**8.3 Microbiology and adequate sampling**

A series of studies consistently show that staphylococci and Gram-positive bacteria in general are responsible for most CIED infections. Methicillin resistance among *S. aureus* has been reported to various extents, depending on geographic and individual factors [5]. We found the figures of the prevalence of respective pathogens fairly consistent with the results of prior studies and systematic reviews [7, 9, 11, 25, 45, 47, 50–52]. Consistent are also reports of negative cultures despite clinical infection. A reason for this may be previous antibiotic treatment and fastidious microbes [25]. Negative blood cultures should be interpreted with caution and exclusion of infection should not rely exclusively on cultures.

At least two sets of blood cultures (including aerobic and anaerobic cultures) are recommended before starting antibiotic therapy. For patients presenting with acute symptoms, ideally the two sets should be taken at different times within 1 h from peripheral sites. If the clinical presentation is chronic/subacute, guidelines recommend three sets of cultures to be taken from peripheral sites with >6 h between each sample, before antibiotic therapy is started [7]. The point of taking multiple cultures with certain waiting periods is hopes of improved sensitivity and the ability to differentiate between transient and persistent bacteremia. Consistently positive blood cultures with the same pathogen are highly indicative of CIED infection. If purulent drainage is present from the device pocket, a culture can be very useful and more sensitive than other pocket cultures. Percutaneous aspiration of the pocket should, however, not be done because of the risk of introducing microorganisms and possibly causing device infection [14]. When a device is removed, device pocket swabs and tissue culture as well as both proximal and distal lead cultures should be obtained [11]. The lead-tip cultures should be interpreted with caution if extracted through an infected device pocket because of the risk of contamination. Possible femoral extraction would reduce this risk. The clinical situation when lead tip cultures interpreted as unequivocally significant is when there is no sign of pocket infection [25, 50]. After device removal, the recommendation is to obtain new blood cultures after 48–72 h.

### **8.4 Cardiac imaging**

 Echocardiography is a cornerstone for diagnosing CIED infection, visualizing lead or endocardial vegetations, and estimating valve regurgitation and vegetation size. TTE is superior for pericardial effusion and estimations of ventricular

 function and pulmonary pressure. TTE is also convenient for repeated monitoring of vegetations and cardiac function before or after extraction. Transesophageal echocardiography (TEE) is however superior for diagnosing lead and endocardial infection (CIED-LI, CIED-IE), visualizing vegetations, valves and parts of the lead that are difficult to see by TTE. It is also superior for visualizing left-sided endocarditis and perivalvular abscesses. For the diagnosis of CIED-IE, the sensitivity of TEE is >90%, compared to 22–43% for TTE [7]. Hence, both modalities should be used, but in this complimentary manner. Despite the high sensitivity of TEE, it is important keeping in mind that a normal echocardiography does not completely rule out the possibility of CIED infection [5, 7, 10, 11, 14, 30].

It has been demonstrated that TEE cannot distinguish vegetations from sterile thrombi [14, 30]. In studies validating TEE, 5–10% of identified lead masses, first described as vegetations, were concluded to represent incidentally found thrombi [53, 54]. This underlines the importance of a thorough multidisciplinary evaluation using the sum of all findings to assess the patient; masses found on leads in patients without symptoms of infection or positive blood cultures should consequently not be treated with device extraction and antibiotics, but possibly anticoagulants [10].

New imaging modalities (18F-FDG positron emission tomography/computerized tomography, 99mTcHMPAO-WBC) have been studied in a few early reports suggesting slightly increased sensitivity compared to TEE and possibly a high negative predictive value. Limited evidence of their possible added clinical value, high costs, and limited availability so far has not resulted in recommended routine use and guidelines describe them as a possibility to consider in selected and complicated cases. The same approach is recommended for intracardiac echocardiography that possibly may enhance diagnostic accuracy, but just like TEE, is unable to distinguish thrombi from infective vegetations [7, 11, 30].

The role of ordinary chest X-ray has not been studied specifically. Guidelines recommend chest X-ray for patients presenting with acute symptoms as a baseline image during circumstances when full medical records may not be available [7]. Chest computerized tomography or pulmonary angiography can contribute in complicated diagnostic processes by finding septic emboli that constitute a minor Duke criterion.

#### **9. Management**

Successful management of CIED infection is dependent on complete and prompt device removal, long antimicrobial treatment, and reimplantation if the device is still indicated. In a few cases, device removal may not be possible, which substantially reduces the probability of curing the infection. There is a lack of randomized controlled trials to guide management of CIED infection. Most of today's practice is based on the results of observational studies or clinical expertise [25, 55].

