Preventing cardiac implantable electronic device infections

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Preventing Cardiac Implantable Electronic Device Infections Gareth J. Padfield MBChB MRCP PhD, Christian Steinberg MD FRCPC PhD, Matthew T. Bennett MD FHRS, Santabhanu Chakrabarti MBBS MD FRCPC FRCPE FRCPCH(UK) FACC FHRS, Marc W. Deyell MD MSc FHRS, Jamil Bashir MD, FRCSC, Andrew D. Krahn MD FRCPC FHRS www.elsevier.com/locate/buildenv

PII: DOI: Reference:

S1547-5271(15)00881-4 http://dx.doi.org/10.1016/j.hrthm.2015.06.043 HRTHM6342

To appear in:

Heart Rhythm

Cite this article as: Gareth J. Padfield MBChB MRCP PhD, Christian Steinberg MD FRCPC PhD, Matthew T. Bennett MD FHRS, Santabhanu Chakrabarti MBBS MD FRCPC FRCPE FRCPCH(UK) FACC FHRS, Marc W. Deyell MD MSc FHRS, Jamil Bashir MD, FRCSC, Andrew D. Krahn MD FRCPC FHRS, Preventing Cardiac Implantable Electronic Device Infections, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2015.06.043 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Preventing Cardiac Implantable Electronic Device Infections

Prevention of cardiac device infection

Gareth J. Padfield MBChB MRCP PhD, Christian Steinberg MD FRCPC PhD, Matthew T. Bennett MD FHRS, Santabhanu Chakrabarti MBBS MD FRCPC FRCPE FRCPCH(UK) FACC FHRS Marc W. Deyell MD MSc FHRS, Jamil Bashir MD, FRCSC Andrew D. Krahn MD FRCPC FHRS.

Divisions of Cardiology and Cardiovascular Surgery University of British Columbia Vancouver Canada

The authors declare no conflicts of interest

Correspondence and requests for reprints: Andrew D. Krahn, MD, FRCPC, FHRS Professor of Medicine & Head UBC Division of Cardiology Gordon & Leslie Diamond Health Care Centre 2775 Laurel Street, 9th Floor Vancouver, BC Canada V5Z 1M9 (T): (604) 875-4111 Ext. 69821 (F): (604) 875-5504 – Academic (E): [email protected]

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Key words Cardiac implantable devices; Infection; Prevention; Antibiotics; Risk stratification Abbreviations CIED = Cardiac implantable electronic devices COPD = Chronic obstructive pulmonary disease CRT-D = Cardiac resynchronization therapy – defibrillator DRI = Device related infection ICD = Implantable cardioverter defibrillator IV = Intravenous NOAC = Novel oral anti-coagulants OR = Odds ratio PADIT = Prevention of arrhythmia device infection trial PPM = Permanent pacemaker RCT = Randomized controlled trial RR = Relative risk S-ICD = Sub-cutaneous ICD TPW = Temporary pacing wire WRAP-IT = World-wide Randomized Antibiotic Envelope Infection Prevention Trial

Abstract Cardiac implantable electronic devices (CIED) have dramatically improved clinical outcomes in patients with heart disease, and the number of CIED related procedures being performed continues to grow. Unfortunately the rate of device related infection (DRI) is increasing disproportionately to the rate of implantation, with DRI rates being over 2% in many series. This increase in DRI is as a consequence of an increased number of patients with a greater burden of comorbidities, who are more susceptible to infection undergoing more complex device procedures. Identification of high-risk patients is an important component of procedural planning, and targeted therapy and surveillance may be beneficial in certain groups. An understanding of the pathophysiology of DRI has facilitated more effective and widespread use of prophylactic antibiotics, however current guidelines for antibiotic prophylaxis are based on a relatively small evidence base. Clinical equipoise remains regarding the

2

optimal prophylactic regimen and we are continuing to learn how best to manage these patients. In this review we discuss the epidemiology and pathophysiology of DRI and its clinical presentation, the risk factors for DRI and the existing and emerging evidence to support strategies to prevent DRI.

Introduction There now exists a diverse range of cardiac implantable electronic devices (CIED) from

simple

diagnostic

implantable

loop

recorders

to

multisite

cardiac

resynchronization therapy - defibrillators (CRT-D) for the treatment and prevention of systolic heart failure and sudden cardiac death. Cardiac implantable electronic devices increase the longevity and quality of life in patients with heart disease,1 and the rate of CIED implantation continues to increase.2, 3 The increased rate of CIED implantation is largely due to the increased survival of patients with indications for implantable cardioverter defibrillators (ICD), and an expanding number of patients meeting eligibility for CRT, including patients with less severe forms of heart failure,4 and those in whom chronic right ventricular pacing should be avoided.5 As the rate and complexity of CIED implants increases, so too has the rate of device related infection (DRI), the most serious complication associated with CIED. Device related infection is life-threatening,6 and an understanding of the factors that confer the greatest risk of DRI and the best available means of prevention are of crucial importance in the management of patients with CIEDs. In this review we shall discuss the epidemiology and pathophysiology of DRI and its clinical presentation, with a focus on identifying risk factors for DRI and the evidence to support prophylactic antibiotic therapies and emerging trials in this area.

3

Definitions of device related infection Device related infections include infection of any component of the implanted system, ranging from superficial infections of the wound and subcutaneous tissues to infections directly involving prosthetic material manifesting as endovascular or endocardial infection. Unfortunately there are no standardized criteria for diagnosing a DRI and this continues to detract from the quality of data relating to DRI in general. A recent consensus document published in the UK proposed a classification to site and severity of infection (Table 1).7 Unfortunately no specific criteria can wholly encompass the clinical nuances that frequently complicate the diagnosis of DRI, however widespread adoption of standardized criteria should improve our ability to understand the condition.

Epidemiology The number of CIED implant procedures is increasing. An analysis of Medicare beneficiaries in the U.S. found a 10-fold increase in ICD-implants between 1987 and 1995, and a 42% increase between 1990 and 1999.2 Subsequent analyses indicate that the rate of device implantation continues to increase by 10% per year.3 Though most large contemporary analyses have reported infection rates of between 1.5 - 2.5% depending on the patient risk profile (Table 2), there is considerable variability in reported rates of DRI, ranging from close to zero,8 to as high as 20%.9 Unfortunately several studies have demonstrated that the rate of DRI is steadily increasing.2, 10-12 For instance, in an analysis of Medicare beneficiaries, DRI increased by 124%, from 0.94 per 1,000 in 1990 to 2.11 per 1,000 beneficiaries in 1999.2 The US National Hospital Discharge Survey from 1996 to 2003 demonstrates an approximate 0.5-fold % increase in CIED implants yet a 3.1-fold increase in the rate of DRI (2.8-fold for PPM

4

and 6-fold for ICD). In a recent review of over 4 million new and replacement PPM and ICD, in which the overall risk of infection was 1.61%, the incidence of DRI was fairly constant between 1993 and 2004, but subsequently increased from 1.53% to 2.41% in 2008.12 Unfortunately the rate of DRI in general is actually increasing disproportionately to the increase in the rate of CIED implantation,11, 12 however in another large device registry of over 40,000 recipients of permanent pacemakers (PPM), the rate of DRI has remained relatively static over the last 15 years at around 0.8%.13 It is likely therefore that the increase in DRI is more likely to be due to changes in the type of patients selected for CIED implant, as a result of both increased survival of patients with heart disease and the expanding indications for ICD and CRT.14-17 The net result is older, sicker patients undergoing more frequent and higher risk procedures, including an increased number of generator changes. There are also more patients undergoing device implantation at a younger age, meaning an increased number of procedures over the course of the patient’s lifetime.13, 18, 19 This has serious economic implications with standardized adjusted incremental and total admission costs associated with infection estimated to be between $14,360 to $16,498 and $28,676 to $53,349, respectively, depending on CIED type.6

