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Treatment and Prevention of Cardiovascular Implantable Electronic Device (CIED) Infections

  • Peter Phillips
    Correspondence
    Corresponding author: Dr Peter Phillips, Division of Infectious Diseases, St Paul’s Hospital, Rm 667, 1081 Burrard St, Vancouver, British Columbia V6Z 1Y6, Canada. Tel.: +1-604-837-7191; fax: +1-604-806-8527.
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia, Canada
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  • Andrew D. Krahn
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Vancouver General Hospital, Vancouver, British Columbia, Canada

    Division of Cardiology, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada

    Centre for Cardiovascular Innovation, University of British Columbia, Vancouver, British Columbia, Canada
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  • Jason G. Andrade
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Vancouver General Hospital, Vancouver, British Columbia, Canada

    Division of Cardiology, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada

    Centre for Cardiovascular Innovation, University of British Columbia, Vancouver, British Columbia, Canada
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  • Santabhanu Chakrabarti
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Division of Cardiology, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada
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  • Christopher R. Thompson
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Division of Cardiology, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada

    Echocardiography Laboratory, St. Paul’s Hospital, Vancouver, British Columbia, Canada
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  • David J. Harris
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia, Canada

    Vancouver General Hospital, Vancouver, British Columbia, Canada
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  • Jacqueline M. Forman
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    University of British Columbia School of Nursing, Vancouver, British Columbia, Canada
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  • Shahzad S. Karim
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Division of Cardiovascular Surgery, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada

    Royal Columbian Hospital, New Westminster, British Columbia, Canada
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  • Laurence D. Sterns
    Affiliations
    Division of Cardiology, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada

    Royal Jubilee Hospital, Victoria, British Columbia, Canada
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  • Lynn M. Fedoruk
    Affiliations
    Division of Cardiovascular Surgery, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada

    Royal Jubilee Hospital, Victoria, British Columbia, Canada
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  • Eric Partlow
    Affiliations
    Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia, Canada

    Royal Jubilee Hospital, Victoria, British Columbia, Canada
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  • Jamil Bashir
    Affiliations
    St. Paul’s Hospital, Vancouver, British Columbia, Canada

    Vancouver General Hospital, Vancouver, British Columbia, Canada

    Centre for Cardiovascular Innovation, University of British Columbia, Vancouver, British Columbia, Canada

    Division of Cardiovascular Surgery, University of British Columbia, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada
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Open AccessPublished:August 09, 2022DOI:https://doi.org/10.1016/j.cjco.2022.07.010

      Abstract

      An expanded role for cardiac implantable electronic devices (CIEDs) in recent decades reflects an aging population and broader indications for devices, including both primary prevention and management of dysrhythmias. CIED infection is one of the most important device-related complications and has a major impact on mortality, quality of life, healthcare utilization, and cost. Unfortunately, the investigation and management of CIED infection remain complex, often necessitating complete and timely removal of the device and leads in order to eradicate the infection. In addition, the translation of knowledge from an extensive literature to a disparate group of medical practitioners has often been inadequate. This review of CIED infection management highlights the significant advances made during the past decade, including diagnostic criteria, advanced imaging, and next-generation sequencing for culture-negative cases or those in which uncertainty remains. We also outline the role and indication for powered lead extraction, the process of antibiotic choice and treatment duration, considerations related to the timing and location for reimplantation, and preimplantation risk stratification and associated interventions to reduce the risk of CIED infection.

      Résumé

      L’élargissement du rôle des dispositifs électroniques cardiaques implantables (DECI) au cours des dernières décennies reflète le vieillissement de la population et les indications plus vastes des dispositifs, notamment dans la prévention primaire et la prise en charge des dysrythmies. Les infections liées aux DECI sont l’une des plus importantes complications liées aux dispositifs et ont des conséquences majeures sur la mortalité, la qualité de vie, l’utilisation et les coûts des soins de santé. Malheureusement, le dépistage et la prise en charge des infections liées aux DECI demeurent complexes et nécessitent souvent le retrait complet et rapide du dispositif et des sondes en vue d’éradiquer l’infection. De plus, l’application des connaissances issues d’une vaste littérature à un groupe disparate de médecins praticiens a souvent été inadéquate. La présente revue sur la prise en charge des infections liées aux DECI illustre les avancées importantes réalisées au cours de la dernière décennie, notamment les critères diagnostiques, l’imagerie avancée et le séquençage de prochaine génération des cas à culture négative ou de ceux pour lesquels des incertitudes demeurent. Nous avons aussi décrit le rôle et les indications d’extraction des sondes fonctionnelles, le processus du choix des antibiotiques et de la durée du traitement, les considérations relatives au moment et au lieu de la réimplantation, et la stratification du risque en préimplantation et les interventions associées afin de réduire le risque d’infections liées aux DECI.
      Cardiac implantable electronic devices (CIEDs) are medical devices that regulate cardiac rate and rhythm (eg, pacemakers, implantable cardioverter-defibrillators [ICDs], and cardiac resynchronization therapy [CRT] devices), as well as diagnostic devices such as implantable cardiac monitors. The use of CIEDs increased as a result of a combination of changing population demographics. In 2018-2019, among devices implanted in Canadian hospitals (inpatient or day surgeries), 22,770 were accounted for by pacemakers and defibrillators, including both de novo implants and revision procedures for the 1-year period.
      Canadian Institute for Health Information
      Implantable medical devices in Canada: insights into high-volume procedures and associated costs.
      Along with the rising implant rates has come the realization that the systems themselves have increased in complexity, moving from single-chamber fixed-rate pacemakers to include multi-chamber, rate-responsive pacemakers that are capable of cardioversion and defibrillation (ICDs) and/or CRT. Indeed, in recent years, dual-chamber pacing has become much more frequently used than single-chamber pacing, with the major increases in device implantation being driven by ICDs and CRT-capable devices.
      Canadian Institute for Health Information
      Implantable medical devices in Canada: insights into high-volume procedures and associated costs.
      ,
      • Wilkoff B.L.
      • Boriani G.
      • Mittal S.
      • et al.
      Impact of cardiac implantable electronic infection: a clinical and economic analysis of the WRAP-IT Trial.
      CIED infection has a major impact on mortality, quality of life, healthcare utilization, and costs.
      • Wilkoff B.L.
      • Boriani G.
      • Mittal S.
      • et al.
      Impact of cardiac implantable electronic infection: a clinical and economic analysis of the WRAP-IT Trial.
      ,
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      CIED infection increased the risk of in-hospital mortality by more than 2-fold, with an estimated in-hospital 30-day mortality from CIED infection of 5%-8%.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      A retrospective cohort study of all CIED implantations (n = 17,584) between April 2013 and March 2016 in Ontario identified 215 patients (1.2%) who developed infection, including 88 early-onset (day 0-30), 85 mid-onset (day 31-182), and 42 late-onset (day 183-365) infections. The total mean 1-year health costs were highest for late-onset infections ($113,778 in Canadian dollars [CAD]), followed by mid-onset (CAD$85,302), and then early-onset (CAD$75,415) infections; by contrast, the costs for uninfected patients were CAD$25,631.
      • Daneman N.
      • Homenauth E.
      • Saskin R.
      • et al.
      The predictors of economic burden of early-, mid- and late-onset cardiac implantable electronic device infections: a retrospective cohort study in Ontario, Canada.
      A single-centre retrospective analysis of CIED infection-related costs in Quebec demonstrated a median cost of CAD$26,879 per patient.
      • Gitenay E.
      • Molin F.
      • Blais S.
      • et al.
      Cardiac implantable electronic device infection: detailed analysis of cost implications.
      A recent worldwide survey demonstrated considerable regional disparities and variable adherence to clinical practice guidelines for the prevention and management of CIED infection.
      • Traykov V.
      • Bongiorni M.G.
      • Boriani G.
      • et al.
      Clinical practice and implementation of guidelines for the prevention, diagnosis and management of cardiac implantable electronic device infections: results of a worldwide survey under the auspices of the European Heart Rhythm Association.
      The purpose of this document is to provide a synopsis of the current literature and various guideline recommendations relevant to CIED infections. This document is intended for a broad range of clinicians who may encounter patients with a CIED and a clinical presentation compatible with device-related infection. This includes family practitioners, emergency room physicians, internists, cardiologists, cardiac surgeons, and infectious diseases physicians.

