Cardiac implantable electronic devices (CIEDs), including the permanent pacemaker (PPM), implantable cardiac defibrillator (ICD), and cardiac resynchronization therapy (CRT) devices, provide life-saving intervention for a variety of clinically indicated cardiac conditions. However, their associated short-term and long-term outcomes are not without risk. One serious complication resulting in significant morbidity and mortality is device-related infection (CIED infection). The clinical presentation of CIED infection includes a spectrum of both native and foreign tissue involvement as follows: superficial incisional infection, pocket infection, pocket erosion, bacteremia with or without signs of pocket infection, and/or echocardiographic evidence of lead involvement. Occult bacteremia without an obvious alternative source is also accepted as probable CIED infection.
While positive blood cultures with the identification of lead and/or valvular vegetations by echocardiography establish a diagnosis of CIED-related endocarditis (CIED-RE), additional criteria are often called upon to help define the diagnosis when the presentation is less overt. In a recent guideline document by the European Heart Rhythm Association and endorsed by multiple other scientific bodies, criteria were expanded to include: positive cultures of the extracted lead in case of negative blood cultures, presence of lead vegetations on echocardiography with or without valvular vegetations, abnormal metabolic activity around the CIED generator, and/or leads detected by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) or radiolabeled leukocytes single-photon emission computed tomography/CT ( Table 12.1 ) [ , ].
|‘Definite’ CIED-RE = presence of either 2 major criteria or 1 major + 3 minor criteria|
|‘Possible’ CIED-RE = presence of either 1 major + 1 minor criteria or 3 minor criteria|
|‘Rejected’ CIED-RE = patients who did not meet the aforementioned criteria|
CIEDs have the capacity to act as a nidus for infection thereby increasing the risk for the development of infective endocarditis. While the rate of device implantation continues to rise as device technology and capabilities advance, a recent study identified cardiac device involvement in 7% of all infective endocarditis cases [ ]. This highlights the value of evidence-based guidelines to underscore best practices for the prevention, identification, and management of this serious complication. In this chapter, we review the various clinically relevant themes concerning CIED-RE recognizing the continuum of presentation of CIED infection as mentioned above. The epidemiology, diagnosis, and microbiology will be explored as well as the current clinical evidence, and its gaps, supporting the most up-to-date guidelines for the management and prevention of such infections. To illustrate the challenges associated with the condition let us consider a hypothetical albeit typical case encountered in modern practice.
Case Study–initial presentation
A 73-year-old gentleman presents with fevers and chills. He has a history of aortic valve stenosis and ischemic cardiomyopathy. Several years prior to presentation, he underwent coronary artery bypass graft (CABG) surgery and aortic valve replacement with a bioprosthetic valve. Shortly thereafter he received an implantable defibrillator for primary prevention. Subsequently, he developed high-grade atrioventricular block with high ventricular pacing burden. Three months ago, he underwent upgrade of his device to support CRT. Ejection fraction at the time was 25%. Relevant past medical history includes hypertension, diabetes mellitus, gout, and chronic renal insufficiency. Medications include diuretics, beta-blockers, angiotensin receptor blockers, and a tapered dose of prednisone for a recent gout flare-up of his left shoulder. A synovial fluid tap demonstrated uric acid crystals. Exam was notable for temperature of 101.2°F, heart rate of 100 bpm, blood pressure of 100/70 with a respiratory rate of 20/min. Leukocytosis with a leftward shift of the differential along with above findings support a sepsis syndrome. Two of two blood cultures are confirmed positive for gram-positive cocci in clusters. The pocket site appears slightly swollen but there is no redness, tenderness, or localized warmth. The incision line appears intact with no exudate or dehiscence.
As we contemplate the appropriate investigations for our patient; let us consider some relevant points we should take into account as we consider the potential diagnosis and appropriate management. Infective endocarditis is highly suggested by his presenting symptoms and bacteremia in the presence of intravascular leads and a prosthetic valve. Regardless of definitive involvement of the CIED, infective endocarditis here would be CIED-RE. A high level of suspicion is appropriate even if classic criteria for infective endocarditis have not been met, a point we revisit later in this chapter.
The incidence of infective endocarditis remained relatively constant from 1950 to 2000 at approximately 3.6–7 cases per 100,000 patient-years [ ]. In recent years there has been a change, however, with studies demonstrating an increase in the incidence of infective endocarditis in patients not previously known to have predisposing heart conditions [ ]. This is most likely due to an increase in invasive procedures, prosthetic valves, and CIEDs all recognized as potential predisposing factors by virtue of their violation of normal body barriers and invasion of the intravascular space [ ].
The CIED era began in the 1960s with the development and use of PPMs and subsequently expanded to include ICDs, and CRT devices [ ]. Between 2000 and 2012, the Danish Pacemaker and ICD Register (DPIR) reported an increase of 158% and 535% in the implantation of PPMs and ICDs, respectively [ ]. This evolution is a consequence of growing indications for various cardiac conditions with improved medical technological capability to treat an aging population frequently beset with significant medical comorbidities [ ]. The incidence of CIED-RE has varied across studies [ ]. CIED-RE was first reported in the early 1970s in the context of PPMs and has been growing in incidence ever since. In one study, CIED-RE accounted for approximately 10% of all cases of infective endocarditis [ , ]. A common clinical observation has been borne out in at least one prospective cohort study that found the majority of cardiac device infections involve the subcutaneous generator pocket, of which, 10%–23% resulted in CIED-RE [ ]. These results were in agreement with a retrospective study that reported 20% of cases resulted in CIED-RE [ ]. CIED-RE has risen in recent decades; a longitudinal study conducted over a period of nearly 30 years showed that the number of CIED-RE cases increased significantly in the last decade in parallel with an increase in CIED implantation [ ]. Carrasco et al. reported PPM endocarditis accounted for 6.1% of all cases of infective endocarditis and affected 3.6 per 1000 of all implanted pacemakers [ ]. Ominously, as reported by multiple investigators, the rate of CIED-RE seems to have outstripped implantation rates [ ].