Pathophysiology and Microbiology The vast majority of DRI is caused by gram-positive staphylococci, predominantly Staphylococcus aureus, which accounts for 60–80% of cases, with coagulase-negative strains of staphylococci causing an important minority of DRI.10, 20-23 Gram-positive bacilli (Pseudomonas, Corynebacterium and Proprionibacterium species)20 and fungi (mainly Candida species) are infrequently isolated as the cause of infection. Microbial contamination most frequently occurs via the skin during surgical manipulation, but

5

seeding of the device may occur by hematogeneous spread. Biofilm formation is a key process in bacterial colonization and resistance to antimicrobials, particularly with staphylococcal species.7 Devices are susceptible to pathogen colonization, especially when there is an exposed plastic surface.24 Designing devices to minimize the extent of exposed polyurethane surfaces of CIED may reduce the likelihood of clinical infection.25 Similarly the impregnation of CIED with bactericidal drugs during manufacture may also confer protection against DRI,26 although clinical trials testing such adaptations have not been performed to date. Microbial culture is of crucial importance in the diagnosis and treatment of DRI. Sub-clinical infection often goes unrecognized, particularly when caused by more indolent organisms or in patients with a diminished inflammatory response. Analyses of the CIED pocket tissue and peripheral blood of entirely asymptomatic CIED patients has demonstrated the presence of pathogenic bacterial flora.27-29 Whether such cases represent true infection or simple colonization is unknown. There is increased diversity of bacterial flora and activation of inflammatory signaling in CIED patients compared to healthy controls,27 and the presence of such organisms may explain the development of infections remote from device manipulation or other forms of bacterial inoculation.

Clinical Presentation

6

Symptoms Early recognition of DRI allows earlier treatment, which may improve clinical outcome. Understanding of the modes of presentation with DRI is important for all healthcare professionals caring for patients with CIEDs. Device related infection most frequently presents with signs of inflammation localized to the pocket (69%), and less frequenly

with

a

pocket

infection

accompanied

by

additional

systemic

symptoms/signs such as malaise, anorexia, nausea and fever (20%). Occasionally systemic symptoms will occur in the absence of signs of pocket infection (11%).30-32 Importantly device related infection is frequently latent with no obvious symptoms at all. Post-operative fever within the first 24 hours of an implant is a particularly important sign that DRI may have occurred,33 although this is highly variable (2978% of DRI cases). Not infrequently DRI will present with frank pocket erosion and exposure of the generator itself, however signs may be subtler than this, and adherence of the overlying skin to the tissues surrounding the device may be the only sign of DRI (Figure 1). Such an appearance should always prompt further investigation and intensified observation, preferably by a cardiac device specialist. Blood accumulation in the pocket can be intensely inflammatory, and distinguishing between infection and hematoma may be difficult. Purely mechanical factors relating to the size and position of the device may cause device erosion in a minority of cases, however distinguishing between these and truly infected devices is difficult. Pocket breakdown generally equates to co-existent infection and should be treated as such with extraction of the device where it is safe to do so. 34

Timing of presentation

7

Most DRI occurs within months post-procedure (median 52 days), although there is marked variability and presentation frequently occurs later.30-33, 35 For instance Sohail et al., observed a median time from implantation to infection of 425 and 125 days for PPMs and ICDs respectively.20 In a Dutch registry of patients undergoing device procedures, 28% had an early infection (<1 month), 35% a late infection (1-12 months) and 37% a delayed infection (>12 months). Very delayed infection (>24 months) occurred in 24% of patients presenting with a DRI.36 Presentation DRI in the first year are more likely to be characterised by typical signs of pocket inflammation, whereas those who present later more frequently exhibit device erosion and endocarditis. Positive cultures are detected in 81-93% of patients with DRI

30, 31

with

the highest yield with tissue biopsy in pocket infection, or lead cultures with lead infection (63-93%), in contrast to blood cultures (51%-68%).31,

37-39

Generally

speaking less virulent organisms such as Staph. Epidermidis are associated with later infection, whereas more virulent species such as Staph. Aureus present early with more overt signs of infection, however the timing of manifest infection can be highly variable.36, 40, 41

Identifying patients at risk of developing device related infections Several risk factors for the development of DRI have been identified (Table 3). An understanding of these risk factors can aid prevention and the early detection and treatment of DRI in high-risk groups.

Patient related factors

8

Most patient-related risk factors for DRI relate to co-morbidities that confer a relative state of immunosuppression, and generally predispose to increased morbidity and mortality.42 These include such conditions as renal dysfunction,36, 43-45 heart failure,43, 45 49

diabetes mellitus,36, 43, 45, 46 chronic obstructive airways disease,47, 48 malignancy,22, a history of DRI, both advancing age43,

corticosteroid use

22

50

and younger age,13 long term

and the presence of indwelling catheters.

50, 51

Patient at risk of

bleeding such as those treated with anti-coagulants are at particularly increased risk of DRI.36, 44

Renal dysfunction - Patients with renal dysfunction are particularly prone to DRI, 43-45

36,

and tend to be more severely affected with higher rates of septicaemia,

endovascular vegetation, and mortality.42,

52

In a nested case-control study of 75

patients with DRI derived from a cohort of 3410 patients (2.2% rate of infection), renal dysfunction was associated with an increase in the rate of infection [OR=4.64 (1.48 to 14.62); p=0.04], with every increase in serum creatinine of just 0.11 mg/dL being associated with a 25% relative increase in the risk of DRI.36 Similarly, in a large cohort of patients (n=4,856) undergoing device procedures, an elevated creatinine was predictive of DRI [OR=4.8 (2.1-10.7); p<0.001], and the risk of infection increased in association with the severity of renal disease.43 Patients undergoing CRT with renal dysfunction requiring dialysis are at markedly increased risk of infection [HR=13.39 (2.73–65.62); p=0.0001].44

Heart Failure - Patients with heart failure are similarly at increased risk of developing DRI, and this is becoming increasingly more relevant as the rate of device implantation (namely CRT) in this patient population increases. In the study discussed

9

above by Bloom, et al, of 4856 patients undergoing device procedures, DRI was associated with heart failure [OR=2.35 (1.2–4.4]; p=0.009).43 More recently Mittal et al., observed an even greater risk of DRI associated with heart failure in a cohort of 1651 patients [OR=3.16 (1.39-7.19; p=0.004]. In a study looking specifically at patients with heart failure undergoing CRT implants the DRI rate was 4.3% (1.7%/year incidence), 30% of which were complicated by endocarditis.44

Diabetes Mellitus - Diabetes is a frequent co-morbid factor with both renal dysfunction and heart failure yet also carries a strong, independent association with DRI.36, 43, 53 Mittal, et al. observed 44% and 27% prevalence of diabetes in those with and without DRI respectively (OR=2.18 (0.98-4.84; p=0.05),

45

and in Bloom et al.’s

study 42% and 14% (OR=3.22 (1.5-6.7); p=0.001).43 In another study of 157 patients undergoing epicardial ICD procedures and sternotomy, diabetes was the only predictor of DRI (OR=13.94 (3.05-63.74; p<0.001).46 Control of hyperglycemia is an important therapeutic goal in the perioperative period.53

Other risk factors - Advancing age increases the risk of DRI,43,

50

however

interestingly in one of the largest studies examining risk factors for DRI which included over 40,000 patients, younger patients were actually those most at risk of developing DRI.13 It is likely that this discrepancy is due to competing risk factors associated with the extremes of age. Although older patients are more likely to suffer from co-morbidities that a confer a relative state of immunosuppression and an increased risk of DRI, younger patients are more likely to out-live their generators and develop complications such as lead fracture, and are therefore more likely to have to undergo multiple procedures increasing the risk of DRI. Long-term use of

10

corticosteroids confers a state of immunosuppression, impairs wound healing and thins the skin, and substantially increases the risk of DRI.22 Chronic obstructive airways disease has also been related to an increased risk of device infection, likely as a result of immunosuppression through disease activity and concomitant steroid use.47, 48

Immunosuppression related to the human immunodeficiency virus and other

immunosuppressant drugs are also likely to be important determinants of DRI. Interestingly male gender has been identified as a risk factor for DRI,43, 45 although DRI occurring in women is associated with increased mortality.54 The reasons for these observations are unclear though may relate to higher rates of co-morbidity in men, and differing patterns of presentation and rapidity of treatment occurring in men and women. Trauma to the pacemaker site has also been identified as a risk factor, presumably through the introduction of bacteria and hematoma formation, and patients should be warned of this potential complication. Mittal et al., identified seven independent predictors for infection: early pocket re-exploration; male sex; diabetes; upgrade procedure; heart failure; hypertension; and glomerular filtration rate <60 mL/min, and created a weight adjusted composite risk score to identify low risk (score 0-7; 1% infection), medium risk (score 8-14; 3.4% infection), and high risk (score ≥15; 11.1% infection) patients. This scoring system was used to identify patients likely to benefit from the use of an antibiotic impregnated device (see below) however the potential value of routine application of this scoring system in clinical practice has yet to be determined.