In the case of suspected CIED infection, initially two or three blood cultures (depending on urgency) should be taken, followed by the initiation of empiric antibiotic treatment. After that, it is important to determine whether the device should be removed or not [7].

#### **9.1 Device removal**

 Results from several retrospective studies have shown that complete and early device removal (despite its rare but potentially fatal complications) together with antibiotics is more effective than medical therapy alone with dramatically lower figures for mortality and infection relapse [9, 41, 56]. A multivariate analysis of a large CIED infection cohort showed a sevenfold increase in 30-day mortality for patients treated

#### *Cardiac Implantable Electronic Device-Related Infections DOI: http://dx.doi.org/10.5772/intechopen.86395*

with medical therapy alone compared to the combination with device removal [41]. In a large retrospective study of patients in Cleveland, 97% (pocket infection and CIED-IE) were cured by extraction combined with antibiotics [45]. Therefore, complete device removal is the general recommendation for established CIED infection [7, 11].

What is the implication of this for our previous presented clinical categories? The most benign case is that of post-implantation inflammation, where the device should not be removed. However, a close follow-up is important: what is first perceived as inflammation can later be interpreted as early symptoms of infection [7]. If symptoms instead are accordant with device pocket infection (complicated or uncomplicated), device removal is inevitable. That is also the case for the more extensive infections, definite CIED-LI and CIED-IE.

 Remaining are two diagnostically more difficult categories: "possible CIED-LI" and "probable CIED infection" (occult bacteremia) for which guidelines recommend that device removal is considered while the patient is under continued observation with repeated echocardiography and blood cultures. Evaluation by physicians with specific expertise in CIED infection is always recommended when a diagnosis is established, but is also an option for *suspected* infection if the investigation is complicated [11]. Additional radiology could strengthen a diagnosis in the case of complications of CIED infection such as septic arthritis, spine infection, pulmonary embolism, vein thrombosis, or metastatic abscess [7, 25]. If available, new modalities such as FDGpositron emission tomography/computerized tomography might play a role by adding information in complex cases. In the case of bacteremia of an unknown source, all removable non-CIED sources of infection (such as intravenous lines) should be taken out [11]. A single positive blood culture without other symptoms is not sufficient for immediate device removal but the identified pathogen can give vital information. As mentioned in previous sections, CIED infection is more likely with Gram-positive bacteremia. *S. aureus* should not be neglected and instead always regarded as a possible pathogen, requiring further investigations in search of a source [11]. In the case of *S. aureus* bacteremia where there are no clinical or echocardiographic findings supporting CIED infection, earlier American Heart Association guidelines have mentioned six parameters associated with CIED infection [14]:


 A scientific statement from the Heart Rhythm Society stresses that early diagnosis and lead extraction Within three days of diagnosis were associated with lower mortality in a small study [11, 40]. British guidelines recommend extraction as early as possible, but not later than within two weeks of diagnosis [7]. CIED infection can also occur for surgically implanted devices with epicardial leads. Basically, what has been stated for ordinary leads is also valid for epicardial leads. Complete device removal is recommended, after analyzing the risk of surgery for the individual patient compared to the risk from CIED infection. For localized pocket infection though, a practice of cutting the epicardial leads, only extracting the portion close to the pocket is used [11].

## **9.2 Antibiotic treatment**

For patients with suspected post-operative inflammation, the use of antibiotics is controversial. It is reasonable to first consider if continued observation is sufficient. If needed, guidelines recommend a short oral course [7]. For all other clinical categories, some antimicrobial treatment is recommended. A multidisciplinary approach involving infectious disease specialists and individual adaptations depending on the patient's risk factors and comorbidities is essential.

 A basic principle is to start with broad empirical treatment, if systemic infection is suspected. At this stage, treatment should target both Gram-positive, including methicillin-resistant *S. aureus* (MRSA), and Gram-negative bacteria [11]. The duration of antibiotic treatment is counted from the first negative culture after device removal and depends on a number of factors including the specific pathogen, extent of device infection, and existence of complications, if the device has been successfully removed or not. As with other parts of management, there is a lack of solid evidence and the choice of antibiotics and treatment durations are primarily based on expert opinion and experience [11]. Examples of regimens from current guidelines are provided in **Tables 1** and **5**, but it is also important to always consider local resistance patterns. The category "uncomplicated device pocket infection" by definition does not include systemic infection. However, some of these patients will eventually develop sepsis and therefore it is reasonable to start empiric therapy. Once a pathogen is identified through cultures, treatment should be modified accordingly.

