Intravascular Device infections, Septic Phlebitis/Arteritis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has an intravascular device related infection? What should you expect to find?

The clinical manifestations of catheter related infections can be divided into local infections that occur at the insertion site or systemic infections, which include central line associated blood stream infections (CLABSI).
Local catheter infections occur at the exit site, along the subcutaneous tract (tunnel infection), along the body and tip of the catheter within the intravascular compartment, and/or as a pocket infection.
Local catheter infections can present with signs and symptoms of phlebitis (warmth, pain, tenderness, erythema, induration or palpable venous cord) at or around the catheter exit site.

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Systemic catheter infections present with bacteremia or fungemia in the presence of signs and symptoms of systemic infection, such as fever, chills, and hypotension in the absence of hypovolemia or a cardiac event.

How did the patient develop an intravascular device related infection? What was the primary source from which the infection spread?

Biofilm colonization of an intravascular catheter is a prerequisite for subsequent infection, and there are four recognized sources of colonization:

Extraluminal source due to migration of skin organisms from the insertion site: This route is mainly implicated in short-term catheters (<14 days)
Intraluminal source from the catheter hub, catheter tubing connection: This route is mainly implicated in long term catheters (>30 days).
Contaminated infusate through the catheter
Hematogenous seeding from another focus of infection

Which individuals are at greater risk of developing an intravascular device related infection?

Risk factors for acquiring this type of infection include:

Patients with prolonged hospitalization before catheterization
Long duration of catheterization (>5 days)
Heavy microbial colonization at catheter site
Hematologic malignancy patients with heavy use of blood products
Patients with burns
Total parenteral nutrition through the catheter
Use of femoral or jugular site
Failure to maintain aseptic technique for the insertion and care of the catheters as insertion during a medical emergency
Cancer patients receiving Interleukin 2

Beware: there are other diseases that can mimic an intravascular device related infection:

Local: chemical phlebitis, allergic reaction, extravasation of infusate
Systemic: secondary blood stream infection due to systemic infection as pneumonia, endocarditis

What laboratory studies should you order and what should you expect to find?

Results that confirm the diagnosis

Microbiological evidence implicating the catheter as the source of infection is necessary for diagnosis.
Cultures should be obtained before the initiation of antibiotics.
Local catheter infection can be associated with systemic infection but is unreliable in predicting it with a sensitivity of 3%.
Whenever there is purulence at the catheter exit site, drainage should be swabbed for culture and gram staining.
Diagnostic methods of systemic CLABSI can be divided according to catheter removal or salvage.
In low risk patients (i.e., immunocompetent and those with no intravascular devices, no evidence of severe sepsis or septic shock, no evidence of infection at catheter insertion site and no bacteremia or fungemia), it is advisable to monitor these subset of patients without catheter removal while assessing the possibility of CLABSI.

Catheter sparing methods

Simultaneous quantitative blood cultures: By obtaining quantitative blood cultures simultaneously from a central venous catheter (CVC) and a peripheral vein percutaneously, a 3-fold or greater colony count from the CVC than from the blood obtained percutaneously implicates that the CVC is the source of infection.
Differential time to positivity: As blood cultures are usually monitored by an automated culture system in which cultures are continuously monitored for growth and quantitative blood cultures are not available in all centers, CLABSI can be diagnosed if blood drawn from the CVC becomes positive for bacterial growth 2 or more hours before a simultaneously drawn blood from a peripheral vein. This method, however, could be compromised when the patient is taking antibiotics through the CVC.
Quantitative blood cultures drawn through a CVC: This method is used when peripheral blood cultures are not withdrawn at the time of culture. Diagnosis of CRBSI can be made if CVC withdrawn blood grows more than or equal to 100 CFU/ml. This method, however, is unable to differentiate between CRBSI and high-grade bacteremia.
Acridine orange leukocyte cytospin: A rapid diagnostic microscopy method within 30 minutes; this method, however, has not been widely tested.
Endoluminal brush: A tapered nylon brush on a steel wire is passed through the catheter hub and lumen, withdrawn, then placed in a container that is sonicated and vortexed. The solution is then cultured onto blood agar plates. Counts greater than 100 CFU/ml are considered positive. This technique carries the risks of arrhythmias, embolization, and inciting bacteremia due to disruption of existing biofilm, so it has not been widely used.