Procedural related factors

11

Post-operative hematoma formation is a major risk factor for DRI.36, 44, 55, 56 This is particularly important as several precautions can be taken to reduce the peri-operative bleeding risk. Anticoagulants are associated with an increased risk of DRI,36, 43 and a balance must therefore be struck between the risk of peri-operative bleeding and that of thrombo-embolic events. In a recent meta-analysis of trials including nearly 6000 patients undergoing device surgery, the combined incidence of bleeding complications was 4.6%, ranging from 2.2% on no therapy; 2.5% for patients on interrupted anticoagulant therapy; 2.8% for uninterrupted anti-coagulants 3.9% for mono anti-platelet therapy, 9.4% for dual anti-platelet therapy to as much as 14.6% associated with a heparin bridging strategy. The recent BRUISE CONTROL trial randomized patients at a relatively high risk of stroke treated with warfarin undergoing cardiac device surgery to uninterrupted warfarin or to heparin bridging,57 and demonstrated that a heparin bridging strategy is associated with a significantly increased risk of clinically significant pocket hematoma (16% versus 3.5%; p<0.001). Device related infections were not reduced in the uninterrupted warfarin arm, however as pocket hematoma is such a powerful predictor of infection it is likely that avoiding heparin bridging will be advantageous with respect to DRI. It is still unclear as to how best manage peri-operative novel oral anti-coagulant (NOAC) drugs in order to balance the risk of hematoma formation and peri-procedural thromboembolic events in patients undergoing CIED surgery. A recent survey of Canadian centers indicates significant variation in practice with approximately 80% of centers discontinuing NOACs prior to device surgery. Heparin bridging was avoided in 70% of centres.58 In this study the rate of bleeding was highly variable (0-30%), although in a small study of patients undergoing device surgery on uninterrupted NOAC therapy the rate of bleeding events was reassuringly low at around 2.5%.59 The

12

BRUISECONTROL 2 trial will assess the safety and efficacy of interrupted versus uninterrupted Dabigatran in patients undergoing device surgery. Similarly dual antiplatelet therapy significantly increases the rate of bleeding complications following device surgery and if the procedure can be safely delayed until dual antiplatelet therapy can be discontinued this is preferable.

Procedural complexity is associated with the development of DRI. Even the addition of a second lead is associated with a substantial increase in the risk of infection. In a cohort of 2019 patients Chauhan et al., observed an infection rate of 0.6% versus 2.1% in patients with single versus dual chamber devices [OR=3.36 (1.23-9.15); p=0.031],60 possibly due to an increased reoperation rate for dislodgement of the atrial lead (5.2% versus 1.0%). These findings were mirrored in similar retrospective trials by Raand et al. [OR=5.5 (1.73-17.47); p=0.002], and Neary et al., [OR=3.21 (1.198.70); p=0.018],35 and Sohail et al., similarly demonstrated that the risk of infection is significantly higher if more than 2 leads are implanted [OR=5.41 (1.44-20.29); p=0.01].22 In another cohort of 2891 patients Mittal et al., observed an infection rate of 1.2% in patients implanted with an ICD compared to 3.5% in patients with a CRTD. Additional leads may be a surrogate indicator for increased patient morbidity and procedure time, although additional leads may precipitate increased intra-vascular thrombosis and provide a greater nidus for infection. In patients who require a defibrillator for prevention of SCD but do not have bradycardia or a requirement for anti-tachycardia pacing, the subcutaneous ICD (S-ICD) offers potential advantages by avoiding the need for intravascular components. The S-ICD has performed well in large multi-center registries,61,

62

though it still requires head to head comparisons

with traditional transvenous ICDs in clinical trials. Whether an S-ICD reduces DRI

13

per se is unknown however the process of extraction is simplified if DRI occurs. A recent registry reported an infection rate associated with the S-ICD of approximately 5.6%, with only a 1.2% rate of system extraction, and in another 4% and 2.2% respectively.61 Careful case planning may simplify a device procedure by rationalizing the indication for device therapy and relative benefits of each tier of device complexity.

Re-operation probably confers the greatest risk of DRI, and this has been observed consistently in multiple studies.13, 35, 43-45, 50, 56, 63, 64 The risk is particularly high if reoperations are performed following a very recent device procedure.33,

44, 56, 63

In a

large prospective study of 6000 patients implanted with a PPM or an ICD followed over 1 year (overall infection rate 0.68%), de-novo implants were associated with approximately half the risk of DRI than repeat procedures or generator changes [adjusted OR=0.46 (0.24-0.87); p=0.02]. However, if a revision was performed during the same admission as a previous device procedure the risk of DRI increased 15-fold [adjusted OR=15.04 (6.70-33.73); p<10-4].33 In a recent retrospective review of patients undergoing CIED extraction for infection, 5.4% of patients required a second CIED extraction due to infection, with 3.9% occurring within the 1st year of reimplantation. Therefore if repeat interventions can be deferred (or avoided completely) this is preferable, however the optimal timing has not been defined. An assessment of clinical stability and the urgency of re-operation should allow the most appropriate strategy for a given individual.

Pre-operative fever is a significant risk factor for DRI [OR=5.83 (2.00-16.98); p<0.001],33 supporting the notion that if patients have active or suspected infection

14

device related procedures should be deferred until infection has fully resolved or been excluded. If necessary alternative chronotropic support should be provided, however the use of a temporary pacemaker wire (TPW) is also associated with a significant increase in the rate of infection [2.46 (1.09-5.13); p<0.001].33 In Chauhan et al’s, series nearly half of the patients with a DRI had a TPW in place compared to 14.6% in those without an infection [OR= 5.21 (1.99-13.60); p=0.002)]. Insertion of a TPW should therefore be avoided unless there exists life-threatening bradycardia unresponsive to pharmacologic intervention, or there is a high risk of bradycardia occurring that cannot be treated safely. Isoprenaline or adrenaline may also be used to provide pharmacological chronotropic support in most circumstances and this may avoid the use of a TPW. Although unsupported by good evidence, a ‘temporarypermanent’ system may be an option if acute pacing is required in the context of significant infection.65 Here an active fixation lead can be tunneled a short distance from the internal jugular and attached to a permanent generator fixed to the skin with an iodine impregnated adhesive dressing. If a TPW is in-situ the risk of DRI increases substantially with time and antibiotic therapy should be initiated and a permanent system implanted as soon as possible following placement of a TPW.

Operative considerations

15

Attention should be given to the available resources and infrastructure of the implanting institution. Although robust data supporting specific practice in this aspect of CIED implantation are sparse, appropriate facilities are crucial. Operating rooms should be equipped with positive pressure ventilation, preferably in a dedicated device lab.66 Operator training and experiential volume influence the rate of DRI, as illustrated by an analysis of Medicare data where increased rates of DRI were associated with a lack of procedural experience [OR=2.47 (1.18 to 5.17); p=0.01 for <11 devices per year versus >29 per year].67 Similarly, Mounsey et al, observed that an experiential volume of <100 cases was associated with an increased risk of DRI [OR=3.76 (1.21-11.64); p=0.01].63 Assisting nursing and technical staff should also have a thorough understanding of aseptic technique and the steps involved in the procedure.

