OVERVIEW: What every practitioner needs to know

Are you sure your patient has CIED infection? What should you expect to find?

Infection is a serious complication of cardiovascular implantable electronic devices (CIED) and is associated with significant morbidity and mortality. CIED infection can present as generator pocket infection or systemic infection (bacteremia or endocarditis). While diagnosis of pocket infection is typically made based on inflammatory changes (swelling, pain, erythema, drainage, erosion) at the pulse generator site, diagnosis of CIED-related systemic infection is based on positive blood cultures with or without echocardiographic evidence of vegetations on CIED leads or heart valves. Empiric therapy for CIED infection should include vancomycin, as staphylococci are the most common causative pathogens. Once diagnosis is confirmed, complete removal of CIED, including cardiac leads, is necessary to cure the infection. Retrospective risk adjusted data indicate that attempted antibiotic therapy without device removal during the initial treatment is associated with increased 1-year mortality compared to prompt device removal early during the initial course of antibiotic therapy. A new device can be implanted once the infected pocket has been adequately debrided and repeat blood cultures after device removal are negative for at least 72 hours. Treatment duration for CIED pocket infection is 10-14 days, whereas therapy for device-related bacteremia ranges from 2 to 4 weeks depending on the organism. CIED-related valvular endocarditis should be managed according to endocarditis treatment guidelines.

Patients with a CIED may develop left-sided endocarditis without evident involvement of the CIED. In these instances the likely pathogens are those typically causing less invasive endocarditis, i.e. viridans group and other streptococci, enterococci, and HACEK organisms. In the absence of evidence suggesting CIED lead infection or associated endocarditis, these episodes of endocarditis can be treated in the standard manner without CIED removal. In patients with prosthetic valve endocarditis, especially those with infection caused by staphylococci or in whom prosthetic valve replacement surgery is required, it is prudent to remove the CIED during the course of treatment (or at surgery) in order to minimize the risk of relapse.

  • History: Patients with CIED infection may experience symptoms limited to device pocket (pain, redness, swelling, or drainage) or present with systemic signs and symptoms of infection (fever, chills, sweating, malaise, anorexia). Pocket infection is more common in early-onset illness (within 1 year of device implantation), whereas the majority of patients with late-onset infection (>1 year after device implantation) present with systemic infection with or without pocket involvement.

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  • Physical examination: Patients with CIED pocket infection typically present with erythema, induration, tenderness, or purulent drainage from the generator site (most frequently placed in pectoral area). Occasionally, the device can erode through the skin. The majority of patients with device-related systemic infection (bacteremia with or without complicating endocarditis) present with fever, hypotension, embolic lesions (septic pulmonary emboli due to right sided cardiac involvement), or evidence of metastatic seeding in bones or joints.

How does a patient develop CIED infection? What is the primary source from which the infection spreads?

  • CIED pocket infections typically originate from contamination of the device generator, leads, or pocket tissues during implantation procedure, whereas CIED-related endocarditis typically results from hematogenous seeding of the device leads or cardiac valves from a distant source of bacteremia.

  • Reported rate of CIED infection ranges from 0.9 to 13%. Implantable cardioverter defibrillators (ICDs) have a several-fold higher rate of infection compared with permanent pacemakers. Patient undergoing CIED revision or replacement procedures are also at higher risk than de novo implantation.

Which individuals are of greater risk of developing CIED infection?

  • Risk factors for CIED infection can be classified as patient-related, device-related, or implantation procedure-related.

  • P-related risk factors include age, chronic steroid therapy, anticoagulation (predisposing patients to post-implantation pocket hematoma), diabetes mellitus, heart failure, renal failure, immunosuppressive therapy, or presence of a central venous catheter (risk factor for bacteremia and subsequent device seeding) are the most significant predisposing conditions.

  • Device characteristics associated with increased risk of infection include abdominal generator placement, use of epicardial leads (rare these days), more than two transvenous leads, multiple device revisions, and previous history of CIED infection.