      Background

      Clinical manifestations of cardiac device infections vary from local pocket infection (eg, erythema or frank purulent discharge of the generator-pocket site) and/or cutaneous mechanical erosion of the generator/leads to systemic symptoms due to bloodstream infection or endocarditis. In a recent prophylaxis study conducted mainly in Canada, among 128 patients with CIED infections who required surgical intervention, evidence of pocket infection and/or erosion was seen in 73%, and bloodstream infection and/or endocarditis in 38%.
      • Krahn A.D.
      • Longtin Y.
      • Phillippon F.
      • et al.
      Prevention of Arrhythmia Device Infection Trial: the PADIT Trial.
      Most often, pocket infection develops due to perioperative contamination of the leads or generator,
      • Da Costa A.
      • Lelièvre H.
      • Kirkorian G.
      • et al.
      Role of the preaxillary flora in pacemaker infections: a prospective study.
      or erosion of the generator through the skin. Deeper infection of the transvenous portion of the leads develops due to intravascular tracking from a pocket infection or hematogenous seeding from a remote source.
      • Uslan D.Z.
      • Sohail M.R.
      • Sauver JL St.
      • et al.
      Permanent pacemaker and implantable cardioverter defibrillator infection. A population-based study.
      Although most CIED infections are believed to result from the device implantation procedure, the recent Prevention of Arrhythmia Device Infection Trial (PADIT) of intensive antimicrobial prophylaxis showed no significant effect on the overall risk of infection over and above that provided by standard preoperative antimicrobial prophylaxis.
      • Longtin Y.
      • Gervais P.
      • Birnie D.H.
      • et al.
      Impact of choice of prophylaxis on the microbiology of cardiac implantable electronic device infections: insights from the prevention of arrhythmia device infection trial (PADIT).
      One proposed explanation for this finding is that the proportion of CIED infections that have their onset postimplantation may be greater than previously thought.
      • Longtin Y.
      • Gervais P.
      • Birnie D.H.
      • et al.
      Impact of choice of prophylaxis on the microbiology of cardiac implantable electronic device infections: insights from the prevention of arrhythmia device infection trial (PADIT).

      Incidence

      In comparison to devices without transvenous leads (eg, leadless pacemakers, subcutaneous ICDs, and loop recorders), those that do have transvenous leads have been associated with a higher incidence of CIED infection, including pacemakers (1.19%), ICDs (1.91%), CRT-pacemakers (2.18%), and CRT-defibrillators (3.35%).
      • Olsen T.
      • Jorgensen O.D.
      • Nielsen J.C.
      • et al.
      Incidence of device-related infection in 97,750 patients: clinical data from the complete Danish device-cohort (1982-2018).
      The incidence rates are also higher with replacement, compared to de novo, CIED implants.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Olsen T.
      • Jorgensen O.D.
      • Nielsen J.C.
      • et al.
      Incidence of device-related infection in 97,750 patients: clinical data from the complete Danish device-cohort (1982-2018).
      The use of a subcutaneous ICD has been demonstrated to be non-inferior to a transvenous ICD, with respect to device-related complications during a median follow-up of 49 months, including vis à vis infections, which occurred in 0.93% and 1.89% of cases, respectively.
      • Knops R.E.
      • Olde Nordkamp L.R.A.
      • Delnoy P.H.M.
      • et al.
      Subcutaneous or transvenous defibrillator therapy.
      Recent experience with the Reveal LINQ implantable cardiac monitor (loop recorder; Medtronic, Minneapolis, MN) demonstrated a low infection rate at a median follow-up of 16 months, with 8 cases (0.56%) requiring device explantation, which included 3 with pocket-site erosion among 1420 patients.
      • Diederichsen S.Z.
      • Haugan K.J.
      • Hojberg S.
      • et al.
      Complications after implantation of a new-generation insertable cardiac monitor: results from the LOOP study.
      Leadless pacemakers rarely become infected.
      • El-Chami M.F.
      • Bonner M.
      • Holbrook R.
      • et al.
      Leadless pacemakers reduce risk of device-related infection: review of the potential mechanisms.
      ,
      • El-Chami M.F.
      • Bockstedt L.
      • Longacre C.
      • et al.
      Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up.
      In a prospective study of 725 patients implanted with a leadless pacemaker, no systemic infections were documented during a 6-month follow-up period.
      • Reynolds D.
      • Duray G.Z.
      • Omar R.
      • et al.
      A leadless intracardiac transcatheter pacing system.
      In an observational cohort study involving 6219 patients with a leadless pacemaker and 10,212 patients with a transvenous pacemaker, at 2 years of follow-up, the incidence of infection was < 0.16% and 0.6%, respectively (see Supplemental Data from El-Chami et al.
      • El-Chami M.F.
      • Bockstedt L.
      • Longacre C.
      • et al.
      Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up.
      ).
      • El-Chami M.F.
      • Bockstedt L.
      • Longacre C.
      • et al.
      Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up.

      Microbiology

      Coagulase-negative staphylococci (CoNS; 42%-77%, using the number of isolates as the denominator, because polymicrobial infections will result in the total number of cultured organisms exceeding the number of patients studied) account for the majority of CIED infections, followed by Staphylococcus aureus (10%-30%), gram-negative bacilli (6%-11%), Streptococcus spp. (3%-10%), Enterococcus spp. (0.4%-10%), Cutibacterium spp (formerly Propionibacterium spp.; 0.8%-8%), and fungi (0.4%-1.4%).
      • Sandoe J.A.
      • Barlow G.
      • Chambers J.B.
      • et al.
      Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. Report of a joint working party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS), British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE).
      Methicillin-resistant staphylococci (both coagulase-negative and -positive) account for approximately one third of all cases.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      The proportion of patients with CIED infection due to methicillin-resistant Staphylococcus aureus (MRSA) was 15% in a large single-centre US study that included 816 consecutive patients undergoing device removal for confirmed infection.
      • Hussein A.A.
      • Baghdy Y.
      • Wazni O.M.
      • et al.
      Microbiology of cardiac implantable electronic device infections.
      In contrast, a large, single-centre Italian study identified MRSA as the etiologic agent in only 19 of 1204 consecutive patients (1.6%) undergoing device removal for suspected CIED infection during the same time period.
      • Bongiorni M.G.
      • Tascini C.
      • Tagliaferri E.
      • et al.
      Microbiology of cardiac implantable electronic device infections.
      Similarly, confirmed CIED infections due to MRSA in the PADIT trial accounted for < 5% of patients in the control arm, with patients enrolled from mainly Canadian and some Dutch centres.
      • Longtin Y.
      • Gervais P.
      • Birnie D.H.
      • et al.
      Impact of choice of prophylaxis on the microbiology of cardiac implantable electronic device infections: insights from the prevention of arrhythmia device infection trial (PADIT).

      Risk factors

      A systematic review and meta-analysis of CIED infection that included 60 studies and 206,528 patients was published in 2015.
      • Polyzos K.A.
      • Konstantelias A.A.
      • Falagas M.E.
      Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis.
      Host-related factors include the following: chronic kidney disease (odds ratio [OR] = 3.02 [95% confidence interval {CI} 1.38-6.64]) or end-stage renal disease (OR = 8.73 [95% CI 3.4-22.3]); previous CIED infection (OR = 7.84, [95% CI 1.94-31.6]); long-term corticosteroid use (OR = 3.44 [95% CI 1.6-7.3]); anticoagulant use (OR = 1.59 [95% CI 1.01-2.4]); diabetes mellitus (OR = 2.08 [95% CI 1.62-2.67]); chronic obstructive pulmonary disease (OR = 2.95 [95% CI 1.78-4.90]); malignancy (OR = 2.23 [95% CI 1.26-3.95]); and heart failure (OR = 1.65 [95% CI 1.14-2.39]).
      • Polyzos K.A.
      • Konstantelias A.A.
      • Falagas M.E.
      Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis.
      Procedure-related factors include the following: postoperative hematoma (OR = 8.46 [95% CI 4.0-17.8]); reintervention for lead dislodgment (OR = 6.37 [95% CI 2.9-13.8]); device replacement or revision (OR 1.98 [95% CI 1.46-2.70]); preimplant temporary pacing (OR = 2.31 [95% CI 1.36-3.92]); and an inexperienced operator, defined as one who has performed less than 100 previous procedures (OR = 2.85 [95% CI 1.23-6.58]).
      • Polyzos K.A.
      • Konstantelias A.A.
      • Falagas M.E.
      Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis.
      Device-related factors include the presence of epicardial leads (OR = 8.09 [95% CI 3.4-18.9]; abdominal generator pocket (OR = 4.0 [95% CI 2.4-6.4]), and positioning of 2 or more leads (OR = 2.02 [95% CI 1.11-3.69]).
      • Polyzos K.A.
      • Konstantelias A.A.
      • Falagas M.E.
      Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis.
      PADIT was a recent, large cluster crossover trial of conventional vs intensive antimicrobial prophylaxis performed in 19,603 patients that identified 5 non-modifiable risk factors for CIED infection. These include the following: younger age; procedure type (ICD, CRT, or revision/upgrade procedure); renal dysfunction; an immunocompromised state; and prior CIED procedures.
      • Birnie H.
      • Wang J.
      • Alings M.
      • et al.
      Risk factors for infections involving cardiac implanted electronic devices.
      The study generated the novel PADIT infection risk score, which was internally validated.
      • Birnie H.
      • Wang J.
      • Alings M.
      • et al.
      Risk factors for infections involving cardiac implanted electronic devices.
      Another large, CIED infection prophylaxis study (World-wide Randomized Antibiotic Envelope Infection Prevention Trial [WRAP-IT]) enrolled close to 7000 patients and identified risk factors for infection; these include modifiable procedural factors such as longer procedure time, implant location (non-left pre-pectoral), perioperative glycopeptide antibiotic (vs non-glycopeptide), anticoagulant and/or antiplatelet use, and capsulectomy.
      • Tarakji K.G.
      • Mittal S.
      • Kennergren C.
      • et al.
      Risk factors for CIED infection after secondary procedures: insights from the WRAP-IT Trial.