#### **9.3 Reimplantation**

After removal of infected devices, it is crucial to always thoroughly reassess the need for a new CIED. Some patients no longer meet an original indication because of improvements in heart rhythm or function. Others have a strong personal opinion and do not accept a new implantation [11]. For some patients, another type of device can reduce possible risks of infection relapse (device downgrade and alternative devices are further described under prevention). The percentage of patients with CIED infection not requiring a replacement device has ranged from 13 to 52% in different studies [25].


*iv: intravenously, q8h: every 8 hours, q12h: every 12 hours, and q24h: every 24 hours.\* All doses may require adjustment due to impaired renal function.* 

#### **Table 5.**

*Examples of guideline regimens for empiric antibiotic treatment.* 

*Cardiac Implantable Electronic Device-Related Infections DOI: http://dx.doi.org/10.5772/intechopen.86395* 

Clearance of infection is a prerequisite before hardware can be reimplanted. The optimal timing of reimplantation is however not known as no prospective trials have been done. According to recommendations from the Heart Rhythm Society, it is reasonable to await a 72 h period of negative blood cultures before reimplantation, also mentioning that there are single center studies indicating that reimplantation the same day as device extraction is possible for isolated pocket infections [11]. The existence of undrained abscesses or other sources of infection would demand further postponing of these suggested waiting times. It is also recommended that a new device is placed on the contralateral side, an attempt to reduce the risk of seeding the new device from a prior tissue infection [9]. If remains of valvular infection are suspected, the waiting period should be extended to at least 14 days according to the European Society of Cardiology guidelines [5]. British guidelines, illustrating that there is no unanimity here, recommends reimplantation to whenever possible be delayed until signs of infection have resolved suggesting 7–10 days [7].

 The pacemaker-dependent patient poses a special challenge. Some form of temporary pacing is needed as a bridge to reimplantation. Common problems of traditional temporary pacing are frequent loss of capture, undersensing, and that the systems in general are large and inconvenient, all this confining the patent to stay immobilized in a hospital bed during antibiotic treatment before reimplantation. Studies of "semi-permanent" systems with active fixation leads and an external reusable pacemaker have shown that this practice is safe, reduces hospital stays, and makes the patient more mobile [11, 57]. However, these studies have so far only included a smaller number of patients and therefore are not able to rule out that the risks for relapsing infection earlier observed with temporary pacing still holds [58]. Therefore, all sorts of temporary pacing should still be regarded as a risk factor and avoided if possible, even though this semi-permanent technique probably is a way to reduce adverse events [5]. For ICD-patients with high risk of sudden cardiac death, the wearable cardioverter defibrillator can be a promising option. This noninvasive device is worn under normal clothing safely and effectively treats ventricular tachyarrhythmias, thus offering bridging to ICD reimplantation, (if the indication still holds) without increasing the risk of CIED infection relapse [59].

#### **9.4 Management when device removal is not possible**

 Despite all known benefits of device removal, there are a small proportion of the patients that either decline device removal or are considered medically unfit for device removal. For many of these patients, it is likely that extraction will require surgical intervention and often they may be more or less dependent on a device (for instance CRT) that is not considered possible to reimplant. They may also have other, permanent, sources of infection or a short life expectancy [11]. There is not much evidence to guide the management of these patients, but various smaller reports have described very varied outcomes. Some describe patients being cured with medical therapy alone. Others describe the strategy of partial device removal (only generator), which is possible for nonpacemaker-dependent patients, with cure rates in a wide range from 13 to 71%. There are also reports of ICD patients with 100% failure [7].

British guidelines include regimens for attempts to salvage devices with medical therapy alone [7]. These consist of different combinations of antibiotics (for instance daptomycin and vancomycin), aiming to break through biofilm and are based on combinations that have salvaged infected non-CIED prosthetic materials and other devices. The duration of therapy is often 6 weeks. There is no known test to evaluate this therapy besides observation and blood cultures after the end of a course. Infection relapse is equivalent to a failure to salvage the device. In that case (unless the decision about device removal does not change), the only option is a palliative strategy of life-long suppressive antibiotic treatment. Patients in this

group are usually cardiovascularly stable and have responded well to antibiotics with clinical improvement and cleared bloodstream infection. This strategy can obviously only be applied to a few selected patients and the outcome is also unclear. Compared to curative strategies, this should be regarded as a last resort [11].

