Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America^a

General

• 1

  Catheter cultures should be performed when a catheter is removed for suspected catheter-related bloodstream infection (CRBSI); catheter cultures should not be obtained routinely (A-II).

• 2

  Qualitative broth culture of catheter tips is not recommended (A-II).

• 3

  For central venous catheters (CVCs), the catheter tip should be cultured, rather than the subcutaneous segment (B-III).

• 4

  For cultures of an anti-infective catheter tip, use specific inhibitors in the culture media (A-II).

• 5

  Growth of >15 colony-forming units (cfu) from a 5-cm segment of the catheter tip by semiquantitative (roll-plate) culture or growth of >10² cfu from a catheter by quantitative (sonication) broth culture reflects catheter colonization (A-I).

• 6

  When catheter infection is suspected and there is a catheter exit site exudate, swab the drainage to collect specimens for culture and Gram staining (B-III).

Short-term catheters, including arterial catheters

• 7

  For short-term catheter tip cultures, the roll plate technique is recommended for routine clinical microbiological analysis (A-II).

• 8

  For suspected pulmonary artery catheter infection, culture the introducer tip (A-II).

Long-term catheters

• 9

  Growth of <15 cfu/plate of the same microbe from both the insertion site culture and the catheter hub culture strongly suggests that the catheter is not the source of a bloodstream infection (A-II).

• 10

  If a venous access subcutaneous port is removed for suspected CRBSI, send the port to the microbiology laboratory for qualitative culture of the port reservoir contents, in addition to the catheter tip (B-II).

Intravenous Catheter Cultures: Recommendations

Evidence Summary

Clinical findings are unreliable for establishing the diagnosis of intravascular device–related infection because of their poor sensitivity and specificity. The most sensitive clinical finding, fever, has poor specificity. Inflammation or purulence around the insertion site has greater specificity but poor sensitivity [4, 15]. Blood cultures that are positive for S. aureus, coagulase-negative staphylococci, or Candida species, in the absence of other identifiable sources of infection, should increase the suspicion for CRBSI [16–18]. Improved symptomatology within 24 h after catheter removal suggests but does not prove that the catheter is the source of infection [19].

Laboratory criteria for diagnosing intravascular catheter-related infections are precise, but differences in definitions and methodologies among various studies have made data difficult to compare [4, 18]. When a catheter segment is submitted for culture, it is adequate to culture only the catheter tip and not the subcutaneous portion of the catheter [20]. If a pulmonary artery catheter is removed because of suspected infection, the highest yield is to culture the introducer, rather than the catheter itself [21]. Semiquantitative (roll plate) or quantitative catheter culture techniques (luminal flushing or sonication methods) are the most reliable diagnostic methodologies and have much greater specificity than broth cultures [22–25]. A recently inserted catheter (i.e., one that had been indwelling for <14 days) is most commonly colonized from a skin microorganism along the external surface of the catheter. Thus, the roll-plate method has high sensitivity. Intraluminal spread of microbes from the catheter hub into the bloodstream is increasingly important for long-term catheters (i.e., those that have been indwelling ≥14 days). In some studies, the roll-plate method was less sensitive than other methods that also sampled the internal surface of such catheters [10, 26], but other studies have not found this to be the case [27]. For subcutaneous ports, culture of the material inside the port reservoir is more sensitive than catheter tip culture for the diagnosis of CRBSI [28–30].

Antimicrobial coatings may lead to false-negative culture results [31, 32]. For silver sulfadiazine– or chlorhexidine-coated catheters, specific inhibitors can abrogate this effect, but this is not the case for minocycline- or rifampin-coated catheters [31, 32]. The specific components of the inhibitor solution to be used when culturing silver sulfadiazine or chlorhexidine can be found elsewhere [31].

Various methods have been used to diagnose a catheter-related infection without catheter removal. In one method, a moist cotton swab can be used to do a semiquantitative culture of a 3-cm radius around the catheter insertion site, and alginate swabs can be used to sample the inner surface of each catheter hub (1 swab per hub). Swab samples are streaked on blood agar plates. Growth of >15 cfu/plate of the same microbe from the insertion site swab sample and hub swab sample cultures and from a peripheral blood culture suggests CRBSI [33]. This approach also has good negative predictive value for CRBSI when <15 cfu/plate are detected on insertion site and hub swab sample cultures.

Blood Cultures: Recommendations

• 11

  Obtain blood cultures prior to initiation of antibiotic therapy (A-1)

• 12

  Where available, a phlebotomy team should draw the blood samples for culture (A-II).

• 13

  Skin preparation for percutaneously drawn blood samples should be carefully done with either alcohol or tincture of iodine or alcoholic chlorhexidine (>0.5%), rather than povidone-iodine; allow adequate skin contact and drying time to mitigate blood culture contamination (A-I).

• 14

  If a blood sample is obtained through a catheter, clean the catheter hub with either alcohol or tincture of iodine or alcoholic chlorhexidine (>0.5%) and allow adequate drying time to mitigate blood culture contamination (A-I).

• 15

  For suspected CRBSI, paired blood samples drawn from the catheter and from a peripheral vein should be cultured before initiation of antimicrobial therapy, and the bottles should be appropriately marked to reflect the site from which the cultures were obtained (A-II).

• 16

  If a blood sample for culture cannot be drawn from a peripheral vein, it is recommended that ≥2 blood samples should be obtained through different catheter lumens (B-III). It is unclear whether blood samples for culture should be obtained through all catheter lumens in such circumstances (C-III).

