**7. Pathogenesis**

There are two basic mechanisms of infection, either bacterial contamination at the time of implant or hematogenous seeding of the device during bacteremia from a distant focus of infection [5].

 Excluding rare cases of contamination during manufacturing, it can occur perioperatively by anyone handling the device or via the air of the operation theater. Without ventilation with laminar flow, it is likely that coagulase-negative staphylococci on skin squamae, either from the patient or any of the operating staff, are present in the air. An example of this is the *en passant* finding in one study where 14 unused sterile leads were placed on the operation table during a CIED implantation. One of the leads was positive for *Staphylococcus epidermidis* after culturing [7, 43]. During implantation and possible later manipulations or revisions, skin incisions always carry the risk of skin flora contaminating the wound and eventually the device [7, 20]. It is a common notion that most CIED infections are the result of contamination at the time of implantation, which is supported by the proven effect of surgical site prophylaxis [16].

 The alternative, and less common, pathway involves hematogenous seeding from a distant focus. In this case, the type of pathogen is critical to the risk of infection with *S. aureus* conferring the highest risk, whereas the risk of CIED infection from gram-negative bacteremia is low [20].

The common conceptual separation of local device pocket infection from infection involving leads and bacteremia serves a purpose for describing pathogenesis or planning preventive strategies. In practice, it is however often hard to differentiate between the two [5]. Once the generator pocket is infected, bacteria can migrate along the leads to finally reach intracardiac structures. And although pocket infection most often is due to perioperative contamination, hematogenous seeding to the pocket is also a possibility [14]. The eventual consequence of CIED infection can be the forming of vegetations anywhere on the lead and on the tricuspid valve as well as the right atrial or ventricular endocardium. Septic pulmonary embolism is a frequent complication of device endocarditis [5].

However, pathogenesis cannot be reduced to blood stream or wound contamination. It is the result of specific interactions between the device, the microbe, and the host [14]. Risk factors related to the patient (host) and device have been discussed in earlier sections. Additionally, there are specific device factors related to surface features and chemical interactions between pathogens and devices affecting pathogen adherence. The development of devices with better surface properties in this regard

is an important topic under current exploration, although not currently relevant in clinical practice, and therefore beyond the scope of this chapter [7, 11, 16, 20]. Finally, there are specific virulence factors, all related to microbial ability to adhere to device surfaces that are crucial for establishing CIED infection. The most important of these is the ability to form biofilm [20, 25, 44]. This reduces the effectiveness of the normal immune system response to infection, supplies a barrier against antibiotic penetration, and (by metabolic downregulation) makes bacteria less susceptible to antibiotics.