## **9.5 Risks associated with device removal**

 Device removal should be performed in specialized centers with expertise in the procedure and acute cardiac surgery backup available [30]. Percutaneous procedures have become the most used method as procedural risks are lower compared to open surgery. In case of failures with a percutaneous technique, a conversion to open surgery is common. Removal of leads engrafted in cardiac tissue can be dangerous. Over time, fibrous anchoring tends to develop between leads and vascular and cardiac structures. Inter-lead anchoring is also common. The major procedural complications are related to these anchorings and accidental tears or perforations of either the superior vena cava or parts of the myocardial wall with resulting dramatic bleeding and tamponade. Lead fracture often requires shifts to open surgery and can cause life threatening arrhythmias. To reduce risks, new techniques with locking stylets, photoablation of fibrous attachments, and less invasive methods aided by thoracoscopy have been developed [30, 60, 61]. In experienced centers, procedure mortality is low, between 0.1 and 0.6% [5]. If removal employs this type of special equipment, or concerns a lead implanted more than a year ago, the procedure is referred to as *extraction* as compared to *explantation* [11].

A number of procedural risk factors have been identified one of the more evident being elapsed time since lead implantation, which is related to the fibrous anchorings. Other risk factors are female sex, multiple leads (lead-lead anchoring), operator inexperience, and radiological findings of calcification involving leads. ICD is a risk factor as the device is bigger and more complex. In particular, the coils are suspected of stimulating fibrotic growth between device and myocardium and some extracting operators choose to only implant single coils for this reason [60].

 In the case of very large vegetations, there is risk of pulmonary embolism. For very large vegetation, a shift to open surgery is common. There is uncertainty about how large vegetations should be for this shift to benefit the patient. Guidelines state that additional data are needed and recommend individualized decisions for vegetations >2 cm in diameter [5].

#### **10. Prevention**

 As CIED infection results in substantial morbidity and mortality as well as high and rising costs for health care systems, good prevention is essential. The first subsection here is valid for all device patients. The following, covering secondary prevention, is specific for CIED infection patients. Being an essential and integrated part of all CIED infection management, it is not always specifically referred to as prevention. Finally, we give an outline of new therapies and devices with possible implications for all potential devices.

#### **10.1 Primary prevention**

Before implantation, the patient must be evaluated for clinical signs of infection. Fever during the last 24 h before implantation is a risk marker for later CIED infection. Signs of systemic infection should always result in elective implantations being postponed and acute procedures should be avoided until the infectious episode is resolved [7]. Perioperative antibiotics reduce the risk of infection. A randomized controlled

#### *Cardiac Implantable Electronic Device-Related Infections DOI: http://dx.doi.org/10.5772/intechopen.86395*

study was interrupted after having enrolled 649 patients, showing an infection rate of 3.4% for the placebo group versus 0.6% in the antibiotics group [11]. When risk markers are studied, neglected perioperative antibiotics are one of the more consistent predictors of infection risk. Intravenous administration of a cephalosporin or penicillinase resistant penicillin 1 h before procedural start or vancomycin 2 h before start are commonly used [11]. Repeated dosing after skin closure or general postoperative antibiotic use is not recommended. Except for TYRX™ (see Section 10.3), there is so far no support in evidence for local installation of antibiotics or antiseptics into the device pocket [7, 62].

 Implantation should ideally take place in a designated CIED laboratory fulfilling requirements for ventilation suitable for device surgery. This is underlined by the fact that it is not unusual with perioperative CIED contamination today and many CIEDs are implanted in catheterization laboratories with lower ventilation requirements than operation theaters [7]. Implantation should be carried out with an aseptic technique, in an environment observing operating theater discipline. Alcoholic chlorhexidine (2%) should be used to prepare the skin over the operative site. Devices and surgical equipment should be left uncovered for the minimum possible time [7].

Risk of infection is also related to operator experience and the aggregated operation volumes of different centers—at least it has been shown that very small volumes are related to higher risk of complications: a study of Medicare recipients showed that physicians implanting 1–10 ICDs annually had higher complication rates than physicians implanting more than 29 devices [63]. A US registry study found a complication rate of 3.8% at centers performing fewer than 24 implants a year compared to 3.1% at centers implanting more than 110 devices a year [64]. British guidelines stress the importance of supervision of junior operators (with lower operation volumes) by senior operators. They also speculate about if a lack of supervision is more common for generator exchange procedures, which have a higher risk of infection than de novo implants, but often are viewed as simple and "straightforward procedures" [7].