Methods requiring catheter removal

Semiquantitative CVC tip culture (roll plate method): This is where the distal segment of the CVC is cut and rolled against a blood agar plate at least four times before the plate is incubated overnight. A colony count of greater than or equal to 15 CFU/ml suggests catheter colonization. If catheter colonization is associated with a positive peripheral blood culture growing the same organism, then CRBSI is diagnosed.
Quantitative catheter segment cultures: A fixed length of catheter is immersed in broth, sonicated, and vortexed to release organisms into suspension that can be plated out and counted quantitatively. A count greater than or equal to 100 CFU per catheter segment is considered positive for colonization. If catheter colonization is associated with a positive peripheral blood culture growing the same organism, then CRBSI is diagnosed. The sonication method is more sensitive than the semiquantitative roll plate method in long-term catheters, as it releases organisms from both the external and internal surface of the catheter.
Microscopy of stained catheters: By using gram stain or arcidine orange stain; this method has not been widely used as it is labor intensive.

What imaging studies will be helpful in making or excluding the diagnosis of intravascular device related infection?

An ultrasound may be needed if septic thrombosis is suspected (often associated with persistent bacteremia after 72 hours of appropriate therapy).
High resolution computed tomography should be used to evaluate for vena cava septic thrombosis when suspected (often associated with persistent bacteremia after 72 hours of appropriate therapy).
Echocardiography (preferably transesophageal) should be considered in infections due to Staphylococcus aureus, Staphylococcus lugdunensis, persistently positive blood cultures for enterococcus, the presence of a prosthetic valve with enterococcal bacteremia, and whenever endocarditis is suspected.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has an intravascular device related infection, what therapies should you initiate immediately?

An Infectious Disease specialist should be consulted in complicated infections (patients with hemodynamic instability, endocarditis, suppurative thrombophlebitis, persistent blood stream infection despite 72 hours of appropriate therapy, osteomyelitis, active malignancy, or immunosuppresion). In addition, Infectious Disease assistance is needed in multi-drug resistant organisms, uncommon organisms, and in considering antibiotic lock therapy.

Management of intravascular device infections depends on the organism identified and the type of device that can be divided into:

Short-term peripheral venous catheters
Short-term central venous catheters and arterial catheters
Long-term central venous catheters; tunneled CVCs, CVCs with implantable ports and peripherally inserted central catheters (PICC)

Management of local infection

The risk of catheter associated infection, with or without suppurative thrombophlebitis, in short-term peripheral venous catheters is very low, but, when pain, induration, erythema, or exudate is associated with these catheters, the catheter should be removed and any exudate at the insertion site should be submitted for gram staining and routine culture. Culture for fungi and acid-fast organisms is indicated in immunocompromised patients.
Short-term CVC and arterial catheters should be removed and cultured if the patient has erythema or purulence at the insertion site.

For long-term central venous catheter

If tunnel infection or port abscess is found, catheter removal is indicated, with incision and drainage if needed and 7-10 days of systemic antibiotic therapy in the absence of concomitant bacteremia or candidemia.
Uncomplicated exit site infections (without systemic signs of infection, positive blood culture, or purulence) should be managed with topical antimicrobial agents depending on the exit site culture results (mupirocin ointment for S. aureus and ketoconazole or lotrimin ointment for Candida).
If complicated exit site infection is found (systemic signs of infection, positive blood culture, or puss is present), then systemic antimicrobials are indicated, and catheter is removed if systemic antibiotics fail.

Management of systemic infection (CLABSI)

Empiric antimicrobial therapy is often initiated when CLBSI is suspected.
Therapy is then tailored according to culture and sensitivity results.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

As gram-positive cocci are the most common pathogens causing CLABSI and methicillin resistance is increasingly prevalent, vancomycin should be started empirically.
In centers at which methicillin resistant S. aureus (MRSA) have high prevalence of isolates with minimum inhibitory concentration for vancomycin greater than 2mcg/ml or the patient has a contraindication for vancomycin, then daptomycin is the preferred alternative.
Linezolid should not be used for empiric therapy for CLABSI, as it is associated with worse outcome.
Antibiotics used for empiric gram-negative coverage should be based on local resistance patterns and antimicrobial susceptibility data. Initial options include fourth-generation cephalosporin, carbapenem, or combined B-lactam/B-lactamase inhibitors with or without an aminoglycoside (in patients with neutropenia, severe sepsis, multi-drug resistant gram-negative bacilli colonization, or prior infection, a combination of two different classes of antibiotics is preferred as the prevalence of resistant gram-negative infections is increased).
Empiric treatment with an antifungal is recommended if the patient has the following risk factors: total parenteral nutrition, prolonged use of broad spectrum antibiotics, hematologic malignancy, stem cell or solid organ transplantation, femoral catheter, and colonization with Candida species at multiple sites.
Echinocandin is recommended for empiric therapy. Fluconazole can be used in patients without azole exposure in the previous 3 months and in centers at which the prevalence of Candida glabrata and Candida krusei is low.

