Europace Advance Access originally published online on July 25, 2008
Europace 2008 10(9):1067-1072; doi:10.1093/europace/eun191
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Implantable Cardioverter-Defibrillators
High prevalence of asymptomatic bacterial colonization of rhythm management devices
1 Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg-Strasse, D-30625 Hanover, Germany; 2 Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany; 3 Helmholtz Center for Infection Research (former GBF), Braunschweig, Germany
Manuscript submitted 21 May 2008. Accepted after revision 2 July 2008.
* Corresponding author. Tel: +49 511 532 3453; fax: +49 511 532 8158. E-mail address: pichlmaier.maximilian{at}mh-hannover.de
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Abstract |
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Aims: Recent work has been focused on causes of and risk factors for rhythm management device infections. The aim of this study was to elucidate whether patients may be asymptomatic carriers of bacteria on their rhythm management device, possibly allowing later manifestation of infection.
Methods and results: A total of 108 devices were changed for battery depletion between April 2005 and February 2006 in asymptomatic patients who were examined for evidence of bacterial DNA on the device and in the surrounding tissue using single strand conformation polymorphism analysis (SSCP). Follow-up was for 23.4 months. In 47.2% of the patients, bacterial DNA was demonstrated on the device, which had been in place for 64.1 months. The sequences identified bacterial strains that are untypical for clinical device infections. Staphylococci were demonstrated in only 3.7% of the patients and they became symptomatic within the observation interval; all others remained asymptomatic. The known risk factors for device infections did not correlate with the demonstration of bacterial DNA in this population. Common cohabitation was identified among the strains found.
Conclusion: A large proportion of patients carry bacteria on their pacemaker or implantable cardioverter defibrillator asymptomatically. The strains found differ from those commonly seen in clinically evident device infections. Common risk factors for device infection did not correlate with the presence of DNA.
Key Words: Infection, Rhythm management devices, Pacemakers, Defibrillators, Risk factors, Device changes
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Introduction |
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Rhythm management devices such as pacemakers (PMs) and implantable cardioverter defibrillators (ICDs) are an essential part of anti-arrhythmic therapy.1
Currently, 
83 000 PMs and 35 000 ICDs are implanted every year in Germany with a growing tendency (German Institute for Quality Control). Besides the increasing spectrum of indications for the implantation,2 the basic surgical techniques and the surface material of the hardware have only changed marginally over the past 20 years. There has, however, been a surge in the incidence of bacterial infections of such devices throughout the world.3–5 This has given rise to a vivid discussion about the management of these device infections, and there is also a huge body of information on the causes of and risk factors predisposing to such infections.6–13 Factors such as renal failure,14,15 diabetes and congestive heart failure,14 the number of previous operations,14,16–18 increasing number of leads,18 indwelling central venous lines,18 experienced bacteraemias,19 and vegetations on the leads10,20 have all been shown to predispose to the infection, whereas the steroid treatment has been discussed controversially.3,15 Similarly, previous attempts of conservative treatment of device infections have been associated with a high incidence of fulminate infections.7 Although the clinical focus rests on prevention, there is considerable uncertainty about the actual mechanism of device infections.16,21 On the basis of the clinical presentation, cases may be divided into three groups: (i) isolated device pocket infections early after the implantation (<3 months), (ii) secondary infections of the indwelling transvenous leads (lead endocarditis) (any time after the implantation), and (iii) late pocket/device infections (1–10 years). Early infections are usually caused by organisms that are introduced at the time of surgery and present most often with abscess formation or frank purulent wound dehiscence.16,21 Lead endocarditis—unless associated with an early infection—is thought to be caused by transient bacteraemias, usually gram-positive bacteria, and maintained by biofilm formation on the artificial materials.10,22 It typically presents with systemic signs of infection.19 Here, the device pocket is usually involved only by the retrograde spread along the leads. However, the latent device pocket infections prove to be difficult to diagnose and may even be overlooked at the first instance.13,23 In these latent infections, the origin of the causative organisms often remains unresolved.24 Although Staphylococcus aureus is more often associated with lead endocarditis and early pocket infections, the proportion of other organisms such as Staphylococcus epidermidis is higher in the latent pocket infections.25 Additionally, it remains unclear, whether bacteria, once they enter the surgical wound containing an artificial material such as a rhythm management device, causes an infection or whether the patient’s defence mechanism possibly with the help of peri-operatively administered antibiotics deals with a proportion thereof. Thus, indirect evidence from studies on prophylactic antibiotic treatment explain a regular contamination of the surgical field with the typical skin-associated bacteria.18,26,27 The question remains, however, whether bacteria may remain dormant, possibly in the state of equilibrium with the host defence mechanisms until something changes this equilibrium and infection becomes overt.28 Alternatively, it may be speculated that a cohabitation of various different bacteria behaves yet different to isolated strains or may even prepare the grounds for more pathogenic organisms. The aim of this study was to elucidate whether patients are asymptomatic carriers of bacteria on their rhythm management device. Furthermore, it was of interest that what strains and communities of micro-organisms may be present and whether there are predisposing factors in a positive patient population.