Postoperative hematomas are a consistently found risk factor. If possible, antithrombotic treatment and anticoagulation should be discontinued prior to the procedure. If a pause in anticoagulation is not deemed possible, it is however better to continue with ordinary warfarin doses than discontinuing and trying to bridge with heparin as this is related to a significant increase in pocket hematomas [7]. As for new oral anticoagulants (NOACs), there are less data, but studies suggest that there is no difference in pocket hematoma between interrupted and continued NOAC regimens [65].

#### **10.2 Secondary prevention**

The most effective preventive measure against CIED infection is to avoid unnecessary CIED implants in the first place. For patients with CIED infection, a reassessment of the risks and benefits of the device before reimplantation is crucial, and a significant proportion of the patients do actually not meet indications for reimplantation. As the risk is also associated with various properties of the device, this reevaluation can also result in a device downgrade, for instance from a more complex to a simpler device, or from two defibrillator coils to one on an ICD. An option is also to change from transvenous leads to epicardial leads, or more commonly, to choose some of the newer devices described below.

 A general principle of CIED infections is to remove all hardware, but if this is not possible, as much as possible should be removed. Examples of the latter is the isolated removal of the generator for nonpacemaker-dependent patients who refuse lead extraction or the practice of cutting the leads and removing the proximal part together with the generator when epicardial lead extraction is regarded too risky, all based on the presumption that the generator accounts for the biggest infection burden in a CIED and that its removal is a simple procedure compared to lead extraction.

 The risk of infection is less with peripheral cannulae than cuffed central venous catheters and patients can be treated with peripheral cannulae for very long periods, as long as the cannulae are changed every 72 h [66]. In fact, the risk of infection for any vascular access increases with time in situ. A central venous catheter also increases the risk of venous thrombosis reducing access options for future CIED placement. For some patients, though, siting cannulae can become very complicated and alternative strategies are needed as oral administration during CIED infection is not a safe procedure. Peripherally installed catheters (PICC or "midline") may in that case be a better alternative than central venous catheters [7].

As mentioned in previous sections, temporary pacing with an intravenous pacing wire is associated with higher risk of infection relapse and should if possible be avoided for CIED infection patients. If central venous catheters are used, potential future access sites for CIEDs (contralateral prepectoral to existing CIED) should be avoided if possible. Semi-permanent pacing with screw-in leads is probably better than traditional temporary pacing, but both techniques should be avoided unless the patient is dependent on pacing. It seems that this is not only valid for CIED infection patients (and thereby also an example of primary prevention); for acute patients, it is becoming more common to directly implant a pacemaker, rather than using temporary pacing with higher risk of future CIED infection [7, 58, 67].

#### **10.3 Alternative device systems**

 A leadless pacemaker suitable for VVI-pacing can be implanted in the right ventricle through femoral venous access. It is a means of avoiding the traditional complications associated with leads or generator pockets, and studies have shown promising results with lower complication rates compared to transvenous CIEDs [68, 69]. However, to our knowledge, no randomized controlled studies have yet compared leadless and transvenous pacemakers. Also, no long-term studies have yet been completed. In situations with limited venous access as well as reimplantation after CIED infection for high risk patients, leadless pacing should be considered.

A subcutaneous ICD is an alternative to transvenous systems that can be considered as an option for reimplantation in patients with high risk of CIED infection relapse. With this system, complications related to leads or vascular access are avoided. It has proved to be as effective as an ordinary ICD in treating life-threatening arrhythmias, but it is unsuitable for patients needing pacing, resynchronization therapy, or antitachycardia pacing [70–72].

Since 2001, the noninvasive wearable cardioverter defibrillator has been available to provide temporary protection against sudden cardiac death. It safely and effectively detects and terminates ventricular arrhythmias and should be considered as a bridging therapy to ICD reimplantation. As a reassessment of the indications should take place before every reimplantation, the wearable cardioverter defibrillator also has the potential of bridging to a device downgrade [59, 73, 74].

 In addition to perioperative systemic antibiotics, an antibiotic envelope (TYRX™) has been developed, wrapping the device and slowly releasing antibiotics (minocycline and rifampin) in the device pocket. A meta-analysis of five prior studies including 4490 patients showed that use of the envelope is associated with significantly lowering the CIED infection rate, although the included studies were not randomized controlled trials [75]. Other studies have particularly showed benefits among patients categorized as high risk individuals for early CIED infection (risk factors, **Table 2**) [76]. As the envelope is costly and its use is not yet routine, this selected patient group is probably the most promising to start with, although there are cost-benefit studies indicating a role for this envelope as a standard of care for all patients, at least in the context of the US health care system [77].

Current evidence does not support the use of prophylactic antibiotics for dental procedures or other invasive procedures that do not involve direct device manipulation [11].
