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Microbiology of Cardiac ImplantableElectronic Device Infections
Ayman A. Hussein, MD, Yacoub Baghdy, MD, Oussama M. Wazni, MD, Michael P. Brunner, MD, Ghazal Kabbach, MD,Mingyuan Shao, MS, Steven Gordon, MD, Walid I. Saliba, MD, Bruce L. Wilkoff, MD, Khaldoun G. Tarakji, MD, MPH
ABSTRACT
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OBJECTIVES This study reports a high-volume tertiary care center experiencewith themicrobiology of cardiac implantable
electronic devices (CIED) infections with assessment of temporal trends and profiles of late versus early infections.
BACKGROUND The rates of CIED infections have been increasing. With changing demographics, patient and device
characteristics, prophylactic measures, and the wide use of broad-spectrum antibiotics, there is need for updated
contemporary data on the microbiology of CIED infections.
METHODS The study included 816 consecutive patients with confirmed CIED infections who underwent transvenous
lead extraction at our institution between the years 2000 and 2011. Blood cultures were obtained in addition of pocket
swabs, pocket capsule, and leads.
RESULTS Staphylococcal species remained the most common pathogens in CIED infections (68.4%), especially
coagulase-negative species (37.6%). Methicillin-resistant staphylococci were the pathogens in 33.8% of all CIED
infections and accounted for 49.4% of all staphylococcal infections. Gram-negative pathogens were identified in 8.9% of
cases, whereas 13.2% were with negative cultures. CIED infections related to streptococci (2.5%), enterococci (4.2%),
anaerobes (1.6%), fungi (0.9%), and mycobacteria species (0.2%) were less common. Of pocket infections, 49.5%
occurred more than 1 year after pocket manipulation, and 53.6% of these were related to coagulase-negative staphy-
lococci. In contrast, most endovascular infections were related to Staphylococcus aureus. The proportions of culture
negative infections have increased (p < 0.0001).
CONCLUSIONS The study provides contemporary data on the microbiology of CIED infections. The rates of methicillin
resistance seem to be greater than those reported from the preceding decade. (J Am Coll Cardiol EP 2016;2:498–505)
T he use of cardiac implantable electronicdevices (CIED) has increased over the courseof the past decade (1). In parallel, there has
been an increase in CIED infections at a rate that seemsto have followed a faster disproportionate trend tothe rate of increase of newly implanted devices (2,3).
Despite increasing awareness of the seriousness ofCIED infections, the institution of infection controlpractices, the administration of prophylactic antibi-otics at the time of implants or system revisions,as well as improvement in CIED and lead design,CIED infections continue to occur and are lifethreatening (4,5).
m the Section of Cardiac Electrophysiology and Pacing, Cleveland Clin
orted that they have no relationships relevant to the contents of this pap
nuscript received October 30, 2015; revised manuscript received Decemb
Importantly, the demographics and risk factors ofpatients receiving CIED implants seem to havechanged over time, which could explain the trends inCIED infection rates (4). CIED implant recipients areincreasingly older and have multiple coexisting ill-nesses (6–8). Similarly, the implants of devices that areat higher risk of infection due to hardware burden orthe inherent characteristics of their recipients, suchas dual chamber pacemakers and defibrillators orcardiac resynchronization therapy devices, have in-creased over time (7,9). Importantly, a significant andincreasing proportion of such devices are implanted inpatientswho are older than 70 or 80 years of age (10,11).
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With changing demographic, patient, and devicecharacteristics, the institution of measures to preventCIED infections and the wide use of broad-spectrumantibiotics, it remains unknown whether there hasbeen a parallel change in the epidemiology of micro-organisms in CIED infections over time. Similarly,although many infections are thought to be related tothe index implant procedures or system revisions, asignificant number of pocket or endovascularinfections occur more than 1 year after device-relatedinterventions, and it remains unknown whether thereare microbiological differences in early versus lateCIED infections.