• 17

  A definitive diagnosis of CRBSI requires that the same organism grow from at least 1 percutaneous blood sample culture and from the catheter tip (A-I) or that 2 blood samples for culture be obtained (1 from a catheter hub and 1 from a peripheral vein) that meet CRBSI criteria for quantitative blood cultures or DTP (A-II). Alternatively, 2 quantitative blood cultures of samples obtained through 2 catheter lumens in which the colony count for the blood sample drawn through one lumen is at least 3-fold greater than the colony count for the blood sample obtained from the second lumen, and in which both samples meet the criteria outlined in recommendation 17, should be considered to indicate possible CRBSI (B-II). In this circumstance, the interpretation of blood cultures that meet the DTP criteria is an unresolved issue (C-III).

• 18

  For quantitative blood cultures, a colony count of microbes grown from blood obtained through the catheter hub that is at least 3-fold greater than the colony count from blood samples obtained from a peripheral vein best defines CRBSI (A-II).

• 19

  For DTP, growth of microbes from blood drawn from a catheter hub at least 2 h before microbial growth is detected in blood samples obtained from a peripheral vein best defines CRBSI (A-II).

• 20

  Quantitative blood cultures and/or DTP should be done before initiation of antimicrobial therapy (A-II).

• 21

  Evidence is insufficient to recommend that blood cultures be routinely obtained after discontinuation of antimicrobial therapy for CRBSI (C-III).

Evidence Summary

Recommendations

• 22

  When denoting the duration of antimicrobial therapy, day 1 is the first day on which negative blood culture results are obtained (C-III).

• 23

  Vancomycin is recommended for empirical therapy in heath care settings with an increased prevalence of methicillin-resistant staphylococci; for institutions with a preponderance of MRSA isolates that have vancomycin MIC values >2 μg/mL, alternative agents, such as daptomycin, should be used (A-II).

• 24

  Linezolid should not be used for empirical therapy (i.e., in patients suspected but not proven to have bacteremia) (AI).

• 25

  Empirical coverage for gram-negative bacilli should be based on local antimicrobial susceptibility data and the severity of disease (e.g., a fourth-generation cephalosporin, carbapenem, or β-lactam/β-lactamase combination, with or without an aminoglycoside) (A-II).

• 26

  Empirical combination antibiotic coverage for MDR gram-negative bacilli, such as P. aeruginosa, should be used when CRBSI is suspected among neutropenic patients, severely ill patients with sepsis, or patients known to be colonized with such pathogens, until the culture and susceptibility data are available and de-escalation of antibiotic therapy can be performed (A-II).

• 27

  In addition to coverage for gram-positive pathogens, empirical therapy for suspected CRBSI involving femoral catheters in critically ill patients should include coverage for gram-negative bacilli and Candida species (A-II).

• 28

  Empirical therapy for suspected catheter-related candidemia should be used for septic patients with any of the following risk factors: total parenteral nutrition, prolonged use of broad-spectrum antibiotics, hematologic malignancy, receipt of bone marrow or solid-organ transplant, femoral catheterization, or colonization due to Candida species at multiple sites (B-II).

• 29

  For empirical treatment of suspected catheter-related candidemia, use an echinocandin or, for selected patients, fluconazole (A-II). Fluconazole can be used for patients without azole exposure in the previous 3 months and in health care settings where the risk of C. krusei or C. glabrata infection is very low (A-III).

• 30

  Antibiotic lock therapy should be used for catheter salvage (B-II); however, if antibiotic lock therapy cannot be used in this situation, systemic antibiotics should be administered through the colonized catheter (C-III).

• 31

  Four to 6 weeks of antibiotic therapy should be administered to patients with persistent fungemia or bacteremia after catheter removal (i.e., occurring >72 h after catheter removal) (A-II for S. aureus infection; C-III for infection due to other pathogens), to patients who are found to have infective endocarditis or suppurative thrombophlebitis, and to pediatric patients with osteomyelitis; 6–8 weeks of therapy should be used for the treatment of osteomyelitis in adults (figures 1 and 2) (A-II).

• 32

  Long-term catheters should be removed from patients with CRBSI associated with any of the following conditions: severe sepsis; suppurative thrombophlebitis; endocarditis; bloodstream infection that continues despite >72 h of antimicrobial therapy to which the infecting microbes are susceptible; or infections due to S. aureus, P. aeruginosa, fungi, or mycobacteria (A-II). Short-term catheters should be removed from patients with CRBSI due to gram-negative bacilli, S. aureus, enterococci, fungi, and mycobacteria (A-II).

• 33

  For patients with CRBSI for whom catheter salvage is attempted, additional blood cultures should be obtained, and the catheter should be removed if blood culture results (e.g., 2 sets of blood cultures obtained on a given day; 1 set of blood cultures is acceptable for neonates) remain positive when blood samples are obtained 72 h after the initiation of appropriate therapy (B-II).

• 34

  For long-term and short-term CRBSI due to less virulent microbes that are difficult to eradicate (e.g., Bacillus species, Micrococcus species, or Propionibacteria), catheters should generally be removed after blood culture contamination is ruled out on the basis of multiple positive culture results, with at least 1 blood culture sample drawn from a peripheral vein (B-III).

• 35

  In uncomplicated CRBSI involving long-term catheters due to pathogens other than S. aureus, P. aeruginosa, Bacillus species, Micrococcus species, Propionibacteria, fungi, or mycobacteria, because of the limited access sites in many patients who require long-term intravascular access for survival (e.g., patients undergoing hemodialysis or with short-gut syndrome), treatment should be attempted without catheter removal, with use of both systemic and antimicrobial lock therapy (B-II).