  • Factors related to implantation procedure that predispose to subsequent infection include use of temporary pacing leads before permanent device implantation, failure to administer prophylactic antibiotics before implantation, operator inexperience, fever within 24 hours of implantation, and post-operative hematoma at the pocket site.

Beware: there are other diseases that can mimic disease CIED infection:
  • In the early post-operative period, it may be difficult to distinguish a pocket hematoma from an infected device generator. Also, patients who present with bacteremia without any inflammatory signs at the device pocket present a significant diagnostic challenge and echocardiography is needed to identify or exclude underlying device lead infection or valvular endocarditis. Occasionally, septic jugular thrombophlebitis can mimic device-related endovascular infection, and CT or MRI is needed to exclude this possibility.

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

Results consistent with the diagnosis
  • All patients with suspected CIED infection should have complete blood count (CBC) with differential, electrolytes, serum creatinine, C-reactive protein (CRP), chest x-ray, and two sets of blood cultures drawn at admission. If there is drainage from the pocket site, a swab should also be sent for bacterial cultures.

  • Patients in whom infection is limited to CIED pocket will frequently have normal lab studies.

  • All patients with positive blood cultures should undergo transesophageal echocardiography (TEE) to detect any vegetations on CIED leads or heart valves.

  • A positron- emission tomography (PET)/computed tomography (CT) can be helpful to confirm or exclude CIED infection in cases where clinical findings (for suspected pocket infection) or TEE images (for bacteremic patients) are indeterminate.

  • CT scan of the chest may be considered in cases in which suspected pulmonary emboli.

  • If the decision is made to explant the device, swabs and tissue specimens from generator pocket should be submitted for bacterial cultures.

  • Sonication of the explanted generator and leads can be a useful adjunctive measure to enhance microbial detection.

  • Mycobacterial and fungal stains and cultures should be considered in cases of chronic or recurrent infection where bacterial cultures are negative.

  • Lead tip cultures should be submitted in cases of device-related endovascular infection. However, results should be interpreted with cautions, as lead tips can get contaminated as they are dragged through an infected pocket.

Results that confirm the diagnosis
  • CIED pocket infection is essentially a clinical diagnosis. Microbiologic confirmation can be obtained by swab or tissue cultures from the generator pocket, or sonication of the explanted device, and is helpful to choose appropriate antimicrobial therapy.

  • Diagnosis of device-related systemic infection requires confirmation by positive blood cultures.

What imaging studies can be helpful in making or excluding the diagnosis of CIED infection?

  • TEE is the most important and useful imaging modality in cases of suspected device-related endovascular infection, including endocarditis.

  • CT scan may be helpful to exclude septic jugular venous thrombosis and to identify septic pulmonary emboli as a complication of right-sided endocarditis.

  • Chest x-rays are not helpful in the diagnosis of CIED infection.

  • A PET/CT scan can be helpful to confirm or exclude the diagnosis of CIED infection in cases where clinical or TEE findings are indeterminate.

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

If you determine the patient has CIED infection, what therapies should you initiate immediately?

Cardiology (preferably electrophysiology) and Infectious Diseases service should be consulted in all cases of suspected or confirmed CIED infection.

Key principles of therapy

Optimal management of CIED infection includes the following:

  • Complete removal of infected device including all leads

  • Sending pocket swab and tissue for cultures; send the leads for culture. (If available in the laboratory, send device and leads for sonication with culture of the sonicate)

  • Appropriate antimicrobial therapy directed at causative pathogen

  • Implantation of a new device once acute infection has cleared

Removal of infected device

  • Cardiology (EP) service should be consulted in all cases of suspected or confirmed CIED infection.

  • Complete removal of the infected device, including generator and leads is a requisite for curing acute infection and preventing relapse.

  • Patients should be assessed as to whether they need ongoing device therapy. This information is critical to decide if and when a new device should be implanted.