CIED-RE most often occurs early after implant. In a nationwide cohort study of first-time implants including 43,048 patients and 168,343 patient-years follow-up, the incidence of early-onset (presenting within the first year) CIED-RE more than doubled that of late onset CIED-RE across all types of implants [ ]. Early-onset CIED-RE, when defined as presenting during hospitalization or within 3 months following discharge, is attributable to intraoperative contamination during the index device implantation procedure. CIED-RE carries a high mortality of 24% for early-onset endocarditis in one report [ ]. In another, mortality rates ranged from 31% to 66% without device removal, which decreased to 18% with CIED removal and intensive medical care [ ]. The same authors reported that infective endocarditis and ejection fraction were the strongest predictors of in-hospital mortality in patients with CIED infection. Of note, while seasonal bacteremia has been described in the literature, Maille et al. report a seasonal variation with respect to pocket infection (with or without endocarditis), but not endocarditis alone [ ]. Lastly, CIED infections including CIED-RE impose a considerable financial burden on the health-care sector [ , ]. In-hospital costs are estimated to be at least $146,000 per case in the United States [ ].
As device implants have increased in frequency over the past two decades, particularly among an older and sicker population, a variety of patient factors have contributed to the increased incidence of CIED-RE. Comorbidities associated with a higher risk of infection include: diabetes mellitus, renal insufficiency, particularly end-stage renal disease, malignancy, congestive heart failure, chronic obstructive pulmonary disease (COPD), and use of anticoagulants and/or immunosuppressive drugs, especially corticosteroids [ , , ].
A recent prospective study identified the following host factors predisposing patients to device-related endocarditis: malnutrition, malignancy, diabetes mellitus, skin disorders, and the use of steroids and/or anticoagulants [ ]. Additional studies establish diabetes mellitus, dialysis, use of vitamin K antagonists, a history of infective endocarditis, CIED infection, and valve disease as conditions associated with increased risk [ , ]. Concomitant chronic conditions impair the ability to mount an appropriate immune response, thereby setting up a backdrop which predisposes patients to the development of CIED-RE [ ]. The use of vitamin K antagonists increases the incidence of postoperative hematoma, which is recognized as an independent risk factor for infective endocarditis [ ].
CIED-RE was the third most common (16%) presentation of CIED infection in a study conducted by Sohail et al. [ ]. The study reported that chronic dialysis, COPD, and skin condition had statistical significance with ICD infections. However, other conditions including diabetes mellitus, heart failure, malignancy, or immunosuppression therapy were not statistically significant risk factors [ ].
One recent study reported 82% of patients presenting with ICD infection had evidence of pocket infection, while 18% had evidence of systemic infection, only 14% presented with electrode and/or valvular vegetations [ ]. When comparing patients with systemic infections to patients with pocket infections, the presence of a femoral venous catheter was found to increase the risk of systemic infection [ ]. Further, patients with ICD infections were found to be older than those without PPM/ICD infections [ ].
While some studies found elderly men more likely to present with CIED-RE, others found no significant difference [ , , ]. Ozcan et al. in a study of a large national registry reported CABG to be associated with decreased infective endocarditis risk [ ]. This low risk could be explained by a selection bias favoring CABG patients; sicker patients were less likely to undergo surgery. Patients with CIED endocarditis were more likely to be male, of advanced age, and diabetic compared to patients with infective endocarditis without cardiac device [ ]. With increasing longevity of patients with significant comorbidities and their high risk for CIED infection and CIED-RE, the assessment of comorbidities at the time of CIED implant becomes critical.
Presence of skin lesions, poor dentition, or indwelling catheters provides ingress points for organisms as does bowel inflammation or neoplasm. Skin or gut colonization with drug-resistant or particularly virulent organisms pose respective threats as skin microbes are the most commonly implicated offenders [ ]. The latter consideration in turn should serve as a reminder against indiscriminate use of antibiotics to prevent emergence and perpetuation of resistant strains. Screening nasal swabs for methicillin-resistant Staphylococcus aureus (MRSA) and treating carriers with mupirocin ointment are established surgical practices with demonstrated positive effect [ ].
Irregular surfaces on CIEDs provide a safe harbor for infecting microorganisms. Infecting microorganisms create a biofilm which effectively shields against antimicrobial agents. While different microorganisms are more or less effective at creating this biofilm, device and lead surfaces prove more or less hospitable to the same. Under electron microscopy, lead insulation material demonstrates an irregular surface of crypts and valleys that provide a natural habitat for microorganisms to multiply and spread. The continuous biofilm provides scaffolding for the microorganisms to migrate along the leads such that a pocket infection routinely extends into the intravascular portions of the leads [ ]. Microorganisms can never be presumed confined to one lead but not others. Gram-positive bacteria are most likely to be isolated from infected CIEDs (70%–90%). While coagulase-negative staphylococci (CoNS) species are normally encountered as harmless skin colonizers, once adherent to devices they can colonize in sufficient numbers to become invasive infectious agents. Staphylococcus species are the most likely causative agents for bacteremia with almost equal distribution among methicillin-resistant and sensitive strains in some series. The increase in methicillin-resistant species noted in recent years is a worrisome trend. Insulation materials surrounding leads are more likely to provide microbes with a hospitable surface than metal (usually titanium) encasing the generator [ , ].