      Management

      An approach to the diagnosis and treatment of CIED infection is outlined in the management algorithm (Fig. 1).
      Figure thumbnail gr1
      Figure 1Management algorithm (adapted with permission from DeSimone and Sohail
      • DeSimone D.C.
      • Sohail M.R.
      Approach to diagnosis of cardiovascular implantable-electronic-device infection.
      and the American Society for Microbiology). CIED, cardiovascular implantable electronic device; FDG-PET/CT, flourine-18-fluorodeoxyglucose positron emission tomography-computed tomography; TEE, transesophageal echocardiogram; TTE, transthoracic echocardiogram; WBC SPECT/CT, 99mTc-hexamethypropylene amine oxime labeled autologous white blood cell single-photon emission computerized tomography/computerized tomography.
      a Pocket-site findings: unequivocal signs of pocket infection include discharge, or erosion through the overlying skin. If suspect only superficial infection (eg, cellulitis, stitch abscess), particularly in the 1st month after implantation, then draw blood cultures and consider empiric trial of oral anti-staphylococcal therapy without device removal (see Differential Diagnosis section in text). If the clinical diagnosis of pocket infection is uncertain, then consider FDG-PET/CT or WBC SPECT/CT. b Suspect endocarditis: eg, constitutional symptoms (eg, fevers), septic pulmonary emboli, new regurgitant murmur. c TTE, then do TEE: In addition to providing a new baseline study for future comparison, TTE offers complementary information
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      and may shorten the duration needed for a TEE procedure, which in some cases may not be well tolerated. Given the evidence for improved survival associated with early removal of infected devices within 1 week of hospitalization,
      • Lin A.Y.
      • Saul T.
      • Aldaas O.
      • et al.
      Early versus delayed lead extraction in patients with infected cardiovascular implantable electronic devices.
      orders for both studies (TTE and TEE) may be submitted simultaneously in order to minimize delays, but with the expectation that the TTE preferably would be done first. This is also consistent with the proposed Canadian benchmark for an urgent echocardiogram within 7 days,
      • Munt B.
      • O’Neill B.J.
      • Koilpillai C.
      • et al.
      Treating the right patient at the right time: access to echocardiography in Canada.
      which in this circumstance is the TEE rather than just the TTE. d Consider other imaging for extent of disease, other source, etc (eg, FDG-PET/CT or WBC SPECT/CT; intracardiac echocardiography). If FDG-PET/CT not available or findings are equivocal, then consider WBC SPECT/CT. FDG-PET/CT can be utilized in both early and late CIED infection.
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      e CIED extraction: At device removal, obtain pocket-site tissue (+/– swabs) for culture, and submit the whole device and leads in a sterile container to the microbiology laboratory for sonication prior to culture. f Antibiotic duration: The start is timed from the date of CIED extraction or from the date when blood cultures became negative, whichever occurred last. g Lead endocarditis antibiotic duration: (a) Staphylococcus aureus, 4 wk; (b) other bacteria, 2 wk. h Pocket-infection antibiotic duration: (i) infection: 10–14 d; or (ii) erosion through skin without purulence or discharge: 7–10 d. Antibiotic intravenously until blood cultures confirmed negative, then may complete therapy orally. i Consider CIED extraction according to blood cultures
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      : (i) extract if single blood culture is positive for S. aureus, or Candida spp, or multiple blood cultures are positive for coagulase-negative staphylococcus or Cutibacterium spp. (formerly Proprionibacterium spp.) when no other source is identified; (ii) extract if recurrent or persisting bacteremia or fungemia due to any organism when no other source is identified; (iii) consider extraction if blood culture is positive for alpha-hemolytic or beta-hemolytic streptococci, or enterococci; and (iv) retain the CIED for bacteremia due to pneumococcus or gram-negative bacilli, and repeat blood cultures 2 wk later after antibiotic completed. j Response to oral antibiotic: For suspected superficial pocket-site infection, a trial of therapy is recommended for 7-14 d with an anti-staphylococcal regimen (see Differential Diagnosis section in text).

      Diagnosis

      Triage and referral

      Patients suspected of having a CIED infection should be evaluated by a multidisciplinary team including a cardiologist and/or cardiac surgeon experienced in CIED infections, and an infectious diseases specialist, with input from imaging specialists.
      • Chen W.
      • Dilsizian V.
      Is 18F-flurodeoxyglucose positron emission tomography/computed tomography more reliable than clinical standard diagnosis for guiding patient management decisions in cardiac implantable electronic device infection?.
      This approach is applicable to those who develop symptoms at the generator pocket site and/or unexplained fever or bloodstream infection.
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      If uncertainty remains regarding the diagnosis after investigations, then a lead-extraction program clinician should be consulted. The triage and referral process is outlined in the triage algorithm (Fig. 2).
      Figure thumbnail gr2
      Figure 2Triage algorithm for suspected or confirmed cardiovascular implantable electronic device (CIED) infection.

      Clinical assessment

      Although CIED infections are most often encountered during the first 6 months following device implantation, they continue to occur for years beyond that time.
      • Harper M.W.
      • Uslan D.Z.
      • Greenspoon A.J.
      • et al.
      Clinical presentation of CIED infection following initial implant versus reoperation for generator change or lead addition.
      Infections limited to the device pocket site tend to occur somewhat earlier than those that are systemic. In a recent study that included a 36-month follow-up time, pocket-only and systemic infections occurred a mean of 174 days and 258 days after the procedure, respectively.
      • Sohail M.R.
      • Corey G.R.
      • Wilkoff B.L.
      • et al.
      Clinical presentation, timing, and microbiology of CIED infections: an analysis of the WRAP-IT Trial.
      Symptoms and signs associated with CIED infection include those related to the device pocket site (eg, pain, erythema, warmth, swelling, ulceration, and drainage) and/or systemic symptoms (eg, fever, chills), and those related to metastatic sites of infection (eg, left- or right-sided endocarditis, osteomyelitis).
      • Harper M.W.
      • Uslan D.Z.
      • Greenspoon A.J.
      • et al.
      Clinical presentation of CIED infection following initial implant versus reoperation for generator change or lead addition.
      Laboratory studies should include blood cultures (prior to antibiotic initiation), complete blood counts and differential, and C-reactive protein level. Normal results for these investigations do not exclude CIED infection. Arterial emboli and cutaneous signs of endocarditis are seldom present in CIED-related infection unless left-sided valve involvement is present.

      Considerations for novel CIEDs

      Leadless pacemakers

      These devices, which have no subcutaneous generator pocket and no transvenous leads, rarely become infected.
      • El-Chami M.F.
      • Bockstedt L.
      • Longacre C.
      • et al.
      Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up.
      For patients with these devices, blood cultures and echocardiography are required only if symptoms or signs suggest systemic infection (eg, fever, chills).

      Subcutaneous ICDs

      Infections usually occur within the first year and may present with inflammatory changes at the pocket site and/or the parasternal lead incision site, but systemic infection is rare.
      • Baddour L.M.
      • Weiss R.
      • Mark G.E.
      • et al.
      Diagnosis and management of subcutaneous implantable cardioverter-defibrillator infections based on process mapping.
      As a result, the diagnostic evaluation of patients suspected to have a subcutaneous-ICD infection does not routinely include blood cultures or echocardiography. A trial of empiric antibiotic therapy should be given to patients with suspected superficial infection and those in whom the diagnosis remains uncertain, before device extraction is considered.
      • Baddour L.M.
      • Weiss R.
      • Mark G.E.
      • et al.
      Diagnosis and management of subcutaneous implantable cardioverter-defibrillator infections based on process mapping.
      Further investigation (eg, a nuclear medicine study) may be needed in order to clarify the diagnosis.

