Catheter-Related Bloodstream Infection

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.

References

1. Al-Hwiesh AK, Abdul-Rahman IS. Successful prevention of tunneled, central catheter infection by antibiotic lock therapy using vancomycin and gentamycin. Saudi J Kidney Dis Transpl 2007;18(2):239-47.  [PubMed]

2. Alvarez-Lerma F, Palomar M, Olaechea P, Otal JJ, Insausti J, Cerda E. [National Study of Control of Nosocomial Infection in Intensive Care Units. Evolutive report of the years 2003-2005]. Med Intensiva 2007;31(1):6-17. [PubMed]

3. Anaissie E, Samonis G, Kontoyiannis D, et al. Role of catheter colonization and infrequent hematogenous seeding in catheter-related infections. Eur J Clin Microbiol Infect Dis 1995;14(2):134-7. [PubMed]

4. Andes DR, Urban AW, Acher CW, Maki DG. Septic thrombosis of the basilic, axillary, and subclavian veins caused by a peripherally inserted central venous catheter. Am J Med 1998;105(5):446-50. [PubMed]

5. Angel-Moreno A, Boronat M, Bolanos M, Carrillo A, Gonzalez S, Perez Arellano JL. Candida glabrata fungemia cured by antibiotic-lock therapy: case report and short review. J Infect 2005;51(3):e85-7. [PubMed]

6. Arbo MJ, Fine MJ, Hanusa BH, Sefcik T, Kapoor WN. Fever of nosocomial origin: etiology, risk factors, and outcomes. Am J Med 1993;95(5):505-12. [PubMed]

7. Armstrong CW, Mayhall CG, Miller KB, et al. Clinical predictors of infection of central venous catheters used for total parenteral nutrition. Infect Control Hosp Epidemiol 1990;11(2):71-8. [PubMed]

8. Bailey E, Berry N, Cheesbrough JS. Antimicrobial lock therapy for catheter-related bacteraemia among patients on maintenance haemodialysis. J Antimicrob Chemother 2002;50(4):615-7. [PubMed]

9. Benezra D, Kiehn TE, Gold JW, Brown AE, Turnbull AD, Armstrong D. Prospective study of infections in indwelling central venous catheters using quantitative blood cultures. Am J Med 1988;85(4):495-8. [PubMed]

10. Bjornson HS. Pathogenesis, prevention, and management of catheter-associated infections. New Horiz 1993;1(2):271-8. [PubMed]

11. Bjornson HS, Colley R, Bower RH, Duty VP, Schwartz-Fulton JT, Fischer JE. Association between microorganism growth at the catheter insertion site and colonization of the catheter in patients receiving total parenteral nutrition. Surgery 1982;92(4):720-7. [PubMed]

12. Bleyer AJ, Mason L, Russell G, Raad, II, Sherertz RJ. A randomized, controlled trial of a new vascular catheter flush solution (minocycline-EDTA) in temporary hemodialysis access. Infect Control Hosp Epidemiol 2005;26(6):520-4. [PubMed]

13. Blot F. Diagnosis of catheter-related infections. In: Seifert H, Jansen B, Farr B, eds. Catheter-related infections. New York: Marcel Dekker; 2005:37-76.

14. Blot F, Nitenberg G, Chachaty E, et al. Diagnosis of catheter-related bacteraemia: a prospective comparison of the time to positivity of hub-blood versus peripheral-blood cultures. Lancet 1999;354(9184):1071-7. [PubMed]

15. Blot F, Schmidt E, Nitenberg G, et al. Earlier positivity of central-venous- versus peripheral-blood cultures is highly predictive of catheter-related sepsis. J Clin Microbiol 1998;36(1):105-9. [PubMed]

16. Blot SI, Depuydt P, Annemans L, et al. Clinical and economic outcomes in critically ill patients with nosocomial catheter-related bloodstream infections. Clin Infect Dis 2005;41(11):1591-8 Epub 2005 Oct 25. [PubMed]

17. Boktour M, Hanna H, Ansari S, et al. Central venous catheter and Stenotrophomonas maltophilia bacteremia in cancer patients. Cancer 2006;106(9):1967-73. [PubMed]

18. Boorgu R, Dubrow AJ, Levin NW, et al. Adjunctive antibiotic/anticoagulant lock therapy in the treatment of bacteremia associated with the use of a subcutaneously implanted hemodialysis access device. Asaio J 2000;46(6):767-70. [PubMed]