SEE PAGE 506
TABLE 1 Baseline Characteristics of 816 Consecutive Patients
Who Underwent Lead Extraction or Removal for Device Infection
at the Cleveland Clinic, 2000 and 2011 (N ¼ 816)
Age, yrs 69.3 � 15.0
Female 26.4
Caucasian 88.3
Weight, kg 84.6 � 22.2
Heart failure 48.2
Ischemic cardiomyopathy 30.1
Dilated cardiomyopathy 11.5
Coronary disease 53.1
Valvular heart disease 10.2
Hypertension 59.7
Diabetes mellitus 31.9
Dyslipidemia 43.8
Stroke 10.2
TIA 2.6
Peripheral vascular disease 11.4
Venous thromboembolism 12.0
COPD 16.0
Liver disease 3.4
ESRD 7.9
Atrial fibrillation 44.3
Prior CABG 29.2
Prior valve surgery 10.0
Prior endocarditis 3.3
Steroid use 2.7
Pacemaker 48.2
Defibrillator 51.8
Pacemaker dependent 20.5
Coronary sinus lead 15.2
Number of leads 2 (2–3)
Prior pocket reintervention 36.7
Anticoagulant therapy 31.6
Positive cultures
Pocket swab 44.2
Blood 54.5
Pocket tissue 52.9
Lead 63.9
Hardware only, other cultures negative 8.7
Values are mean � SD, %, or median (interquartile range).
This study reports a 12-year experience with themicrobiology of CIED infections from a high-volumetertiary care center and assesses temporal trends ofpathogens and the microbiological profiles of lateversus early infections.
METHODS
All 816 consecutive patients with confirmed CIEDinfections who underwent device and transvenouslead extraction or removal at the Cleveland Clinicbetween 2000 and 2011 were included. The clinicalfeatures, characteristics, and presentation of deviceinfection were entered into a prospectively main-tained data registry. All patients were evaluated andfollowed by an electrophysiologist and an infectiousdisease specialist from the infective endocarditis andcardiac device infection service. In our practice, wehave established a multidisciplinary center for themanagement of CIED infections that includes, but isnot limited to, cardiac electrophysiologists, infectiousdisease specialists, cardiac imaging specialists, radi-ologists, and cardiac surgeons.
The microbiological profiles and temporal trendswere assessed in the overall population, which wasthen categorized into 2 groups based on the initialclinical presentation for the comparison of microbi-ology in early and late infections. The first groupincluded patients who presented with signs andsymptoms of device pocket infection with or withoutsystemic symptoms. The second group included pa-tients with endovascular infections who had systemicsigns and symptoms of infection and a clinical historysupported by microbiology and in most patients byechocardiographic imaging. In patients with clinicalfeatures of endovascular infection, transesophagealechocardiographs were obtained. In all patients, aclinical consensus was reached between the man-aging electrophysiologist and the infectious disease
specialist regarding the need for device andlead extraction.
Blood cultures were obtained from all pa-tients before the extraction procedures andbefore the initiation of antibiotic therapy at
our institution. For patients who were referred fromother institutions on antibiotic therapy, every effortwas made to obtain all culture data from the referringinstitutions, and these were updated in our clinicalrecords. At the time of the extraction procedure, de-vice pocket swab cultures were sent when there wasevidence of purulent drainage in the pocket. Thefibrotic capsule was excised fully in all patients and
FIGURE 1 Microbio
Lead Extraction or R
2000 and 2011
MRSA ¼ methicillin-
ylococcus aureus; MR
MSCoNS ¼ methicilli
resistant Enterococcu
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Microbiology of CIED Infections A U G U S T 2 0 1 6 : 4 9 8 – 5 0 5
500
tissue material was also cultured. Cultures were alsoobtained from all extracted lead tips and any attachedfibrotic tissue.
