Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis

INTRODUCTION — The diagnosis of a catheter-related bloodstream infection (CRBSI) is based on epidemiologic, clinical, and laboratory criteria. The clinical features and diagnosis of CRBSI will be reviewed here.

Issues related to the epidemiology, pathogenesis, treatment, and prevention of CRBSI are discussed in detail separately. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology" and "Intravascular non-hemodialysis catheter-related infection: Treatment" and "Routine care and maintenance of intravenous devices".)

Issues related to infection associated with hemodialysis catheters are discussed separately. (See "Tunneled hemodialysis catheter-related bloodstream infection (CRBSI): Management and prevention" and "Central venous catheters: Overview of complications and prevention in adults", section on 'Catheter-related infection'.)

DEFINITIONS FOR SURVEILLANCE — To standardize surveillance, the United States Centers for Disease Control and Prevention introduced the term laboratory-confirmed bloodstream infection (LCBI) [1]. An LCBI must meet at least one of the following criteria:

●Patient has a noncommensal bacterial or fungal pathogen cultured from one or more blood specimens, and the pathogen is not related to an infection at another site. Certain nonculture based microbiologic testing on blood specimens may also be used to meet this definition if they identify to the genus or species level; however, catheter tip cultures should not be used in place of blood specimens.

●Patient has a common commensal organism (eg, coagulase-negative staphylococcus) in two or more blood cultures collected on different days or from different sites that is not related to an infection at another site and that occurs in the setting of one of the following signs or symptoms: fever (>38.0°C), chills, or hypotension.

●For patients ≤1 year of age, signs and symptoms include: fever (>38.0°C), hypothermia (<36.0°C), apnea, and bradycardia.

For surveillance purposes, a central line-associated bloodstream infection (CLABSI) refers to a primary bloodstream infection (BSI) meeting at least one of the LCBI criteria above in a patient with a central line in place for >2 consecutive calendar days [1-3]. Multiple studies have now identified the importance of validating publicly reported CLABSI rates due to variations in detection and reporting methods [4,5].

For clinical and research purposes, the diagnosis of a catheter-related bloodstream infection (CRBSI) is based on clinical and laboratory criteria that are stricter than those for CLABSI, in an effort to better ensure that the catheter is the source of the infection. Since some BSIs are due to sources other than the catheter which may not be easily recognized, the CLABSI surveillance definition may overestimate the true incidence of CRBSI secondary to central lines [2]. However, CRBSI may occur with any intravascular catheter, not just central lines.

CLINICAL MANIFESTATIONS

General presentation — Clinical manifestations of catheter-related bloodstream infection (CRBSI) may include fever, inflammation, or purulence at the catheter insertion site, hemodynamic instability, and altered mental status. Catheter dysfunction (as occurs with intraluminal clot) may be observed. Clinical signs of sepsis that start abruptly after catheter infusion suggest infusate contamination. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology", section on 'Infusate contamination' and 'Other specimens' below.)

Fever and abrupt onset of septic physiology are the most common clinical manifestations of CRBSI; however, both are also associated with other causes of infection as well as noninfectious etiologies [6]. Presence of inflammation or purulence at the insertion site has high specificity (94 to 99 percent) but poor sensitivity (<5 percent) for CRBSI (table 1) [7].

Local signs are absent in almost 60 percent of CRBSI, particularly with older age, critical illness, immunosuppression, catheters in place one week or less, and jugular/femoral sites. Local signs observed in the first seven days following insertion are highly predictive of CRBSI [8,9].

Clinical improvement within 24 hours following catheter removal is suggestive of CRBSI (but not sufficient for definitive diagnosis) [10]. Indications for catheter removal are discussed in detail separately. (See "Intravascular non-hemodialysis catheter-related infection: Treatment", section on 'Selecting a catheter management strategy'.)

Complications — CRBSI may be associated with complications including septic thrombophlebitis, infective endocarditis (IE), and metastatic infection. Clinical manifestations reflecting these complications may be present at the time of initial presentation and/or may develop subsequently. These conditions can occur in the context of CRBSI or independently of CRBSI:

●Septic thrombophlebitis – Septic thrombophlebitis refers to venous thrombosis associated with inflammation in the setting of bacteremia; it should be suspected in patients with CRBSI and persistent bacteremia after 72 hours of appropriate therapy. Clinical manifestations may include fever, erythema, a palpable tender cord, and/or purulent drainage [11-13]. Complications include septic pulmonary emboli and secondary pneumonia; these may also be presenting manifestations of the infection [14]. The presence of venous thrombosis may be established via duplex ultrasonography [15]; the microbiologic diagnosis may be based on blood culture. (See "Catheter-related septic thrombophlebitis".)