19. Bouza E, Alvarado N, Alcala L, Munoz P, Rabadan PM, Rodriguez-Creixems M. An instant procedure to demonstrate catheter-tip colonization may help clinicians. Diagn Microbiol Infect Dis 2006;56(3):255-60 Epub 2006 Jul 18. [PubMed]

20. Bouza E, Alvarado N, Alcala L, Perez MJ, Rincon C, Munoz P. A randomized and prospective study of 3 procedures for the diagnosis of catheter-related bloodstream infection without catheter withdrawal. Clin Infect Dis 2007;44(6):820-6 Epub 2007 Feb 6. [PubMed]

21. Bouza E, Alvarado N, Alcala L, et al. A prospective, randomized, and comparative study of 3 different methods for the diagnosis of intravascular catheter colonization. Clin Infect Dis 2005;40(8):1096-100 Epub 2005 Mar 17. [PubMed]

22. Bouza E, Munoz P, Burillo A, et al. The challenge of anticipating catheter tip colonization in major heart surgery patients in the intensive care unit: are surface cultures useful? Crit Care Med 2005;33(9):1953-60. [PubMed]

23. Bouza E, Sousa D, Munoz P, Rodriguez-Creixems M, Fron C, Lechuz JG. Bloodstream infections: a trial of the impact of different methods of reporting positive blood culture results. Clin Infect Dis 2004;39(8):1161-9. [PubMed]

24. Broom J, Woods M, Allworth A, et al. Ethanol lock therapy to treat tunnelled central venous catheter-associated blood stream infections: Results from a prospective trial. Scand J Infect Dis 2008;40(5):399-406. [PubMed]

25. Brun-Buisson C, Doyon F, Carlet J. Bacteremia and severe sepsis in adults: a multicenter prospective survey in ICUs and wards of 24 hospitals. French Bacteremia-Sepsis Study Group. Am J Respir Crit Care Med 1996;154(3 Pt 1):617-24. [PubMed]

26. Brunkhorst FM, Eberhard OK, Brunkhorst R. Discrimination of infectious and noninfectious causes of early acute respiratory distress syndrome by procalcitonin. Crit Care Med 1999;27(10):2172-6. [PubMed]

27. Castagnola E, Moroni C, Gandullia P, et al. Catheter lock and systemic infusion of linezolid for treatment of persistent Broviac catheter-related staphylococcal bacteremia. Antimicrob Agents Chemother 2006;50(3):1120-1. [PubMed]  

28. Centers for Disease Control. CDC definitions for nosocomial infections. In; 2004:1-18.

29. Centers for Disease Control. Update: Delayed onset Pseudomonas fluorescens bloodstream infections after exposure to contaminated heparin flush--Michigan and South Dakota, 2005-2006. MMWR Morb Mortal Wkly Rep 2006;55(35):961-3. [PubMed] 

30. Cercenado E, Ena J, Rodriguez-Creixems M, Romero I, Bouza E. A conservative procedure for the diagnosis of catheter-related infections. Arch Intern Med 1990;150(7):1417-20. [PubMed]

31. Circiumaru B, Baldock G, Cohen J. A prospective study of fever in the intensive care unit. Intensive Care Med 1999;25(7):668-73. [PubMed]    

32. Claeys R, Vinken S, Spapen H, et al. Plasma procalcitonin and C-reactive protein in acute septic shock: clinical and biological correlates. Crit Care Med 2002;30(4):757-62. [PubMed]

33. Cober MP, Johnson CE. Stability of 70% alcohol solutions in polypropylene syringes for use in ethanol-lock therapy. Am J Health Syst Pharm 2007;64(23):2480-2. [PubMed]

34. Collignon PJ. Intravascular catheter associated sepsis: a common problem. The Australian Study on Intravascular Catheter Associated Sepsis. Med J Aust 1994;161(6):374-8. [PubMed]

35. Crnich CJ, Maki DG. The promise of novel technology for the prevention of intravascular device-related bloodstream infection. I. Pathogenesis and short-term devices. Clin Infect Dis 2002;34(9):1232-42 Epub 2002 Apr 2. [PubMed]

36. Cunha BA. Fever in the critical care unit. Crit Care Clin 1998;14(1):1-14. [PubMed] 

37. Cunha BA. Fever in the intensive care unit. Intensive Care Med 1999;25(7):648-51. [PubMed]

38. Curtin J, Cormican M, Fleming G, Keelehan J, Colleran E. Linezolid compared with eperezolid, vancomycin, and gentamicin in an in vitro model of antimicrobial lock therapy for Staphylococcus epidermidis central venous catheter-related biofilm infections. Antimicrob Agents Chemother 2003;47(10):3145-8. [PubMed]