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Methods |
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Sampling
From April 2005 to February 2006, devices explanted from asymptomatic patients electively admitted mostly due to battery depletion were prospectively collected. A tissue biopsy from the device pocket was also performed. They were transferred to a sterile container and immediately stored at –80°C. The devices and biopsies were then examined for evidence of bacterial DNA. Informed consent was obtained from all patients according to the declaration of Helsinki, and the Institutional Review Committee approved the study.
DNA extraction and microbial community analysis
The biofilms were collected from the devices with a sterile scalpel and rinsing with TE buffer; the DNA was extracted using the Fast-DNA-Spin-Kit for soil (Bio 101, CA, USA). Primers chosen for the amplification of bacterial 16S rRNA genes were forward primer Com1 and reverse primer Com2-Ph.29 The phosphorylated strand of the polymerase chain reaction (PCR) products was digested by lambda exonuclease (New England Biolabs, Schwalbach, Germany) and further purified using the Mini-elute-Kit (Qiagen, Hilden, Germany). The remaining single-stranded DNA was dried under vacuum. The DNA was then resuspended in denaturizing single strand conformation polymorphism analysis (SSCP) loading buffer (47.5% formamide, 5 mM sodium hydroxide, 0.12% Bromophenol Blue, and 0.12% xylene cyanol) and subjected to electrophoresis. Gels were run at 400 V for 17 h at 20°C in a Macrophor electrophoresis unit (LKB Bromma, Sweden) and subsequently silver-stained.30 Single bands were excised from the gels and eluted in the extraction buffer at 95°C for 15 min. Extracts were centrifuged and the DNA in the supernatant fluid was used for a PCR with the above primers. The PCR product was cleaned (Mini-elute-Kit, Qiagen, Hilden, Germany) and sequenced with a sequencing kit (DYEnamic ET Terminator cycle sequencing kit, Amersham Biosciences, Freiburg, Germany) and both primers. The product was cleaned with the Dye Ex Spin Kit (Qiagen, Hilden, Germany) and the sequence was analysed on an ABI PRISMTM 337 DNA-Sequencer and 3100 Genetic Analyser. Sequences were compared using the BLAST programme and the databases of EMBL and GenBank. The phylogenetic analysis was carried out using the ClustalX software for sequence alignments.31 Tree topologies were reconstructed with UPGMA algorithm with 1000 bootstrap replications with the software MEGA3.1. using the EMBL database.32,33 Several control runs including ‘out-of-the- box’ devices were performed to exclude contamination.