●Infective endocarditis – IE refers to infection of one or more heart valves. IE should be suspected in patients with CRBSI or bacteremia >48 to 72 hours with a pathogen associated with IE. (See "Right-sided native valve infective endocarditis" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

Echocardiographic evaluation is warranted for patients with signs and symptoms of IE (eg, new murmur or embolic phenomena), persistent bacteremia, or the presence of a prosthetic valve or other endovascular foreign body [16,17]. Patients with Staphylococcus aureus bacteremia also warrant echocardiographic evaluation. Echocardiographic examination is not used routinely for infants and children with bacteremia or CRBSI who do not have other indicators of endocarditis.

●Metastatic musculoskeletal infection (such as septic arthritis, osteomyelitis, orthopedic hardware infection) – Bacteremia may be associated with seeding of joints, bone, or orthopedic hardware. The diagnosis of septic arthritis should be suspected in patients with acute onset of at least one swollen, painful joint. Osteomyelitis should be suspected in the setting of new or worsening musculoskeletal pain. Orthopedic hardware infection should be suspected in the setting of pain at the site of prosthetic material. These conditions are discussed further separately. (See "Septic arthritis in adults" and "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis" and "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Laboratory findings — Blood cultures positive for an organism commonly associated with CRBSI (eg, S. aureus, coagulase-negative staphylococci, enterococci, Candida species, Klebsiella species, E. coli) should raise suspicion for CRBSI, particularly in the absence of other identifiable sources of infection [18-21]. (See 'Interpreting blood culture results' below.)

The microbiology of catheter infections is discussed in detail separately. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

Other laboratory tests (such as white blood cell count, C-reactive protein, procalcitonin) may provide clues to an infectious process but are not specific for CRBSI [22-25].

DIAGNOSIS

Clinical approach — The diagnosis of catheter-related bloodstream infection (CRBSI) should be suspected in patients with fever, chills, or hypotension in the setting of a catheter placed at least 48 hours prior to development of symptoms; however, these manifestations are also associated with other causes of infection as well as noninfectious etiologies [6].

Physical examination findings of erythema, pain, swelling, or purulence at the central line insertion site should also raise suspicion for CRBSI. Such patients should also be evaluated for signs and symptoms reflecting complications of CRBSI, including septic thrombophlebitis, endocarditis, and metastatic musculoskeletal infection (see 'Complications' above). In addition, patients with other indwelling devices (such as cardiac implantable electronic devices, orthopedic hardware, or vascular grafts) should be evaluated carefully for infections at these sites. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Arteriovenous graft creation for hemodialysis and its complications", section on 'Graft infection'.)

In the setting of suspected CRBSI, blood cultures should be obtained, ideally prior to the initiation of antibiotic therapy [26]. (See 'Collecting specimens for culture' below.)

For patients who are clinically stable, antimicrobial therapy may be deferred while awaiting blood culture results. For patients with signs of clinical instability, initiation of empiric antimicrobial therapy (after blood cultures have been obtained) is appropriate. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Empiric antibiotic therapy (first hour)'.)

If blood cultures establish the presence of a bloodstream infection (BSI) (see 'Interpreting blood culture results' below), the patient should be evaluated for alternative sources. Clinical history and physical examination should be performed to evaluate for signs and symptoms suggestive of an alternative source for BSI (such as pulmonary, abdominal, urinary tract, bone/joint, or skin/soft tissue infection). Subsequent diagnostic evaluation should be guided by the clinical evaluation, tailored to individual circumstances; as an example, patients with focal joint pain and an effusion should undergo diagnostic joint aspiration to evaluate for septic arthritis.

Presence of S. aureus BSI should prompt evaluation as outlined separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults".)

Clinical improvement within 24 hours following catheter removal is suggestive of CRBSI (but not sufficient for definitive diagnosis) [10]. Indications for catheter removal are discussed in detail separately. (See "Intravascular non-hemodialysis catheter-related infection: Treatment", section on 'Selecting a catheter management strategy'.)

Collecting specimens for culture

Blood cultures — The blood culture bottles should be labeled to reflect the sites from which the cultures were obtained. Ideally, at least two sets of blood cultures should be obtained from peripheral veins via separate venipuncture sites prior to initiation of antibiotic therapy [27,28].