39. Chambers ST, Pithie A, Gallagher K, Liu T, Charles CJ, Seaward L. Treatment of Staphylococcus epidermidis central vascular catheter infection with 70% ethanol locks: efficacy in a sheep model. J Antimicrob Chemother 2007;59(4):779-82 Epub 2007 Feb 5. [PubMed]

40. Chatzinikolaou I, Zipf TF, Hanna H, et al. Minocycline-ethylenediaminetetraacetate lock solution for the prevention of implantable port infections in children with cancer. Clin Infect Dis 2003;36(1):116-9 Epub 2002 Dec 11. [PubMed]

41. Cheong I, Samsudin LM, Law GH. Methicillin-resistant Staphylococcus aureus bacteraemia at a tertiary teaching hospital. Br J Clin Pract 1996;50(5):237-9. [PubMed]

42. Dannenberg C, Bierbach U, Rothe A, Beer J, Korholz D. Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheter. J Pediatr Hematol Oncol 2003;25(8):616-21. [PubMed]

43. Diamanti A, Basso MS, Castro M, Calce A, Gambarara M. Antibiotic-lock therapy in central venous catheter colonization in patients with intestinal failure. J Infect 2007;54(4):415-6 Epub 2006 Sep 14. [PubMed]

44. Digiovine B, Chenoweth C, Watts C, Higgins M. The attributable mortality and costs of primary nosocomial bloodstream infections in the intensive care unit. Am J Respir Crit Care Med 1999;160(3):976-81. [PubMed]

45. Dimick JB, Pelz RK, Consunji R, Swoboda SM, Hendrix CW, Lipsett PA. Increased resource use associated with catheter-related bloodstream infection in the surgical intensive care unit. Arch Surg 2001;136(2):229-34. [PubMed]

46. Donelli G. Vascular catheter-related infection and sepsis. Surg Infect (Larchmt) 2006;7(Suppl 2):S25-7. [PubMed]  [PubMed]

47. Easom A. Prophylactic antibiotic lock therapy for hemodialysis catheters. Nephrol Nurs J 2000;27(1):75.  [PubMed] 

48. Elwood RL, Spencer SE. Successful clearance of catheter-related bloodstream infection by antibiotic lock therapy using ampicillin. Ann Pharmacother 2006;40(2):347-50 Epub 2006 Jan 31.  [PubMed] 

49. Emori TG, Edwards JR, Culver DH, et al. Accuracy of reporting nosocomial infections in intensive-care-unit patients to the National Nosocomial Infections Surveillance System: a pilot study. Infect Control Hosp Epidemiol 1998;19(5):308-16.  [PubMed] 

50. Fagon JY, Chastre J, Wolff M, et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial. Ann Intern Med 2000;132(8):621-30.  [PubMed]

51. Falk PS, Scuderi PE, Sherertz RJ, Motsinger SM. Infected radial artery pseudoaneurysms occurring after percutaneous cannulation. Chest 1992;101(2):490-5.  [PubMed] 

52. Fatkenheuer G, Buchheidt D, Cornely OA, et al. Central venous catheter (CVC)-related infections in neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003;82(Suppl 2):S149-57 Epub 2003 Sep 9. [PubMed] 

53. Fortun Abete J, Asensio Vegas A, Perez Molina JA, Navas Elorza E, Cobo Reinoso J, Guerrero Espejo A. [The risk factors associated with colonization and bacteremia in non-tunnelled central venous catheters]. Rev Clin Esp 2000;200(3):126-32.  [PubMed] 

54. Fortun J, Perez-Molina JA, Asensio A, et al. Semiquantitative culture of subcutaneous segment for conservative diagnosis of intravascular catheter-related infection. JPEN J Parenter Enteral Nutr 2000;24(4):210-4.  [PubMed] 

55. Fowler VG, Jr., Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med 2003;163(17):2066-72.  [PubMed] 

56. Fowler VG, Jr., Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004;190(6):1140-9. [PubMed] 

57. Fowler VG, Jr., Sanders LL, Sexton DJ, et al. Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious diseases specialists: experience with 244 patients. Clin Infect Dis 1998;27(3):478-86.  [PubMed] 

58. Fry DE, Fry RV, Borzotta AP. Nosocomial blood-borne infection secondary to intravascular devices. Am J Surg 1994;167(2):268-72.[PubMed] 

