Background
Today, the application of implantable pacemakers and cardioverter defibrillators (ICD) represents routine procedures in most hospitals. Because patients are often dependent on these artificial devices, their flawless function is vital. Nevertheless, complications do occur, the most frequent one being bacterial infection. Diagnosis and therapy of implant-associated infections are often difficult, protracted and expensive. Infections of implanted devices are associated with significantly increased morbidity and mortality and cause high health-care costs [
1]. Early infections of pacemaker and ICD devices are usually caused by organisms which are introduced at the time of surgery and present most often with abscess formation or frank purulent wound dehiscence. On the other hand, late infections are the sequel of latent infections, in which the cause of the infection remains unresolved.
The oral cavity is a likely source of bacteria that may elicit infections on pacemaker and ICD devices after systemic transmission. Gingivitis and periodontitis are frequent chronic inflammatory processes belonging to the spectrum of periodontal diseases of the oral cavity affecting the tooth supporting tissues in response to bacterial accumulation. Constantly forming bacterial deposits on the teeth cause a chronic inflammatory response with many stages, ranging from reversible low-level inflammatory gingivitis to irreversible higher-level inflammatory periodontitis that is, if untreated, followed by tooth loss [
2]. In addition to various epidemiological studies demonstrating a potential link between periodontitis and cardiovascular diseases it has been demonstrated that treatment of patients suffering from periodontitis reduces acute parameters of atherosclerosis and improves endothelial function [
3]. During progression of gingival diseases, the epithelium becomes ulcerated to expose the underlying connective tissues and blood capillaries and facilitates entry of biofilm organisms or their products (e.g. bacterial heat-shock proteins) to the circulation [
4]. Pathogens which have entered the bloodstream may adhere to the pacemaker lead that is located in the subcalvian vein on way to the right heart ventricle. Adherent bacteria may grow along the lead to the pacemaker, which is located in a connective tissue pouch for the initiation of an inflammatory reaction.
Therefore the aim of the study was to identify the bacterial composition of the oral cavity and implantable pacemaker and cardioverter defibrillator devices explanted with a diagnosis of infection, to test the hypothesis that the oral cavity is a potential source for pacemaker and ICD infections.
Discussion
Implantations of cardiac pacemakers and cardioverter defibrillators have become indispensable techniques in medical treatment for decreasing the mortality in patients with arrhythmias or cardiomyopathy [
11]. However, infection rates range from 1-12% and can involve the pacemaker/ICD pocket, electrodes, generator or endocardium [
12]. Aside from difficulties to diagnose infections of cardiac devices the classification according to the time course after implantation, similar to prosthetic valve endocarditis (PVE), becomes a useful tool to arrange temporary transvenous pacemaker (TVPM)/ICD infections [
13,
14]. Early infection again occurs as a result of intraoperative contamination and tends to be predominated by
Staphylococcus aureus. Late infection is usually a result of cutaneous erosion of the generator. Microorganisms from the pocket can spread along the electrodes to endocardial surfaces, including the tricuspid valve. An alternative way for late infections includes hematogenous seeding of the endovascular electrode during transient bacteremia from a distant site of infection. Therefore the most common pathogen is
Staphylococcus aureus and other less commonly identified pathogens, including viridans group streptococci, enterococci and gram-negative bacilli [
5].
The diagnosis of pacemaker and ICD infections should be suspected in patients carrying such devices with unexplained fever. These intravascular device infections can be diagnosed through serologic, radiologic, and echocardiographic measurements. The clinical manifestations are variable and depend on the affected component and vary from slight pocket edema with or without erythema, pain and warmth to fever and abscess formation [
15]. The optimal management of pacemaker and ICD infections seems to be a combined medical/surgical approach consisting of complex device removal/re-insertion with prolonged antibiotic therapy.
In cases of device infection in combination with skin perforation the diagnosis is easy, however, the exact timepoint of infection remains unclear. It is possible that a former infection lead to the accumulation of bacteria followed by the skin passage or the skin passage is followed by bacterial migration into the device pouch. Pacemakers that were removed during routine inspections were contaminated with bacterial DNA with a frequency of approximately 70%. Especially in these cases the present study was intended to identify the oral cavity as a likely source of bacterial contamination of pacemaker.
Several epidemiological data have been published that clearly identify chronic inflammatory diseases of the oral cavity, in particular periodontitis, as a risk factor for various systemic conditions, e.g. cardiovascular diseases, stroke, preterm low birth weight and diabetes [
16]. Periodontal diseases are a candidate group of extravascular diseases with adverse systemic effects, because of their chronic and painless character, combined with extensive amounts of bacteria and ulcerative surfaces, which are often a source for a systemic dissemination of inflammatory products and bacteria into blood [
17]. This transmission may be spontaneously, during eating or toothbrushing. The transfer of oral bacteria has been proofen e.g. by the detection of oral pathogens as well as commensal bacteria within atheromatous plaques [
18,
19]. Especially bacteria associated with periodontitis like
Porphyromonas gingivalis are in the focus of interest, because of several virulence mechanisms that are relevant for the pathogenesis of atherosclerosis [
20].