Table I summarizes management of CLABSI according to the causative organism; organisms are in order of prevalence.

Table I.

Organism	Management	Antimicrobials	Comments
Coagulase-negative staphylococci	Short-term CVC and arterial catheter: Catheter can be retained or removed. If catheter is removed, treat with systemic antibiotic for 5-7 days. If catheter is retained, treat with a systemic antibiotic and antibiotic lock therapy for 10-14 days. Long term CVC: Catheter can be retained and patient treated with systemic antibiotic and antibiotic lock therapy for 10-14 days (catheter should be removed if there is no clinical response, relapsing bacteremia and work-up for complicated infection should be done).	Nafcillin or oxacillin, 2 g q4h if methicillin susceptible Vancomycin 15mg/kg q 12h if methicillin resistant Daptomycin 6 mg/kg/day if vancomycin is contraindicated or MIC	Staphylococcus lugdunensis should be managed similar to Staphylococcus aureus because of high risk of metastatic infection.
Staphylococcus aureus	All types of Catheters should be removed. If Uncomplicated (see comments), treat with a systemic antibiotic for 14 days or more. If complicated, treat with systemic antibiotic for 4-6 weeks.	Nafcillin or oxacillin, 2 g q4h if methicillin susceptible Vancomycin 15mg/kg q 12h if methicillin resistant Daptomycin 6 mg/kg/day if vancomycin resistant isolates	Echocardiography (preferably TEE) should be done to rule out endocarditis. Complicated infections include those with high risk of metastatic infection: patients with a retained foreign body, an intravascular prosthetic device, immune suppression, diabetes, persistent bacteremia after 72 hours of catheter removal and appropriate antimicrobials, septic emboli, and endocarditis or suppurative thrombophlebitis.
Enterococcus	Short term CVC and arterial catheter: Catheter should be removed. Treat with a systemic antibiotic for 7-14 days. Long term CVC: Catheter can be retained and patient treated with systemic antibiotic and antibiotic lock therapy for 10-14 days (catheter should be removed if there is no clinical response, relapsing bacteremia and work-up for complicated infection should be done).	Ampicillin 2g q4h or q6h (gentamicin can be added 1 mg/kg q8h) if ampicillin susceptible Vancomycin 15 mg/kg IV q 12h (gentamicin can be added 1 mg/kg q8h) if ampicillin resistant but vancomycin susceptible Linezolid 600 mg q12h or Daptomycin 6 mg/kg/day if ampicillin and vancomycin resistant	Signs and symptoms of endocarditis, persistent bacteremia, or the presence of a prosthetic heart valve should be evaluated by TEE.
Gram-negative organisms	All types of catheters should be removed. Treat with systemic antibiotic for 7-14 days. Long term CVC can be salvaged if vascular access is difficult using systemic and antibiotic lock therapy for 7-14 days (catheter should be removed if no response, and endocarditis, suppurative thrombophlebitis should be ruled out).	Fourth-generation cephalosporin, carbapenem, or combined B-lactam/B-lactamase inhibitors	The first-line treatment for stenotrophomonas maltophilia and Burkholderia cepacia is trimethoprim-sulfamethoxazole. Extended spectrum beta lactamase producing Klebsiella pneumoniae and Escherichia coli should not be treated with cephalosporins or piperacillin-tazobactam, even if the organism is susceptible as it is associated with poor outcome.
Candida species	All types of catheters should be removed. Treat with an antifungal for 14 days after the first negative blood culture.	Caspofungin 70 mg loading dose then 50 mg/day, or micafungin 100 mg/day, or anidulaungin 200 mg loading dose then 100mg/day Fluconazole 400 mg/day if azole- susceptible Lipid formulations of amphotercin B can be used as an alternative
Other gram-positive organisms	Catheter should be removed Treat with systemic antibiotic for 7 days or more.	Vancomycin 15 mg/kg q12h	Diagnosis of CRBSI due to Corynebacterium, Bacillus, and micrococcus species requires at least two positive blood cultures from different sites. Catheter salvage can be attempted if corynebacterium is isolated and non-glycopeptide antibiotic is used.