59. Garcia de la Torre M, Bouza E. [Bacteremia. An old problem]. Enferm Infecc Microbiol Clin 1991;9(10):594-8. [PubMed] 

60. Garrison RN, Richardson JD, Fry DE. Catheter-associated septic thrombophlebitis. South Med J 1982;75(8):917-9. [PubMed] 

61. Gattas DJ, Cook DJ. Procalcitonin as a diagnostic test for sepsis: health technology assessment in the ICU. J Crit Care 2003;18(1):52-8. [PubMed]   

62. Gattuso G, Tomasoni D, Ceruti R, Scalzini A. Multiresistant Stenotrophomonas maltophilia tunneled CVC-related sepsis, treated with systemic and lock therapy. J Chemother 2004;16(5):494-6.  [PubMed] 

63. Giacometti A, Cirioni O, Ghiselli R, et al. Comparative efficacies of quinupristin-dalfopristin, linezolid, vancomycin, and ciprofloxacin in treatment, using the antibiotic-lock technique, of experimental catheter-related infection due to Staphylococcus aureus. Antimicrob Agents Chemother 2005;49(10):4042-5. [PubMed] 

64. Hamilton DJ, Amos D, Schwartz RW, Dent CM, Counts GW. Effect of delay in processing on lysis-centrifugation blood culture results from marrow transplant patients. J Clin Microbiol 1989;27(7):1588-93.  [PubMed] 

65. Hampton AA, Sherertz RJ. Vascular-access infections in hospitalized patients. Surg Clin North Am 1988;68(1):57-71.  [PubMed] 

66. Hanna H, Afif C, Alakech B, et al. Central venous catheter-related bacteremia due to gram-negative bacilli: significance of catheter removal in preventing relapse. Infect Control Hosp Epidemiol 2004;25(8):646-9.  [PubMed] 

67. Hugonnet S, Sax H, Eggimann P, Chevrolet JC, Pittet D. Nosocomial bloodstream infection and clinical sepsis. Emerg Infect Dis 2004;10(1):76-81. [PubMed] 

68. Jernigan JA, Farr BM. Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis. Ann Intern Med 1993;119(4):304-11. [PubMed] 

69. Jurewitsch B, Jeejeebhoy KN. Taurolidine lock: the key to prevention of recurrent catheter-related bloodstream infections. Clin Nutr 2005;24(3):462-5 Epub 2005 Apr 22.  [PubMed] 

70. Jurewitsch B, Lee T, Park J, Jeejeebhoy K. Taurolidine 2% as an antimicrobial lock solution for prevention of recurrent catheter-related bloodstream infections. JPEN J Parenter Enteral Nutr 1998;22(4):242-4. [PubMed]

71. Kaufman J, Demas C, Stark K, Flancbaum L. Catheter-related septic central venous thrombosis--current therapeutic options. West J Med 1986;145(2):200-3.  [PubMed] 

72. Kimura AC, Calvet H, Higa JI, et al. Outbreak of Ralstonia pickettii bacteremia in a neonatal intensive care unit. Pediatr Infect Dis J 2005;24(12):1099-103.  [PubMed] 

73. Koldehoff M, Zakrzewski JL. Taurolidine is effective in the treatment of central venous catheter-related bloodstream infections in cancer patients. Int J Antimicrob Agents 2004;24(5):491-5.  [PubMed] 

74. Korbila IP, Bliziotis IA, Lawrence KR, Falagas ME. Antibiotic-lock therapy for long-term catheter-related bacteremia: a review of the current evidence. Expert Rev Anti Infect Ther 2007;5(4):639-52.  [PubMed] 

75. Laird J, Soutar R, Butcher I. Complications of the ethanol-lock technique in the treatment of central venous catheter sepsis. J Infect 2005;51(4):338. [PubMed] 

76. Laupland KB, Lee H, Gregson DB, Manns BJ. Cost of intensive care unit-acquired bloodstream infections. J Hosp Infect 2006;63(2):124-32. [PubMed]     

77. Leon M, Garcia M, Herranz MA, et al. [Diagnostic value of Gram staining of peri-catheter skin and the connection in the prediction of intravascular-catheter-related bacteremia]. Enferm Infecc Microbiol Clin 1998;16(5):214-8.   [PubMed]