For coagulase-negative staphylococcal species,which are well recognized as common microbiologicalspecimen contaminants, repeated isolation or isola-tion from another source of the same coagulase-negative organism with an identical antibiotic sus-ceptibility profile was required to be adjudicated asculprit organism. The study was approved by theCleveland Clinic Institutional Review Board.
STATISTICAL ANALYSES. All statistical analyseswere performed by using SAS version 9.2 (SAS Insti-tute, Cary, North Carolina). Continuous variablesare presented as mean � SD or median (interquartilerange), as appropriate. The chi-square test was usedfor comparison of proportions. For continuous vari-ables, the Student t test or a nonparametric were usedas appropriate. The Cochran-Armitage trend test wasused to assess trends of culprit micro-organismsover the years. A 2-sided p < 0.05 was consideredsignificant.
RESULTS
PATIENT POPULATION. Between 2000 and 2011, 816consecutive patients with confirmed CIED infectionsunderwent device and transvenous lead extraction orremoval at our institution and were included in thecurrent study. Their clinical characteristics are
logy and Pathogens in 816 Consecutive Patients Who Underwent
emoval for Device Infection at the Cleveland Clinic Between
s species; VSE ¼ vancomycin-sensitive Enterococcus species.
summarized in Table 1. The mean age was 69.3 �15.0 years, most of them were men (73.6%), and themajority were Caucasian (88.3%). Their comorbidconditions included hypertension (53.1%), clinicalheart failure (48.2%), coronary disease (53.1%), atrialfibrillation (44.3%), diabetes mellitus (31.9%),valvular heart disease (10.2%), chronic obstructivepulmonary disease (16.0%), end-stage renal disease(7.9%), and a prior history of stroke (10.2%). A historyof prior coronary bypass surgery was present in29.2%, and 10.0% had prior valve surgery. Only aminority had a history of prior endocarditis (3.3%).
Most patients had defibrillator leads in place(51.8%), and the remaining (48.2%) had pacemakerleads only. Of note, 20.5% of patients were pacemakerdependent, and 15.2% had coronary sinus leads. Inall, the median number of leads in place was 2(interquartile range, 2 to 3).
MICROBIOLOGY. Pathogens were identified in thevast majority of patients (86.8%). The source, fromwhich these micro-organisms were identified, were asfollows: lead or lead material cultures (63.9%), bloodcultures (54.5%), pocket tissue cultures (52.9%), andpocket swab cultures (44.2%). The remaining 13.2% ofpatients had no bacterial or other micro-organismgrowth from any of these cultures.
The distribution of pathogens in CIED infections issummarized in Figure 1. Staphylococcal species wereidentified in the majority of CIED infections in thiscohort (68.4%). Of these, coagulase-negative staphy-lococci were more commonly observed (37.6%) thanStaphylococcus aureus (30.8%). Methicillin-resistantstaphylococci were the pathogens in 33.8% of CIEDinfections and accounted for 49.4% of all staphylo-coccal infections.
Gram-negative bacteria were identified in 8.9% ofCIED infections in this cohort. The remaininginfections were related to enterococci (4.2%; vanco-mycin sensitive 2.8%, vancomycin resistant 1.4%),streptococci (2.5%), anaerobes (1.6%), fungi (0.9%),and mycobacteria species (0.2%).
TRENDS IN MICRO-ORGANISMS IN CIED INFECTIONS. Thetrends in micro-organisms in CIED infections aresummarized in Figure 2. Between 2000 and 2011, theproportions of CIED infections related to coagulase-negative Staphylococcus, Staphylococcus aureus, orEnterococcus species did not seem to have changedover time (p ¼ NS). There was a decreasing trend inthe proportion of CIED infections related tomethicillin-resistant coagulase-negative Staphylo-coccus (p < 0.0001) and methicillin-sensitive Staphy-lococcus aureus (p ¼ 0.02). The proportions ofCIED infections related to methicillin-resistant
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Staphylococcus aureus, methicillin-sensitive coagu-lase-negative Staphylococcus, enterococci, or otherbacteria did not seem to have changed between 2000and 2001 (p ¼ NS). Importantly, the proportions ofculture-negative CIED infections increased over thesame time period (p< 0.0001).