Hair removal may increase the risk of local infection and should be avoided unless the hair will interfere with the procedure.68 If necessary clipping is preferable to shaving.69 Although pre-operative showering or bathing to decolonize the skin is common practice specifically bathing in antiseptic solution did not appear to confer significant benefit in a recent systematic review. However, in a recent and wellconducted study, surgical site infections were significantly reduced in carriers of Staph. aureus undergoing non-device related surgical procedures by performing a total body wash using chlorhexidine in combination with nasal mupirocin administration [7.2% versus 3.4%; RR=0.42 (0.23-0.75)].70 The use of prophylactic antibiotic therapy does carry an increased risk of anti-bacterial resistance in the general population,71 and targeted therapy in high-risk populations is appealing. The increased costs associated with this method need to be considered and whether this

16

approach is applicable to the CIED population also remains unknown and invites further study. Skin cleansing with anti-septic chlorhexidine-alcohol has proven superiority over povidone–iodine scrub in the prevention of surgical site,72 and vascular catheter-related infections,73 and by extrapolation is the preferred means of decontaminating the surgical site and the operator’s hands with regards to CIED implantation. The Comparison of Chlorhexidine and Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation (CHLOVIS) study aims to answer whether one of these treatments has superiority in device related procedures using a high risk population undergoing CRT implant.74 Careful skin disinfection substantially reduces the skin normal flora though does not eradicate it completely.75 The application of an adhesive drape (with or without iodine impregnation) has theoretical benefits in reducing DRI by minimizing the potential for the skin to touch anything that subsequently enters the open wound. They are also useful in maintaining the integrity of the surgical field. There are however no available data to support this practice. A systematic review of seven studies including over 4000 non-CIED procedures actually suggested an increased risk of surgical infection when adhesive drapes were used though whether this truly reflects causation and the relevance to CIED procedures is unclear.76

As with any operative procedure, strict aseptic technique with comprehensive draping of the patient and image intensifier should be employed, with fastidious attention paid to maintaining the sterile field throughout the procedure. All items should remain in their sterile containers until they are ready to be used in order to minimize the opportunity for bacterial colonization. Procedure duration is an important determinant of DRI

50, 77

and the procedure should be performed as swiftly as the limits of safety

17

will allow. A sub-pectoral implant should be considered if there is very little subcutaneous tissue as infection rate will be higher in these cases.78 Although infrequent, an abdominal implant will on occasion be indicated and it should be recognized that these confer a higher risk than standard pre-pectoral implants (0.5% versus 3.2%). Every effort should be made to avoid post-operative hematoma formation,36, 44, 55, 56 and meticulous attention to hemostasis is essential. Hemostasis is readily achieved by the use of diathermy and hemostatic sutures though there are no data to specifically support that this practice reduces infection. Topical fibrin sealants reduce hematoma formation in anti-coagulated patients undergoing device procedures, but their effect on DRI is unknown.79 Cephalic cut down has theoretical advantages in reducing post-operative bleeding by avoiding inadvertent arterial puncture.80 In the event of failed cephalic access or when additional venous access is required ultrasound guided vascular access may also reduce the risk of arterial puncture.81 Excision of redundant pocket tissue at device revision, namely scar tissue and the ‘capsule’ that surrounds the explanted CIED, may be beneficial as they are avascular, and may increase susceptibility to bacterial overgrowth. On this basis some operators advocate for routine capsulectomy and scar reduction at elective generator replacement. A recently published study however reported no difference in infectious complications (1.5% vs. 4.7%, p=0.13) associated with routine pocket revision, despite a significant increase in hematoma formation (6.1% vs. 0.8%, p=0.03).82 The trial was however relatively small (n=258). Another prospective trial addressing the merits of routine capsulectomy is currently underway.83

Elasticated pressure dressings are not proven to reduce hematoma formation

18

following device surgery however there are data that support the use of pressure dressings in patients undergoing breast surgery/lymph node clearance.84 As early wound exploration markedly increases the risk of DRI,33,

44, 56, 63

the temptation to

evacuate a hematoma should be resisted unless skin tension compromises tissue healing. Similarly needle aspiration should not be performed as it does not provide effective evacuation, and may introduce bacteria into the pocket.

Peri-operative antibiotic prophylaxis Multiple non-randomised retrospective studies have demonstrated that the use of perioperative antibiotics is associated with reduced rates of DRI.22, 33, 50 The most robust evidence supporting the use of antibiotic prophylaxis of DRI comes from a prospective double blind randomised placebo controlled trial conducted in 2009 by De Oliveira et al., in which patients undergoing CIED implantation were randomised to receive 1g of intravenous cefazolin immediately before the procedure. Pre procedural antibiotics successfully reduced the incidence of local pocket and procedure related systemic infection from 3.28% to 0.63% (p=0.016) leading to early trial discontinuation.55 There have been several other smaller prospective randomized trials examining peri-operative antibiotic prophylaxis of DRI and two meta-analyses have been published (Table 4).85, 86 Da Costa et al., identified seven randomised trials 63, 87-93

comprised of 2,023 patients undergoing new pacemaker implantation. The

incidence of infection without antibiotics was 3.7% in 1,011 control patients, and 0.5% in 1,012 antibiotic treated patients with a common odds ratio of 0.26 (0.10-0.66; p=0.005).85 In a subsequent meta-analysis86 including six studies (n=1766) designed to address the efficacy of peri-operative intravenous antibiotics versus placebo, 88, 89, 91, 94

55, 63,

intravenous antibiotics plus antiseptics delivered 1 hour before device

19

implant significantly reduced the incidence of DRI compared with no antibiotics [pooled RR=0.13 (0.05-0.36); p<0.00001). Whilst there are robust data to support the use of pre-operative antibiotics in CIED implant, there are few data regarding timing of administration, the need for post-operative antibiotics and local pocket antibiotics. In a meta-analysis by Darouiche, pre-operative prophylaxis was superior to postoperative antibiotics (RR=0.14 (0.03-0.60); p=0.008), however there are no trials that have been designed to formally address this question. The necessary duration of treatment is also poorly established. Although prolonged courses of antibiotics may be useful in DRI in certain circumstances, a study by Dwivedi et al., found no difference in the rate of DRI following 1 week of post-operative antibiotics compared to two days.95

The optimal route of administration is also unknown. In their meta-analysis Darouiche et al., examined two studies comparing systemic versus intra-operative local antibiotics and found them to be equally effective.93, 95 Chaudhry et al., found there to be little additive benefit of local antibiotics on top of systemic antibiotics, and conversely Ramsdale et al., found no benefit of systemic antibiotics in addition to local antibiotics. The route of administration may therefore be of lesser importance in the prevention of DRI provided that pocket concentrations of antibiotic are sufficient. Pocket irrigation with povidone-iodine however did not have a significant effect on DRI in a small study.96 Irrigation of the pocket with saline probably reduces the bacterial concentration, though there is no evidence to indicate that it reduces DRI.