Other device factors impact patient’s risk of developing CIED-RE. These include device type, device size, and lead characteristics. The most consistent device factors that increase risk of infection include the implantation of an ICD rather than a PPM, implantation of two or more leads, and the use of intraoperative temporary pacing [ ].
Device factors, such as the type of plastic polymer, irregularity of its surface, and its shape, can affect bacterial adherence to the device [ ]. The hydrophobic nature of the plastic polymers increases bacterial adherence with the degree of hydrophobicity. Polyvinyl chloride favors more adherence than Teflon, polyethylene more than polyurethane, silicone more than polytetrafluoroethylene, and latex more than silicone; some metals (e.g., stainless steel) favor adherence more than others (e.g., titanium) [ ]. In addition to the coating, irregular device surfaces favor microbial adherence more than a smooth surface.
Implanting physician experience impacts the probability of future CIED-RE. It is evident that procedural factors are strongly associated with the risk of CIED infection. Reopening the pocket, replacement or revision, including generator change, CIED upgrade, and increased procedure time, increases the opportunity of introducing bacteria into the pocket [ , ]. Several operator and hospital factors are additionally associated with infection, including nonelectrophysiology-trained operators; those with lower implant volumes, implantation at a nonteaching hospital, and at a hospital that did not perform CABG surgery, are associated with a higher risk of infection. Procedures performed by physicians in the lower quartile of implantation volumes have a higher risk of infection [ , ]. Single operator procedures have a higher incidence of subsequent infection than procedures performed by two operators [ ].
There is limited data on factors that directly lower risk of infection; however, some studies [ , ] recognize a lower risk of infection associated with implantation of a new system and use of periprocedural antimicrobial prophylaxis [ ]. Several smaller studies [ , ] suggest a significantly lower rate of CIED infection with pectoral transvenous device placement than those implanted abdominally or by thoracotomy. This indicates that a pectoral approach is not only less invasive but may also confer an ancillary benefit of lower infection risk. However, Prutkin et al. report no change in infection rates between left ventricular leads placed transvenously in the coronary sinus or epicardially [ ]. In a recent systematic review, both an abdominal pocket approach as well as epicardial lead placement were implicated in multiple studies as factors associated with an increased risk of infection [ ].
In general, prolonged procedural time and complexity, repeat procedure particularly soon after initial procedure, operator inexperience, and number of operators confer a higher risk of infection. Thus, ICD and CRT device implants are at a higher risk of infection than pacemakers [ ].
Conversely, simple interventions, such as preoperative nasal swab screening for, and local treatment of, MRSA colonization, presurgical skin scrub within the 12 h preceding the procedure, and use of iodine-impregnated adhesive draping film, have demonstrated value in reducing the risk of intraoperative seeding with infective organisms [ , ]. Preprocedural intravenous prophylactic antibiotic administration within an hour of skin incision and adherence to operating room environmental standards of sterility, air humidity, and air exchange are prerequisites of safe implantation standards [ ]. Good surgical techniques minimizing tissue damage and ensuring hemostasis are of paramount importance. The development of a hematoma increases the risk of subsequent infection multifold [ ]. In one study, 7.6% of patients with a clinically significant hematoma went on to develop device infection within a year [ ]. A hematoma not only provides suitable substrate for bacterial growth but by increasing tension within the pocket may devitalize tissue immediately surrounding the device or force dehiscence of the suture line allowing skin colonizers access into the pocket. Healing is impeded and a continued patent portal for skin organisms is created. Furthermore, reintervention to alleviate the hematoma raises infection risk. Indeed, the most common reasons for early reintervention have consistently been hematoma or lead dislodgement. Decisions regarding periprocedural anticoagulation are thus consequential. While conventional wisdom calls for anticoagulation cessation before procedure and bridging with heparin, recent studies and anecdotal experience have shown increased safety with continuation of anticoagulation with warfarin and direct oral anticoagulants [ ]. This is likely a result of fluctuations accompanying reinstitution of anticoagulation with unfractionated heparin. Low-molecular-weight heparin is associated with an unacceptable increase in the incidence of hematoma formation and should be avoided. Evidence to support the best management approach with novel anticoagulants is limited at this time and remains an area of active research. While many practitioners will continue the use of aspirin and/or other antiplatelet agents, the risk presented by these agents is amplified by concurrent anticoagulation therapy.
Pocket lavage with an antibiotic solution is standard surgical practice. In a recent randomized trial, high-risk patients receiving an absorbable antibiotic-releasing envelope had a lower risk of infection although infection rates in the control arm were less than assumed based on historical controls. The envelope releases minocycline and rifampin during the first week and is expected to be completely absorbed in 9 weeks [ ]. While use of the envelope appears to be an effective intervention in reducing the risk of CIED infection, questions remain as to the most appropriate and cost-effective use of this tool [ ]. Postprocedural systemic antibiotic therapy, however, remains controversial and in view of a negative recent randomized trial should not be pursued.