78. Linares J, Sitges-Serra A, Garau J, Perez JL, Martin R. Pathogenesis of catheter sepsis: a prospective study with quantitative and semiquantitative cultures of catheter hub and segments. J Clin Microbiol 1985;21(3):357-60. [PubMed]

79. Lugauer S, Regenfus A, Boswald M, et al. A new scoring system for the clinical diagnosis of catheter-related infections. Infection 1999;27 Suppl 1:S49-53. [PubMed]

80. Maki DG. Nosocomial bacteremia. An epidemiologic overview. Am J Med 1981;70(3):719-32. [PubMed]

81. Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clin Proc 2006;81(9):1159-71. [PubMed]

82. Maki DG, McCormick RD, Uman SJ, Wirtanen GW. Septic endarteritis due to intra-arterial catheters for cancer chemotherapy. I. Evaluation of an outbreak. II. Risk factors, clinical features and management, III. Guidelines for prevention. Cancer 1979;44(4):1228-40. [PubMed]

83. Malanoski GJ, Samore MH, Pefanis A, Karchmer AW. Staphylococcus aureus catheter-associated bacteremia. Minimal effective therapy and unusual infectious complications associated with arterial sheath catheters. Arch Intern Med 1995;155(11):1161-6. [PubMed]

84. Marik PE. Fever in the ICU. Chest 2000;117(3):855-69. [PubMed]

85. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348(16):1546-54. [PubMed]

86. Mermel LA. Prevention of intravascular catheter-related infections. Ann Intern Med 2000;132(5):391-402. [PubMed]

87. Mermel LA, Farr BM, Sherertz RJ, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis 2001;32(9):1249-72.[PubMed]

88. Mermel LA, McCormick RD, Springman SR, Maki DG. The pathogenesis and epidemiology of catheter-related infection with pulmonary artery Swan-Ganz catheters: a prospective study utilizing molecular subtyping. Am J Med 1991;91(3B):197S-205S. [PubMed]

89. Merrer J, De Jonghe B, Golliot F, et al. Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. Jama 2001;286(6):700-7. [PubMed]

90. Metcalf SC, Chambers ST, Pithie AD. Use of ethanol locks to prevent recurrent central line sepsis. J Infect 2004;49(1):20-2. [PubMed]

91. Mortara LA, Bayer AS. Staphylococcus aureus bacteremia and endocarditis. New diagnostic and therapeutic concepts. Infect Dis Clin North Am 1993;7(1):53-68. [PubMed] 

92. Moyer MA, Edwards LD, Farley L. Comparative culture methods on 101 intravenous catheters. Routine, semiquantitative, and blood cultures. Arch Intern Med 1983;143(1):66-9. [PubMed]

93. Muller B, Becker KL, Schachinger H, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 2000;28(4):977-83. [PubMed]

94. Murray CK, Hoffmaster RM, Schmit DR, et al. Evaluation of white blood cell count, neutrophil percentage, and elevated temperature as predictors of bloodstream infection in burn patients. Arch Surg 2007;142(7):639-42. [PubMed]

95. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32(8):470-85. [PubMed]

96. Nguyen MH, Peacock JE, Jr., Tanner DC, et al. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med 1995;155(22):2429-35. [PubMed]

97. Nucci M, Colombo AL, Silveira F, et al. Risk factors for death in patients with candidemia. Infect Control Hosp Epidemiol 1998;19(11):846-50.[PubMed]

98. O'Grady N P, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 2002;30(8):476-89. [PubMed]

99. O'Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51(RR-10):1-29. [PubMed]

100. Onland W, Shin CE, Fustar S, Rushing T, Wong WY. Ethanol-lock technique for persistent bacteremia of long-term intravascular devices in pediatric patients. Arch Pediatr Adolesc Med 2006;160(10):1049-53. [PubMed]

101. Opilla MT, Kirby DF, Edmond MB. Use of ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 2007;31(4):302-5. [PubMed] 

102. Ostrosky-Zeichner L, Pappas PG. Invasive candidiasis in the intensive care unit. Crit Care Med 2006;34(3):857-63. [PubMed]

103. Pawar M, Mehta Y, Kapoor P, Sharma J, Gupta A, Trehan N. Central venous catheter-related blood stream infections: incidence, risk factors, outcome, and associated pathogens. J Cardiothorac Vasc Anesth 2004;18(3):304-8.[PubMed]

 104. Peacock SJ, Curtis N, Berendt AR, Bowler IC, Winearls CG, Maxwell P. Outcome following haemodialysis catheter-related Staphylococcus aureus bacteraemia. J Hosp Infect 1999;41(3):223-8. [PubMed]