Choice of antibiotic

20

A high proportion of DRI is caused by Methicillin sensitive staphylococcal species,20 and a

β-Lactam antibiotic such as oxacillin and its derivatives or a cephalosporin are

often the preferred choice of antibiotic. Current guidelines recommend a firstgeneration cephalosporin, such as cefazolin 1 hour prior to the procedure.97 However, significant geographical variation in bacterial antibiotic resistance exists, and hospital based protocols for the prevention of infection need to be established in close liaison with a Microbiologist. For example in a study of over 50,000 isolates from 495 hospitals in 26 European countries, methicillin resistant Staphylococcus aureus prevalence varied from 1% - >40%. Methicillin resistance amongst staphylococcal species is becoming increasingly problematic. In a recent study of 286 patients with CIED infection, of which 86% were caused by staphylococcal species (90% coagulase negative) 30.5% were methicillin-resistant though all of these strains were susceptible to vancomycin.98 Vancomycin is recommended for patients undergoing CIED surgery with a known history of MRSA colonisation or infection and is also a useful alternative in patients who are allergic to cephalosporins or penicillin.97 Some advocate the use of vancomycin in addition to a

β-Lactam antibiotic as this provides

broad gram-positive and some gram-negative cover, whilst providing maximum efficacy against both methicillin sensitive and resistant organisms.99 The routine use of vancomycin however is likely to contribute to the emergence of resistant bacteria, and given the considerable variation in the prevalence of MRSA, a more targeted approach in high-risk populations may be prudent. There are several other antimicrobial agents that have utility in the treatment of infective endocarditis, though are not generally used as prophylactic antibiotics. Daptomycin has generally excellent activity against Staph aureus with low rates of resistance with good penetrance into biofilm.100, 101 Daptomycin is approved in the treatment of right-sided endocarditis,102

21

and although there is relatively little data on its efficacy in DRI it is a reasonable 2nd or 3rd line agent in this setting. Although exhibiting less activity in the presence of a biofilm, clindamycin and linezolid are also reasonable second or third line options in the treatment of endocarditis.7,

103

Teicoplanin has similarly broad activity against

gram-positive organisms, and also has the advantage of a once a day dosing regimen. In the uncommon circumstance where first line antibiotics are not suitable, these agents may be of use in the prevention of DRI, though clinical evidence is lacking to support routine administration for prophylaxis.

Timing of antibiotic therapy Appropriate timing of antibiotic administration is crucial in order to achieve a bactericidal concentration of antibiotic in the tissues during the procedure. The lag time between administration of antibiotic and peak tissue concentration will vary between antibiotics, and is also affected by the presence of foreign bodies (CIEDs), scar tissue, the pH of the tissue concerned, and the vasoconstrictive effect of surgery itself. Delay in the administration of antibiotics may lead to insufficient protection against DRI, and pre-operative antibiotics should therefore be given sufficiently early prior to the procedure. Regarding the most widely used and generally recommended antibiotics, Cefazolin, has a half-life of 1.6 hours and Vancomycin has a half-life of 612 hours and both reach peak tissue concentrations between 30-60 minutes following infusion.104,

105

Vancomycin requires a slower rate of infusion (1g/hr) to prevent

systemic vasodilatation and erythema. Intravenous antibiotics should therefore be administered 1-2 hours prior to surgery.97

The PADIT study

22

Although peri-operative antibiotic prophylaxis is widely employed, most studies have been small and conclusions have been drawn on the basis of association rather than causation. Clinical equipoise remains regarding the optimal combination of agents, the need for post-operative therapy, and the value of topical prophylaxis.99 The ongoing Prevention of Arrhythmia Device Infection Trial (PADIT) is using a cluster crossover randomized trial design to test the hypothesis that antimicrobial prophylaxis suggested by current guidelines 1, 7, 97 provide insufficient protection against DRI, and that the incremental use of properly selected antimicrobials surrounding the procedure will substantially reduce the risk of infection.99 Using a primary endpoint of hospitalization for DRI, PADIT will test the efficacy of multifaceted approach to antibiotic prophylaxis comprised of; 1) combination therapy with intravenous vancomycin and cefazolin preoperatively in order to ensure adequate coverage of virtually all gram-positive bacteria, including ß-lactam-resistant cocci; 2) a topical antimicrobial wash of the device pocket prior to skin closure with bacitracin (in order to minimise bacterial concentration within the pocket); and 3) a 2 day course of postoperative oral cephalosporin or clindamycin. Although all three components of this regimen are used globally, few centres employ all three consistently.99 PADIT is not designed to inform on the individual merits of each component of the prophylactic regimen, though aims to identify shortcomings in current practice. PADIT aims to focus on high-risk patients, namely those undergoing generator replacement surgery, system/lead revision or CRT device implantation/upgrade. Important secondary outcomes will examine the potential adverse effects of increased antibiotic use by monitoring antibiotic-related adverse events including C. difficile infection and any other hospitalization due to adverse events from antibiotic therapy. PADIT will also include a cost benefit analysis.

23

Novel topical antibiotic delivery The Tyrx® minocycline and rifampicin-eluting antibacterial envelope from Medtronic, is polypropylene mesh coated with an antibacterial infiltrated polyacrylate bio-resorbable polymer, designed to contain a CIED within the surgical pocket. The envelope has demonstrated efficacy in pre-clinical studies and has also shown promise in recent non-randomised registries.45,

106, 107

Mittal et al., observed an

infection rate of 0.6% in a cohort of 1240 patients undergoing CIED implantation using the envelope compared to 1.5% rate in 1651 matched historical controls. In a non-randomised registry the infection rate was 0.4% in 260 patients, compared to 3% in a matched control population of 639 patients undergoing a CIED procedure without the mesh,106 and in the multi-centre retrospective COMMAND registry, the short-term infection rate was 0.5% of 621 patients.107 These results are encouraging, however the efficacy of the envelope still requires rigorous assessment in a randomized trial. The World-wide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT), is a phase IV randomized, prospective, multi-center, single blinded, post-market, interventional clinical study that aims to recruit over 6000 patients and is designed to evaluate the effect of the envelope on rates of major DRI in high risk patients (generator replacement, device upgrade or revision, or de-novo CRT-D implant).108 Hydrogen peroxide has known bactericidal properties, however its use to prevent DRI remains untested in formal trials. An intra-pocket hydrogen peroxide impregnated gauze is currently being tested in clinical trials.83

Conclusions

24

The rate of DRI has increased disproportionately to an increased rate of CIED implantation, predominantly as a result of higher-risk patients undergoing device surgeries of increasing complexity. Several risk factors for DRI have been identified, and interventions to reduce DRI may be employed at all stages of care of CIED patients, from patient selection to peri-operative management and follow-up (Figure 2). Our methods of preventing DRI however still require refinement, particularly in high-risk patient populations. Intensified antibiotic therapy in these patients may positively impact on clinical outcomes and novel adjuvant therapies aimed at delivering high concentrations of antibiotic to the pocket show promise in early studies. A greater awareness of the magnitude of this clinical problem is a key component in improving the care of patients with CIED.

Figure Legends Figure 1. Examples of device related pocket infection displaying a range of abnormal appearances. Upper left - subtle skin changes associated with underlying infection including thinning and mild discoloration; Upper middle – erythema and swelling of an infected pocket; Upper right; skin erythema with central region of necrosis; Lower left - suppurative infection with erythema and thinning of skin along line of tension with device erosion and protrusion; Lower middle - pocket infection with granulation tissue surrounding a central communicating sinus; Lower right - En-bloc dissection of infected device performed to ensure eradication of infected tissue. Figure 2. Summary of interventions to minimize the risk of device related infection.

25

Table 1 Classification

Description

Post-operative

Presentation within 30 days of operation with wound

wound inflammation

inflammation or ‘stitch abscess’ occurring in the absence of definite evidence of infection and not necessarily requiring antimicrobial therapy.

Uncomplicated

Cellulitis confined to the generator site including purulent

generator infection

discharge; abscess or fistula formation; device erosion in the absence of systemic involvement

Complicated

Generator infection plus involvement of any part of the lead

generator infection

or development of systemic involvement.*

Lead infection

Symptoms and signs systemic involvement* in the presence of suggestive echo findings. Definite infection requires the presence of major Duke criteria.109 Possible lead infection also includes systemic signs/symptoms and major Duke criteria but no supporting echo evidence.**

Table 1: Summary of diagnostic classification of cardiac device related infection proposed by the joint working party of the British Society for Antimicrobial Chemotherapy, British Heart Rhythm Society, British Cardiovascular Society, British Heart Valve Society and British Society for Echocardiography.7 *Systemic involvement defined as the presence of positive blood cultures or systemic symptoms/signs consistent with infection. **Pulmonary emboli are considered supportive evidence of lead infection in the absence of definite evidence of infection.