A working diagnosis of CIED infection and possible endocarditis is accepted. Intravenous vancomycin is initiated pending culture results and consultation with infectious disease specialists is sought. Tests to corroborate the diagnosis are performed. Chest X-ray images show bilateral congestion and parenchymal lung involvement. A transesophageal echocardiography (TEE) demonstrates severely depressed ejection fraction estimated at 20%, highly mobile echogenic masses involving the right ventricular lead as well as evidence of moderate tricuspid regurgitation. The maximum diameter of the lead-related vegetation is 21 mm. The prosthetic aortic valve appears to function normally and there are no echodensities suggestive of vegetation. A CT scan with contrast demonstrates multiple abscesses in both lung fields ( Fig. 12.1 ).
The definitive diagnosis of CIED-RE requires the combination of clinical, microbiological, and echocardiography findings [ ]. In both patients with and without cardiac devices, clinical suspicion for infective endocarditis must remain high. In the United States and other developed countries, many of the classic findings and embolic presentations associated with a more subacute or chronic presentation of infective endocarditis may not be found. More acute disease with nonspecific presentations and respiratory symptoms, musculoskeletal manifestations, and fever may be the only manifestation(s) [ , ]. CIED-RE must be suspected in any patient with a CIED and isolated fever or staphylococcal bacteremia [ , ].
Patients suspected of having infective endocarditis should be clinically evaluated with the modified Duke criteria as the primary diagnostic schema [ ]. The modified Duke criteria are the currently accepted diagnostic criteria for the diagnosis of infective endocarditis, and are able to stratify patients into definite, possible, and rejected endocarditis. Definite infective endocarditis is defined as any patient satisfying either two major criteria, one major criterion and three minor criteria, or five minor criteria [ ]. Both possible and rejected infective endocarditis are not discussed further in this chapter.
All patients with suspected endocarditis in the setting of CIED should have at least two sets of blood cultures drawn at the time of initial evaluation before initiation of antimicrobial therapy [ ]. The diagnostic workup for suspected infective endocarditis should also include an echocardiogram [ ]. While the modified Duke criteria are both sensitive and specific for infective endocarditis, its specific use in the setting of CIED-RE has not been directly studied [ ]. Many cases of device-related endocarditis have been defined in practice and research as endocarditis confirmed by the modified Duke criteria in patients with known cardiac devices. However, due to a lower sensitivity in this patient population, the modified Duke criteria are less applicable herein [ ]. More recent modifications to the Duke criteria have been suggested, are aimed at addressing this clinical dilemma, and include amending the major criteria to include either the presence of lead vegetation(s) [ , ], local device infection [ ], or adding additional criteria (e.g., positive cultures of the extracted lead in the case of negative blood cultures) [ ]. Though it is established that blood cultures are the cornerstone for the diagnosis of infective endocarditis and CIED-RE, the modified Duke criteria fail to address whether TEE or transthoracic echocardiography (TTE) is indicated for definitive diagnosis of CIED-RE.
In 2007, criteria for the level of appropriateness for the use of TTE/TEE were developed by the American College of Cardiology Foundation, the American Society of Echocardiography (ASE), and other key subspecialty groups to guide the use of echocardiography for selected patient indications, including infective endocarditis. Within this study the use of TEE received the highest score for level of appropriateness when managing/diagnosing endocarditis with a moderate or high pretest probability (e.g., bacteremia, especially staphylococcal, or fungemia) and with persistent fever in a patient with an intracardiac device [ ].
The use of TEE in the diagnosis of CIED-RE is further supported by studies which have shown that TTE is considered inadequate as the sole imaging modality in any patient with a permanent intracardiac device [ , ]. TEE is more sensitive and is superior to TTE for the detection of vegetations and complications, such as abscess formation [ , , , ], and its use is recommended in the vast majority of cases, especially when TTE image quality is poor or implanted devices are present [ ]. Patients with suspected CIED infection who either have positive blood cultures or have negative blood cultures but have had recent antimicrobial therapy before blood cultures were obtained should undergo TEE for CIED infection or valvular endocarditis [ ]. Ultimately, in the absence of specific contraindications, TEE should be considered mandatory in all patients with an intracardiac device [ ]. In terms of cost-effectiveness, TEE should be the first imaging modality used for cases of suspected infective endocarditis, particularly in the setting of staphylococcal bacteremia, due to the significant rate of endocarditis [ , , , ].
While TEE is preferred and can provide excellent intracardiac resolution, factors such as inability to sedate patients due to recent food ingestion or lack of available TEE services may preclude its use [ ]. When TEE is not clinically possible or must be delayed, early TTE should be performed [ ]. Although TTE will not definitively exclude vegetations or abscesses, many findings identified by TEE also can be detected on TTE and it will allow identification of very-high-risk patients, establish the diagnosis in many, and guide early treatment decisions [ ]. In patients with a negative TTE, exceptional TTE image quality, no prosthetic device, and a low probability of infective endocarditis, it is reasonable to delay TEE while alternative diagnoses are sought. However, outside of this clinical scenario, TEE is strongly preferred due to its superior diagnostic yield for both native- and prosthetic-valve infective endocarditis [ ].