• 36

  After a positive blood culture result is reported that may represent CRBSI, automated standardized treatment advice can be formulated to improve compliance with Infectious Diseases Society of America (IDSA) guidelines (B-II).

• 37

  Urokinase and other thrombolytic agents are not recommended as adjunctive therapy for patients with CRBSI (B-I).

• 38

  If a catheterized patient has a single positive blood culture that grows coagulase-negative Staphylococcus species, then additional cultures of blood samples obtained through the suspected catheter and from a peripheral vein should be performed before the initiation of antimicrobial therapy and/or catheter removal to be certain that the patient has true bloodstream infection and that the catheter is the likely source (A-II).

Evidence Summary

Antibiotic therapy for catheter-related infection is often initiated empirically. The initial choice of antibiotics will depend on the severity of the patient’s clinical disease, the risk factors for infection, and the likely pathogens associated with the specific intravascular device (figure 3 and table 4). In the largest published comparative trial of CRBSI treatment involving antimicrobial therapy and catheter removal, 88% of 169 patients had a successful microbiologic outcome when evaluated 1–2 weeks after the end of treatment, and there was an 83% microbiologic success rate among 98 cases of CRBSI due to S. aureus [52]. Coagulase-negative staphylococci are the most common cause of catheter-related infection. Most of these pathogens exhibit methicillin resistance, and this should be considered when choosing empirical therapy for catheter-related infection [53, 54]. Vancomycin is associated with a lower clinical success rate in treating MRSA bacteremia if the MIC is ≥2 μg/mL [55, 56]. Standardized treatment advice can be formulated for each CRBSI on the basis of these guidelines. When such standardized treatment advice is automatically delivered to treating physicians, compliance with the guidelines increases significantly [57].

There are no compelling data to support specific recommendations for the duration of therapy for device-related infection. However, the Expert Panel’s recommendations are presented in figures 1–4. Management of CRBSI should be distinguished on the basis of the removal or retention of the catheter, and a distinction should be made between complicated CRBSI, in which there is suppurative thrombophlebitis, endocarditis, osteomyelitis, or possible metastatic seeding, and uncomplicated CRBSI (figures 1–4). Intravenous administration of thrombolytic agents, such as urokinase, should not be used as adjunctive treatment for CRBSI [58, 59].

Recommendations

• 39

  Peripheral intravenous catheters with associated pain, induration, erythema, or exudate should be removed (A-I).

• 40

  Any exudate at the insertion site should be submitted for Gram staining, routine culture, and additional culture for fungi and acid-fast organisms, as indicated, when assessing immunocompromised patients (A-II).

Evidence Summary

Phlebitis involving short-term, peripheral intravenous catheters is often unrelated to catheter-related infection [60, 61]. The risk of CRBSI, with or without suppurative thrombophlebitis, from such catheters is very low [6].

Recommendations

• 41

  For patients who are hospitalized in the intensive care unit with a new onset of fever but without severe sepsis or evidence of bloodstream infection, obtain blood samples for culture from the nontunneled CVC, the arterial catheter (if present), and percutaneously, instead of performing routine catheter removal (B-II). Consider culture of samples obtained from the insertion site and catheter hubs, if available, as noted above (A-II).

• 42

  The CVC and arterial catheter, if present, should be removed and cultured if the patient has unexplained sepsis or erythema overlying the catheter insertion site or purulence at the catheter insertion site (B-II).

• 43

  For patients with unexplained fever, if blood culture results are positive, if the CVC or arterial catheter was exchanged over a guidewire, and if the catheter tip has significant growth, then the catheter should be removed and a new catheter placed in a new site (B-II).

Evidence Summary

Diagnosis and management of illness among patients with a nontunneled CVC or arterial catheter and unexplained fever are summarized in table 1 and figures 1 and 3. CVCs in patients with fever and mild-to-moderate disease should not routinely be removed, because the majority of the catheters from patients with suspected catheter-related infection are sterile [62]. Recent studies suggest that the risk of arterial CRBSI approaches that associated with short-term CVCs [63–65].

One study found that 1 in 4 patients with S. aureus colonization of an intravascular catheter subsequently developed S. aureus bacteremia if they did not receive immediate anti-staphylococcal antibiotics [66]. Similarly, other studies have found that S. aureus and Candida catheter colonization, compared with catheter colonization due to enterococci or gram-negative bacilli, was more likely to be associated with CRBSI and that CRBSIs due to S. aureus and Candida species were more likely to be associated with complications than CRBSIs due to enterococci or gram-negative bacilli [26, 67].

The diagnostic evaluation for new onset of fever in patients hospitalized in the intensive care unit is a daily problem for intensive care physicians [68]. New onset of fever often leads to the removal of intravascular catheters and the reinsertion of new catheters over a guidewire or into another site. However, few of these patients have a catheter-related infection [33, 50, 69]. For hemodynamically stable patients without documented bloodstream infection and without prosthetic valves, pacemakers, or recently placed vascular grafts, systematic catheter removal may not be necessary for new onset of fever. Catheter removal only when bloodstream infection is documented or when there is hemodynamic instability reduces unnecessary catheter removal [70]. Nevertheless, if a catheter is to be removed for suspected catheter-related infection and the patient is at high risk for mechanical complications during catheter reinsertion, a guidewire exchange of the catheter can decrease the risk of mechanical complications [71]. The tip of the removed catheter should be sent for culture. If the tip has positive culture results, this newly inserted catheter should be replaced a second time, because bacterial contamination of the newly inserted catheter can be expected.

Recommendations

• 44

  Patients with tunnel infection or port abscess require removal of the catheter, incision and drainage if indicated, and 7–10 days of antibiotic therapy (A-II) in the absence of concomitant bacteremia or candidemia.