Table 2 Year Author 1994 1994 1998 1998 2001 2006 2007 2007 2009 2009 2009 2010 2010 2010

60

Chauhan Mounsey63 Smith110 Spinler46 Mela111 Bloom43 Sohail22 Klug33 Lekkerkerker 36 de Oliveira55 Margey112 Nery35 Romeyer-Bouchard44 Cengiz50

Study design Case control Open, RCT Case control Case control Case control Case control Nested case control Case control Case control Blinded RPCT Case control Nested case control Case control Case control

Study size

DRI rate

2019 656 1821 202 1700 4856 12770 (58) 6319 3410 649 3105 2417 (75) 290 833

0.8% 2% 1.2% 4.5% 1.7% 1.5% 0.2% 0.6% 2.2% 2% 1.26% 0.99% 4.48% 6.84%

26

2010 2012 2014

Johansen13 Raad56 Mittal45

Case control Nested case control Case control

46299 NR (53) 1651

0.70% NA 1.51%

Table 2: Study design, size and infection rates in studies of DRI. For nested case controls the number of controls used for comparison are presented in parentheses. NA = Not applicable; NR = Not reported; R(P) CT = randomized (placebo) controlled trial.

Table 3 Risk factor

Odds Ratios

References

2.3-2.5 1.6 1.6-14.6 13.9 2.0-9.0# 2.8 2.4-3.2 2.2-11.6 2.6-4.8 (17.1) 5.8 NR 2.5-5.2 2.8 NR

43, 50

Patient related factors Age (>60) Age (<60) Male Steroids COPD Anticoagulants Congestive cardiac failure Diabetes Renal dysfunction (dialysis) Pre-operative fever Prior infection Temporary pacing wire Vascular catheter Wound trauma Procedure related factors Antibiotics De-novo implant Device revision Early device revision Additional leads CRT Abdominal implant Defibrillator patch Hematoma Operator experience Procedure time

0.1-0.6 0.3-0.5 2.2-11.5 15-16.6 1.3 - 5.5 4.3 - 7.6 6.3 3.1 4.7-15.1 2.47*-3.8** NR†

13 13, 43, 45 43 47, 48 36, 43 56

,

22, 35, 36, 43, 45, 46 36, 43, 44 33, 113 33 33, 60 50 50

13, 22, 43, 45, 50, 55, 63 13, 22, 43 22, 33, 35, 36, 43, 44, 46, 50, 55, 110, 113 33, 44, 56, 63 13, 22, 35, 56, 60 45, 112 112 111 44, 55, 56, 111 63, 67 44, 63

Table 3: Risk factors for device related infection. Uni-variate risk factor analysis from a variety of studies. Odds ratios reflect range of point estimates across studies. See on-line appendix for details. #Hazard ratio; *Operator experience <100 cases; **Operator experience <11cases/year. NR=not reported. †Mean procedure time approximately 20 minutes longer in cases associated with DRI. COPD = Chronic obstructive airways disease.

27

Table 4 Ye ar

Author

Design

198 1

Muers92

Open Random ised

431 (234 / 197)

198 4

Bluhm87

Open Random ised

100 (50/50)

198 4

Ramsda le 93

500 (250/250)

198 6

Bluhm

198 7

Glieca

199 3

Lüningh ake 91

Open Random ised Double blind placebo controlle d RCT Open Random ised Open Random ised

199 4

Mounse y 63

199 8

da Costa85

200 9

de Oliveira

88

89

N Total (Active/Co ntrol)

Antibioti cs Prior

Antibiotics Post

Foll ow up

Flucloxac illin 1g plus BenPen 600mg IV 1 hr preprocedure . Cloxacilli n 2g IV 1 hr preprocedure .

Flucloxacil lin 1g plus Ben-Pen 600mg IV @ 1 and 6 hours

23 (940) mont hs

Cloxacillin 1g IV q.i.d for 2 days and 1g PO q.i.d for 8 days Nil

Flucloxac illin 2g IV

Flucloxacil lin1g t.i.d for 5 days

200

Nil

213

Cefazedo n 2g IV

Cefazolin 4g IV o.d for 5 days Nil

Open Random ised

473

Metaanalysis

2023 (1012/1011)

Flucloxac illin or Clindamy cin IV for 2 days Variable

106 (52/54)

Not specified

Nil

Variable

Infection rate. Acti Contr ve ol 1.40 2.50% %

P value

1– 43 mont hs

2%

14%

P<0.0 5

1 year

3.20 %

5.20% **

P=0.3 7

14 (735) mont hs 1 week

0%

0%

N/A

0%

12%

P<0.0 5

1248 mont hs 19 (926) mont hs 1-4 years

-

-

P>0.0 5

0%

3.6%

P=0.0 03

0.50 %

3.70%

P=0.0 05

P=0.1 5

Double 649 Cefazolin Nil 6 0.64 3.28% P=0.0 blind mont % 16 (314/335) 1g IV 1 55 placebo hr prehs controlle procedure d RCT Table 4 – Efficacy of perioperative antibiotics for the prevention of device related infection. *Control group received no antibiotics; **Control group received povidone iodine and chlorhexidine scrub

28

References 1.

2.

3. 4. 5.

6.

7.

8.

9.

10.

11.

12.

13.

Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol May 27 2008;51:e1-62. Cabell CH, Heidenreich PA, Chu VH, Moore CM, Stryjewski ME, Corey GR, Fowler VG, Jr. Increasing rates of cardiac device infections among Medicare beneficiaries: 1990-1999. Am Heart J Apr 2004;147:582-586. Crysler J. Market Statistics. Cardiac Arrythmia Device Implant Market2008. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med Dec 16 2010;363:2385-2395. Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, Sherfesee L, Shinn T, Sutton MS, Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block Trial I. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med Apr 25 2013;368:1585-1593. Sohail MR, Henrikson CA, Braid-Forbes MJ, Forbes KF, Lerner DJ. Mortality and cost associated with cardiovascular implantable electronic device infections. Arch Intern Med Nov 14 2011;171:1821-1828. Sandoe JA, Barlow G, Chambers JB, et al. Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. Report of a joint Working Party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS), British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE). J Antimicrob Chemother Feb 2015;70:325-359. Conklin EF, Giannelli S, Jr., Nealon TF, Jr. Four hundred consecutive patients with permanent transvenous pacemakers. J Thorac Cardiovasc Surg Jan 1975;69:1-7. Bluhm G. Pacemaker infections. A clinical study with special reference to prophylactic use of some isoxazolyl penicillins. Acta Med Scand Suppl 1985;699:1-62. Uslan DZ, Sohail MR, St Sauver JL, Friedman PA, Hayes DL, Stoner SM, Wilson WR, Steckelberg JM, Baddour LM. Permanent pacemaker and implantable cardioverter defibrillator infection: a population-based study. Arch Intern Med Apr 9 2007;167:669-675. Voigt A, Shalaby A, Saba S. Rising rates of cardiac rhythm management device infections in the United States: 1996 through 2003. J Am Coll Cardiol Aug 1 2006;48:590-591. Greenspon AJ, Patel JD, Lau E, Ochoa JA, Frisch DR, Ho RT, Pavri BB, Kurtz SM. 16-Year Trends in the Infection Burden for Pacemakers and Implantable Cardioverter-Defibrillators in the United States. J Am Coll Cardiol 2011;58:1001-1006. Johansen JB, Jorgensen OD, Moller M, Arnsbo P, Mortensen PT, Nielsen JC. Infection after pacemaker implantation: infection rates and risk factors

29

14.

15.

16.

17.

18.

19.

20.

21.

22.

23. 24. 25.

26.

27.