Though TEE may be superior to TTE in the diagnosis of CIED-RE, it is not without diagnostic limitations. A notable limitation is the inability to obtain high resolution images of the right ventricle due to the large distance between the ventricle and the transesophageal probe (far-field limitation) [ ]. This can make definitive diagnosis in select patients difficult as older patients with cardiac devices are at a higher risk to develop endocarditis of the tricuspid valve related to the lead [ , ]. While TEE is more sensitive than TTE for the detection of vegetations and other intracardiac manifestations of infective endocarditis, especially in the setting of prosthetic valves, the sensitivity of TTE is highest in right-sided endocarditis [ , ]. For tricuspid vegetations or abnormalities of the right ventricular outflow tract, visualization may be enhanced with TTE rather than TEE, which may indicate the need for complimentary imaging modalities in the diagnosis of CIED-RE [ ]. Additionally, prosthetic valves and pacemaker leads can cause acoustic shadowing and reverberation artifacts, which limit TEE’s detection of infective vegetations and result in suboptimal imaging [ , ]. Ultimately, the failure to visualize a mass adherent to a lead with TEE does not exclude lead infection [ ].
Recent studies have proposed other imaging techniques as an alternative to TTE/TEE. Intracardiac echocardiography (ICE) has been proposed for the definitive diagnosis of valvular involvement in CIED-RE. While ICE maintains superior imaging resolution lost with TTE, it is also superior to TEE in the detection of right-sided valves [ ] without exposing patients to the risks associated with sedation or esophageal intubation [ , ]. However, the use of ICE as a universal diagnostic tool is hindered by its high cost and potential for false positives [ , ].
Other modalities, such as 18F-FDG PET/CT scanning, have been described as supplemental tools in the diagnosis of CIED-RE and related complications [ ]. When the diagnosis of CIED pocket or lead infection is doubtful, 18F-FDG PET/CT scanning might provide adjunctive evidence needed for diagnosis [ ]. However, while the sensitivity and specificity for pocket infection is very high (87% and 100%, respectively), it is associated with a 31% sensitivity and 62% specificity for endocarditis [ ].
As population risk factors change, the microbiology of infective endocarditis changes as well [ ]. Staphylococcus aureus is the most frequent causative organism implicated in infective endocarditis cases [ ]. Evidence from more than 70 million hospitalizations in the United States highlights the dramatic rise in the incidence of S. aureus endocarditis as compared to other pathogenic causes [ ]. Staphylococcal species are the main cause of all CIED infections with S. aureus and CoNS accounting for approximately 60%–80% of cases [ ]. A study conducted by Aydin et al. showed that S. aureus and CoNS accounted for 41% and 24% of CIED infections, respectively [ ]. More than one species of CoNS have been documented in CIED infections [ ]. Moreover, the study reports that other bacterial infectious agents have been less commonly associated with CIED infections, such as Corynebacterium species, Propionibacterium acnes , and gram-negative rods [ ]. Fungal infections have also been rarely reported to cause CIED infection [ ].
The microbes that cause CIED infections may be acquired either endogenously from patients’ skin or exogenously from an inanimate hospital environment or from hospital workers’ hands [ ]. The increase in the infection rate may be secondary to increased health-care contact (intravenous fluids, surgical wounds, prosthetic devices, and hemodialysis) [ ]. The main causative organisms for CIED-RE include common skin flora, such as S. aureus and CoNS, particularly Staphylococcus epidermidis [ , ]. Additionally, other organisms including gram-negative bacilli, nonstaphylococcal gram-positive organisms, and brucella have also been reported in multiple studies [ ].
CIED-RE was the second most common presentation of ICD infections in a study conducted by Sohail et al. [ ]. In a similarly authored publication, CIED-RE was due to S. aureus , CoNS, fungi, and gram-negative bacilli in 41%, 41%, 5%, and 5% of cases, respectively [ ]. A study conducted by Carrasco et al. established staphylococci as the predominant causative agents in 84% of cases followed by enterococci in 12% of cases [ ]. The prevalence of staphylococcal resistance to antibiotics has varied among studies [ , ]. Therefore, it is fair to assume all S. epidermidis and most S. aureus infections to be resistant in the setting of cardiac device infections to dictate empiric antimicrobial therapy [ , ].
Case Study–management and outcome
Preparations are made for an intervention to extract all CIED-related hardware with a transvascular approach. A time block in the hybrid OR is secured with cardiothoracic surgical team on standby. Among other preparations for emergent intervention in case of cardiac or large vein laceration, two units of typed and crossed packed red blood cells are procured. General anesthesia with intraoperative transesophageal monitoring is planned. Continuous monitoring of intraarterial blood pressure and wide bore access to a large vein is in place. The procedure is concluded uneventfully. Temporary venous pacing is in place until such time the team is assured that bacteremia is cleared to allow reimplantation of a permanent CIED at a location remote from original implant.
While the 2010 AHA/HRS scientific statement on CIED infections and their management has largely not been updated since 2010, the HRS has endorsed updated guidelines published by EHRA in 2019 based on additional clinical data published throughout the past decade. The overall approach to the successful management of CIED-RE incorporates both device and lead extraction combined with appropriate antibiotic coverage.
The 2019 EHRA guidelines recommend removal of all components of the device, which includes the device itself as well as all active, abandoned, and/or epicardial leads, to ensure successful treatment of all CIED infections. Any additional transvenous hardware, such as vascular ports or permanent hemodialysis catheters, are also to be removed. This recommendation also extends to patients with infective endocarditis but without definite involvement of the CIED device/hardware [ ].