Blood sampling, antibiotic treatment, and patient follow-up
The patients underwent routine blood testing (white blood cell count and C-reactive protein) pre-operatively and they received a third-generation cephalosporin as single shot antibiotic at the time of surgery. They were discharged from hospital on day 1 or day 2 after surgery following a chest X-ray, inspection of the wound, and a routine PM follow-up. All patients were seen as outpatients within 4–6 weeks following the surgery. At this stage, patients were free of local infection and wound problems as well as the PM function. Further follow-up was either in the outpatient anti-arrhythmia clinic or by questioning the patient’s cardiologist who performed the continued routine device check-ups.
Statistical analysis
Data analysis included the evaluation of pre-operative infectious status, co-morbidities, details of previous operations, the work-up of the intra-operative samples and the events during the time course following the operation with respect to wound healing, and evidence of infection. All data were entered in an Excel Spreadsheet (Microsoft GmbH, Unterschleissheim, Germany) and further analysed using SPSS-Software Version 14.0. Data were expressed as mean with standard deviation or median with ranges. Patients were then divided into two groups according to the presence or the absence of bacterial DNA. Laboratory measurements were compared between the groups using parametric statistics (t-test). Non-parametric statistic was used to compare all other variables between the groups (Pearson 
2 and Mann–Whitney U-test). A value of P < 0.05 was considered significant.
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Results |
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Over a period of 10 months, out of 461 operations performed in connection with rhythm management devices including the removal of the device in 148 operations usually due to battery depletion, 122 were collected. The reasons for failure of device analysis in the remaining 26 instances were failure to obtain the patients consent,9
the emergency nature of the procedure (10 heart transplants), or the explicit wish of patients to keep their device.7 Of the 122 devices, 14 were explanted for clinically evident infection and these patients were excluded from the analysis according to the inclusion criteria. The characteristics of the remaining 108 patients are shown in Table 1. The mean age was 65 years (13–98) and 33 were females. The median interval between the time of device removal and the previous surgical intervention on the device pocket was 63.7 months (Figure 1). Twenty-three patients (21%) had multiple (two or more) previous surgical interventions on the pocket. From all patients, the devices were sampled only in 46 cases, and a biopsy sample was obtained from the device pocket eventually available for testing.
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In 51 (47.2%) patients, it is proved that there is a possibility of extracting bacterial DNA from the device and/or the pocket; in 27.8%, at least one bacterial species could be identified by sequencing (Table 2).
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Most devices showed several bacterial species, in which 16% belongs to the genus Pseudomonas, 11% to Staphylococcus, 10% to Stenotrophomonas, 9% to Rhizobium, and 7% to Propionibacterium (Figure 2). Some species could not be identified with enough certainty (Table 2).
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The observed diversity within the genera was generally low, and only one sequence was found for both the Stenotrophomonas and Rhizobium species. The sequences of some SSCP bands were not identical to any of the described species, and the species most closely related was thus documented. For Staphylococcus, two groups of sequences were determined, but identification of a single species was not possible. The SSCP-band 1 belonged to the group including S. aureus and S. epidermis, whereas SSCP-band 2 fell into the group including Staphylococcus intermedius and Staphylococcus hyicus.
Patients have been followed up post-operatively to a median interval of 24.6 months (7.5–33.1). Fourteen patients (12.9%) died of causes unrelated to the rhythm management device or any form of endocarditis after a median observation interval of 9 months.2–29 Furthermore, three patients (2.7%) died 1 day, 1 month, and 12 months after the operation, respectively. In all cases, Staphylococcus DNA has been isolated from the device only. An infective process was the cause of death in two patients (pneumonia and septic shock, respectively), because a definitive diagnosis of endocarditis was not, however, made at that time (post-mortem examinations were not performed). The fourth patient, in whom Staphylococcus DNA had been identified, had an event recorder removed and no new artificial material was implanted at that time. She remained asymptomatic without any wound infection. None of the remaining patients demonstrated signs of an ongoing or new post-operative infection at the time of the initial 4–6-week follow-up. Neither the patients nor their cardiologist reported direct or indirect symptoms of chronic dwelling device infections such as device dislocation (wandering) or chronic pain syndrome at the last follow-up.