28.

associated with infection in a population-based cohort study of 46299 consecutive patients. Eur Heart J Apr 2011;32:991-998. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med Apr 14 2005;352:1539-1549. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med May 20 2004;350:2140-2150. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med Jan 20 2005;352:225-237. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med May 20 2004;350:2151-2158. Lin G, Meverden RA, Hodge DO, Uslan DZ, Hayes DL, Brady PA. Age and gender trends in implantable cardioverter defibrillator utilization: a population based study. J Interv Card Electrophysiol Jun 2008;22:65-70. Uslan DZ, Tleyjeh IM, Baddour LM, Friedman PA, Jenkins SM, St Sauver JL, Hayes DL. Temporal trends in permanent pacemaker implantation: a population-based study. Am Heart J May 2008;155:896-903. Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, Steckelberg JM, Stoner S, Baddour LM. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol May 8 2007;49:1851-1859. Villamil Cajoto I, Rodriguez Framil M, Van den Eynde Collado A, Jose Villacian Vicedo M, Canedo Romero C. Permanent transvenous pacemaker infections: An analysis of 59 cases. Eur J Intern Med Oct 2007;18:484-488. Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, Steckelberg JM, Stoner SM, Baddour LM. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis Jul 15 2007;45:166-173. Kloos WE, Bannerman TL. Update on clinical significance of coagulasenegative staphylococci. Clin Microbiol Rev Jan 1994;7:117-140. Pfaller MA, Herwaldt LA. Laboratory, clinical, and epidemiological aspects of coagulase-negative staphylococci. Clin Microbiol Rev Jul 1988;1:281-299. Viola GM, Rosenblatt J, Raad, II, Darouiche RO. Comparison of bacterial adherence to titanium versus polyurethane for cardiac implantable electronic devices. Am J Cardiol Jun 15 2013;111:1764-1766. Marsch G, Mashaqi B, Burgwitz K, Bisdas T, Knigina L, Stiesch M, Haverich A, Kuehn C. Prevention of pacemaker infections with perioperative antimicrobial treatment: an in vitro study. Europace Apr 2013;16:604-611. Zou T, Zhang Z, Zou C, et al. Subclinical infections of cardiac implantable electronic devices: insights into the host-bacteria dialog from blood and pocket tissue with pyrosequencing. Int J Cardiol Jul 1 2014;174:545-549. Eberhard J, Stumpp N, Ismail F, Schnaidt U, Heuer W, Pichlmaier M, Kuhn C, Haverich A, Stiesch M. The oral cavity is not a primary source for implantable pacemaker or cardioverter defibrillator infections. J Cardiothorac Surg 2013;8:73.

30

29.

30.

31.

32. 33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

Chu XM, Yu H, Sun XX, An Y, Li B, Li XB. Identification of bacteriology and risk factor analysis of asymptomatic bacterial colonization in pacemaker replacement patients. PLoS One 2015;10:e0119232. Chua JD, Wilkoff BL, Lee I, Juratli N, Longworth DL, Gordon SM. Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann Intern Med Oct 17 2000;133:604-608. Massoure PL, Reuter S, Lafitte S, Laborderie J, Bordachard P, Clementy J, Roudaut R. Pacemaker endocarditis: clinical features and management of 60 consecutive cases. Pacing Clin Electrophysiol Jan 2007;30:12-19. Wilkoff BL. How to treat and identify device infections. Heart Rhythm Nov 2007;4:1467-1470. Klug D, Balde M, Pavin D, et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study. Circulation Sep 18 2007;116:1349-1355. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: this document was endorsed by the American Heart Association (AHA). Heart Rhythm Jul 2009;6:1085-1104. Nery PB, Fernandes R, Nair GM, Sumner GL, Ribas CS, Menon SM, Wang X, Krahn AD, Morillo CA, Connolly SJ, Healey JS. Device-related infection among patients with pacemakers and implantable defibrillators: incidence, risk factors, and consequences. J Cardiovasc Electrophysiol Jul 2010;21:786-790. Lekkerkerker JC, van Nieuwkoop C, Trines SA, van der Bom JG, Bernards A, van de Velde ET, Bootsma M, Zeppenfeld K, Jukema JW, Borleffs JW, Schalij MJ, van Erven L. Risk factors and time delay associated with cardiac device infections: Leiden device registry. Heart May 2009;95:715-720. Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection. Circulation Arrhythmia and electrophysiology 2009129-134. Golzio PG, Vinci M, Anselmino M, Comoglio C, Rinaldi M, Trevi GP, Bongiorni MG. Accuracy of swabs, tissue specimens, and lead samples in diagnosis of cardiac rhythm management device infections. Pacing Clin Electrophysiol Mar 2009;32 Suppl 1:S76-80. Klug D, Wallet F, Lacroix D, Marquie C, Kouakam C, Kacet S, Courcol R. Local symptoms at the site of pacemaker implantation indicate latent systemic infection. Heart Aug 2004;90:882-886. Welch M, Uslan DZ, Greenspon AJ, et al. Variability in clinical features of early versus late cardiovascular implantable electronic device pocket infections. Pacing Clin Electrophysiol Aug 2014;37:955-962. Lowe E, Tayebjee MH, Pratty J, Sandoe JA. Survey of antibiotic prophylaxis for implantable cardiac electronic device (ICED) insertion in England. Int J Cardiol May 31 2012;157:286-287. Habib A, Le KY, Baddour LM, Friedman PA, Hayes DL, Lohse CM, Wilson WR, Steckelberg JM, Sohail MR. Predictors of mortality in patients with cardiovascular implantable electronic device infections. Am J Cardiol Mar 15 2013;111:874-879. Bloom H, Heeke B, Leon A, Mera F, Delurgio D, Beshai J, Langberg J. Renal insufficiency and the risk of infection from pacemaker or defibrillator surgery. Pacing Clin Electrophysiol Feb 2006;29:142-145.

31

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

Romeyer-Bouchard C, Da Costa A, Dauphinot V, Messier M, Bisch L, Samuel B, Lafond P, Ricci P, Isaaz K. Prevalence and risk factors related to infections of cardiac resynchronization therapy devices. Eur Heart J Jan 2010;31:203-210. Mittal S, Shaw RE, Michel K, Palekar R, Arshad A, Musat D, Preminger M, Sichrovsky T, Steinberg JS. Cardiac implantable electronic device infections: incidence, risk factors, and the effect of the AigisRx antibacterial envelope. Heart Rhythm Apr 2014;11:595-601. Spinler SA, Nawarskas JJ, Foote EF, Sabapathi D, Connors JE, Marchlinski FE. Clinical presentation and analysis of risk factors for infectious complications of implantable cardioverter-defibrillator implantations at a university medical center. Clin Infect Dis May 1998;26:1111-1116. Sohail MR, Hussain S, Le KY, Dib C, Lohse CM, Friedman PA, Hayes DL, Uslan DZ, Wilson WR, Steckelberg JM, Baddour LM, Mayo Cardiovascular Infections Study G. Risk factors associated with early- versus late-onset implantable cardioverter-defibrillator infections. J Interv Card Electrophysiol Aug 2011;31:171-183. Landolina M, Gasparini M, Lunati M, et al. Long-term complications related to biventricular defibrillator implantation: rate of surgical revisions and impact on survival: insights from the Italian Clinical Service Database. Circulation Jun 7 2011;123:2526-2535. Khalighi K, Aung TT, Elmi F. The role of prophylaxis topical antibiotics in cardiac device implantation. Pacing Clin Electrophysiol Mar 2014;37:304311. Cengiz M, Okutucu S, Ascioglu S, Sahin A, Aksoy H, Sinan Deveci O, Baris Kaya E, Aytemir K, Kabakci G, Tokgozoglu L, Ozkutlu H, Oto A. Permanent pacemaker and implantable cardioverter defibrillator infections: seven years of diagnostic and therapeutic experience of a single center. Clin Cardiol Jul 2010;33:406-411. Asif A, Salman L, Lopera G, Haqqie SS, Carrillo R. Transvenous cardiac implantable electronic devices and hemodialysis catheters: recommendations to curtail a potentially lethal combination. Semin Dial Sep-Oct 2012;25:582586. Hickson LJ, Gooden JY, Le KY, Baddour LM, Friedman PA, Hayes DL, Wilson WR, Steckelberg JM, Sohail MR. Clinical presentation and outcomes of cardiovascular implantable electronic device infections in hemodialysis patients. Am J Kidney Dis Jul 2014;64:104-110. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control Apr 1999;27:97-132; quiz 133-134; discussion 196. Sohail MR, Henrikson CA, Braid-Forbes MJ, Forbes KF, Lerner DJ. Comparison of mortality in women versus men with infections involving cardiovascular implantable electronic device. Am J Cardiol Nov 1 2013;112:1403-1409. de Oliveira JC, Martinelli M, Nishioka SA, Varejao T, Uipe D, Pedrosa AA, Costa R, D'Avila A, Danik SB. Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial. Circ Arrhythm Electrophysiol Feb 2009;2:29-34.