CIED removal is recommended in the setting of occult bacteremia due to S. aureus , CoNS, Cutibacterium spp. (previously Propionibacterium spp.), and Candida spp., even in the absence of lead and/or valve involvement, or in the case of relapsing bacteremia without another identified source [ ]. This is largely attributed to the risk of potential undetected device infection; however, additional clinical trials are warranted. A notable exception is in the case of nonpseudomonal/ Serratia gram-negative or pneumococcal bacteremia, for which concomitant CIED infection is unlikely and therefore device removal is not indicated [ , ].
Percutaneous transvenous lead extraction is the preferred approach for CIED hardware removal as it results in decreased complications and mortality rates as compared to surgical removal [ , , , ]. Reduced in-hospital mortality and shorter length of hospitalization have been found to be associated with transvenous lead extraction occurring within 3 days of admission [ ]. Surgical approaches should be limited to patients with significant retained hardware after failed percutaneous extraction. One exception for which additional clinical data may provide clarity regarding selection of appropriate hardware removal approach is in the setting of lead vegetations greater than 20 mm [ , , ]. With transvascular lead extraction, large vegetations pose a clinically significant risk of embolization to the pulmonary circulation, which may lead to hemodynamic compromise and has the potential to act as a source of ongoing septic complications. Until additional clinical data can delineate this dilemma further, a surgical versus percutaneous approach should be an individualized decision. The more recent introduction of percutaneous aspiration of large lead vegetations via venovenous extracorporeal circuit with an in-line filter is a new approach requiring evidence-based substantiation [ , , ].
Antibiotic adjunctive therapy for CIED-RE should be initiated with empiric treatment, which typically consists of vancomycin with either a third-generation cephalosporin or gentamicin [ ]. Return of blood culture and sensitivities allow for the adjustment to more targeted antibiotics. Duration of antibiotic therapy is specific to the type of infective endocarditis, either involving a native valve, prosthetic valve, or isolated lead vegetation(s). The selection and duration of appropriate antibiotics is discussed elsewhere in this text ( Chapter 7 : Antimicrobial therapy in infective endocarditis). Thorough debridement of the device pocket, excision of the fibrotic capsule, removal of all nonabsorbable suture material, and sterile normal saline irrigation are essential to ensuring infection control [ , ]. For patients with limited life expectancy, those refusing device removal, or other indications deeming patients not candidates for either surgical or percutaneous CIED removal, long-term antimicrobial suppressive therapy, may be considered. However, long-term suppression of CIED infection has proven to be a challenge with oral agents [ ].
Prior to removal of the device and leads, a thorough evaluation of the clinical context is required to determine the continued need for a replacement of CIED. Estimates ranging from one-third to half of all patients with CIED infection undergoing device removal may no longer require one [ ]. Reversal of the pathologic process that required the initial device, changing clinical circumstances, the development of alternative treatment options, and lack of appropriate indication for its initial placement may explain this change in clinical need. When a replacement device is indicated, the contralateral side is the preferred location for its placement. If clinical context precludes the contralateral side, alternative locations include a subcutaneously placed device in the abdomen (via a tunneled transvenous lead) as well as epicardial implantation [ ]. Current literature guiding the optimal time frame for reimplantation is nonexistent, as such, physician experience and clinical context take precedence [ ]. Repeat blood cultures should be negative for at least 72 h before new CIED implantation. However, in the setting of valvular infection, a minimum of 2 weeks after CIED removal is recommended before placement of new transvenous leads [ ]. An important consideration includes PPM-dependent patients. Unable to be discharged home with a temporary pacemaker, temporary pacing via active-fixation leads connected to external pacing generators or defibrillators is used until a new PPM can be safely implanted. Active-fixation leads should be placed ipsilaterally to the original extraction site, while avoiding the vein previously containing the infected lead, to allow for preservation of the contralateral side for future definitive device placement [ , ].
Possible alternatives to be considered prior to CIED replacement include leadless pacemakers and the S-ICD. Nanostim Leadless Cardiac Pacemaker is a self-contained right ventricular pacemaker that is not yet available for clinical use; however, Micra Transcatheter Pacing System is a clinically available option deemed safe after extraction of infected device/leads in those with preexisting CIED infection [ , , ]. In patients requiring defibrillation capabilities only, reimplantation with an S-ICD provides effective defibrillation therapy and reduces the risk of new infections. When infection does develop, it often does not mount severe life-threatening systemic infections. During a 3-year follow-up period, the EFFORTLESS S-ICD Registry, which is being undertaken to evaluate the safety of the S-ICD, reports a 2.4% infection rate necessitating device removal without any reports of endocarditis [ , , ].