  • Percutaneous extraction is generally considered safe, even in cases in which a large vegetation (>1 cm) is attached to the device leads.

  • Cardiac surgery should be consulted in cases in which infection is complicated by valvular endocarditis, intracardiac abscess formation, perforation, or dehiscence of native or prosthetic valves and cases in which percutaneous extraction fails or poses significant risk to the patient.

Choice and duration of anti-infective therapy

  • Infectious Diseases service should be consulted to guide anti-infective therapy.

  • In cases in which infection is limited to the device pocket, 10-14 days of anti-infective therapy is adequate. Patients can be switched to an oral agent at discharge from the hospital if the organism is susceptible.

  • Patients with device-related bacteremia (without evidence of endocarditis on TEE) should be treated with at least 2 weeks of parenteral anti-infective therapy based on identification and susceptibility of the causative pathogen. Therapy may be extended to 4 weeks in cases of S. aureus bacteremia and in fact is preferred by many infectious disease specialist.

  • Device-related endocarditis should be treated with 4-6 weeks of parenteral antibiotic therapy based on American Heart Association (AHA) guidelines for treatment of infective endocarditis.

Timing of implantation of new device

  • A new device can be placed on the contra-lateral side once the infected device has been removed and blood cultures obtained after device removal are negative for at least 72 hours. In cases where admission blood cultures are negative, a new device may be implanted as soon as infected pocket has been adequately debrided.

  • Implantation of a new device should be delayed for 14 days (from the first negative blood culture) in cases where device infection is complicated by valvular endocarditis.

1. Anti-infective agents

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

  • Staphylococci (S. aureus and coagulase-negative staphylococcus) are the most common pathogens responsible for CIED infection. Therefore, empiric anti-infective therapy for CIED infection should include coverage for both methicillin-susceptible and resistant strains of staphylococci. We recommend empiric treatment with vancomycin while awaiting culture data.

  • Daptomycin can be used as an alternative agent in patients who are allergic or intolerant to vancomycin.

  • Empiric gram-negative coverage with cefepime or a carbapenem (to cover Pseudomonas) should be considered in severely ill patients (hypotensive, requiring ICU stay, or pressor support) and immunocompromised patients while awaiting blood culture results.

  • Anti-infective therapy should be withheld in patient who present with CIED pocket infection only (no systemic signs or symptoms), until the immediate pre-operative time period to maximize the pocket swab and tissue culture yield.

Table I summarizes treatment recommendations for the most common pathogens responsible for CIED infection.

Table I.
Organism Antibiotic Dose Alternative
S. aureus and coagulase-negative staphylococcus (methicillin-susceptible) Nafcillin 2 g q4 Vancomycin or Daptomycin (see below for dosing)
Oxacillin IV 2 g q4
Cefazolin 1-2 g q8h
S. aureus and coagulase-negative staphylococcus (methicillin-resistant) Vancomycin 15-20 mg/kg q12h (monitor serum levels) Daptomycin: 6 mg/kg q24h (4 mg/kg q24h for pocket infection only)
Vancomycin (for pocket infection or Penicllin-resistant organisms) 15-20 mg/kg q12h (monitor serum levels) Daptomycin (dose as above) OR Linezolid (IV or PO): 600 mg q12h
—————- ————– ————————————
Enterococcus Ampicillin plus 12 g/24h IV in 6 equally divided doses plus Ampicillin (12 g/d in 6 divided doses) plus
Gentamicin (Amp+Gent combination preffered for device related endocarditis) 3 mg/kg/24h IV or IM in 3 equally divided doses Ceftriaxone 4 gm/d in 2 divided doses) (for device related endocarditis)
Pseudomonas aeruginosa Cefepime 1-2 g IV q12h Ciprofloxacin (IV): 400 mg q12h OR
Meropenem 500 mg IV q6h piperacillin/tazobactam:3.375 g q6h OR
Imepenem 500 mg IV q6h

Aztreonam: 1-2 g q8hr

2. Next list other key therapeutic modalities.
  • Optimal management of CIED infection includes timely recognition and treatment of associated complications, such as valvular endocarditis, septic pulmonary emboli, or metastatic seeding of distant organs, such as the liver, spleen, spine, and joints.