      Loop recorders

      As for subcutaneous ICDs, infections involving these devices present with inflammatory changes at the pocket site, but they rarely result in systemic infection.
      • Diederichsen S.Z.
      • Haugan K.J.
      • Hojberg S.
      • et al.
      Complications after implantation of a new-generation insertable cardiac monitor: results from the LOOP study.
      Blood cultures and echocardiography are usually not required in the diagnostic evaluation, except for patients at risk of developing infective endocarditis (IE).

      Differential diagnosis

      Pocket-site infection needs to be clinically differentiated from other causes of inflammation in the vicinity of the device, including superficial skin and soft tissue infection (eg, cellulitis and incisional infection such as a stitch abscess), hematoma, and allergic reactions to dressings, tape, or topical disinfectants, particularly during the first month following device implantation.
      • Baddour L.M.
      • Weiss R.
      • Mark G.E.
      • et al.
      Diagnosis and management of subcutaneous implantable cardioverter-defibrillator infections based on process mapping.
      When superficial infection is suspected, an empiric trial of oral anti-staphylococcal therapy (after blood cultures have been collected) is warranted
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Baddour L.M.
      • Weiss R.
      • Mark G.E.
      • et al.
      Diagnosis and management of subcutaneous implantable cardioverter-defibrillator infections based on process mapping.
      for 7-14 days. Antibiotic options include cephalexin monotherapy (or in combination with doxycycline or trimethoprim-sulfamethoxazole), or monotherapy with clindamycin, trimethoprim-sulfamethoxazole, doxycycline, or linezolid. The use of linezolid is often restricted to infectious diseases specialists due to cost, toxicity, and concerns related to the possible development of resistance. Resolution of the superficial inflammation avoids the need for device removal and may be documented with serial photographs; however, close follow-up is needed in order to detect recurrence. If uncertainty continues regarding the presence of pocket-site infection, then a nuclear medicine study should be considered (see Nuclear Medicine section).

      Microbiology investigations

      At the time of first seeking medical attention for unexplained febrile illness, or possible “lower respiratory tract infection,” patients with a CIED should have a minimum of 2 sets of blood cultures collected prior to initiation of any empiric antibiotic therapy. For those suspected of having CIED infection (eg, pocket-site symptoms), at least 3 sets of blood cultures should be drawn at the initial evaluation, before initiation of any empiric antimicrobial therapy.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      Any positive blood cultures should be followed up with repeat blood cultures 48-72 hours later, and should be repeated every 48 hours until they are negative.
      When the CIED is explanted, generator pocket tissue gram stain and culture should be obtained, rather than just swabs. The sensitivity for organism recovery from tissue specimens from the pocket site (69%) has been greater than that of pocket swab cultures (31%).
      • Dy Chua J.
      • Abdul-Karim A.
      • Mawhorter S.
      • et al.
      The role of swab and tissue culture in the diagnosis of implantable cardiac device infection.
      The whole explanted device and leads should be submitted to the microbiology laboratory in a sterile container for sonication prior to culture. CIED device sonication disrupts the hardware-related biofilm and has been associated with increased recovery of bacterial isolates.
      • Rohacek M.
      • Erne P.
      • Kobza R.
      • et al.
      Infection of cardiovascular implantable electronic devices: detection with sonication, swab cultures, and blood cultures.
      Advance notification of the microbiology laboratory that an explanted device will be submitted for sonication and culture can facilitate processing of the specimen.
      If bacterial cultures are negative, then mycobacterial and fungal cultures can be requested along with polymerase chain reaction testing on any residual specimens for organisms missed on routine culture. Recent experience suggests an improved yield on microbiology specimens for a causative organism in 95% of patients with the addition of sonication fluid undergoing both conventional cultures and next-generation sequencing.
      • Olsen T.
      • Justesen U.S.
      • Nielsen J.C.
      • et al.
      Microbiological diagnosis in cardiac implantable electronic device infections detected by sonication and next-generation sequencing.
      Next-generation sequencing is most relevant for patients whose conventional cultures remain negative; however, its limitations include restricted availability at reference laboratories, and in some cases, difficulty differentiating true pathogens from false positives due to specimen contamination.
      Lead-tip cultures may be positive in patients with isolated pocket infection, given that the leads are withdrawn through an infected pocket site.
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      In the absence of other evidence of lead endocarditis (eg, positive blood cultures, echocardiogram, or nuclear medicine study findings), a positive lead-tip culture does not warrant a prolongation of antibiotic therapy duration.
      Percutaneous aspiration of the generator pocket should not be performed as part of the diagnostic evaluation of suspected CIED infection,
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      given the risk of inadvertent pocket-site contamination, in addition to the difficulty of evaluating the significance of organisms that may be skin contaminants from the procedure. Also, collection of a preoperative culture obtained by passing a swab through a draining sinus may give misleading results and is discouraged.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).

      Imaging

      Echocardiography

      A transthoracic echocardiogram, and then also a transesophageal echocardiogram (TEE), should be obtained for suspected CIED-related endocarditis (eg, positive blood cultures, history of constitutional symptoms, or presentation suggestive of right-sided endocarditis with septic pulmonary emboli). Intracardiac echocardiography has demonstrated high sensitivity for detection of vegetations on cardiac devices and has at times been utilized during lead extraction, but it is not routinely performed.
      • Caiati C.
      • Luzzi G.
      • Pollice P.
      • Favale S.
      • Lepera M.E.
      A novel clinical perspective on new masses after lead extraction (ghosts) by means of intracardiac echocardiography.
      TEE should be done to evaluate the left-sided heart valves, even if transthoracic views have demonstrated lead-adherent masses.
      A lead mass is not an uncommon TEE finding, and in the absence of other evidence of infection, it is unlikely to represent IE and should not prompt lead (and CIED) removal.
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Downey B.C.
      • Juselius W.E.
      • Pandian N.G.
      • Estes N.A.
      • Link M.S.
      Incidence and significance of pacemaker and implantable cardioverter-defibrillator lead masses discovered during transesophageal echocardiography.
      A study of TEE (ordered for various reasons) findings among 153 patients with pacemakers or ICDs showed a device lead mass in 25 patients (16%).
      • Downey B.C.
      • Juselius W.E.
      • Pandian N.G.
      • Estes N.A.
      • Link M.S.
      Incidence and significance of pacemaker and implantable cardioverter-defibrillator lead masses discovered during transesophageal echocardiography.
      IE was diagnosed in 17 patients, of whom 8 (47%) had a lead mass on TEE. No evidence of an infective process was seen in the other 17 patients (72%) who had a demonstrable lead mass by TEE. In the same study, among 136 TEE examinations performed for indications other than suspected IE, lead masses were noted in 13 studies (10%), but only one patient was judged to have IE.
      Echocardiography in limited pocket-site infection previously has been considered unnecessary in patients with negative blood cultures (collected prior to antibiotics) and no other clinical suspicion of systemic infection or endocarditis.
      • Sandoe J.A.
      • Barlow G.
      • Chambers J.B.
      • et al.
      Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. Report of a joint working party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS), British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE).
      ,
      • DeSimone D.C.
      • Sohail M.R.
      Approach to diagnosis of cardiovascular implantable-electronic-device infection.
      ,
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      However, both a transthoracic echocardiogram and a TEE have now been recommended, in a recent international guideline,
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      for all patients with CIED infection. Whether the addition of echocardiography to the management of patients with clinical evidence of infection limited to the pocket site is associated with improved patient outcomes remains unclear. Furthermore, detection of a noninfectious lead thrombus or fibrous adhesion in such patients may result in unnecessarily prolonged antibiotic treatment. Nuclear medicine studies (fluorodeoxyglucose positron emission tomography/computed tomography [FDG-PET/CT] or white blood cell single-photon emission computerized tomography/computerized tomography [WBC SPECT/CT], as outlined below) may help clarify the significance of lead masses detected on echocardiography.