Blood values potentially pointing to an ongoing infection were unrelated to the presence of DNA (Table 1). The parameters associated with a weakened immune response or predisposition to repetitive bacteraemias are given in Table 3. None of these shows a statistically significant correlation with the presence or the absence of DNA. Immunosuppression includes essentially long-term steroid treatment. For diabetes, types I and II were analysed separately. Chronic heart disease was defined as a secured diagnosis of coronary heart disease, clinically evident heart failure (New York Heart Association classes III and IV), or long-standing hypertension requiring three or more drugs for treatment. Renal failure was defined as a calculated glomerular filtration rate 
60, and previous antibiotic refers to any course of antibiotic treatment for more than 10 days because the previous operation was documented or the patient remembered. The data reliability was weak for previous bacteraemias and central venous lines when compared with the previous antibiotic, so they were not analysed. A subgroup analysis of those patients previously operated in our own department (n = 70) similarly yielded no further insight into possible parameters making bacterial DNA in the pockets more or less likely (Table 4). All patients had received antibiotic prophylaxis, and the pockets were always rinsed with povidone iodine.
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Discussion |
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Bacterial infections of rhythm management devices are becoming more frequent throughout the world.3
–5,34 Most intriguing among the three types of clinically relevant infections is the latent, slowly progressive pocket infection. Whereas in overt early pocket or lead infections, typical organisms can usually be identified and cultured; in the latent type, at most 20–30% may be identified by traditional culture methods.10,23 Whether there is a proportion of bacteria that cannot be cultured under standard conditions or whether these are sterile inflammatory processes remains unclear. The question is whether organisms, if present, have been there at the beginning and remain dormant, whether they were introduced, for example, by haematogeneous spread, or whether they may only be part of a complex synergism, allowing more pathogenic types to settle at a later stage to develop a full blown infection. The aim of this study was to find out how many patients are asymptomatic carriers of bacteria on their rhythm management device, what strains and communities of micro-organisms are present, and whether there are predisposing factors in a positive patient population when compared with overt device infections.
In this series, it was possible to extract bacterial DNA from the device and/or the device pocket in 47.2% of the 108 asymptomatic patients undergoing elective device replacements. However, it may be speculated that there are a number of false negatives, provided that the methods sensitivity threshold may be assumed to be roughly 1000 organisms. Assuming that DNA is rapidly degraded in a living organism as soon as bacteria die,35–37 it may be concluded that these organisms are indeed a part of functioning microcosm rather than being molecular remnants of contamination during previous operations. The pre-operative observation interval, i.e. the time from the last surgical intervention on the pocket and the current operation, was 63.1 months. The patients had thus explicitly been asymptomatic and 96.3% of those did not develop any signs or symptoms of an infectious process following the present operation, where the old pocket was always used for the new device throughout a median follow-up of 24.5 months (only for four patients <1 year, minimum 9 months). The patients may thus be classified truly asymptomatic concerning the bacterial DNA found.
DNA was isolated from the device in 29.6%, the pocket biopsy in 26.9%, and both in 10.2% of cases. This suggests that the organisms thrive not only on the device surface but also in the tissue surrounding the latter. In fact, the distribution may point to a lesser capability of the organisms to form biofilms when compared with the more typical bacterial strains causing clinically evident infections such as S. aureus.19,22,28,38 Washing the device prior to physically scraping deposits from the surface may thus have eliminated some DNA and explain the lower hit rate on the devices as supposed to the soft tissue biopsy. In 60.9% of the positive samples, definitive bacterial species could be identified from the isolated DNA. This figure improved following a learning curve to 75% after the first one-fourth of the samples. The most common organism found in this series was Pseudomonas followed by Stenotrophomonas and Rhizobium. Although Stenotrophomonas maltophila is known as an opportunistic pathogen occurring usually with pathogens such as S. aureus and Pseudomonas aeruginosa, the Pseudomonas and Rhizobium species found are mainly known from the phyllosphere of plants.39 The latter have, however, been reported to cause clinical Rhizobium radiobacter infections.40 In 15.5% of the cases, more than one bacterial strain could be identified and there was a pattern of typical cohabitation. Pseudomonas commonly coexisted with Stenotrophomonas and Rhizobium, whereas the Propionibacterium acnes group remained isolated. The Staphylococci were found to have cohabitants in as many as 75% of the cases. Whether this indicates that there exists a harmless biofilm community, in which infections is overwhelmed by pathogens, e.g. Staphylococci and P. acnes, or less simple explanations are required remains to be seen in future studies.