  • In patients who have existing catheters for hemodialysis, chemotherapy, or infusion of other medications, these central venous catheters should also be removed for source control and to prevent relapse of infection.

What complications could arise as a consequence of CIED infection?

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

  • Complications from CIED infection can be categorized into:

    Complication resulting from CIED infection: These include lead or valvular endocarditis, septic thrombosis or metastatic seeding to other organs.

    Lead extraction complications: Most transvenous leads are removed percutaneously. Potential complications of percutaneous extraction include damage to tricuspid valve, subclavian vein laceration, pneumo- or hemothorax, or myocardial rupture. Moreover, infected vegetations can detach from transvenous leads during percutaneous extraction and result in septic pulmonary emboli.

  • Most patients with CIED pocket infection do well, provided there are no significant complications during device lead extraction.

  • Device-related endovascular infection (bacteremia with or without endocarditis) is associated with significant in-hospital mortality ranging from 10 to 20%.

  • Risk factors for poor outcome include symptomatic heart failure at presentation, chronic steroid use, renal failure, active malignancy, device-related endocarditis, and infection with S. aureus.

Add what-if scenarios here:

  • Fungal or mycobacterial causes of CIED infection should be considered in immunocompromised patients and situations in which bacterial cultures are negative.

  • If large (>3 cm) vegetations are noted on device leads, lead extraction approach should be carefully discussed between the cardiologists and cardiac surgeons.

How do you contract CIED infection and how frequent is this disease?

Reported rates of CIED vary based on the study period and population included in the study cohort. In general, more recent data suggest the rate of CIED infection in contemporary practice ranges from 0.5 to 5%. For unclear reasons, ICDs appear to have 2- to 3-fold higher rates of infection compared to permanent pacemakers.

Risk factors for early-onset CIED infection are mostly related to events surrounding implantation of the device that may increase the risk of device generator, lead, or pocket contamination. These include failure to provide appropriate and timely anti-infective prophylaxis, operator inexperience, length and complexity of implantation procedure, and number of device leads.

Late-onset CIED infections may arise from indolent pocket infection with slow-growing biofilm associated bacteria introduced in the generator pocket during initial implantation or subsequent device revision or from hematogenous seeding of device leads or the generator pocket from a distant source of bacteremia.

Recent epidemiologic data have revealed a disturbing trend of disproportionate rise in rate of CIED infections compared to rate of device implantation. Precise reasons for this discrepancy are unclear but may be related to more complex devices being implanted in patients with multiple comorbid conditions.

What pathogens are responsible for this disease?

Staphylococci, including S. aureus and coagulase-negative Staphylococcus, are the most common pathogens responsible for CIED infection. This is partly because of frequent skin colonization with these organisms and their ability to bind to prosthetic devices and produce biofilms. Moreover, S. aureus and coagulase-negative staphylococci are the leading cause of community and health-care associated catheter-related bacteremias with the potential to seed the device pocket or leads during an episode of bloodstream infection.

Gram-negative bacteria are infrequently isolated in cases of CIED infection. Occasionally, other skin organisms, such as Propionibacterium, Corynebacterium, and Micrococcus, can be isolated from infected generator pockets. Polymicrobial device infections are reported but are rare.

Fungal or mycobacterial infections of cardiac devices are rare and usually a subject of case reports and small case series. Among fungi, Candida species are the most frequently reported, followed by a few cases of Aspergillus CIED infection. Occasionally, non-tuberculous mycobacteria may be isolated from the generator pocket or blood cultures. These pathogens should be included in the differential diagnosis in immunocompromised patients and in cases in which routine bacterial cultures are negative.