      Nuclear medicine

      The 2 relevant studies for CIED infection are whole-body fluorine-18 (18F)-FDG- PET/CT and 99mTc-hexamethypropylene amine oxime labeled (99mTc-HMPAO) autologous-WBC SPECT/CT (also referred to as WBC SPECT/CT). 18F-FDG is a glucose analog, with a positron-emitting radionuclide fluorine-18. The accumulation of 18F-FDG in tissue is a marker of the metabolic process of glucose uptake in tissues, which may be increased in various conditions including neoplastic, inflammatory, and infectious diseases. By contrast, radiolabeled leukocytes accumulate at sites of leukocyte recruitment, which is more specific for infection. Performance of FDG-PET/CT is optimized in regard to both sensitivity and specificity by dietary preparation in order to reduce physiological uptake of FDG by cardiomyocytes.
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      Patients scheduled for an early-morning FDG-PET/CT study should have at least one high-fat/low-carbohydrate meal (dinner) the evening before, followed by a 12-hour fast. For late-morning or early-afternoon studies, a high-fat/low-carbohydrate breakfast should be followed by at least a 4-hour fast beforehand.
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      Prolonged antibiotic use has been associated with reduced sensitivity for both FDG-PET/CT and WBC SPECT/CT.
      • Chen W.
      • Dilsizian V.
      Is 18F-flurodeoxyglucose positron emission tomography/computed tomography more reliable than clinical standard diagnosis for guiding patient management decisions in cardiac implantable electronic device infection?.
      The advantages of these whole-body functional imaging tools compared to echocardiography or CT are possible earlier diagnosis before the development of anatomic abnormalities and potentially additional information regarding embolism and extracardiac sites of infection.
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      ,
      • Chen W.
      • Dilsizian V.
      Is 18F-flurodeoxyglucose positron emission tomography/computed tomography more reliable than clinical standard diagnosis for guiding patient management decisions in cardiac implantable electronic device infection?.
      Among patients with suspected CIED infection, the nuclear medicine studies have been most helpful in those for whom diagnostic uncertainty continues following the initial investigations, including echocardiography. For example, when a pocket-site infection is suspected but the clinical findings are inconclusive, or if systemic symptoms are present with or without bacteremia, but with negative echocardiography and no local findings to indicate pocket infection.
      A meta-analysis of 14 studies with 18F-FDG PET-CT showed a pooled sensitivity and specificity for pocket infections of 96% and 97%, respectively.
      • Mahmood M.
      • Kendi A.
      • Farid S.
      • et al.
      Role of 18F-FDG PET/CT in the diagnosis of cardiovascular implantable electronic device infections: a meta-analysis.
      In contrast, the sensitivity and specificity for lead infection and CIED endocarditis were lower, at 76% and 83%, respectively.
      • Mahmood M.
      • Kendi A.
      • Farid S.
      • et al.
      Role of 18F-FDG PET/CT in the diagnosis of cardiovascular implantable electronic device infections: a meta-analysis.
      However, a number of the studies were not designed specifically to detect IE and lacked the dietary preparation protocol used to ensure suppression of myocardial physiological uptake of 18F-FDG.
      • Juneau D.
      • Golfam M.
      • Hazra S.
      • et al.
      Positron emission tomography and single-photon emission computed tomography imaging in the diagnosis of cardiac implantable electronic device infection. A systematic review and meta-analysis.
      Although mild increased physiological uptake of 18F-FDG related to normal wound healing occurs in the first few months after device implantation, it can be differentiated from infection
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      on the basis of reduced intensity and localization to the junction between the leads and the connector.
      • Sarrazin J.F.
      • Phillippon F.
      • Tessier M.
      • et al.
      Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections.
      In contrast, uptake around the generator and over the leads favors a pocket infection.
      • Sarrazin J.F.
      • Phillippon F.
      • Tessier M.
      • et al.
      Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections.
      Timely access to a PET-CT scan is limited in some regions. Although published experience using WBC SPECT/CT for this indication is more limited, it may be more readily available, and in one study, the sensitivity and specificity for detection of CIED infection were 94% and 100%, respectively.
      • Erba P.A.
      • Solini M.
      • Conti U.
      • et al.
      Radiolabeled WBC scintigraphy in the diagnostic workup of patients with suspected device-related infections.
      A retrospective study limited to 48 consecutive patients being evaluated for CIED infection who had undergone both studies compared the performance of FDG-PET/CT and WBC SPECT/CT. The diagnostic sensitivity, specificity, positive and negative predictive values were, respectively, 80%, 91%, 80%, and 91% for FDG-PET/CT, and 60%, 100%, 100%, and 85% for WBC SPECT/CT.
      • Calais J.
      • Touati A.
      • Grall N.
      • et al.
      Diagnostic impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography and white blood cell SPECT/computed tomography in patients with suspected cardiac implantable electronic device chronic infection.
      WBC SPECT/CT has lower sensitivity but higher specificity than FDG PET-CT for CIED infection.
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      In summary, the indication for a nuclear medicine study in suspected CIED infection is for those patients for whom there is diagnostic uncertainty, and who are categorized as “possible” by either the 2019 international CIED Infection criteria
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      or the Duke-Li IE criteria.
      • Li J.S.
      • Sexton D.J.
      • Mick N.
      • et al.
      Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.
      The preferred investigation, if available, is FDG-PET/CT, given its higher sensitivity, speed, and practicality.
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      ,
      • Juneau D.
      • Golfam M.
      • Hazra S.
      • et al.
      Positron emission tomography and single-photon emission computed tomography imaging in the diagnosis of cardiac implantable electronic device infection. A systematic review and meta-analysis.
      The role of WBC SPECT/CT is use for patients without ready access to FDG-PET/CT, or for whom results are equivocal using FDG- PET/CT.
      • Dilsizian V.
      • Budde R.P.J.
      • Chen W.
      • et al.
      Best practices for imaging cardiac device-related infections and endocarditis: A JACC: Cardiovascular Imaging Expert Panel statement.
      ,
      • Chen W.
      • Dilsizian V.
      Is 18F-flurodeoxyglucose positron emission tomography/computed tomography more reliable than clinical standard diagnosis for guiding patient management decisions in cardiac implantable electronic device infection?.
      ,
      • Juneau D.
      • Golfam M.
      • Hazra S.
      • et al.
      Positron emission tomography and single-photon emission computed tomography imaging in the diagnosis of cardiac implantable electronic device infection. A systematic review and meta-analysis.

      Other imaging

      A chest radiograph should be performed in all patients with suspected CIED infection.
      Right-sided endocarditis may present with a clinical picture that mimics pneumonia and/or pleurisy. Pulmonary CT angiography may need to be considered in patients presenting with what appears to be recurrent pneumonia
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      if other investigations are nondiagnostic regarding the possibility of septic pulmonary emboli due to CIED-related endocarditis.

      Diagnostic criteria for CIED infection

      The utility of the modified Duke criteria (Duke-Li criteria) for the diagnosis of CIED-related lead infection and/or valvular IE has not been established.
      • Sandoe J.A.
      • Barlow G.
      • Chambers J.B.
      • et al.
      Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. Report of a joint working party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS), British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE).
      ,
      • Li J.S.
      • Sexton D.J.
      • Mick N.
      • et al.
      Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.
      Diagnostic classification criteria for CIED infection (pocket, and/or IE) have recently been proposed by an international group convened by the European Heart Rhythm Association (EHRA), as outlined in Table 1.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      This classification is based on the merging of the modified Duke criteria
      • Li J.S.
      • Sexton D.J.
      • Mick N.
      • et al.
      Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.
      and the European Society of Cardiology (ESC) 2015 guidelines for the management of IE,
      • Habib G.
      • Lancellotti P.
      • Antunes M.J.
      • et al.
      2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM).
      but it has yet to be validated.
      Table 1Recommendations for diagnosis of CIED infections and/or IE: the Novel 2019 International CIED Infection Criteria
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      “Definite” CIED clinical pocket/generator infection = generator pocket shows swelling, erythema, warmth, pain, and purulent discharge/sinus formation, or deformation of pocket, adherence and threatened erosion, or exposed generator or proximal leads

      “Definite” CIED/IE = presence of either 2 major criteria or 1 major + 3 minor criteria

      “Possible” CIED/IE = presence of either 1 major + 1 minor criteria or 3 minor criteria

      “Rejected” CIED/IE diagnosis = patients who did not meet the aforementioned criteria for IE
      Major criteria
      Microbiology:
      A. Blood cultures positive for typical microorganisms found in CIED infection and/or IE (coagulase-negative staphylococci, S. aureus)

      B. Microorganisms consistent with IE from 2 separate blood cultures:  a. Viridans streptococci, Streptococcus gallolyticus (S. bovis), HACEK group, S. aureus; or  b. Community-acquired enterococci, in the absence of a primary focus