The identified spectrum of bacteria proved that it is very different from that commonly cultured from overtly infected devices. This is partially in keeping with the literature, in which atypical bacteria have been occasionally demonstrated on rhythm management devices, especially if there is no clinical evidence for infection.19,41,42 Thus, S. aureus or S. epidermidis were only found in four cases (3.7% overall and 11% of the colonized devices). This latter finding is in agreement with the work by Dy,24 who demonstrated positive tissue culture results from asymptomatic device pockets for S. aureus. This seems quite unusual, assuming the in vivo settings match the in vitro culture conditions under which the bacteria thrive excellently. Indeed, in Dy’s series, a significant number of patients became clinically apparent in terms of infection. Furthermore, the reported follow-up of 8 weeks seems rather short. In our series, three of the patients demonstrating Staphylococcus died within 1 year and the two of them in whom the cause of death was infectious process, died within 1 month of the device exchange. A diagnosis of endocarditis was likely, but not secured, so that the relevance of this detail remains unresolved. The Staphylococcus strain was isolated in the fourth patient from an explanted event recorder, so that in the absence of a newly implanted device, a clinical consequence of colonialization is not really expected. This leaves one asymptomatic carrier of Staphylococci unaccounted for this series in terms of clinical outcome, making the common assumption that Staphylococci will almost always cause a clinically apparent picture plausible.
A series of typical clinical parameters were looked at in terms of being possible predisposing factors to the demonstrated asymptomatic colonialization of the devices. However, none of the classical risk factors and device/pocket-related factors associated with device infections showed a significant correlation with the presence of bacterial DNA. Similarly, in those patients, who had their previous operation on the device system in our hospital, there were no factors typically associated with a higher risk of infection that could be linked to the presence of bacterial DNA. Therefore, there appears to be distinct differences in the host–bacteria interaction and the mechanism of introduction and perseverance of infection between pathogenic and non-pathogenic organisms. These need to be characterized in a comparison between clinically infected and asymptomatic device pockets in the future.
Finally, from the results presented here it remains unclear from where the bacteria came, although it seems suggestive that they were introduced at the time of the previous operation as has been suggested in the literatures.16,21 However, the possibility of a secondary settlement in the pocket cannot be ruled out.19,28
There are recognized limitations of this work. One is that despite the high sensitivity of the techniques employed, a number of false negatives must be assumed. Similarly, false positives, although unlikely, cannot be entirely ruled out, though at least contamination has been excluded. There may be a problem of sample size and further investigations are warranted. The important question of whether there is a pathogenic potential in the asymptomatic colonialization of rhythm management devices cannot be answered from these data. A further shortcoming is the fact that due to the amplification process, it is not possible to draw conclusions about the quantity of bacteria on and around the device and this may indeed be an important factor in terms of pathogenicity. In this series, the identification of species was based on short base pair sequences (375 bp), so that a definitive identification was not always possible.
It may be concluded that among PM and defibrillator patients, there appears to be a high proportion of silent carriers of bacteria on the device. The strains identified are not commonly associated with frank device infections. Furthermore, the strains classically associated with device infections were rarely found in this context. Typical predisposing factors for device infections—primary as well as secondary—are also absent in these patients. A role of these organisms in definitive device infections possibly in terms of synergism or biofilm preparation or even prevention remains unresolved and warrants further investigation.
Conflict of interest: none declared.
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