EARLY VERSUS LATE CIED INFECTIONS. Of all CIEDinfections, 430 patients (52.6%) had pocket infections;the remaining patients had endovascular infections.
In the group of patients with CIED pocket infec-tion, 50.5% had early infections defined as occurringwithin 1 year after device implantation or last pocketintervention. The remaining 49.5% of pocketinfections occurred more than 1 year after devicepocket manipulation. Coagulase-negative staphylo-cocci were isolated in most early (40.0%) and late(53.6%) pocket infections, but were more likely tobe observed in late pocket infections (Table 2).Staphylococcus aureus was more likely to be theidentified pathogen in early infections (30.2% vs.16.3%). In contrast, negative cultures were morelikely in late pocket infections (23.9% vs. 16.7%). Thestaphylococcal resistance profiles were different be-tween early and late pocket infections withmethicillin-resistant species being more common inlate infections (34.4% vs. 29.8%) and methicillin-sensitive staphylococci being more common in earlypocket infections (40.5% vs. 35.4%) (Table 2).
In the group of patients with CIED endovascularinfection (n ¼ 386), 29.8% had early infections within1 year after implantation or last pocket intervention.The remaining 70.2% had late CIED endovascular in-fections that occurred more than 1 year after pocketmanipulation. In endovascular infections, Staphylo-coccus aureus accounted for most early (51.7%) andlate (44.5%) infections. The overall distribution oforganisms was not different in early or late CIEDendovascular infections (p ¼ NS) (Table 2). This wasalso true for staphylococcal resistance profiles(p ¼ NS) (Table 2). Concomitant infections in endo-vascular infections were identified in 85 patients(22.0% of all endovascular infections). Theseincluded abscesses elsewhere (n ¼ 39), osteomyelitis(n ¼ 16), septic arthritis (n ¼ 14), pneumonia (n ¼ 7),cellulitis (n ¼ 3), discitis (n ¼ 2), meningitis (n ¼ 2),urosepsis (n ¼ 2), and tooth infection (n ¼ 1).
DISCUSSION
The current study provides an updated contempo-rary epidemiology of the microbiology of CIEDinfections requiring extraction. It is the largest reportto date on this topic and used multiple sources
for microorganism cultures including lead or leadmaterial, blood, pocket tissue, and pocket swabcultures. There were multiple observations withdirect implications for clinical practice and patientmanagement.
This topic is becoming increasingly relevant inclinical practice due to an increase in the number ofCIED implants but, most important, due to increase inCIED infections (2,3). In fact, the longevity of patientswith cardiac disease has increased and the number ofsystem revisions or upgrades that a patient wouldrequire in a lifetime will increase in parallel. The riskof a CIED infection, a time-dependent variable, wouldlikely follow a similar trend and the rates of CIEDinfections have indeed shown a disproportionatetrend to increasing CIED implants (2,3). CIEDinfections carry not only a significant risk ofmorbidity but a risk of death up to 66% if leftuntreated, and this is decreased to about 18% withantibiotics and extraction (1,12–14). The eradication ofinfection requires complete removal of the devicesand all lead material (1,12–14), with inherent risks tosurgical or transvenous extractions.