105. Pennington CR, Pithie AD. Ethanol lock in the management of catheter occlusion. JPEN J Parenter Enteral Nutr 1987;11(5):507-8. [PubMed]

106. Pittet D, Rangel-Frausto S, Li N, et al. Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU patients. Intensive Care Med 1995;21(4):302-9. [PubMed]

107. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs, and attributable mortality. Jama 1994;271(20):1598-601.[PubMed]

108. Povoa P, Almeida E, Moreira P, et al. C-reactive protein as an indicator of sepsis. Intensive Care Med 1998;24(10):1052-6. [PubMed]

109. Raad, II, Sabbagh MF. Optimal duration of therapy for catheter-related Staphylococcus aureus bacteremia: a study of 55 cases and review. Clin Infect Dis 1992;14(1):75-82.[PubMed]

110. Raad I. Intravascular-catheter-related infections. Lancet 1998;351(9106):893-8. [PubMed]

111. Raad I, Baba M, Bodey GP. Diagnosis of catheter-related infections: the role of surveillance and targeted quantitative skin cultures. Clin Infect Dis 1995;20(3):593-7. [PubMed] 

112. Raad I, Costerton W, Sabharwal U, Sacilowski M, Anaissie E, Bodey GP. Ultrastructural analysis of indwelling vascular catheters: a quantitative relationship between luminal colonization and duration of placement. J Infect Dis 1993;168(2):400-7. [PubMed]

113. Raad I, Chatzinikolaou I, Chaiban G, et al. In vitro and ex vivo activities of minocycline and EDTA against microorganisms embedded in biofilm on catheter surfaces. Antimicrob Agents Chemother 2003;47(11):3580-5. [PubMed]

114. Raad I, Davis S, Khan A, Tarrand J, Elting L, Bodey GP. Impact of central venous catheter removal on the recurrence of catheter-related coagulase-negative staphylococcal bacteremia. Infect Control Hosp Epidemiol 1992;13(4):215-21.[PubMed]

115. Raad I, Hachem R, Tcholakian RK, Sherertz R. Efficacy of minocycline and EDTA lock solution in preventing catheter-related bacteremia, septic phlebitis, and endocarditis in rabbits. Antimicrob Agents Chemother 2002;46(2):327-32. [PubMed]

116. Raad I, Hanna H, Boktour M, et al. Management of central venous catheters in patients with cancer and candidemia. Clin Infect Dis 2004;38(8):1119-27.[PubMed]

117. Raad I, Hanna H, Dvorak T, Chaiban G, Hachem R. Optimal antimicrobial catheter lock solution, using different combinations of minocycline, EDTA, and 25-percent ethanol, rapidly eradicates organisms embedded in biofilm. Antimicrob Agents Chemother 2007;51(1):78-83. [PubMed]

118. Raad I, Hanna H, Maki D. Intravascular catheter-related infections: advances in diagnosis, prevention, and management. Lancet Infect Dis 2007;7(10):645-57. [PubMed]

119. Raad I, Hanna HA, Alakech B, Chatzinikolaou I, Johnson MM, Tarrand J. Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections. Ann Intern Med 2004;140(1):18-25. [PubMed]

120. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. Jama 1995;273(2):117-23. [PubMed]

121. Rello J, Ochagavia A, Sabanes E, et al. Evaluation of outcome of intravenous catheter-related infections in critically ill patients. Am J Respir Crit Care Med 2000;162(3 Pt 1):1027-30. [PubMed]

122. Rex JH, Bennett JE, Sugar AM, et al. Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and the Candidemia Study Group. Clin Infect Dis 1995;21(4):994-6. [PubMed]

123. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 1994;331(20):1325-30. [PubMed]

124. Richards M, Thursky K, Buising K. Epidemiology, prevalence, and sites of infections in intensive care units. Semin Respir Crit Care Med 2003;24(1):3-22. [PubMed]

125. Riedel S, Bourbeau P, Swartz B, et al. The Timing of Specimen Collection for Blood Cultures in Febrile Patients with Bacteremia. J Clin Microbiol 2008. [PubMed] 

126. Rijnders BJ, Peetermans WE, Verwaest C, Wilmer A, Van Wijngaerden E. Watchful waiting versus immediate catheter removal in ICU patients with suspected catheter-related infection: a randomized trial. Intensive Care Med 2004;30(6):1073-80 Epub 2004 Mar 4. [PubMed] 