How do these pathogens cause CIED infection?

Staphylococci are frequent skin colonizers and the most common cause of CIED infection because of their ability to bind to prosthetic devices and produce biofilms. Moreover, S. aureus and coagulase-negative staphylococci are the leading causes of community and health-care associated catheter-related bacteremias with potential to seed device pocket or leads during an episode of bloodstream infection.

CIED infection due to enterococci and gram-negative bacteria usually result from a distant source of bacteremia, such as urinary or gastrointestinal tract and catheter-related bloodstream infection with subsequent device seeding.

What other clinical manifestations may help me to diagnose and manage CIED infection?

Occasionally, positive blood cultures are the sole manifestation of an underlying CIED infection. This is especially true in cases of S. aureus bacteremia in which the rate of underlying device infection ranges from 30 (late-onset infection) to 50% (early-onset infection). Consequently, in patients who develop bacteremia in the setting of an implanted cardiac device without another identifiable source of bloodstream infection, underlying device infection should be strongly considered and TEE should be performed to investigate further.

Underlying device infection must be considered in patients who develop recurrent or relapsing bacteremia even if a TEE shows no evidence of device lead involvement or valvular endocarditis and there are no inflammatory signs at the generator pocket. A PET/CT scan may be helpful in this situation. Infectious Diseases service should be consulted to help manage these difficult cases as device explantation may be necessary to cure infection.

What other additional laboratory findings may be ordered?

Although TEE is the mainstay of diagnosing device-related endocarditis, additional investigations may be necessary to identify or exclude associated complications, such as septic venous thrombosis, vertebral osteomyelitis, septic arthritis, or abscesses in liver, spleen, or kidney. Choice of imaging modality depends on the suspected site of metastatic seeding. For instance, MRI may be the diagnostic test of choice for evaluating spine infection, whereas ultrasound or CT scan may be more appropriate to assess presence or absence of liver, spleen, or kidney involvement. If infected CIED is not MRI compatible, then PET/CT scan may be helpful to evaluate sites of metastatic seeding.

How can CIED infection be prevented?

  • Strict adherence to aseptic techniques is the cornerstone of preventing intra-operative contamination of device leads or the generator pocket.

  • All patients should receive pre-operative antibiotic prophylaxis 1 hour before the implantation procedure. Effectiveness of antibiotic prophylaxis has been proven in randomized clinical trials.

  • Cefazolin is the drug of choice for primary prophylaxis. Vancomycin is an alternative agent that can be used in patients who are allergic or intolerant to beta-lactams or have known colonization with methicillin-resistant S. aureus (MRSA).

  • Additional measures for prevention of CIED infection may include use of mupirocin nasal ointment for decolonization in the preoperative period for patients with known MRSA colonization and use of chlorhexidine-based solutions for skin preparation prior to device implantation.

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

Baddour, LM, Epstein, AE, Erickson, CC. “Update on cardiovascular implantable electronic device infections and their management”. A scientific statement from the American Heart Association. vol. 121. Circulation 2010. pp. 458-77. (First comprehensive guidelines form AHA that address diagnosis and management of CIED infections and include recommendations regarding timing of re-implantation. Recommendations are ranked based on the strength of available evidence. The AHA document also identifies areas in need of further research.)

Sohail, MR, Uslan, DZ, Khan, AH. “Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections”. J Am Coll Cardiol. vol. 49. 2007. pp. 1851-9. (Authors propose Mayo Clinic guidelines for management of CIED infections based on their institutional experience. Key elements include shorter duration of anti-infective therapy for CIED lead infections (2 weeks) and implantation of new device after 72 hours of negative blood cultures. These guidelines serve as the foundation for updated AHA scientific statement addressing CIED infection management published in 2010.)