      C. Microorganisms consistent with IE from persistently positive blood cultures:  a. ≥ 2 positive blood cultures of blood samples drawn >12 h apart; or  b. All of 3 or a majority of ≥ 4 separate cultures of blood (first and last samples drawn ≥ 1 h apart); or  c. Single positive blood culture for Coxiella burnetii or phase I IgG antibody titre > 1:800
      Imaging positive for CIED infections and/or IE:
      D. Echocardiogram (including ICE) positive for:  a. CIED infection:i. Clinical pocket/generator infectionii. Lead-vegetation b. Valve IEi. Vegetationsii. Abscess, pseudoaneurysm, or intracardiac fistulaiii. Valvular perforation or aneurysmiv. New partial dehiscence of prosthetic valve

      E. 18F-FDG PET/CT (caution should be taken in case of recent implants) or radiolabelled WBC SPECT/CT detection of abnormal activity at pocket/generator site, along leads or at valve site

      F. Definite paravalvular leakage by cardiac CT
      Minor criteria
      a. Predisposition such as predisposing heart condition (eg, new-onset tricuspid valve regurgitation) or injection drug use

      b. Fever (temperature > 38oC)

      c. Vascular phenomena (including those detected only by imaging): major arterial emboli, septic pulmonary emboli, infectious (mycotic) aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s lesions

      d. Microbiologic evidence: positive blood culture that does not meet a major criterion as noted above or serologic evidence of active infection with organism consistent with IE or pocket culture or leads culture (extracted by noninfected pocket)
      18F-FDG PET/CT, whole body fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography; CIED, cardiovascular implantable electronic device; HACEK, Haemophilus aphrophilus, (now called Aggregatibacter aphrophilus), Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eichenella corrodens, and Kingella kingae; ICE, intracardiac echocardiography; IE, infective endocarditis; S. aureus, Staphylococcus aureus; WBC SPECT/CT, 99mTc-hexamethypropylene amine oxime labeled autologous white blood cell single-photon emission computerized tomography/computerized tomography.

      Antimicrobial Management

      Empiric and directed treatment

      After collection of blood cultures, vancomycin is usually recommended for empiric treatment of a pocket infection
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      . Daptomycin is an acceptable alternative for patients who cannot tolerate vancomycin.
      • Durante-Mangoni E.
      • Casillo R.
      • Bernardo M.
      • et al.
      High-dose daptomycin for cardiac implantable electronic device-related infective endocarditis.
      Consideration of empiric antimicrobial coverage for patients with possible CIED infection and a suspected bacteremic presentation should take into account clinical findings and epidemiologic factors and the need for inclusion of coverage for gram-negative bacilli pending blood culture results. Patients who are afebrile, are hemodynamically stable, and have a normal peripheral white blood cell count are unlikely to have bacteremia.
      • Esquer Garrigos Z.
      • George M.
      • Khalil S.
      • et al.
      Predictors of bloodstream infection in patients presenting with cardiovascular implantable electronic device pocket infection.
      Such patients who do not have systemic inflammatory response syndrome (SIRS) criteria (temperature > 38.3oC or < 36oC, pulse > 90/min, respirations > 20/min, white blood cell count > 12.0 or < 4.0 × 109/L) or blood pressure with a < 90 mm Hg or > 40 mm Hg drop from baseline may have antibiotic therapy withheld until operative cultures are collected, in order to optimize the intraoperative culture yield.
      • Esquer Garrigos Z.
      • George M.
      • Khalil S.
      • et al.
      Predictors of bloodstream infection in patients presenting with cardiovascular implantable electronic device pocket infection.
      Directed treatment is based upon final culture and susceptibility results.

      Duration of treatment

      The duration of treatment for the various CIED infection presentations is outlined in Table 2.
      Table 2Duration of antimicrobial therapy for CIED infection when the device can be removed
      Extent of infectionDuration
      Duration is counted from the date of device explantation or (for those with bacteremia) the date blood cultures became negative, which ever occurred last.35
      Pocket site
      Provided blood cultures collected prior to administration of antibiotics were negative.
      ,
      Treatment can be changed from intravenous to an active oral antibiotic once susceptibility results are available and the infected CIED has been removed.28
      7–14 d
      • Sandoe J.A.
      • Barlow G.
      • Chambers J.B.
      • et al.
      Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. Report of a joint working party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS), British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE).
      ,
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
       Pocket-site infection10–14 d
       CIED erosion through skin without obvious purulence7–10 d
      Blood cultures positive
      Blood cultures positive or no blood cultures performed prior to administration of antibiotics.
       Valve vegetation
      Treatment as for endocarditis.28,35,47
      4–6 wk
      • Baddour L.M.
      • Wilson W.R.
      • Bayer A.
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
       Lead vegetation:
      Uncomplicatedas for TEE-negative
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      Complicated (eg, septic phlebitis, osteomyelitis)4–6 wk
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
       TEE-negative:
      Staphylococcus aureus4 wk
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      non-S. aureus2 wk
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      CIED, cardiovascular implantable electronic device; TEE, transesophageal echocardiogram.
      Duration is counted from the date of device explantation or (for those with bacteremia) the date blood cultures became negative, which ever occurred last.
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      Provided blood cultures collected prior to administration of antibiotics were negative.
      Treatment can be changed from intravenous to an active oral antibiotic once susceptibility results are available and the infected CIED has been removed.
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      § Blood cultures positive or no blood cultures performed prior to administration of antibiotics.
      Treatment as for endocarditis.
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      ,
      • Baddour L.M.
      • Wilson W.R.
      • Bayer A.
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.

      Removal of Infected CIED

      Lead extractions should be performed only in facilities that provide adequate support for a lead-extraction program, including the management of complications. This support includes the immediate availability of a cardiac surgeon and surgical team with equipment to perform a thoracotomy or sternotomy.
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      Recommendations for the requirements for physicians and surgeons regarding training and maintenance of competency for CIED therapies, including device implantation and extraction, have been published by the Canadian Heart Rhythm Society Task Force.
      • Yee R.
      • Karim S.K.
      • Bashir J.
      • et al.
      Canadian Heart Rhythm Society task force report on physician training and maintenance of competency for cardiovascular implantable electronic device therapies: executive summary.
      Transvenous lead extraction (TLE) is usually accomplished with either the laser sheath technique or a rotating sheath technique.

      Lee SY, Allen IE, Diaz C, et al. Efficacy and mortality of rotating sheaths versus laser sheaths for transvenous lead extraction: a meta-analysis [e-pub ahead of print]. J Interv Card Electrophysiol. https://doi.org/10.1007/s10840-021-01076-x.

      The indications for complete device and lead removal are outlined in Table 3. All patients should have blood cultures collected 48-72 hours after CIED removal.
      Table 3Surgical considerations for CIED removal and replacement in the setting of infection
      Indications for complete device and lead removal
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      • CIED pocket infection, as evidenced by findings such as abscess formation, device erosion, skin adherence, or chronic draining sinus without clinically evident involvement of the transvenous portion of the lead system, or

      • Valvular and/or lead endocarditis, or

      • Valvular endocarditis without definite involvement of the lead(s) and/or device, or

      • Bloodstream infection as outlined in the management algorithm in Figure 1.
      Timing considerations for new device implantation
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      ,
      • Arshad V.
      • Baddour L.M.
      • Lahr B.D.
      • et al.
      Impact of delayed device re-implantation on outcomes of patients with cardiovascular implantable electronic device related infective endocarditis.
      • Blood cultures should be repeated after device removal and should be negative for at least 72 h before new device placement.

      • New device implantation should be delayed for at least 14 d after CIED system removal when there is evidence of CIED-endocarditis. The delay of at least 14 d has been associated with a survival benefit, particularly when a valve vegetation has been demonstrated.
      • Arshad V.
      • Baddour L.M.
      • Lahr B.D.
      • et al.
      Impact of delayed device re-implantation on outcomes of patients with cardiovascular implantable electronic device related infective endocarditis.


      • New device implantation should be delayed until any other undrained site of infection has undergone adequate source control (eg, psoas abscess).
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      CIED, cardiovascular implantable electronic device.
      Improved survival has been associated with prompt removal of the device and leads following determination of the diagnosis of CIED infection.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Lin A.Y.
      • Saul T.
      • Aldaas O.
      • et al.
      Early versus delayed lead extraction in patients with infected cardiovascular implantable electronic devices.
      ,
      • Le K.Y.
      • Sohail M.R.
      • Friedman P.A.
      • et al.
      Impact of timing of device removal on mortality in patients with cardiovascular implantable electronic device infections.
      In a recent study, delayed CIED extraction (defined as beyond the 7th hospital day) was associated with increased 1-year mortality for patients with bacteremia or localized pocket infection.
      • Lin A.Y.
      • Saul T.
      • Aldaas O.
      • et al.
      Early versus delayed lead extraction in patients with infected cardiovascular implantable electronic devices.
      Removal of the device and leads is recommended by percutaneous transvenous extraction. However, if lead vegetations are > 20-30 mm, then either an alternate surgical extraction method or percutaneous aspiration of vegetations prior to transvenous extraction should be considered.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Wilkoff B.L.
      • Love C.J.
      • Byrd C.L.
      • et al.
      Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management.
      CIED removal is not indicated for a superficial or incisional infection without involvement of the device and/or leads.