Here we used 16S rDNA based metagenomics to evaluate the bacterial composition of non-infected and infected pacemakers. This approach allowed a relatively comprehensive description of dominant microbial communities associated with pacemakers. The detection of bacteria on asymptomatic rhythm heart management devices removed for battery exchange has been shown [
21], the present study was aimed to identify the oral cavity as a potential source for bacteria colonizing non-infected and infected devices. We found that non-infected pacemakers are frequently contaminated with bacteria and if bacteria were found, skin microorganisms were dominating. Infected pacemakers were prevalently colonized by
Propionibcterium acnes and
Staphylococcus where
Staphylococcus epidermidis was most often detected. If bacteria were identified on pacemaker they were only irregularly isolated in the oral cavity. The oral, respectively periodontal health condition of patients with non-infected and infected pacemakers showed no remarkable difference. From the present study the oral cavity could be excluded with high certainty as a bacterial source for late pacemaker and ICD infections. Although, the present study simply address bacteria located at the gingival margin, bacteria colonizing other oral niches are unlikely relevant for inflammatory process induced by bacteremia. These bacteria become swallowed on a regular basis and do not have access to the bloodstream.
The present study describes for the first time the microbiota of a patient group with non-infected or infected pacemakers using the SSCP technique. In contrast to methods using specific 16S rDNA primers the SSCP method is aimed to detect diverse dominant bacterial genera or species in a biofilm consortium with a detection limit of approximately 1000 CFU/ml (colony forming units/ml) as determined in a series of preliminary experiments (data not presented). To identify bacterial consortia in diverse habitats a metagenomic approach is helpful, because of the potential identification of bacteria, irrespective of their taxonomical classification, which is not possible by searching for known genera or species. For the present study no state-of-the-art whole-microbiome sequencing method was used. In contrast to pyrosequencing techniques that may detect even single copies of individual 16s rRNA gene copies, SSCP analysis detects dominant bacterial species in biofilm community. This approach is more suitable to identify bacteria that initiate inflammatory processes. Although different antibiotic regimes were used in the test and control groups, the bacterial biofilm composition could be comprehensively analyzed by SSCP analyses, because detection does not rely on viability.
Chua et al. [
14] found that 42% of all patients with pacemakers had a delayed infection and it is of fundamental interest to reveal how these infections occur. Local perioperative wound contamination and colonisation by haematogenous routes are the two most advocated mechanisms, but none has been fully validated.
Propionibacterium acnes and
Staphylococcus were present in a frequent number of non-infected pacemaker specimens and represent bacteria commonly found on skin. It is likely that pacemakers are contaminated by these microorganisms during the surgical procedure. In a previous publication Pichlmaier et al. (2008) found
Pseudomonas (16%),
Staphylococcus (11%),
Stenotrophomonas (10%),
Rhizobium (9%) and
Propionibacterium (7%) most commonly in asymptomatic rhythm management devices. This spectrum of bacteria is very different from that commonly found in infected pacemakers, however, overgrowth of opportunistic bacteria and a concomitant decrease of commensal bacteria is a plausible explanation [
22]. Da Costa et al. [
23] strongly supported the hypothesis that pacemaker-related infections are mainly the result of local contamination during implantation. They found that patients with delayed infections (16–29 months) had the same strain of microorganisms cultured from infected device pockets as was isolated from the skin and pocket at device implantation. Also, the fact that nearly all cultured microorganisms are part of the skin flora supports the hypothesis of wound contamination during the device procedure. The data of the present study support this mode of infection.
For infected pacemakers a more diverse microbiota was identified, however, again commensal skin bacteria were most frequently detected.
Staphylococcus epidermidis was most frequently detected on pacemakers with a diagnosis of inflammation and is known to be responsible for severe nosocomial infections. Recently, the microbiology of cardiac device infections were investigated by culture and in this study
Staphylococcus aureus and coagulase-negative staphylococci were most frequently isolated [
24]. In the present study no gram-negative bacteria were identified, which is in contrast to publications that report gram-negative bacteria in 4-15% of the specimens [
14,
25]. A lower sensitivity to gram-negative bacteria of the used universal primers may be an explanation.
Propionibacterium acnes and
Staphylococcus aureus were identified in 4 out of 10 cases in dental plaque using specific primers after they have been identified on infected pacemakers. These bacteria belong to the normal oral microbiota according to the HOMD database (
http://www.homd.org). It may be possible that these bacteria have been transferred from the oral cavity to the generator leads and pacemaker to initiate infection, however, the low frequency observed and the low number of these bacteria generally found in the oral cavity makes this imagine unlikely. The observation that non-infected pacemakers and infected pacemakers are most frequently contaminated with skin pathogens makes it likely that they were incooperated during surgery and initiate infection after a latent period within the tissue pouch.
One intriguing observation was the similar periodontal health condition between patients with non-infected and infected pacemakers. Sensitive parameters characterizing the previous and actual periodontal disease activity were recorded and no significant differences were observed. While the parameter BOP accurately determines the actual inflammatory reaction of the periodontal tissues, the number of residual teeth enables a good impression of disease activity through live, because teeth were lost in elderly most often due to periodontitis. In 2005 in Germany elderly between 65 and 74 years had approximately 14.2 teeth, which is in good agreement to the data of the two groups enrolled in the present study [
26]. From the present data it could not be excluded that the low number of teeth in the infected pacemaker group is a result of extensive tooth extractions due to the repeated surgical interventions. In accordance to several publications analyzing risk factors for pacemaker and ICD infections the present study identified no correlation between pacemaker infection and oral or periodontal health conditions of the patient [
24,
27]. However, periodontitis is a proven risk factor for cardiovascular diseases and any patient with an incooperated pacemakers or ICDs should avoid any inflammatory reaction of the oral tissues affecting the systemic inflammatory burden.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JE, CK, AH and MS participated in the design of the study, interpreted the data and drafted the manuscript. All authors read and approved the manuscript. NS did the microbiological analysis and US, FI, WH and MP have made substantial contributions to data acquisition and clinical sampling. All authors read and approved the final manuscript.