In our cohort, staphylococcal species accounted formost CIED infections, which is consistent withprevious reports (6,15–20), but the rates of coagulase-negative staphylococcal infections seemed to be morecommon in the European literature (21). Publisheddata (19) from the 1990s (the decade preceding theperiod covered by this study) reported coagulase-negative staphylococci in 42% of CIED infection,methicillin-sensitive Staphylococcus aureus in 25%,and methicillin-resistant Staphylococcus aureus in4%. Although the coagulase-negative rates weresomewhat similar to the prior decade, an importantobservation in our study is that 15% of CIED in-fections were related to methicillin-resistant Staphy-lococcus aureus, an alarming rate compared with theprior decade. Despite the lack of a trend in methicillinresistance over the period covered by this study, thecomparison to published data from the previousdecade (19) suggests an increase in methicillin resis-tance. Furthermore, 1 in 3 CIED infections was causedby a methicillin-resistant staphylococcal organism,and one-half of all staphylococcal infections weremethicillin resistant. Compared with the Europeanliterature (21) covering the same time period as thecurrent study, the overall rates of methicillin resis-tance were significantly higher in the current report,but there seemed to be an increasing trend in theEuropean report. Overall, these signals of increasingmethicillin-resistant organisms may reflect the com-mon inappropriate use of broad-spectrum antibioticsand suggest the acquisition of culprit organisms in
FIGURE 2 Trends in Microbiology in Cardiac Implantable Electronic Device Infections
Abbreviations as in Figure 1.
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health care environments in a significant proportionof patients, which has implications for empiricaltherapy. In general, culprit organisms in CIED in-fections may be acquired either from the patient’sown skin or exogeneously from the health care envi-ronment. An association has been reported betweenpre-axillary flora and the pathogens isolated fromCIED infections (17), which supports the theory ofendogenous acquisition. On the other hand, low-levelcolonization with methicillin-resistant species hasbeen reported in individuals with no recent healthcare contact or antibiotic exposure (22), but thedisproportionate frequency of drug-resistant staphy-lococci in CIED infections suggests that the healthcare environment is the source of acquisition of theseorganisms (23,24).
Nonstaphylococcal infections such as anaerobes,Gram-negative bacilli, Candida, and nontuberculousmycobacteria account only for a minority of CIED
infections (18,19,25–27). Clinicians need, however, toremain alert to the possibility of these infections dueto their serious clinical course if not managedappropriately.
In this study, an assessment of the trends in culpritmicro-organisms in CIED infections between 2000 and2011 showed mostly absence of significant trends inthe epidemiology of these pathogens. This suggeststhat the host factors, that is, changing epidemiology ofpatients receiving CIEDs or the type of devices beingimplanted (4,7–11), did not impact the epidemiology ofculprit organisms, but the findings suggest increasingmethicillin resistance compared with the priordecade, as discussed. Importantly, the proportions ofculture-negative CIED infections seemed to haveincreased over time, which could reflect the wide andsometimes inappropriate use of antibiotics. This trendis consistent with rates of culture negative endo-carditis of about 11% observed in Europe (21), which
TABLE 2 Microbiology of Early Versus Late Cardiac Implantable Electronic Device
Pocket or Endovascular Infections
Early Infection (%) Late Infection (%) p Value
Pocket infections, n 217 213
Bacterial type <0.001
Staphylococcus aureus 30.2 16.3
Coagulase-negative Staphylococcus 40.0 53.6
Enterococcus 0.5 0.0
Negative cultures 16.7 23.9
Others 12.6 6.2
Staphylococcal resistance 0.04
Methicillin resistant 29.8 34.4
Methicillin sensitive 40.5 35.4
Endovascular infections, n 115 213
Bacterial type 0.6
Staphylococcus aureus 51.7 44.5
Coagulase-negative Staphylococcus 27.6 26.1
Enterococcus 5.7 8.1
Negative cultures 3.4 7.1
Others 11.5 14.2
Staphylococcal resistance 0.6
Methicillin resistant 42.5 39.8
Methicillin sensitive 36.8 30.8
FIGURE 2 Continued
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highlight the importance of obtaining culture materialbefore the initiation of antibiotics, whenever possible.
Another observation in this study is that one-halfof CIED pocket infections occurred more than 1 yearafter device implantation or last pocket inter-vention. Importantly, coagulase-negative staphylo-cocci accounted for most early and late pocketinfections but were more likely to be observed in latepocket infections, accounting for more than one-halfof all late CIED pocket infections. It is very possiblethat these latent infections developed in an indolentfashion over time and were acquired at the time ofpocket manipulation. In contrast, Staphylococcusaureus was more likely to be culprit in early than lateCIED pocket infections, which highlights the moreaggressive nature of this pathogen.