For circumstances in which this is not feasible, one blood culture set may be drawn from a peripheral vein and the other blood culture set may be drawn from the catheter [29]. However, higher blood culture contamination rates when drawing off of a catheter can increase the rate of positive blood culture results, even when peripheral cultures are negative [30]. For this same reason, blood cultures should not be drawn solely from the catheter, since colonization with skin contaminants can reduce the specificity and the positive predictive value of the blood culture results [26,31-33].

For blood culture collection through a catheter, cultures should be obtained from the catheter after removal of the old needleless connector (which was protected with an antiseptic barrier cap) or through a new connector after the old connector (protected by a barrier cap) is discarded [31]. In the setting of a multilumen catheter, it is uncertain whether blood cultures should be drawn through all catheter lumens [34,35].

Catheter tip cultures are no longer recommended for CRBSI diagnosis, given low positive predictive value; historically, catheter tip cultures were part of CRBSI diagnostic criteria [36-38].

A dedicated phlebotomy team can help to standardize practice to reduce blood culture contamination rates [39]. In one study, education regarding the importance of obtaining blood cultures by venipuncture rather than from central lines was associated with a substantial reduction in blood culture contamination rates as well as cost savings [40]. Issues related to blood culture collection technique (including skin disinfection and adequate time for drying) are discussed separately. (See "Detection of bacteremia: Blood cultures and other diagnostic tests".)

Other specimens — In the setting of suspected infusate contamination (eg, clinical signs of sepsis that start abruptly after catheter infusion), the infusate should be sent for culture. The diagnosis of infusate contamination is confirmed by isolation of the same organism from the infusate and percutaneous blood culture (often an uncommon gram-negative bacillus). (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology", section on 'Infusate contamination'.)

Interpreting blood culture results — In the absence of other identifiable sources of infection, the following blood culture results may be attributed to CRBSI:

●One or more blood culture bottles positive for S. aureus, enterococci, Enterobacteriaceae (eg, Escherichia coli, Klebsiella species, Enterobacter species), Pseudomonas aeruginosa, Candida species

●Two or more blood culture bottles positive for coagulase-negative staphylococci or other common commensals (eg, Corynebacterium species [not Corynebacterium diphtheriae], Cutibacterium species, Bacillus species [not Bacillus anthracis], viridans group streptococci)

Interpreting blood cultures positive for coagulase-negative Staphylococcus (CoNS) can be challenging, since CoNS is both the most common blood culture contaminant as well as one of the most common causes of CRBSI. A high proportion of positive blood cultures performed on samples drawn from multiple sites (both peripherally and through the suspected catheter) is the best indicator for true CRBSI due to this organism [19,41].

In the setting of a single catheter-drawn blood culture positive for coagulase-negative staphylococci or other potential skin contaminant, with concomitant negative peripheral-drawn blood cultures, the findings may be attributable to catheter colonization, rather than CRBSI. However, the culture results must be interpreted in the clinical context (eg, fever without other sources could be attributable to a catheter infection). Presence of persistent fever requires repeat blood cultures and repeat clinical evaluation for alternative sources of fever. (See 'Collecting specimens for culture' above and "Intravascular non-hemodialysis catheter-related infection: Treatment", section on 'Management of catheter colonization'.)

For circumstances in which peripheral blood cultures are not obtained, positive blood cultures obtained through a catheter may be presumed to reflect true infection, in the absence of other identifiable sources of infection and in the presence of correlating clinical symptoms.

Patients with positive blood culture results should be evaluated carefully for other sources of infection, as well as complications of CRBSI. (See 'Differential diagnosis' below.)

Comparing the time to positive culture between blood cultures drawn from a central line and blood cultures drawn peripherally (known as differential time to positivity [DTTP]) has been used as a tool for diagnosis of CRBSI, particularly in those with cancer [42,43], but the predictive value of this approach is uncertain [1,44]. The technique requires equal volumes of blood (from central line and peripheral vein) obtained for culture at the same time with accurate labeling. For providers who utilize this test, the DTTP is interpreted as evidence that the central line is infected if blood obtained from the peripheral vein starts growing bacteria >2 hours after blood obtained from the central line.

While a negative DTTP result has been used to suggest an alternative source for gram-negative bacteremia in hematology patients with febrile neutropenia [44], the performance of this tool is poor for many common enteric gram-negative bacteria [45]. In addition, studies evaluating the two-hour cut off for diagnosing and excluding CRBSI have found conflicting results for Candida species and poor results for S. aureus [46-51].