• 45

  For patients with suspected exit site infection, obtain cultures of any drainage from the exit site and blood cultures (A-II).

• 46

  Uncomplicated exit site infections (i.e., those without systemic signs of infection, positive blood culture results, or purulence) should be managed with topical antimicrobial agents on the basis of the exit site culture results (e.g., mupirocin ointment for S. aureus infection and ketoconazole or lotrimin ointment for Candida infection) (B-III).

• 47

  If an uncomplicated exit site infection fails to resolve with topical therapy or if it is accompanied by purulent drainage, then systemic antibiotics should be administered on the basis of the antimicrobial susceptibility of the causative pathogen; the catheter should be removed if treatment with systemic antibiotics fails (B-II).

• 48

  If other vascular sites are unavailable and/or the patient is at increased risk for bleeding diathesis in the setting of CRBSI not complicated by an exit site or tunnel infection, then exchange the infected catheter over a guidewire (B-III). In such situations, an antimicrobial-impregnated catheter with an anti-infective intraluminal surface should be considered for catheter exchange (B-II).

Evidence Summary

Surgically implantable intravascular devices consist of either a tunneled silicone catheter (e.g., Hickman, Broviac, or Groshong catheters) or a subcutaneously implanted port reservoir (e.g., Port-A-Cath). Because the removal of such devices is often a management challenge, it is important to be sure that one is dealing with true CRBSI rather than with contaminated blood cultures (e.g., contaminated due to coagulase-negative staphylococci), catheter colonization without concomitant bloodstream infection, or fever from another source (figures 3 and 4). Microbiologic data suggestive of true CRBSI caused by potential skin flora rather than contamination include the following: multiple blood samples with positive culture results obtained from different sites; quantitative blood cultures performed on samples drawn from a catheter with growth of >15 cfu/mL of blood or isolation of the same organism from a catheter culture and a percutaneous blood culture, especially if a culture performed on blood drawn from the catheter shows growth at least 2 h earlier than a culture performed on blood drawn from a peripheral vein [72]. Although several studies suggest that catheter exchange over a guidewire can be used successfully to manage CRBSI associated with long-term catheters [73], most of these were small, uncontrolled studies with poor definitions, and none of these studies used antimicrobial catheters as a replacement for the infected catheter [73–77]. Management of CRBSI for patients with a long-term CVC or implantable device is summarized in tables 5 and 6 and in figure 2.

Recommendations

• 49

  Indications for catheter removal for children are similar to those for adults (see recommendations 30–32), unless there are unusual extenuating circumstances (e.g., no alternative catheter insertion site). However, the benefits of catheter removal must be weighed against the difficulty of obtaining alternate venous access for an individual patient (A-II).

• 50

  Children treated without catheter removal should be closely monitored with clinical evaluation and additional blood cultures; the device should be removed if there is clinical deterioration or persistent or recurrent CRBSI (B-III).

• 51

  In general, empirical antibacterial therapy for children with CRBSI should be similar to that for adults (see recommendations 21–23) (A-II).

• 52

  Antibiotic lock therapy should be used for catheter salvage (B-II); however, if antibiotic lock therapy cannot be used in this situation, systemic antibiotics should be administered through the colonized catheter (C-III).

Evidence Summary

The pediatric population is diverse, and the probability of infection varies with patient risk factors, the type and location of the device, and the nature of the infusate [78, 79]. Among premature infants, birth weight is inversely proportional to the risk of infection, with infants who have extremely low birth weight (1000–1500 g) having an increased risk, compared with infants who have very low birth weight [80]. Most nosocomial bloodstream infections among pediatric patients are related to the use of an intravascular device [81], and in critically ill neonates, the incidence of CRBSI can be as high as 18 cases per 1000 catheter-days [82]. Most CRBSIs among children are caused by coagulase-negative staphylococci (which account for 34% of cases), followed by S. aureus (25%) [83]. Among neonates, coagulase-negative staphylococci account for 51% of CRBSIs, followed by Candida species, enterococci, and gram-negative bacilli [78, 84]. Infants with short-gut syndrome, a disorder that is clinically defined by malabsorption, diarrhea, steatorrhea, fluid and electrolyte disturbances, and malnutrition, often resulting from anatomic removal of bowel during the newborn period due to necrotizing enterocolitis, are more likely to have CRBSI due to gram-negative bacilli [85].

Several problems arise when the clinical and laboratory definitions of infection established for adults are applied to children [18, 86]. Although specific pediatric blood culture devices are commercially available, difficulty in obtaining blood samples and concerns about drawing a large volume of blood may result in lower volumes of blood being submitted for culture, which would reduce the negative predictive value of the culture. Often, only results from blood samples obtained via the catheter are available to guide patient management. Peripheral cultures are not often performed when catheter cultures are obtained, because venipuncture can be difficult for infants and young children. A recent study suggests that, among pediatric oncology patients with a double lumen CVC, catheter-related infection can be diagnosed by a ≥5-fold difference in colony count between the 2 lumens; this method has 62% sensitivity, 93% specificity, and 92% positive predictive value, compared with a comparison between the colony count for 1 lumen and for a peripheral blood sample [87]. However, validation in a prospective study is needed to confirm these findings. In addition, placement of catheters or changing a catheter over a guidewire is difficult for young children, and catheter removal for diagnostic purposes is often not done out of concern over losing access (figure 3). Because of these limitations, definitive CRBSI can often not be diagnosed in children. In these circumstances, many physicians treat their patients as if they had presumed CRBSI.

