 days after catheter removal should be treated presumptively for endovascular
infection involving ≥4 weeks of antimicrobial therapy in most cases and surgical intervention
when indicated (109).
Suppurative Thrombophlebitis

In all cases, the catheter involved should be removed (71, 139, 143, 149). For peripheral veins,
incision and drainage should be pursued. The infected peripheral vein and any affected
tributaries should be excised when there is suppuration, persistent bacteremia or fungemia, or
metastatic infection, and appropriate antibiotic therapy given (4, 58). Exploratory surgery should
be undertaken when infection extends beyond the vein into surrounding tissue (149). In cases of
peripheral arterial involvement with pseudoaneurysm formation, surgical excision and repair is
mandatory (51, 82).

Heparin is recommended to treat suppurative thrombophlebitis of the great central veins and
arteries (139, 143, 149) but it is not indicated for the routine management of suppurative
thrombophlebitis of peripheral veins (60, 144, 152).

Duration of antimicrobial therapy when the great central veins are involved is the same as that
for endocarditis (4-6 weeks); in most cases, vein excision is not required (71, 139).

In summary, the management of a CR-BSI requires antibiotics, with or without catheter removal,
depending on patient and etiological factors. Due to the high frequency of staphylococcal
infection, it is wise to use a glycopeptide empirically. Extra coverage for Gram-negative bacilli
should be administered in severely ill or immunocompromised patients, as well as for femoral
central venous catheter-related BSI. Once culture and sensitivity results are known, the antibiotic
therapy pursued can be more selective. The Infectious Disease Society of America is preparing
its updated “Guidelines for the Management of Intravascular Catheter–Related Infections"
(Clinical Infectious Diseases 2001; 32:1249–72) to be published in the fall of 2008.

Table 1. Validity Indices (95% Confidence Interval) for Three Commonly

Used Methods of Detecting Catheter-Related Bloodstream Infection

Measure Semiquantitative Differential quantitative blood Differential time to

superficial cultures cultures positivity
Sensitivity 78.6 (59.0-91.7) 71.4 (51.3-86.8) 96.4 (81.7-99.9)
Specificity 92.0 (87.0-95.6) 97.7 (94.3-99.4) 90.3 (85.0-94.3)
Positive predictive 61.1 (43.5-76.9) 83.3 (62.6-95.3) 61.4 (45.5-75.6)
value
Negative predictive 96.4 (92.4-98.7) 95.6 (91.4-98.1) 99.4 (96.6-99.9)
value
Accuracy 90.2 (85.3-93.9) 94.1 (90.0-96.9) 91.2 (86.4-94.7)