      Coexistent LVAD in patients with CIED infection

      Most patients with a left ventricular assist device (LVAD) also have a CIED.
      • Riaz T.
      • Nienaber J.J.
      • Baddour L.M.
      • et al.
      Cardiovascular implantable electronic device infections in left ventricular assist device recipients.
      As for other patients, if the CIED becomes infected, then it should be removed.
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      ,
      • Riaz T.
      • Nienaber J.J.
      • Baddour L.M.
      • et al.
      Cardiovascular implantable electronic device infections in left ventricular assist device recipients.
      However, for those with CIED lead IE or valvular IE, the LVAD would presumably also be infected, making it necessary to initiate chronic suppressive antimicrobial therapy for concomitant LVAD infection.
      • Riaz T.
      • Nienaber J.J.
      • Baddour L.M.
      • et al.
      Cardiovascular implantable electronic device infections in left ventricular assist device recipients.

      New CIED Implantation After Removal of an Infected Device

      A determination should be made as to whether a continued need for a CIED is present.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      Up to one half of patients may not require device reimplantation.
      • Sohail M.R.
      • Uslan D.Z.
      • Khan A.H.
      • et al.
      Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections.
      The replacement device implantation should not be ipsilateral to the extraction site. Preferred alternative locations include the contralateral side, epicardial, internal jugular vein, and leadless (bradycardia pacing) or extravascular implantation (defibrillator). The optimal timing for implantation of a new device is outlined in Table 3.
      Risk-benefit considerations regarding implantation of a new device should include various risk factors for CIED infection (eg, end-stage renal disease with repeated microbial exposure during intravenous access).
      • Polyzos K.A.
      • Konstantelias A.A.
      • Falagas M.E.
      Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis.
      Alternative novel devices should be considered in those at particularly high risk. The use of an extravascular (EV) ICD, such as a subcutaneous ICD, avoids the drawbacks related to transvenous leads and may be associated with a reduced risk of life-threatening systemic infection. The infection rate requiring device removal in the Evaluation of Factors Impacting Clinical Outcome and Cost Effectiveness of the S-ICD (EFFORTLESS) study over a 3-year follow-up period was only 2.4%.
      • Boersma L.
      • Barr C.
      • Knops R.
      • et al.
      Implant and midterm outcomes of the subcutaneous implantable cardioverter-defibrillator registry: The EFFORTLESS Study.
      Leadless pacemakers also have been used successfully in those at high risk for infection, such as dialysis patients.
      • El-Chami M.F.
      • Clementy N.
      • Garweb C.
      • et al.
      Leadless pacemaker implantation in hemodialysis patients: experience with the micra transcatheter pacemaker.

      Bridging for pacemaker-dependent or ICD-dependent patients

      Additional options have been evaluated recently for bridging the time before implantation of a new CIED for patients who are pacemaker-dependent. The traditional temporary transvenous pacing balloon-tipped wire is associated with various complications and largely has been replaced with an active-fixation lead secured through the contralateral internal jugular, axillary, or subclavian vein access attached to an external pulse generator that allows patients to be managed outside the setting of an intensive care unit.
      • Lever N.
      • Ferguson J.D.
      • Bashir Y.
      • Channon K.M.
      Prolonged temporary cardiac pacing using subcutaneous tunnelled active-fixation permanent pacing leads.
      ,
      • Cipriano R.
      • Gupta A.
      • Subzposh F.
      • et al.
      Outcomes of standard permanent active fixation leads for temporary pacing.
      Although not considered to be standard practice,
      • Palmeri N.O.
      • Kramer D.B.
      • Karchmer A.W.
      • Zimetbaum P.J.
      A review of cardiac implantable electronic device infections for the practicing electrophysiologist.
      limited experience supports the role of same-day pacemaker device extraction and placement of a new device in selected patients using an epicardial system,
      • Amraoui S.
      • Sohal M.
      • Li A.
      • et al.
      Comparison of delayed transvenous reimplantation and immediate surgical epicardial approach in pacing-dependent patients undergoing extraction of infected permanent pacemakers.
      ,
      • Al-Maisary S.S.A.
      • Romano G.
      • Karck M.
      • De Simone R.
      Epicardial pacemaker as a bridge for pacemaker-dependent patients undergoing explantation of infected cardiac implantable electronic devices.
      a permanent contralateral device,
      • Mountantonakis S.E.
      • Tshabrunn C.M.
      • Deyell M.W.
      • Cooper J.M.
      Same-day contralateral implantation of a permanent device after lead extraction for isolated pocket infection.
      or a leadless pacemaker system.
      • El-Chami M.F.
      • Bonner M.
      • Holbrook R.
      • et al.
      Leadless pacemakers reduce risk of device-related infection: review of the potential mechanisms.
      For high-risk ICD requirement patients, the bridging options include the following: a wearable cardioverter-defibrillator (eg, LifeVest [Zoll Medical Corporation, Pittsburgh, PA]; currently available only through special access in Canada)
      • Ellenbogen K.A.
      • Koneru J.N.
      • Sharma P.S.
      • et al.
      Benefit of the wearable cardioverter-defibrillator in protecting patients after implantable-cardioverter defibrillator explant: results from the national registry.
      ; a conventional ICD externally connected to a transvenous dual-coil lead
      • Dell'Era G.
      • Prenna E.
      • Ziacchi M.
      • et al.
      Management of patients explanted for implantable cardioverter defibrillator infections: bridge therapy with external temporary ICD.
      ; and continuous electrocardiogram monitoring on a telemetry unit with immediate access to external defibrillation.
      • Debski M.
      • Zabek A.
      • Boczar K.
      • et al.
      Temporary external implantable cardioverter-defibrillator as a bridge to reimplantation after infected device extraction.

      Long-term Indefinite Suppressive Antimicrobial Therapy

      Long-term suppressive therapy should be considered for only those patients who have CIED infection and are not candidates for complete device removal. Such patients may have unacceptable risk of device removal, inability to reimplant, loss of CRT, high risk of reinfection related to inadequate source control of infections at other sites, or life expectancy of less than 1 year.
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Baddour L.M.
      Infectious Diseases Society of America‘s Emerging Infections Network. Long-term suppressive antimicrobial therapy for intravascular device-related infections.
      For this approach to be viable, an initial 4-6-week course of intravenous antibiotic therapy should be given, as for prosthetic valve endocarditis associated with clinical improvement and clearance of bacteremia (if present), followed by long-term suppressive oral antimicrobial therapy.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).

      Prevention

      The pre-procedural, peri-procedural, and post-procedural measures for reducing the risk of CIED infection are outlined in Table 4. Among the pre-procedural measures, the benefit of antibiotic prophylaxis was demonstrated in a double-blind, placebo-controlled trial in which the infection rates for cefazolin (1 gm immediately preoperation) and placebo were 0.63% and 3.28%, respectively (risk ratio 0.19, P = 0.016).
      • de Oliveira J.C.
      • Martinelli M.
      • Nishioka S.A.
      • et al.
      Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial.
      Cefazolin is preferred (intravenously within 1 hour before incision); vancomycin is an alternative (intravenously within 2 hours before incision).
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      ,
      • Kusumoto F.M.
      • Schoenfeld M.H.
      • Wilkoff B.L.
      • et al.
      2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction.
      More recently, the PADIT trial evaluated incremental antimicrobial prophylaxis (cefazolin plus vancomycin IV, plus intraprocedural bacitracin pocket wash, plus 2 days of oral cephalexin post-procedure) vs conventional prophylaxis (cefazolin IV) in a cluster randomized crossover trial in 19,603 patients.
      • Krahn A.D.
      • Longtin Y.
      • Phillippon F.
      • et al.
      Prevention of Arrhythmia Device Infection Trial: the PADIT Trial.
      A lower-than-expected hospitalization rate for infection was observed in the control arm (1.03%), and a trend toward reduced infection was observed in the incremental arm (0.78%) which was not statistically significant (OR = 0.77, 95% CI 0.56 to 1.05; P = 0.10).
      • Krahn A.D.
      • Longtin Y.
      • Phillippon F.
      • et al.
      Prevention of Arrhythmia Device Infection Trial: the PADIT Trial.
      Table 4Prevention of CIED infection
      Pre-procedure measures:
      • Confirm the necessity of a CIED.