Although indications for catheter removal among children should follow the recommendations for adults, because of greater vascular access difficulties in children, it is often necessary to attempt CRBSI treatment without catheter removal. Several studies have reported successful CRBSI management among children without catheter removal [88–90]. Such children should be closely monitored, and the device should be removed in the event of clinical deterioration or recurrence of CRBSI. In contrast, treatment of catheter-associated fungemia without removal of the catheter has a low success rate and is associated with higher mortality [91, 92]. Recent reports involving children with Candida CRBSI found that the addition of antifungal lock therapy led to a high cure rate without catheter removal, but there are insufficient data to recommend routine catheter salvage using this approach for this infection unless there are unusual extenuating circumstances (e.g., no alternative catheter insertion site) [93–95].

Antimicrobial agents that are appropriate for infants and children and the recommended dosages of specific agents, by patient age and weight, are summarized in table 6. Antibiotics should be administered through the catheter. In contrast to the recommendation for adults, empirical antifungal coverage in critically ill patients with femoral catheters is not recommended for children. Antifungal therapy should be initiated when yeast is isolated from a blood culture or when the suspicion of fungemia is high [90, 96–98]. The selection of an appropriate antifungal agent depends on the organism that is isolated and the drug characteristics, including available pediatric dosing information, toxicities, route of administration, and formulations.

Conventional treatment for CRBSI has not been established to be different from that previously described for adults (table 6 and figures 1–4), but certain procedures may not apply to infants and young children. For example, as noted in figures 1 and 2, echocardiographic examination is not used commonly for small infants and children with CRBSI who do not have other indicators of endocarditis. The optimal duration of therapy has not been established for treating catheter-related infection in children with or without catheter removal [89, 90]. Therefore, recommendations regarding the duration of therapy for pediatric patients with CRBSI should mirror adult recommendations. Lastly, antibiotic lock therapy should also be used, with the recognition that dwell times may be variable, based on limited venous access and the necessity to use the catheter.

Recommendations

• 53

  Peripheral blood samples should be obtained for culture from vessels that are not intended for future use in creating a dialysis fistula (e.g., hand veins) (A-III).

• 54

  When a peripheral blood sample cannot be obtained, blood samples may be drawn during hemodialysis from bloodlines connected to the CVC (B-II).

• 55

  In patients with suspected CRBSI for whom blood cultures have been obtained and for whom antibiotic therapy has been initiated, antibiotic therapy can be discontinued if both sets of blood cultures have negative results and no other source of infection is identified (B-II).

• 56

  When a peripheral blood sample cannot be obtained, no other catheter is in place from which to obtain an additional blood sample, there is no drainage from the insertion site available for culture, and there is no clinical evidence for an alternate source of infection, then positive results of culture performed on a blood sample obtained from a catheter should lead to continuation of antimicrobial therapy for possible CRBSI in a symptomatic hemodialysis patient (B-II).

• 57

  The infected catheter should always be removed for patients with hemodialysis CRBSI due to S. aureus, Pseudomonas species, or Candida species and a temporary (nontunneled catheter) should be inserted into another anatomical site (A-II). If absolutely no alternative sites are available for catheter insertion, then exchange the infected catheter over a guidewire (B-II).

• 58

  When a hemodialysis catheter is removed for CRBSI, a long-term hemodialysis catheter can be placed once blood cultures with negative results are obtained (B-III).

• 59

  For hemodialysis CRBSI due to other pathogens (e.g., gram-negative bacilli other than Pseudomonas species or co-agulase-negative staphylococci), a patient can initiate empirical intravenous antibiotic therapy without immediate catheter removal. If the symptoms persist or if there is evidence of a metastatic infection, the catheter should be removed (B-II). If the symptoms that prompted initiation of antibiotic therapy (fever, chills, hemodynamic instability, or altered mental status) resolve within 2–3 days and there is no metastatic infection, then the infected catheter can be exchanged over a guidewire for a new, long-term hemodialysis catheter (B-II).

• 60

  Alternatively, for patients for whom catheter removal is not indicated (i.e., those with resolution of symptoms and bacteremia within 2–3 days after initiation of systemic antibiotics and an absence of metastatic infection), the catheter can be retained, and an antibiotic lock can be used as adjunctive therapy after each dialysis session for 10–14 days (B-II).

• 61

  Empirical antibiotic therapy should include vancomycin and coverage for gram-negative bacilli, based on the local antibiogram (e.g., third-generation cephalosporin, carbapenem, or β-lactam/β-lactamase combination) (table 7) (A-II).

• 62

  Patients who receive empirical vancomycin and who are found to have CRBSI due to methicillin-susceptible S. aureus should be switched to cefazolin (A-II).

• 63

  For cefazolin, use a dosage of 20 mg/kg (actual body weight), rounded to the nearest 500-mg increment, after dialysis (A-II).

• 64

  A 4–6-week antibiotic course should be administered if there is persistent bacteremia or fungemia (i.e., >72 h in duration) after hemodialysis catheter removal or for patients with endocarditis or suppurative thrombophlebitis, and 6–8 weeks of therapy should be administered for the treatment of osteomyelitis (figures 1 and 2) (B-II).

• 65

  Patients receiving dialysis who have CRBSI due to vancomycin-resistant enterococci can be treated with either daptomycin (6 mg/kg after each dialysis session) or oral linezolid (600 mg every 12 h) (B-II).

• 66

  It is not necessary to confirm negative culture results before guidewire exchange of a catheter for a patient with hemodialysis-related CRBSI if the patient is asymptomatic (B-III).