The microbiology of catheter-associated infection is discussed separately. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

DIFFERENTIAL DIAGNOSIS — In patients with suspected catheter-related bloodstream infection (CRBSI), alternative sources for bloodstream infection (BSI) must be considered carefully. This is particularly important because management of CRBSI may require catheter removal, which can be challenging in patients with surgically implantable intravascular devices and in patients with limited vascular access [52].

Issues related to diagnostic evaluation of BSI depends on the organism; issues related to bacteremia due to specific organisms are discussed further separately:

●Coagulase-negative staphylococci (see "Infection due to coagulase-negative staphylococci: Clinical manifestations")

●S. aureus (see "Clinical approach to Staphylococcus aureus bacteremia in adults")

●Gram-negative bacilli (see "Gram-negative bacillary bacteremia in adults")

●Candida (see "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults")

CRBSI may be associated with complications including septic thrombophlebitis, infective endocarditis, and metastatic infection. These conditions can occur in the context CRBSI or independently of CRBSI. (See 'Complications' above.)

Other potential causes of BSI include primary vascular graft infection and mycotic aneurysm:

●Primary vascular graft infection may present with bacteremia, fever, and localized physical findings (such as a draining sinus tract) or may develop secondarily in the context of hematogenous seeding. The diagnosis is based on blood cultures and radiographic imaging [53].

●Mycotic aneurysm can develop when infection of the arterial wall causes development of a new aneurysm or when a pre-existing aneurysm becomes infected secondarily in the setting of bacteremia. The clinical manifestations depend upon the site of the aneurysm and may include a painful, pulsatile, and enlarging mass together with fever and malaise. The mass may be palpable or demonstrable only by imaging. The diagnosis of an aneurysm is based upon imaging (computed tomography), and infection is confirmed by culturing an organism from the blood and/or from the aneurysm wall. (See "Overview of infected (mycotic) arterial aneurysm".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Venous access".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Central line infections (The Basics)")

SUMMARY

●Clinical manifestations – Symptoms and signs of catheter-related bloodstream infection (CRBSI) may include fever, hemodynamic instability, and altered mental status. Catheter dysfunction (as occurs with intraluminal clot) may be observed. Clinical signs of sepsis that start abruptly after catheter infusion suggest infusate contamination. (See 'General presentation' above.)

●Complications – Complications of CRBSI includes infective endocarditis, septic thrombophlebitis, and metastatic musculoskeletal infection. These conditions can occur in the context CRBSI or independently of CRBSI. (See 'Complications' above.)

●Diagnosis – Blood cultures positive for an organism commonly associated with CRBSI (such as Staphylococcus aureus, coagulase-negative staphylococci, enterococci, Candida species, Klebsiella species, and E. coli) should raise suspicion for CRBSI, particularly in the absence of other identifiable sources of infection. (See 'Laboratory findings' above and 'Diagnosis' above.)

The diagnosis of CRBSI should be suspected in patients with fever, chills, or hypotension in the setting of a catheter placed at least 48 hours prior to development of symptoms.

•Obtaining blood cultures – Ideally, at least two sets of blood cultures should be obtained from peripheral veins via separate venipuncture sites prior to initiation of antibiotic therapy. For circumstances in which this is not feasible, one blood culture set may be drawn from a peripheral vein and the other blood culture set may be drawn from a catheter hub. Blood cultures should not be drawn solely from the catheter hub since this site is frequently colonized with skin contaminants. (See 'Blood cultures' above.)

•No role for routine catheter tip cultures – There is no role for routine catheter culture at the time of catheter removal; a positive catheter culture is not diagnostic of CRBSI. (See 'Other specimens' above.)

●Interpreting blood culture results – In the absence of other identifiable sources of infection, the following blood culture results may be attributed to CRBSI in the absence of an alternative etiology (see 'Interpreting blood culture results' above):

•One or more blood culture bottles positive for S. aureus, enterococci, Enterobacteriaceae (eg, Escherichia coli, Klebsiella species, Enterobacter species), Pseudomonas aeruginosa

•One or more blood culture bottles positive for Candida species (except in premature neonates)

•Two or more blood culture bottles positive for coagulase-negative staphylococci or other common commensals (eg, Corynebacterium species [not Corynebacterium diphtheriae], Bacillus species [not Bacillus anthracis], Cutibacterium species, viridans group streptococci)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jeffrey Band, MD, who contributed to an earlier version of this topic review.