Catheter-Related Bloodstream Infection

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

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.


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 (124150151). 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 (295), 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 (1644121138), to up to 35% in prospective studies that did not consider disease severity (34107). The cost per infection is an estimated $25,155-$127,610 (457699).

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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 (31046133).

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 (11133137). 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 (7,11142). 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 (78134).

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 (88111).

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 (297280).

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 (5398103131). 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.

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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 arthritiscellulitis, myonecrosis, necrotizing fascitis or meningitis. The urinary tract is unimportant in most ICU patients as a primary source of infection (84141).

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 (3684). A temperature ≥41.1ºC (106ºF) is usually noninfectious in origin (37).

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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 influenzaeStreptococcus pneumoniaeNeisseria 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%) (49153). 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 (685106). 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 (26140145). 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.

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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 (9126).

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 (223054).

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).

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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.

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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 (21130). 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.

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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 (5287).

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 (65110).

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 (83157), 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 (68104). 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).

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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 JKPseudomonas 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.

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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 (3974117). 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 (581827384347485962,63127135148156) 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 (1240113115), ethanol (243339427590100101105117154) and taurolidine (697073). Table 3 also provides information on ethanol dosages.

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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 (122123) 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.

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Persistent Bloodstream Infection and Infective Endocarditis

For short-term and long-term catheters, persistent bacteremia or fungemia warrants their removal (578396). 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 (71139143149). 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 (458). 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 (5182).

Heparin is recommended to treat suppurative thrombophlebitis of the great central veins and arteries (139143149) but it is not indicated for the routine management of suppurative thrombophlebitis of peripheral veins (60144152).

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 (71139).

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.

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Table 1. Validity Indices (95% Confidence Interval) for Three Commonly Used Methods of Detecting Catheter-Related Bloodstream Infection


Semiquantitative superficial cultures

Differential quantitative blood cultures

Differential time to positivity


78.6 (59.0-91.7)

71.4 (51.3-86.8)

96.4 (81.7-99.9)


92.0 (87.0-95.6)

97.7 (94.3-99.4)

90.3 (85.0-94.3)

Positive predictive value

61.1 (43.5-76.9)

83.3 (62.6-95.3)

61.4 (45.5-75.6)

Negative predictive value

96.4 (92.4-98.7)

95.6 (91.4-98.1)

99.4 (96.6-99.9)


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


Preferred Antimicrobial Agent

Example, dosage

Alternative Antimicrobial Agent


S. aureus






Penicillinase-resistant penicillin

Nafcillin or oxacillin, 2 g q4h

Cefazolin or cefuroxime

Penicillinase-resistant penicillin or cephalosporins are preferred to vancomycin



Vancomycin 15 mg/kg q12h

Linezolid; or daptomycin 6 mg/kg qday; or vancomycin + (rifampin or gentamicin); or trimetoprim-sulphametoxazolalone (if susceptible)

Strains with reduced susceptibility or resistance to vancomycin have been reported


Linezolid or daptomycin

Linezolid 600 mg q12h or daptomycin 6 mg/kg qday


For adults <40 kg, linezolid dose should be 10 mg/kg

Coagulase-negative staphylococci


Penicillinase-resistant penicillin

Nafcillin or oxacillin, 2 g q4h

First-generation cephalosporin or vancomycin or trimetoprim-sulphametoxazol (if susceptible)




Vancomycin 15 mg/kg q12h

Linezolid or quinupristin/dalfopristin

For adults <40 kg, the linezolid dose should be 10 mg/kg

Enterococcus faecalis / Enterococcus faecium





Ampicillin susceptible

Ampicillin or penicillin ± aminoglycoside

Ampicillin 2 g q4h-q6h, or ampicillin ± gentamicin 1 mg/kg q8h



Ampicillin resistant, vancomycin susceptible

Vancomycin ± aminoglycoside

Vancomycin 15 mg/kg q12h ± gentamicin 1 mg/kg q8h


Quinupristin/dalfopristin is not active against E. faecalis

Vancomycin resistant

Linezolid or quinupristin/dalfopristin

Linezolid 600 mg q12h or quinupristin/dalfopristin 7,5 mg/kg q8h


Susceptibility of vancomycin-resistant Enterococci isolates varies; quinupristin/dalfopristin is not active against E. faecalis

Gram-negative bacilli





Escherichi coli and Klebsiella spp. ESBL-negative†

3rd-generation cephalosporin

Ceftriaxone, 1-2 g

Ciprofloxacin or aztreonam

Susceptibility of strains varies

Escherichi coli andKlebsiella spp. ESBL-positive†


Imipenem 500 mg q6h or meropenem 1 g q8h

Ciprofloxacin or aztreonam

Susceptibility of strains varies

Enterobacter spp. And Serratia marcescens


Imipenem 500 mg q6h or meropenem 1 g q8h

Cefepime or Ciprofloxacin

Susceptibility of strains varies

Acinetobacter spp.

Ampicillin/sulbactam or carbapenem

Ampicillin/sulbactam, 3 g q6h; or imipenem 500 mg q6h; or meropenem 1 g q8h


Susceptibility of strains varies

Stenotrophomonas maltophilia


Trimetoprim-sulphametoxazol 3-5 mg/kg q8h

Ticarcillin and clavulanic acid


Pseudomonas aeruginosa

Fourth-generation cephalosporin or carbapenem or piperacillin/tazobactam ± aminoglycoside

Cefepime 2 g q8h; or Imipenem, 500 mg q6h; or meropenem 1 g q8h; or piperacillin/tazobactam 4.5 g q6h, amikacin 15 mg/kg q24h or tobramycin 5-6 mg/kg q24h


Susceptibility of strains varies

Burkholderia cepacia

Trimetoprim-sulphametoxazol or carbapenem

Trimetoprim-sulphametoxazol 3-5 mg/kg q8h; or imipenem 500 mg q6h; or meropenem 1 g q8h








Candida albicans or otherCandida spp.

Echinocandin or fluconazole(if organism is susceptible)

Fluconazole 400-600 mg qday; or caspofungin 70mg/kg load, then 50 mg/kg qday

Lipid amphotericinpreparations

Echinocandin should be used to treat critically ill patients until fungal isolate is identified

†ESBL: extended-spectrum beta-lactamase

Modified from (87)

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


Final concentration of the antimicrobial

Sodium heparin*



5-15 mg/ml



Amphotericin B

2.5-5 mg/ml


 (5, 135, 156)

Ampicillin / amoxicillin

5-10 mg/ml




2 mg/ml




3 mg/ml




5-40 mg/ml


 (1, 148)


2 mg/ml




100 mg/ml




5 mg/ml



Medical grade ethyl alcohol



 (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

Guided Medline Search For Historical Aspects

Catheter-Related Bloodstream Infection