• 67

  Surveillance blood cultures should be obtained 1 week after completion of an antibiotic course for CRBSI if the catheter has been retained (B-III). If the blood cultures have positive results, the catheter should be removed and a new, long-term dialysis catheter should be placed after additional blood cultures are obtained that have negative results (B-III).

Evidence Summary

It is frequently not feasible to obtain a peripheral blood sample for culture from patients who are receiving dialysis [99]. In some patients, the peripheral veins have been exhausted as a result of multiple failed dialysis fistulas or grafts. Moreover, it is important to avoid drawing blood from peripheral veins that will be used for future creation of a fistula or graft, because venipuncture may injure the vein.

A substantial proportion of patients who receive dialysis who have CRBSI are treated successfully in the outpatient setting. Hospitalization is only indicated for patients with severe sepsis or metastatic infection. CRBSI in patients who are undergoing hemodialysis has several unique features that may dictate differences in their management, compared with that of other patients (tables 1 and 7 and figure 2).

CRBSI in patients who are undergoing hemodialysis may be caused by several different pathogens, but such cases are most often due to coagulase-negative staphylococci or S. aureus [99–101]. If possible, antibiotic selection should be made on the basis of pharmacokinetic characteristics that permit dosing after each dialysis session (e.g., vancomycin, ceftazidime, or cefazolin) [102], or antibiotics that are unaffected by dialysis (e.g., ceftriaxone) should be used. The majority of gram-negative organisms causing CRBSI in patients who are undergoing hemodialysis are susceptible to both aminoglycosides and third-or fourth-generation cephalosporins [99, 100], but cephalosporins are preferred, because aminoglycosides carry a substantial risk of inducing irreversible ototoxicity [103]. Validated dosing schedules for cefazolin and vancomycin to ensure therapeutic concentrations have been published (table 8) [104, 105].

Among patients who are undergoing hemodialysis who have CRBSI involving long-term catheters, not only is the catheter the source of the infection, but it is also the vascular access for providing ongoing dialysis. The 4 potential treatment options for such patients are (1) intravenous antibiotics alone, (2) prompt catheter removal with delayed placement of a new long-term catheter, (3) exchange of the infected catheter with a new one over a guidewire, or (4) use of systemic antibiotics and an antibiotic lock in the existing catheter (figure 5) [102]. Administration of intravenous antibiotics alone is not a satisfactory approach, because bloodstream infection recurs in the majority of patients once the course of antibiotics has been completed [101, 106–109]. Moreover, the risk of treatment failure among patients who are undergoing hemodialysis whose CRBSI is treated with antibiotics alone is a 5-fold higher, compared with the risk among patients who undergo catheter removal [110]. For patients whose symptoms resolve after 2–3 days of intravenous antibiotic therapy and who do not have evidence of metastatic infection, guidewire exchange of the catheter is associated with cure rates that are comparable to those associated with immediate removal and delayed placement of a new catheter [74–76, 111, 112]. Patients with hemodialysis-associated CRBSI due to gram-negative pathogens or CRBSI due to coagulase-negative staphylococci may have the catheter retained and be treated with adjunctive anitibiotic lock therapy for 3 weeks, or they may have the catheter exchanged over a guidewire and then receive the same antibiotic course (figure 2).

For antibiotic lock therapy, the antibiotic is combined with heparin and instilled into each catheter lumen at the end of each dialysis session (table 9) [99, 113, 114]. The success rate is 87%–100% for infection due to gram-negative pathogens and 75%– 84% for infection due to Staphylococcus epidermidis, but it is only 40%–55% for hemodialysis-associated CRBSI due to S. aureus [100, 114, 115].

Recommendations

• 68

  Antibiotic lock is indicated for patients with CRBSI involving long-term catheters with no signs of exit site or tunnel infection for whom catheter salvage is the goal (B-II).

• 69

  For CRBSI, antibiotic lock should not be used alone; instead, it should be used in conjunction with systemic antimicrobial therapy, with both regimens administered for 10–14 days (B-II).

• 70

  Dwell times for antibiotic lock solutions should generally not exceed 48 h before reinstallation of lock solution; preferably, reinstallation should take place every 24 h for ambulatory patients with femoral catheters (B-II). However, for patients who are undergoing hemodialysis, the lock solution can be renewed after every dialysis session (B-II).

• 71

  Catheter removal is recommended for CRBSI due to S. aureus and Candida species, instead of treatment with antibiotic lock and catheter retention, unless there are unusual extenuating circumstances (e.g., no alternative catheter insertion site) (A-II).

• 72

  For patients with multiple positive catheter-drawn blood cultures that grow coagulase-negative staphylococci or gram-negative bacilli and concurrent negative peripheral blood cultures, antibiotic lock therapy can be given without systemic therapy for 10–14 days (B-III).

• 73

  For vancomycin, the concentration should be at least 1000 times higher than the MIC (e.g., 5 mg/mL) of the microorganism involved (B-II).

• 74

  At this time, there are insufficient data to recommend an ethanol lock for the treatment of CRBSI (C-III).