Table 2. Intravenous Antimicrobial Treatment of IV Catheter-Related

Bloodstream Infections (CR-BSI) in Adults According to the Pathogen Isolated

Pathogen Preferred Example, Alternative Comments

Antimicrobial dosage Antimicrobial
Agent Agent
 Pathogen Preferred Example, Alternative Comments
Antimicrobial dosage Antimicrobial
Agent Agent
S. aureus
Methicillin- Penicillinase- Nafcillin or oxa Cefazolin or cefuroxi Penicillinase-
susceptible resistant penicillin cillin, 2 g q4h me resistant
penicillin or
cephalosporins
are preferred to
vancomycin
Methicillin-resistant Vancomycin Vancomycin 15 Linezolid; or Strains with
mg/kg q12h daptomycin 6 mg/kg reduced
qday; or vancomycin susceptibility or
+ resistance to
(rifampin or gentami vancomycin
cin); or trimetoprim- have been
sulphametoxazolalon reported
e (if susceptible)
Vancomycin-non- Linezolid or dapto Linezolid 600 Quinupristin- For adults <40
susceptible mycin mg q12h or dalfopristin kg, linezolid
daptomycin 6 dose should be
mg/kg qday 10 mg/kg
Coagulase-negative
staphylococci
Methicillin- Penicillinase- Nafcillin or First-generation
susceptible resistant penicillin oxacillin, 2 g cephalosporin or
q4h vancomycin or
trimetoprim-
sulphametoxazol (if
susceptible)
Methicillin-resistant Vancomycin Vancomycin 15 Linezolid or For adults <40
mg/kg q12h quinupristin/dalfopris kg, the linezolid
tin dose should be
10 mg/kg
Enterococcus
faecalis /
Enterococcus
faecium
Ampicillin Ampicillin or Ampicillin 2 g Vancomycin
susceptible penicillin ± q4h-q6h, or
aminoglycoside ampicillin ±
gentamicin 1
mg/kg q8h
Ampicillin resistant, Vancomycin ± Vancomycin 15 Linezolid Quinupristin/dal
vancomycin aminoglycoside mg/kg q12h ± fopristin is not
 Pathogen Preferred Example, Alternative Comments
Antimicrobial dosage Antimicrobial
Agent Agent
susceptible gentamicin 1 active against E.
mg/kg q8h faecalis
Vancomycin Linezolid or Linezolid 600 Daptomycin Susceptibility of
resistant quinupristin/dalfop mg q12h or vancomycin-
ristin quinupristin/dalf resistant
opristin 7,5 Enterococci
mg/kg q8h isolates varies;
quinupristin/dalf
opristin is not
active against E.
faecalis
Gram-negative
bacilli
Escherichi coli and 3rd-generation Ceftriaxone, 1-2 Ciprofloxacin or aztr Susceptibility of
Klebsiella spp. ESB cephalosporin g q.day eonam strains varies
L-negative†
Escherichi Carbapenem Imipenem 500 Ciprofloxacin or Susceptibility of
coli andKlebsiella sp mg q6h or aztreonam strains varies
p. ESBL-positive† meropenem 1 g
q8h
Enterobacter spp. Carbapenem Imipenem 500 Cefepime or Susceptibility of
And Serratia mg q6h or Ciprofloxacin strains varies
marcescens meropenem 1 g
q8h
Acinetobacter spp. Ampicillin/sulbact Ampicillin/sulba Susceptibility of
am or carbapenem ctam, 3 g q6h; strains varies
or imipenem
500 mg q6h; or
meropenem 1 g
q8h
Stenotrophomonas Trimetoprim- Trimetoprim- Ticarcillin and
maltophilia sulphametoxazol sulphametoxazo clavulanic acid
l 3-5 mg/kg q8h
Pseudomonas Fourth-generation Cefepime 2 g Susceptibility of
aeruginosa cephalosporin or q8h; or strains varies
carbapenem Imipenem, 500
or piperacillin/tazo mg q6h; or
bactam ± meropenem 1 g
aminoglycoside q8h; or
piperacillin/tazo
bactam 4.5 g
q6h, amikacin 1
 Pathogen Preferred Example, Alternative Comments
Antimicrobial dosage Antimicrobial
Agent Agent
5 mg/kg q24h
or tobramycin 5-
6 mg/kg q24h
Burkholderia Trimetoprim- Trimetoprim-
cepacia sulphametoxazol sulphametoxazo
or carbapenem l 3-5 mg/kg q8h;
or imipenem
500 mg q6h; or
meropenem 1 g
q8h
Fungi
Candida albicans or Echinocandin Fluconazole Lipid amphotericinpr Echinocandin
otherCandida spp. or fluconazole(if 400-600 mg eparations should be used
organism is qday; to treat critically
susceptible) or caspofungin 7 ill patients until
0mg/kg load, fungal isolate is
then 50 mg/kg identified
qday

†ESBL: extended-spectrum beta-lactamase

Modified from (87)

Table 3. Antimicrobials Used for Catheter Lock-Therapy in Patients with

Catheter-Related Bloodstream Infection

Antimicrobial Final concentration of Sodium References

the antimicrobial heparin*
Amikacin 5-15 mg/ml Yes (43)
Amphotericin B 2.5-5 mg/ml Yes (5, 135, 156)
Ampicillin / amoxicillin 5-10 mg/ml Yes (48,127)
Ciprofloxacin 2 mg/ml No (148)
Fluconazole 3 mg/ml Yes (135)
Gentamicin 5-40 mg/ml Yes (1, 148)
Linezolid 2 mg/ml Yes (38)
Piperacillin 100 mg/ml Yes (18)
Vancomycin 5 mg/ml Yes (18)
Medical grade ethyl alcohol 70% No (24, 33, 101)
*Antimicrobial solutions with the desired agent are mixed with 1% sodium heparin to achieve a
final concentration of 100 U/ml of heparin in a volume sufficient to fill the catheter lumen/s