127. Robinson JL, Tawfik G, Saxinger L, Stang L, Etches W, Lee B. Stability of heparin and physical compatibility of heparin/antibiotic solutions in concentrations appropriate for antibiotic lock therapy. J Antimicrob Chemother 2005;56(5):951-3. [PubMed] 

128. Rodriguez D, Park BJ, Almirante B, et al. Impact of early central venous catheter removal on outcome in patients with candidaemia. Clin Microbiol Infect 2007;13(8):788-93.[PubMed] 

129. Rosen AB, Fowler VG, Jr., Corey GR, et al. Cost-effectiveness of transesophageal echocardiography to determine the duration of therapy for intravascular catheter-associated Staphylococcus aureus bacteremia. Ann Intern Med 1999;130(10):810-20.[PubMed] 

130. Safdar N, Fine JP, Maki DG. Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection. Ann Intern Med 2005;142(6):451-66. [PubMed] 

131. Safdar N, Kluger DM, Maki DG. A review of risk factors for catheter-related bloodstream infection caused by percutaneously inserted, noncuffed central venous catheters: implications for preventive strategies. Medicine (Baltimore) 2002;81(6):466-79. [PubMed] 

132. Safdar N, Maki DG. Inflammation at the insertion site is not predictive of catheter-related bloodstream infection with short-term, noncuffed central venous catheters. Crit Care Med 2002;30(12):2632-5. [PubMed] 

133. Safdar N, Maki DG. The pathogenesis of catheter-related bloodstream infection with noncuffed short-term central venous catheters. Intensive Care Med 2004;30(1):62-7. [PubMed] 

134. Salzman MB, Isenberg HD, Shapiro JF, Lipsitz PJ, Rubin LG. A prospective study of the catheter hub as the portal of entry for microorganisms causing catheter-related sepsis in neonates. J Infect Dis 1993;167(2):487-90. [PubMed] 

135. Schinabeck MK, Long LA, Hossain MA, et al. Rabbit model of Candida albicans biofilm infection: liposomal amphotericin B antifungal lock therapy. Antimicrob Agents Chemother 2004;48(5):1727-32. [PubMed] 

136. Segura M, Llado L, Guirao X, et al. A prospective study of a new protocol for 'in situ' diagnosis of central venous catheter related bacteraemia. Clin Nutr 1993;12(2):103-7. [PubMed] 

137. Seymour VM, Dhallu TS, Moss HA, Tebbs SE, Elliot TS. A prospective clinical study to investigate the microbial contamination ofa needleless connector. J Hosp Infect 2000;45(2):165-8. [PubMed] 

138. Soufir L, Timsit JF, Mahe C, Carlet J, Regnier B, Chevret S. Attributable morbidity and mortality of catheter-related septicemia in critically ill patients: a matched, risk-adjusted, cohort study. Infect Control Hosp Epidemiol 1999;20(6):396-401. [PubMed]   

139. Strinden WD, Helgerson RB, Maki DG. Candida septic thrombosis of the great central veins associated with central catheters. Clinical features and management. Ann Surg 1985;202(5):653-8. [PubMed]

140. Suprin E, Camus C, Gacouin A, et al. Procalcitonin: a valuable indicator of infection in a medical ICU? Intensive Care Med 2000;26(9):1232-8.[PubMed] 

141. Tambyah PA, Maki DG. Catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497 catheterized patients. Arch Intern Med 2000;160(5):678-82. [PubMed] 

142. Tietz A, Frei R, Dangel M, et al. Octenidine hydrochloride for the care of central venous catheter insertion sites in severely immunocompromised patients. Infect Control Hosp Epidemiol 2005;26(8):703-7. [PubMed] 

143. Topiel MS, Bryan RT, Kessler CM, Simon GL. Treatment of silastic catheter-induced central vein septic thrombophlebitis. Am J Med Sci 1986;291(6):425-8. [PubMed] 

144. Torres-Rojas JR, Stratton CW, Sanders CV, et al. Candidal suppurative peripheral thrombophlebitis. Ann Intern Med 1982;96(4):431-5. [PubMed] 

145. Ugarte H, Silva E, Mercan D, De Mendonca A, Vincent JL. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med 1999;27(3):498-504. [PubMed] 

146. Valles J, Leon C, Alvarez-Lerma F. Nosocomial bacteremia in critically ill patients: a multicenter study evaluating epidemiology and prognosis. Spanish Collaborative Group for Infections in Intensive Care Units of Sociedad Espanola de Medicina Intensiva y Unidades Coronarias (SEMIUC). Clin Infect Dis 1997;24(3):387-95. [PubMed] 