Evidence Summary

Antibiotic lock therapy for CRBSI is used in conjunction with systemic antibiotic therapy and involves installing a high concentration of an antibiotic to which the causative microbe is susceptible in the catheter lumen. In 14 open trials of CRBSI involving long-term catheters with catheter retention and administration of standard parenteral therapy without the adjunctive use of antibiotic lock therapy, the average success rate was 67%. The likelihood of success varies with the site of infection (e.g., tunnel or pocket infection are unresponsive to salvage) and with the microbe causing the infection (e.g., co-agulase-negative staphylococci are likely to respond; S. aureus and P. aeruginosa are not). Recurrent bacteremia after parenteral therapy is more likely to occur if that therapy is administered through a retained catheter than if the catheter is removed [116]. This likely reflects the inability of most antibiotics to achieve therapeutic concentrations needed to kill microbes growing in a biofilm [117–122]. Antibiotic concentrations must be 100 to 1000 times greater to kill sessile bacteria within a biofilm than to kill planktonic bacteria [117–122]. Because the majority of infections involving long-term catheters or totally implanted catheters are intraluminal, eradication of such infections is attempted by filling the catheter lumen with supratherapeutic concentrations of antibiotics and leaving them indwelling for hours or days, thereby creating an antibiotic lock. In 21 open trials of antibiotic lock therapy for CRBSI involving long-term catheters, with or without concomitant parenteral therapy, catheter salvage without relapse occurred in 77% of episodes. Two controlled clinical trials of the use of antibiotic lock therapy together included only 92 patients, and treatment was successful in 58% of the control subjects and 75% of the patients treated with an antibiotic lock [123, 124]. Compared with bacterial infection, Candida CRBSI is more difficult to eradicate with antibiotic lock therapy [93, 125–127]. In the largest published series on the use of antibiotic lock for CRBSI due to S. aureus, treatment failure was observed in one-half of the cases [114]. Antibiotic lock solutions contain the desired antimicrobial concentration (table 9), and they are usually mixed with 50–100 units of heparin or normal saline in sufficient volume to fill the catheter lumen (usually 2–5 mL). Rapidly decreasing antibiotic concentrations may occur over time in the distal lumen of hemodialysis catheters instilled with an antibiotic lock, especially among ambulatory patients with femoral catheters [128]. Thus, to maintain a concentration of vancomycin that is >1000 times the MIC₉₀ of staphylococci during the entire dwell time, a concentration of 5 mg/mL is preferred, and the antibiotic lock fluid should be changed at least every 48 h.

Although the duration of antibiotic lock therapy has varied substantially among different studies (3–30 days), most studies have used a 2-week duration. Vancomycin, cefazolin, and ceftazidime remain stable in heparin solutions at 25°C and 37°C for several days [129]. Not all antibiotic-heparin combinations can be used, because precipitation occurs when some antibiotics are mixed with heparin, especially with increasing antibiotic concentrations [130]. Table 9 lists antibiotic lock solutions that can be used without the risk of precipitation.

The use of an antibiotic lock does not obviate the need for systemic antimicrobial therapy. However, when blood cultures have become negative and signs of sepsis have resolved, systemic antimicrobial therapy can be given orally in some patients. The combination of an orally administered, well-absorbed antibiotic (clindamycin, doxycycline, a fluoroquinonolone, or linezolid) and an antibiotic lock that can be left in place for 24–48 h may be more practical in some cases of outpatient management of CRBSI with coagulase-negative staphylococci [129].

Catheters that are in place for <2 weeks are most often infected extraluminally, and patients with catheters in place for longer periods may also have evidence of extraluminal infection [10]. Antibiotic lock therapy is unlikely to have any impact on extraluminal infection.

Other antimicrobial locks are being evaluated for the treatment of CRBSI. One pediatric CRBSI study had a high success rate using a 70% ethanol antimicrobial lock [131].

On occasion, symptomatic patients with catheters have multiple catheter-drawn blood cultures that are positive for co-agulase-negative staphylococci or, more rarely, gram-negative bacilli, but also have concurrent percutaneous blood cultures with negative results. Such patients can be considered to have an intraluminally colonized catheter. If these colonized catheters are left in place, patients may go on to develop a true CRBSI. Therefore, if such catheters cannot be removed, antibiotic lock therapy without systemic therapy can be given through the retained catheter.

Coagulase-Negative Staphylococcus Species

S. aureus

Enterococcus Species

Gram-Negative Bacilli

Candida Species

Other Gram-Positive Microorganisms

Recommendations

• 106

  Suppurative thrombophlebitis should be suspected in patients with persistent bacteremia or fungemia (i.e., patients whose blood culture results remain positive after 3 days of adequate antimicrobial therapy) without another source of intravascular infection (e.g., endocarditis) (A-II).

• 107

  A diagnosis of suppurative thrombophlebitis requires the presence of positive blood culture results plus the demonstration of a thrombus by radiographic testing (e.g., computed tomography, ultrasonography, or other methods) (A-II).

• 108

  Surgical resection of the involved vein for patients with suppurative thrombophlebitis should be limited to patients with purulent superficial veins or patients in whom the infection extends beyond the vessel wall, as well as patients who experience failure of conservative therapy with an appropriate antimicrobial regimen (A-II).

• 109

  The role of heparin use in this setting is unresolved (C-III).

• 110

  Patients with suppurative thrombophlebitis due to CRBSI should receive a minimum of 3–4 weeks of antimicrobial therapy (B-III).

Evidence Summary

Suppurative thrombophlebitis may involve central or peripheral veins or arteries and result in high-grade and persistent bacteremia or fungemia [205–210]. Patients who undergo chemotherapy for malignancy and patients with solid tumors who develop S. aureus CRBSI may be at increased risk for suppurative thrombophlebitis, because S. aureus is the most common offending organism [207, 211–214]. Septic pulmonary emboli and other metastatic infections may complicate this condition [207, 215]. Patients may remain febrile and bacteremic or fungemic for prolonged periods of time despite the initiation of appropriate antimicrobial therapy; however, few patients have physical examination findings that suggest the diagnosis of suppurative thrombophlebitis [216]. Only a minority of patients require surgery for the definite resolution of suppurative thrombophlebitis.