      • Delay the CIED surgery if infection is present or glycemic control is suboptimal.
      • de Vries F.E.
      • Gans S.
      • Solomkin J.S.
      • et al.
      Meta-analysis of lower perioperative blood glucose target levels for reduction of surgical-site infection.


      • Remove transvenous pacing and central venous lines if possible.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Polyzos K.A.
      • Konstantelias A.A.
      • Falagas M.E.
      Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis.


      • Reduce the risk of pocket hematoma:

       • Avoid postoperative low-molecular-weight heparin bridging anticoagulant therapy where possible.
      • Robinson M.
      • Healey J.S.
      • Eikelboom J.
      • et al.
      Postoperative low-molecular-weight heparin bridging is associated with an increase in wound hematoma following surgery for pacemakers and implantable defibrillators.


       • For low-risk patients (atrial fibrillation and CHA2DS2-VASc score < 4), anticoagulation can be interrupted for the procedure and restarted when the bleeding risk is reduced.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).


       • For higher-risk patients (atrial fibrillation and CHA2DS2-VASc score of ≥ 4, previous embolic events or mechanical valve), anticoagulation can be continued with warfarin or non-vitamin-K oral anticoagulants.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Birnie D.H.
      • Healey J.S.
      • Wells G.A.
      • et al.
      Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2).
      ,
      • Birnie D.H.
      • Healey J.S.
      • Wells G.A.
      • et al.
      Pacemaker or defibrillator surgery without interruption of anticoagulation.
      The target INR on the day of surgery in the BRUISE CONTROL study was ≤ 3.0 (≤ 3.5 for a mechanical valve); otherwise, surgery was postponed.
      • Birnie D.H.
      • Healey J.S.
      • Wells G.A.
      • et al.
      Pacemaker or defibrillator surgery without interruption of anticoagulation.


       • If possible, discontinue antiplatelet agents 5–10 d before CIED surgery.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Kutinsky I.B.
      • Jarandilla R.
      • Jewett M.
      • Haines D.E.
      Risk of hematoma complications after device implant in the clopidogrel era.


      • Chest-hair removal should be done with electric clippers (not razors) close to the time of surgery.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).


      • Antimicrobial prophylaxis at the time of CIED placement (see text, Prevention section).
      • Krahn A.D.
      • Longtin Y.
      • Phillippon F.
      • et al.
      Prevention of Arrhythmia Device Infection Trial: the PADIT Trial.
      ,
      • de Oliveira J.C.
      • Martinelli M.
      • Nishioka S.A.
      • et al.
      Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial.
      ,
      • Tarakji K.G.
      • Mittal S.
      • Kennergre C.
      • et al.
      Antibacterial envelope to prevent cardiac implantable device infection.
      Peri-procedural measures:
      • Surgical preparation should include alcoholic chlorhexidine 2% rather than povidone-iodine.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).


      • Patients at high risk of CIED infection should be considered for the application of the antibiotic envelope, per the WRAP-IT study.
      • Tarakji K.G.
      • Mittal S.
      • Kennergre C.
      • et al.
      Antibacterial envelope to prevent cardiac implantable device infection.
      Risk can be readily calculated using the online PADIT risk calculator (https://padit-calculator.ca/).
      Post-procedural measures:
      • Avoid hematoma drainage/evacuation unless tense, severe pain, or wound dehiscence.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).


      • Delay, or if possible avoid, further device reintervention or revision.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      BRUISE CONTROL, Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial; CHA2DS2-VASc score, Congestive Heart Failure, Hypertension, Age (≥ 75 Years) (doubled), Diabetes Mellitus, Stroke (doubled), Vascular Disease, Age (65-74) Years, Sex Category (female); CIED, cardiovascular implantable electronic device; INR, international normalized ratio; PADIT, Prevention of Arrhythmia Device Infection Trial; WRAP-IT, World-wide Randomized Antibiotic Envelope Infection Prevention Trial.
      The use of the Medtronic (Minneapolis, MN) TYRX antibacterial-eluting envelope (minocycline and rifampin for at least 7 days into the pocket environment) with CIED implantation was recently evaluated for the prevention of infection in an RCT involving 6983 patients (the WRAP-IT study). The 12-month infection-related event rates were 0.7% and 1.2% for the envelope and control groups, respectively (hazard ratio 0.60, 95% CI 0.36-0.98; P = 0.04).
      • Tarakji K.G.
      • Mittal S.
      • Kennergre C.
      • et al.
      Antibacterial envelope to prevent cardiac implantable device infection.
      The benefit was noted for pocket infections associated with high-powered devices (ICD and CRT-defibrillator). More episodes of bacteremia or CIED-related endocarditis occurred in the envelope group, a difference that was not statistically significant (hazard ratio = 1.57, 95% CI 0.61-4.05).

      Antimicrobial prophylaxis for invasive procedures in patients with CIEDs

      Antimicrobial prophylaxis is not recommended for dental or other invasive procedures (not directly related to device manipulation) to prevent CIED infection.
      • Blomstrom-Lundqvist C.
      • Traykov V.
      • Erba P.A.
      • et al.
      European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      Secondary prophylaxis is only recommended for the incision and drainage of infection at other sites or for replacement of an infected device.
      • Darouiche R.M.
      • Mosier M.
      • Voigt J.
      Antibiotics and antiseptics to prevent infection in cardiac rhythm management device implantation surgery.

      Microbiological Studies in Cases of CIED Removal for Noninfectious Reasons

      Routine microbiological studies should not be conducted on CIEDs that have been removed for noninfectious reasons.
      • Baddour L.M.
      • Epstein A.E.
      • Erickson C.C.
      • et al.
      Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association.
      A number of studies have found positive cultures for various bacteria in specimens obtained from pocket sites or sonication fluid of extracted generator or leads in up to one-third or more of patients who underwent device removal for other indications in the absence of any clinical suspicion of device infection.
      • Lin G.
      • Zou T.
      • Dong M.
      • et al.
      Risk stratifying and prognostic analysis of subclinical cardiac implantable electronic devices infection: insight from traditional bacterial culture.
      • Rohacek M.
      • Weisser M.
      • Kobza R.
      • et al.
      Bacterial colonization and infection of electrophysiological cardiac devices detected with sonication and swab culture.
      • Kleemann T.
      • Becker T.
      • Strauss M.
      • et al.
      Prevalence of bacterial colonization of generator pockets in implantable cardioverter defibrillator patients without signs of infection undergoing generator replacement or lead revision.
      However, still unclear is what proportion of these positive cultures represent subclinical colonization with bacteria of relatively low pathogenicity vs false-positive results due to specimen contamination. Furthermore, the finding of a positive culture in these patients with possible “subclinical CIED infection” was predictive of subsequent development of clinical CIED infection during follow-up in only a small proportion of patients, ranging from 2% to 7.5%.
      • Lin G.
      • Zou T.
      • Dong M.
      • et al.
      Risk stratifying and prognostic analysis of subclinical cardiac implantable electronic devices infection: insight from traditional bacterial culture.
      • Rohacek M.
      • Weisser M.
      • Kobza R.
      • et al.
      Bacterial colonization and infection of electrophysiological cardiac devices detected with sonication and swab culture.
      • Kleemann T.
      • Becker T.
      • Strauss M.
      • et al.
      Prevalence of bacterial colonization of generator pockets in implantable cardioverter defibrillator patients without signs of infection undergoing generator replacement or lead revision.
      • Chu X.M.
      • Li B.
      • An Y.
      • Li X.B.
      • Guo J.H.
      Genetic identification and risk factor analysis of asymptomatic bacterial colonization on cardiovascular implantable electronic devices.

      Conclusion

      CIED infections account for considerable morbidity and mortality. Recently, a number of promising diagnostic advances have helped minimize the underdiagnosis and overdiagnosis of CIED infections, both of which are associated with unfavourable consequences. The recent progress in risk stratification and infection prevention measures is particularly important. Optimal management requires the early involvement of clinicians with experience in CIED infection, including those at the regional device-extraction facility. Coordination of care among all providers involved, spanning the range from the primary care provider to the device implantation and extraction clinician, is essential.

      Acknowledgement

      Kelly Hsu provided support for manuscript preparation.

      Funding Sources

      The authors have no funding sources to declare.

      Disclosures

      P.P. discloses the following conflicts of interest: clinical research and training grants from Pfizer; speakers bureau for Cubist. J.G.A. reports grants and personal fees from Medtronic; grants from Baylis; personal fees from Biosense-Webster, Biotronik, Bayer, and Bristol-Meyers Squibb-Pfizer Alliance. The other authors have no conflicts of interest to disclose.

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