147. Vandijck DM, Hoste EA, Blot SI, Depuydt PO, Peleman RA, Decruyenaere JM. Dynamics of C-reactive protein and white blood cell count in critically ill patients with nosocomial Gram positive vs. Gram negative bacteremia: a historical cohort study. BMC Infect Dis 2007;7:106. [PubMed] 

148. Vercaigne LM, Sitar DS, Penner SB, Bernstein K, Wang GQ, Burczynski FJ. Antibiotic-heparin lock: in vitro antibiotic stability combined with heparin in a central venous catheter. Pharmacotherapy 2000;20(4):394-9. [PubMed]   

149. Verghese A, Widrich WC, Arbeit RD. Central venous septic thrombophlebitis--the role of medical therapy. Medicine (Baltimore) 1985;64(6):394-400.[PubMed]

150. Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. Jama 1995;274(8):639-44. [PubMed]

151. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34(2):344-53. [PubMed]

152. Walsh TJ, Bustamente CI, Vlahov D, Standiford HC. Candidal suppurative peripheral thrombophlebitis: recognition, prevention, and management. Infect Control 1986;7(1):16-22. [PubMed]

153. Weber DJ, Sickbert-Bennett EE, Brown V, Rutala WA. Comparison of hospitalwide surveillance and targeted intensive care unit surveillance of healthcare-associated infections. Infect Control Hosp Epidemiol 2007;28(12):1361-6.[PubMed]

154. Werlin SL, Lausten T, Jessen S, et al. Treatment of central venous catheter occlusions with ethanol and hydrochloric acid. JPEN J Parenter Enteral Nutr 1995;19(5):416-8. [PubMed]

155. Wing EJ, Norden CW, Shadduck RK, Winkelstein A. Use of quantitative bacteriologic techniques to diagnose catheter-related sepsis. Arch Intern Med 1979;139(4):482-3. [PubMed]

156. Winn MP, McDermott VG, Schwab SJ, Conlon PJ. Dialysis catheter 'fibrin-sheath stripping': a cautionary tale! Nephrol Dial Transplant 1997;12(5):1048-50. [PubMed]

157. Zeylemaker MM, Jaspers CA, van Kraaij MG, Visser MR, Hoepelman IM. Long-term infectious complications and their relation to treatment duration in catheter-related Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2001;20(6):380-4. [PubMed]

 

Tables

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

Measure	Semiquantitative superficial cultures	Differential quantitative blood cultures	Differential time to 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 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)
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 Antimicrobial Agent	Example, dosage	Alternative Antimicrobial Agent	Comments
S. aureus
Methicillin-susceptible	Penicillinase-resistant penicillin	Nafcillin or oxacillin, 2 g q4h	Cefazolin or cefuroxime	Penicillinase-resistant penicillin or cephalosporins are preferred to vancomycin
Methicillin-resistant	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
Vancomycin-non-susceptible	Linezolid or daptomycin	Linezolid 600 mg q12h or daptomycin 6 mg/kg qday	Quinupristin-dalfopristin	For adults <40 kg, linezolid dose should be 10 mg/kg
Coagulase-negative staphylococci
Methicillin-susceptible	Penicillinase-resistant penicillin	Nafcillin or oxacillin, 2 g q4h	First-generation cephalosporin or vancomycin or trimetoprim-sulphametoxazol (if susceptible)
Methicillin-resistant	Vancomycin	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	Vancomycin
Ampicillin resistant, vancomycin susceptible	Vancomycin ± aminoglycoside	Vancomycin 15 mg/kg q12h ± gentamicin 1 mg/kg q8h	Linezolid	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	Daptomycin	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 q.day	Ciprofloxacin or aztreonam	Susceptibility of strains varies
Escherichi coli andKlebsiella spp. ESBL-positive†	Carbapenem	Imipenem 500 mg q6h or meropenem 1 g q8h	Ciprofloxacin or aztreonam	Susceptibility of strains varies
Enterobacter spp. And Serratia marcescens	Carbapenem	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	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
Fungi
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

Antimicrobial	Final concentration of the antimicrobial	Sodium heparin*	References
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

Palmer HR, et al.  Clinical and microbiological implications of time-to-positivity of blood cultures in patients with Gram-negative bacilli bacteremia.  Eur J Clin Microbiol Infect Dis 2013;32:955-999.

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