Because infected intravascular thrombus and intraluminal abscess may remain intact after catheter removal, this infection may become manifest after catheter removal [209]. When peripheral veins are involved, many older children and adult patients have localized pain, erythema, and edema, and a smaller subset of patients demonstrate an abscess, palpable cord, or purulent drainage [206, 217, 218]. A patient with suppurative thrombophlebitis caused by a peripheral arterial catheter may present with a pseudoaneurysm or embolic lesions of the involved hand [205, 210]. Patients with suppurative thrombophlebitis of the great central veins may have ipsilateral neck, chest, or upper extremity swelling [208, 209, 219]. There are no randomized studies to guide the optimal choice or duration of antibiotics, use of anticoagulants, thrombolytic agents, or excision of the involved vessel, but anticoagulation with heparin should be considered [220].

Recommendations

• 111

  Catheter withdrawal is required in the management of catheter-related infective endocarditis (A-II).

• 112

  TEE should be done for patients with CRBSI who have any of the following: a prosthetic heart valve, pacemaker, or implantable defibrillator; persistent bacteremia or fungemia and/or fever >3 days after initiation of appropriate antibiotic therapy and catheter removal, in addition to a search for metastatic foci of infection, as indicated; and any case of S. aureus CRBSI in which duration of therapy less than 4–6 weeks is being considered (A-II).

• 113

  Unless the clinical condition of the patient dictates otherwise, perform a TEE at least 1 week after the onset of bacteremia or fungemia and consider repeating the TEE for patients with a high index of suspicion for infective endocarditis in whom the initial TEE had negative findings (B-II).

• 114

  Assess for suppurative thrombophlebitis as noted above (B-II).

• 115

  Infective endocarditis cannot be ruled out by negative transthoracic echocardiograph findings alone (B-II).

Evidence Summary

Colonized intravascular catheters are the most commonly identified source of nosocomial endocarditis and account for one-to two-thirds of reported cases [24, 25, 34, 221–224]. Staphylococci are the main etiologic agents, followed by Enterococcus and Candida species [24, 25]. The risk of nosocomial endocarditis is greatest among patients with S. aureus bacteremia who have prosthetic heart valves, pacemakers, malignancy, or who are receiving dialysis through a catheter [24, 25, 34, 44, 225, 226].

There are no data from randomized clinical trials to establish the indications for TEE, but clinical examination has a low sensitivity for diagnosing infective endocarditis. A TEE should be offered to all patients with S. aureus bacteremia, with the possible exception of patients whose fever and bacteremia resolve within 3 days after catheter removal who have no underlying cardiac predisposing conditions for endocarditis and no clinical signs of endocarditis [135].

Repeatedly positive blood culture results and/or unchanged clinical status for 3 days after catheter removal usually reflects serious sequelae of CRBSI, such as suppurative thrombophlebitis, endocarditis, or metastatic foci of infection.

Recommendations

• 116

  When extrinisic contamination of infusate or catheter flush or lock solutions is suspected, public health authorities should be alerted and the suspected product should be set aside for culture (A-II).

• 117

  Establish a case definition for patients who are likely to have been exposed, including a time period, risk factors, and location of the patients (A-II).

• 118

  A case-control study should be used to establish risk factors for infection and to help elucidate potential sources of contamination (B-II).

• 119

  Establish relatedness of the suspected organisms by reviewing the antibiotic susceptibility patterns, followed by molecular fingerprinting, such as pulsed-field gel electrophoresis, polymerase chain reaction, or multilocus sequence typing (A-II).

• 120

  Investigation of contamination involves a thorough review of potential breaches in infection control practices in the hospital pharmacy and at the point of delivery of the infusate. This requires interviews with health care personnel and observation of practices in the health care setting (A-II).

• 121

  Cultures of potential point-source contaminants in the environment should be performed, including intravenous medications administered to patients (A-II).

• 122

  During the investigation, heightened surveillance to detect new cases should be instituted (A-II).

• 123

  Following identification of a source, there should be ongoing surveillance to confirm eradication of the source of infection (A-II).

Evidence Summary

Outbreaks of CRBSI occur infrequently and are most commonly caused by contaminated infusate [4]. These infections can be difficult to recognize and are sufficiently uncommon that they may go unnoticed by clinicians. Any fluids administered through an intravenous catheter can become contaminated, either during the manufacturing process or while being prepared or administered in the health care setting. Numerous outbreaks of bloodstream infection related to contaminated, intravenously administered products have been reported [227–237]. In addition, medical equipment can become contaminated because of inadequate infection-control practices [238–254]. In some instances, health care workers have adulterated intravenous narcotics for illicit use and have contaminated the narcotics in the process [255].

Bacteria that are most often implicated in contamination of infusate include gram-negative bacilli capable of reproducing at room temperature, such as Klebsiella species, Enterobacter species, Serratia species, Burkholdaria cepacia, Ralstonia pickettii, and Citrobacter freundii [4]. Gram-negative bacilli that are unusual human pathogens or that are frequently found in the environment should alert the clinician to the possibility of contaminated infusate.

Because the clinical picture of contaminated infusate is the same as that of bloodstream infection due to other causes, contamination of infusate often will not be detected unless there is a cluster of unusual bloodstream infections or several patients develop a bloodstream infection due to the same organism. Contaminated infusate should be suspected when no other infection is present that would account for a bloodstream infection or when the abrupt onset of shock occurs in association with infusion of parenteral medication or fluid.

Contamination in the hospital pharmacy should be suspected if an increase in bloodstream infection due to the same microorganism occurs among patients on different hospital units. Suspected contamination should prompt an immediate and thorough investigation. Assistance from public health authorities may be required, especially if related outbreaks occur in multiple health care settings.