2. Other key therapeutic modalities.

Antimicrobial lock therapy (ALT)

Antimicrobial lock solution consists of 2-3 ml of an antimicrobial drug for which the organism is susceptible, often mixed with an anticoagulant, which is used to fill the lumen of the catheter.
This solution can be used in prevention and management of CLABSI.
This solution should achieve sufficient concentrations to kill microbes growing in the biofilm; 100-1000 times greater to kill sessile bacteria within a biofilm than to kill planktonic bacteria.
ALT should only be used in conjunction with systemic antimicrobial therapy (both administered for 7-14 days) for management of CRBSI when catheter salvage is the goal, and the solution should be changed at least every 48 hours because of decreasing antibiotic concentration over time.
ALT should not be used if there is exit site, tunnel or pocket infection, or evidence of extraluminal infection.
ALT should not be used in the management of CRBSI due to S. aureus or Candida, unless there is no alternative catheter insertion site due to difficulty in eradication and high failure rate.
In patients with negative peripheral blood cultures but multiple positive blood cultures drawn via the catheter growing coagulase-negative staphylococci or gram-negative bacilli, ALT can be given for 10-14 days without systemic therapy, to eradicate the catheter colonization and prevent CLABSI.

What complications could arise as a consequence of an intravascular device related infection?

What should you tell the family about the patient's prognosis?

Uncomplicated CLABSI is associated with better outcome than complicated infection, in which there is suppurative thrombophlebitis, endocarditis, osteomyelitis, or metastatic seeding of infection.
CLABSI independently increase hospital stay, from 10-20 days, with an added cost ranging from $3,000 to $56,000.
Mortality rates associated with CLABSI are not consistent in the literature, as the rate is dependent on the pathogen and host factors (as neutropenia and complicated infection).
CLABSI caused by S. aureus is associated with a 10-20% risk of deep seated infection, such as endocarditis or osteomyelitis.

Add what-if scenarios here:

If the CVC or arterial catheter was exchanged over a guidewire and the catheter tip has significant growth, and the patient is still having positive blood culture, then the new catheter should be removed and a new catheter should be placed in a new site.
If the catheter tip in a febrile patient grows S. aureus but blood cultures are negative, then the patient should be treated with systemic antibiotics for 5-7 days and monitored for ongoing infection, clinically and with blood cultures as needed.
If the catheter tip in a febrile patient grows other than S. aureus but blood cultures are negative, then the patient should be monitored for ongoing infection, clinically and with blood cultures as needed.
If catheter was removed because of S. aureus CLABSI, a new catheter can be put in only after blood cultures become negative.
If catheter cannot be removed when indicated because of CLABSI (no alternative access, the patient has significant bleeding diathesis), then catheter should be exchanged over a guidewire and an antimicrobial impregnated catheter (minocycline-rifampin or second-generation chlorhexidine-silver sulfadiazine) should be used for exchange.

How do you contract an intravascular device related infection and how frequent is this disease?

It is estimated that about 200 million intravascular devices are used yearly in the United States, of which about 5-7 million are CVCs.
It is estimated that at least 80,000 CLABSI occur in US Intensive care Units (ICUs) each year, about 300,000 total cases in the United States annually.
A recent systemic review of 200 published prospective studies estimated that point incidence rates, expressed as infections per 1000 catheter days, range from 0.5 with peripheral intravenous catheters, 1.6 for cuffed and tunneled catheters, 1.7 for arterial catheters, 2.4 for PICCs, and 2.7 for short-term non-cuffed and non-medicated CVCs.

What pathogens are responsible for this disease?

In order of prevalence, the most common microbes causing CLABSI in percutaneously inserted, non-cuffed catheters are coagulase-negative staphylococci, S. aureus, Candida species, and enteric gram-negative bacilli, whereas for surgically implanted catheters and peripherally inserted CVCs, they are coagulase negative staphylococci, enteric gram-negative bacilli, S. aureus, and P. aeruginosa.

How do these pathogens cause disease?