CIED-RE is associated with a high prevalence of both short- and long-term complications, as such, guidelines for the appropriate prevention and acute management of this condition are essential to avoid increased morbidity and mortality. A recent prospective study identified the following associated complications: concomitant valve involvement (37.2%), heart failure (15.3%), and persistent bacteremia during the index hospitalization (15.8%) [ ]. A high rate of severe complications (72% of patients) was identified by a recent study, which enrolled patients admitted for acute management of CIED-RE over nearly three decades. In-hospital complications included persistent sepsis (most common) followed by cardiac complications (e.g., heart failure), stroke, and abscess formation [ ]. Patients receiving antibiotics with or without device extraction had an early in-hospital mortality rate of 24%, while a rate of 21% was established in those who underwent CIED extraction with antibiotic therapy. Infective complications (e.g., sepsis and pneumonia) were responsible for half of these deaths with the remaining due to cardiovascular causes (e.g., cardiogenic shock and ventricular arrhythmia). Of note, 94% of CIED extractions were conducted surgically, which may account for such a high mortality rate [ ]. Reported complications associated with lead extraction include septic pulmonary emboli, ongoing sepsis, arrhythmia, perforation necessitating emergency thoracotomy, arteriovenous fistulae, and tricuspid valve damage [ ]. Of note, neither endocarditis nor cardiovascular complications were responsible for the 12% late mortality rate, defined as occurring beyond 3 months postdischarge. In those surviving beyond the initial hospitalization and acute management of CIED-RE, there were no reported cases of CIED-RE relapses [ ].
As evidenced by the above study, device removal in the setting of CIED-RE is not without its risks. Further, recurrent infection is a possible complication in those undergoing reimplantation of a new CIED. However, appropriate antibiotic coverage and confirmation of negative blood cultures for 72 h prior to reimplantation, with the exception of patients with valvular involvement, are essential measures for mitigating this risk [ ].
While CIED infection is associated with an in-hospital mortality rate ranging from 5%–8%, the rate associated with CIED-RE is even higher, as high as 29% from one recent retrospective study [ , ]. Both in-hospital and long-term mortality rates are highest in those unable to undergo CIED extraction and remain on long-term suppressive antimicrobial therapy [ ].
An important consideration as it pertains to clinical outcomes is that patients with CIEDs have an adverse cardiac risk profile capable of confounding the clinical picture of CIED-RE. Patients requiring device implantation are typically of advanced age and have a higher prevalence of comorbid conditions, such as diabetes mellitus. One recent prospective study identified a high rate of complications, with concomitant valve infection being most significant, as well as high short- and long-term mortality rates, particularly with the presence of valvular involvement. While device removal did not improve in-hospital survival, it was associated with higher survival at 1 year [ ].
With respect to long-term outcomes, recent evidence identifies the type of CIED infection at presentation to be a strong predictor of 1-year mortality rate, in which patients with clinical evidence of endovascular infection were twice as likely to die within the first year after CIED extraction as those with pocket infection alone [ , ]. Another recent retrospective study showed double the risk of death in device-related infective endocarditis as compared with pocket infection with or without bacteremia [ , ].
Among all CIED infections, variables shown to increase mortality include systemic embolization, moderate to severe tricuspid regurgitation, abnormal right ventricular function, and abnormal renal function [ , ]. Notably, however, the presence of lead vegetations as well as their size and mobility have not been identified as independent predictors of mortality. As such, it can be inferred that pulmonary emboli secondary to lead vegetation are unable to explain the increased mortality among patients with endovascular infection [ , , ].
Due to the increasing incidence of CIED-RE, the associated increased morbidity and mortality, and increased need for lead removal [ , ], prevention of CIED-RE is imperative for prolonged health and well-being in CIED-implanted patients. Several preventative measures, which are divided between pre- and post-CIED implantation as well as intraoperatively, have been validated and are recommended to aid in the prevention of CIED-RE. Not all recommendations have been specifically indicated for device-related endocarditis, but rather to decrease infection rate associated with CIEDs. Due to the strong correlation between CIEDs and CIED-RE, these recommendations are therefore applicable [ ].
Before device implantation, it is imperative to ensure patients do not have clinical signs of infection and, if present, implantation should be postponed [ , ]. Once signs of systemic infections have been excluded, prophylactic antibiotic administration is recommended as it significantly reduces the risk of device infection [ ]. Most widely used is a first-generation cephalosporin, such as cefazolin, which should be administered within 1 h of the procedure. Vancomycin is an alternative option, which may be indicted in patients with confirmed MRSA exposure (i.e., MRSA-positive nasal swab) or penicillin allergy, and should be administered within 2 h of the procedure [ ]. For those with vancomycin allergy, clindamycin or linezolid is an additional alternative [ ]. Antibiotic prophylaxis is similarly recommended if subsequent invasive manipulation of the CIED is required. Meticulous preoperative antiseptic preparation of the surgical site is warranted.
During CIED implantation
During the procedure, strict aseptic technique should be followed [ ]. If a patient has limited subcutaneous tissue and/or poor nutrition with increased risk for erosion, a retropectoral pocket should be placed to reduce likelihood of infection [ ]. Prevention of hematoma intraoperatively is recommended, and can be achieved by meticulous cautery of bleeding sites, packing the pocket with antibiotic-soaked sponges to provide tamponade while leads are being placed, the application of topical thrombin in anticoagulated patients, and/or irrigation of the pocket to reveal persistent bleeds. Low-molecular-weight heparin predisposes to hematoma formation and should therefore be avoided. If a hematoma develops, evacuation is recommended when there is evidence of increased tension on the skin to avoid the introduction of skin flora into the pocket [ ].