For endovascular CIED infections, most of thoseseemed to have occurred more than 1 year after im-plantation or pocket manipulation. In contrast topocket infections, Staphylococcus aureus accountedfor most early and late endovascular CIED infections,and it seemed that methicillin resistance was more
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: The
study provides contemporary micorobiological profiles
of CIED infections showing primarily that staphylo-
coccal species account for most of these infections and
that the rates of culture-negative CIED infections have
increased over time. The study also shows that the
rates of methicillin resistance seemed to be higher
than those reported in the preceding decade. The
study provides important information for the clinical
management of CIED infections and highlights the
importance of proper use of antibiotics in CIED
infections.
TRANSLATIONAL OUTLOOK: The findings have
implications for clinical practice, primarily the use of
initial empirical therapy in CIED infections, and highlight
the importance of obtaining cultures before initiation of
antibiotics in suspected CIED infections. The findings
also suggest that a large proportion of CIED infections
are from organisms that are acquired in health care
environments and would indicate the importance of
preventive measures.
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common in endovascular versus pocket infections.This observation also highlights the likelihood ofacquisition in health care environments. Althoughthe original source of endovascular infections couldnot be identified with certainty in the current report,concomitant infections could be identified in 22% ofall endovascular infections, suggesting that clinicalinvestigation to identify concomitant infections is ofimportance to guide further management.
STUDY LIMITATIONS. A large proportion of patientswho undergo transvenous lead extraction for CIEDinfections at our institution are referred from othercenters across the United States. As such, the de-nominator of all implants is difficult to estimate, andthe study could not assess the specific incidence ratesof infection. Only patients who underwent extractionof their devices were included in this registry, and thestudy does not include patients with CIED infectionsin whom extraction was not performed due tocomorbidities or patient preference. Although mate-rial was sent for culture from multiple sources, thegenerators were generally not cultured and returnedto the manufacturers for quality testing. The pocketcapsules are generally excised in full and cultured inour practice, which minimizes the effect of absence ofgenerator cultures. Another caveat is that the dataincluded in this study included only infections ofdevices with leads as an endovascular component.The use of heart rhythm devices without endovas-cular components such as subcutaneous defibrillatorsor loop recorders is increasing in clinical practice, andthe microbiology of infections of these devices meritsinvestigation.
CONCLUSIONS
In a large population of patients with confirmed CIEDinfections undergoing lead extraction, staphylococcalspecies remain the most common pathogens in CIEDinfections, especially coagulase-negative species.One-third of CIED infections involve methicillin-resistant staphylococci, which are more likely to beacquired in health care environments. One-half ofall pocket infections occur more than 1 year afterpocket manipulation, and more than one-half ofthese late infections are related to coagulase-negative
staphylococci and are likely to have been acquired atthe time of the index pocket intervention. In contrast,most endovascular infections are related to Staphy-lococcus aureus. Over the course of 12 years, there didnot seem to be a temporal trend in the epidemiologyof culprit organisms, which suggests that the chang-ing epidemiology of host factors did not affect thedistribution of culprit pathogens over the years.However, the rates of methicillin resistance seemedto be higher than those reported in the precedingdecade, which raises concerns regarding the wide useof broad-spectrum antibiotics and likelihood ofacquisition in health care environments.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.Khaldoun G. Tarakji, Cardiac Pacing and Electrophys-iology, Department of Cardiovascular Medicine/J2-2,Cleveland Clinic Foundation, 9500 Euclid Avenue,Cleveland, Ohio 44195. E-mail: [email protected].
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KEY WORDS cardiac implantable electronicdevices, defibrillator, infection,microbiology, pacemaker, transvenous leadextraction