Catheters create an anatomic connection between the contaminated environment (particularly the contaminated skin of the patient and hands of medical personnel) and the sterile intravascular compartment. Various microorganisms can colonize the catheter surface, intraluminally or extraluminally due to many factors that promote colonization. The material of which the catheter is made and its surface irregularity and thrombogenicity are important; host factors, such as fibrin and fibronection, form a sheath around the foreign body, promoting microbial attachment. Intrinsic factors produced by microorganisms, including coagulase negative staphylococci, S. aureus, P. aeruginosa and Candida species promote biofilm formation.
Biofilms are complex cellular agglomerations of microorganisms, embedded in a self-produced matrix composed mainly of polysaccharides, enriched with metallic cations, such as calcium, iron, and magnesium, which make them as a solid wall preventing engulfment and killing by polymorphonuclear leukocytes, preventing contact with antimicrobial agents.

What other additional laboratory findings may be ordered?

Procalcitonin, the precursor of the hormone calcitonin, is a hormokine produced by various tissues in the body in response to inflammation and infection and has shown promise as a marker of bacterial and fungal blood stream infections.

How can intravascular device related infections be prevented?

Catheter related infections can be prevented by implementing the following measures:

Educating health care workers regarding the proper insertion and maintenance of catheters.
Performing hand hygiene before catheter insertion
Using maximal sterile barrier precautions, including the use of a cap, mask, sterile gown, sterile gloves, and a sterile full body drape for the insertion of CVCs, PICCs, or guidewire exchange.
Using an all-inclusive catheter kit.
Using a 2% chlorohexidine-based skin antiseptic in patients older than 2 months before CVC and arterial catheter insertion, and the antiseptic should be allowed to dry according the manufacturer’s recommendation before insertion
Avoiding the use of femoral veins for central venous access in adults and preferring the subclavian vein instead, unless the access is for hemodialysis where subclavian vein should be avoided because of the risk of stenosis.
Using tunneled catheters if placement is anticipated to be for long term (more than 1 month).
Using ultrasound guidance to place CVCs to reduce the number of attempts required to successfully cannulate the vein.
Removing nonessential catheters.
Replacing peripheral catheters every 72-96 hours, whereas there is no need for replacing CVCs, PICCs, hemodialysis, or arterial catheters unless clinically indicated.
Routinely replacing administration sets every 4-7 days, unless blood, blood products, or fat emulsions are given through it in which case the administration set should be replaced within 24 hours of initiating the infusion.
Using antimicrobial/antiseptic impregnated CVCs. Where catheters are coated with minocycline-rifampin or chlorhexidine-silver sulfadiazine, the usage of such catheters is recommended in patients whose catheter is expected to remain longer than 5 days and the CLABSI rate is not decreasing after implementation of staff education, sterile barrier precautions and usage of more than 0.5% chlorhexidine preparation as skin antiseptic.
Using antimicrobial lock solutions by which an antimicrobial solution is used to fill a catheter lumen and then allowed to dwell for a period of time. Antibiotics used include vancomycin, gentamicin, ciprofloxacin, minocycline, amikacin, cefazolin, cefotaxime, and ceftazidime. Antiseptics are also used as alcohol and taurolidine. These agents are usually combined with anticoagulant, such as heparin or EDTA. Most preparations are prepared at hospital pharmacies. Using this technique is recommended in patients with long-term catheters who have a history of multiple CLABSI despite adherence to aseptic technique.
Using chlorhexidine-impregnated sponges over the CVC insertion site for short-term catheters if CRBSI rate is not decreasing after implementation of staff education, sterile barrier precautions and usage of more than 0.5% chlorohexidine preparation as skin antiseptic.
Using a 2% chlorhexidine wash for daily skin cleansing.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

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. vol. 81. 2006 Sep. pp. 1159-71. (Superb review of the issue of intravascular device associated infections.)

Mermel, LA, Allon, M, Bouza, E. “Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 49. 2009 Jul 1. pp. 1-45. (IDSA Guidelines that are essential for clinicians and infection control practitioners in the diagnosis and treatment of catheter-related infections.)

O’Grady, NP, Alexander, M, Burns, LA. “Guidelines for the Prevention of Intravascular Catheter related Infections”. Clin Infect Dis. vol. 52. 2011 May. pp. e162-93. IDSA Guidelines that review and grade the evidence for prevention of catheter associated infections.)

Raad, I, Hanna, H, Maki, D. “Intravascular catheter-related infections: advances in diagnosis, prevention, and management”. Lancet Infect Dis. vol. 7. 2007 Oct. pp. 645-57. (Scholarly review of the issue of catheter related infections.)

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