New advances regarding perioperative antibiotic administration and the use of antibacterial envelopes to further reduce infection rates, though not yet standard of care, show promising results. To determine whether incremental perioperative administration of antibiotics would be effective in the reduction of device infection, the Prevention of Arrhythmia Device Infection Trial (PADIT) was conducted. Preprocedural cefazolin was supplemented with preprocedural vancomycin, intraprocedural bacitracin pocket wash, and 2-day postprocedural oral cephalexin. While study results were not statistically significant, the treatment group experienced reduced infection rates [ ]. New technology using a nonabsorbable antibacterial envelope placed around the device generator has shown significant reduction in CIED infection [ , ]. Specifically the TYRX antibacterial envelope has been associated with a significantly lower major CIED infection rate in both ICD and CRT implantation without increased risk for hematoma formation [ ]. The Wrap-IT Trial is the most recent randomized controlled trial, which assessed the safety and efficacy of an absorbable, antibiotic-eluting envelope. Adjunctive use of an antibacterial envelope resulted in a significantly lower incidence of major CIED infections than standard-of-care infection-prevention strategies alone, without a higher incidence of complications [ ]. Due to fewer pocket infections in the treatment group than control group and a higher amount of infective endocarditis cases in the treatment group than the control group, the translatability of these findings to CIED-RE remains questionable.
Currently there are no data to support the administration of postoperative antibiotic therapy, and as such, it is not recommended due to the risk of adverse drug events, the promotion of drug-resistant organisms, and increased cost [ ].
Historically, dental hygiene and antibiotic prophylaxis for invasive procedures have been targeted as areas of concern regarding CIED infection and CIED-RE. Prevention efforts have focused on oral health because viridans group streptococci are normal oral flora and were reported to cause approximately 20% of infective endocarditis cases. The AHA and other major society guidelines previously recommended prophylactic antibiotic therapy to prevent endocarditis in patients with underlying cardiac conditions who underwent dental procedures [ ]. However, as previously described herein, more recent evidence has shown a predominance of staphylococci as the causative pathogens implicated in CIED infections, thereby suggesting antibiotic prophylaxis for dental procedures is of little or no value. In the rare event of a device infection due to an oral pathogen, it is most likely to have arisen from a bacteremia due to poor oral hygiene and periodontal disease after a common daily event such as toothbrushing, flossing, or chewing food, and not related to dental office procedures [ , ].
Recent recommendations regarding prophylaxis for patients prior to dental procedures are now largely not recommended [ ]. It is now recommended that all patients with CIEDs maintain good oral hygiene. While French infective endocarditis prophylaxis guidelines have dramatically reduced prophylactic indications and Britain’s National Institute for health and Clinical Excellence advised against endocarditis prophylaxis for any dental, gastrointestinal, genitourinary, or respiratory tract procedures [ ], ESC and AHA guidelines provide further specifications. The 2015 ESC guidelines recommend using dental prophylaxis only for those at highest risk of developing infective endocarditis. The 2007 AHA guidelines reduced the recommended scope of cardiac conditions for which dental prophylaxis is reasonable to four clinical settings: patients with prosthetic valves or valve material; those with previous infective endocarditis; a subset of congenital heart diseases; and cardiac transplantation recipients who develop cardiac valvopathy [ ].
Following the implementation of these recommendations, an appreciable increase in infective endocarditis cases and/or death became apparent across many studies while some studies showed a decrease in endocarditis cases [ , ]. However, the past 5 years have shown a rebound in case load to levels observed prior to the implementation of the updated guidelines [ , ], indicating that stricter regulations may need to be revisited [ ]. However, in these follow-up studies, pathogen-specific data were either not present or not clearly stratified, which brings into question whether the recent increase is attributable to normal oral flora or alternative pathogens [ , ]. The current 2015 AHA guidelines endorse proper and continuous dental hygiene following CIED implantation to significantly reduce the likelihood of future endocarditis. Ultimately, the AHA recommendation is to focus efforts on good oral hygiene maintenance and to hold endocarditis prophylaxis prior to oral procedures [ ].
Dental disease is almost entirely preventable if patients are compliant with four measures, which in turn help to reduce the incidence of bacteremia and the subsequent risk for recurrent infective endocarditis. These measures include: (1) keep teeth free of plaque; (2) adopt dietary measures, such as decreasing or eliminating sugar and other refined carbohydrate intake; (3) maintain routine follow-up with your family dentist for close monitoring of oral hygiene and the early identification and eradication of oral disease; and (4) use of high-concentration fluoridated toothpaste daily [ ].
Beyond these measures, efforts to prevent intravascular catheter–related bacteremia may also reduce the incidence of health-care-associated infective endocarditis. This can be accomplished by quality improvement interventions, such as care bundles or checklists consisting of strict hand hygiene, use of full-barrier precautions during the insertion of central catheters, cleaning the site with chlorhexidine, avoiding a femoral site, when possible, and removing any unnecessary catheters [ ].
As primary and secondary prevention indications for cardiovascular implantable electronic devices have expanded over the past two decades, a consortium of device-, patient-, and procedural-related factors have contributed to the increased incidence of device-related endocarditis. Prevention, prompt diagnosis, and proper management of CIED-RE represent a multitude of opportunities to prevent significant morbidity and mortality in such a patient population of advanced age with adverse cardiac risk profiles and an array of comorbid conditions. Device extraction is critical to the management of CIED-RE along with adjunctive antibiotic therapy. However, relevant data from randomized clinical trials are exceedingly lacking and current management guidelines are largely based on observational studies and expert opinion. This clinical dilemma begets a need for additional randomized clinical trials to guide the refinement of strategies aimed at reducing the development of CIED-RE and its associated outcomes.