Klug, D, Balde, M, Pavin, D. “Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study”. Circulation. vol. 116. 2007. pp. 1349-55. (Largest study to analyze risk factors for CIED infection. Factors that increased odds of infection include fever within 24 hours of implantation, use of temporary pacing leads, and re-intervention, whereas denovo implantation and prophylactic antibiotics were protective.)

Dy Chua, J, Abdul-Karim, A, Mawhorter, S. “The role of swab and tissue culture in the diagnosis of implantable cardiac device infection”. Pacing Clin Electrophysiol. vol. 28. 2005. pp. 1276-81. (Data from this study suggests that tissue cultures have higher yield in identifying causative pathogens for CIED pocket infection compared to swab cultures.)

Uslan, DZ, Dowsley, TF, Sohail, MR. “Cardiovascular implantable electronic device infection in patients with Staphylococcus aureus bacteremia”. Pacing Clin Electrophysiol. vol. 33. 2009. pp. 407-13. (Patients with ICDs and prosthetic heart valves were more likely to develop CIED-related endocarditis in the setting of. S. aureus bacteremia.)

de Oliveira, JC, Martinelli, M, Nishioka, SA. “Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial”. Circ Arrhythm Electrophysiol. vol. 2. 2009. pp. 29-34. (Largest and most definitive study to support the benefit of primary prophylactic anti-infective therapy for prevention of CIED infection.)

Le, KY, Sohail, MR, Friedman, PA. “Clinical predictors of cardiovascular implantable electronic device-related infective endocarditis”. Pacing Clin Electrophysiol. vol. 34. 2011 Apr. pp. 450-9. (Investigators of this study propose a prediction model (based on the results of their multivariable analysis) to predict the likelihood of CIED-related endocarditis and to identify patients who should undergo TEE for futher evaluation.)

Sohail, MR, Eby, EL, Ryan, MP, Gunnarsson, C, Wright, LA, GREENSPON, AJ. “Incidence, Treatment Intensity, and Incremental Annual Expenditures for Patients Experiencing a Cardiac Implantable Electronic Device Infection: Evidence From a Large US Payer Database 1-Year Post Implantation”. Circulation: Arrhythmia and Electrophysiology. vol. 9. 2016. pp. e003929(Largest study to date to analyze cost of managing CIED infections based on clinical presentation. Authors conclude that the management of CIED infections results in a substantial healthcare burden with a significant increase in annual expenditures the year after implant when device infection occurs.)

Sohail, MR, Baddour, LM. “Role of PET Imaging in Management of Implantable Electronic Device Infection*”. JACC Cardiovasc Imaging. vol. 9. 2016. pp. 291-293. (An overview of role of PET/CT in the diagnosis of CIED infection, limitations of the published data, and future direction of research in this field.)

Sohail, MR, Palraj, BR, Khalid, S. “Predicting risk of endovascular device infection in patients with Staphylococcus aureus bacteremia (PREDICT-SAB)”. Circulation: Arrhythmia and Electrophysiology. vol. 8. 2015. pp. 137-144. (Among patients presenting with SAB and no signs of pocket infection, the risk of underlying CIED infection can be calculated based on the type of device, number of device-related procedures, and duration of SAB. Patients without any of these high-risk features have a low risk of underlying CIED infection and may be monitored closely without immediate device extraction.)

DeSimone, DC, Sohail, MR. “Management of bacteremia in patients living with cardiovascular implantable electronic devices”. Heart Rhythm. August 2016. (The risk of underlying CIED lead infection in patients presenting with bacteremia depends on several factors, including the type of microorganism isolated in blood cultures, duration and source of bacteremia, type of CIED, and number of device-related procedures. These risk factors must be considered when making decisions regarding the need for further diagnostic imaging and whether to retain or remove the device. Authors propose a novel algorithm for appropriate evaluation and management.)

DRG Codes and expected length of stay

Expected length of stay for CIED pocket infection is 5-7 days, whereas 7-14 days are expected in CIED-related endovascular infection.