32

56.

57.

58.

59.

60.

61.

62.

63.

64.

65. 66.

67.

68. 69. 70.

71.

Raad D, Irani J, Akl EG, Choueiri S, Azar E, Abboud J, Afif C. Implantable electrophysiologic cardiac device infections: a risk factor analysis. Eur J Clin Microbiol Infect Dis Nov 2012;31:3015-3021. Birnie DH, Healey JS, Wells GA, Verma A, Tang AS, Krahn AD, Simpson CS, Ayala-Paredes F, Coutu B, Leiria TL, Essebag V. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med May 30 2013;368:2084-2093. Nascimento T, Birnie DH, Healey JS, Verma A, Joza J, Bernier ML, Essebag V. Managing novel oral anticoagulants in patients with atrial fibrillation undergoing device surgery: Canadian survey. Can J Cardiol Feb 2014;30:231236. Kosiuk J, Koutalas E, Doering M, Sommer P, Rolf S, Breithardt OA, Nedios S, Dinov B, Hindricks G, Richter S, Bollmann A. Treatment with novel oral anticoagulants in a real-world cohort of patients undergoing cardiac rhythm device implantations. Europace Jul 2014;16:1028-1032. Chauhan A, Grace AA, Newell SA, Stone DL, Shapiro LM, Schofield PM, Petch MC. Early complications after dual chamber versus single chamber pacemaker implantation. Pacing Clin Electrophysiol Nov 1994;17:2012-2015. Lambiase PD, Barr C, Theuns DA, et al. Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J Jul 1 2014;35:1657-1665. Weiss R, Knight BP, Gold MR, Leon AR, Herre JM, Hood M, Rashtian M, Kremers M, Crozier I, Lee KL, Smith W, Burke MC. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation Aug 27 2013;128:944-953. Mounsey JP, Griffith MJ, Tynan M, Gould FK, MacDermott AF, Gold RG, Bexton RS. Antibiotic prophylaxis in permanent pacemaker implantation: a prospective randomised trial. Br Heart J Oct 1994;72:339-343. Gould PA, Krahn AD. Complications associated with implantable cardioverter-defibrillator replacement in response to device advisories. JAMA Apr 26 2006;295:1907-1911. Modi SS, Wright DJ, Ramsdale DR. The externally placed 'temporarypermanent' generator. Europace Aug 2009;11:979. Department of Health. Heating and ventilation systems—HTM 03-01: Specialised ventilation for healthcare premises—Part A. In: Department of Health, ed: The Stationary Office, 2007. Al-Khatib SM, Lucas FL, Jollis JG, Malenka DJ, Wennberg DE. The relation between patients' outcomes and the volume of cardioverter-defibrillator implantation procedures performed by physicians treating Medicare beneficiaries. J Am Coll Cardiol Oct 18 2005;46:1536-1540. Mishriki SF, Law DJ, Jeffery PJ. Factors affecting the incidence of postoperative wound infection. J Hosp Infect Oct 1990;16:223-230. Cruse PJ, Foord R. The epidemiology of wound infection. A 10-year prospective study of 62,939 wounds. Surg Clin North Am Feb 1980;60:27-40. Bode LG, Kluytmans JA, Wertheim HF, et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med Jan 7 2010;362:9-17. Deshpande LM, Jones RN. Antimicrobial activity of advanced-spectrum fluoroquinolones tested against more than 2000 contemporary bacterial

33

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

isolates of species causing community-acquired respiratory tract infections in the United States (1999). Diagn Microbiol Infect Dis Jun 2000;37:139-142. Darouiche RO, Wall MJ, Jr., Itani KM, Otterson MF, Webb AL, Carrick MM, Miller HJ, Awad SS, Crosby CT, Mosier MC, Alsharif A, Berger DH. Chlorhexidine-Alcohol versus Povidone-Iodine for Surgical-Site Antisepsis. N Engl J Med Jan 7 2010;362:18-26. Chaiyakunapruk N, Veenstra DL, Lipsky BA, Saint S. Chlorhexidine compared with povidone-iodine solution for vascular catheter-site care: a meta-analysis. Ann Intern Med Jun 4 2002;136:792-801. Etienne CHUdS. Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation (CHLOVIS). http://clinicaltrialsgov/ct2/show/NCT01841242 Last accessed 2015Feb9thNCT01841242. Bashir MH, Olson LK, Walters SA. Suppression of regrowth of normal skin flora under chlorhexidine gluconate dressings applied to chlorhexidine gluconate-prepped skin. Am J Infect Control May 2012;40:344-348. Webster J, Alghamdi A. Use of plastic adhesive drapes during surgery for preventing surgical site infection. Cochrane Database Syst Rev 2013;1:CD006353. Gold MR, Peters RW, Johnson JW, Shorofsky SR. Complications associated with pectoral cardioverter-defibrillator implantation: comparison of subcutaneous and submuscular approaches. Worldwide Jewel Investigators. J Am Coll Cardiol Nov 1 1996;28:1278-1282. Cohen MI, Bush DM, Gaynor JW, Vetter VL, Tanel RE, Rhodes LA. Pediatric pacemaker infections: twenty years of experience. J Thorac Cardiovasc Surg Oct 2002;124:821-827. Milic DJ, Perisic ZD, Zivic SS, Stanojkovic ZA, Stojkovic AM, Karanovic ND, Krstic NH, Salinger SS. Prevention of pocket related complications with fibrin sealant in patients undergoing pacemaker implantation who are receiving anticoagulant treatment. Europace Jul 2005;7:374-379. Kutinsky IB, Jarandilla R, Jewett M, Haines DE. Risk of hematoma complications after device implant in the clopidogrel era. Circ Arrhythm Electrophysiol Aug 2010;3:312-318. O'Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control May 2011;39:S1-34. Lakkireddy D, Pillarisetti J, Atkins D, et al. Impact of Pocket Revision on the Rate of Infection and Other Complications in Patients Requiring Pocket Manipulation for Generator Replacement and/or Lead Replacement or Revision (Make It Clean): A Prospective Randomized Study. Heart Rhythm Jan 24 2015. St. Mary's Hospital S. Decrease Implantation Site Infection (Disinfection I): a Randomized Controlled Trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). 2000- 2015Feb09. http://clinicaltrials.gov/ct2/show/NCT02035410. Last accessed 2015 Feb 09. O'Hea BJ, Ho MN, Petrek JA. External compression dressing versus standard dressing after axillary lymphadenectomy. Am J Surg Jun 1999;177:450-453.

34

85.

86.

87.

88.

89.

90.

91.

92. 93.

94.

95.

96.

97.

98.

99.

Da Costa A, Kirkorian G, Cucherat M, Delahaye F, Chevalier P, Cerisier A, Isaaz K, Touboul P. Antibiotic prophylaxis for permanent pacemaker implantation: a meta-analysis. Circulation May 12 1998;97:1796-1801. Darouiche R, Mosier M, Voigt J. Antibiotics and antiseptics to prevent infection in cardiac rhythm management device implantation surgery. Pacing Clin Electrophysiol Nov 2012;35:1348-1360. Bluhm G, Jacobson B, Julander I, Levander-Lindgren M, Olin C. Antibiotic prophylaxis in pacemaker surgery--a prospective study. Scand J Thorac Cardiovasc Surg 1984;18:227-234. Bluhm G, Nordlander R, Ransjo U. Antibiotic prophylaxis in pacemaker surgery: a prospective double blind trial with systemic administration of antibiotic versus placebo at implantation of cardiac pacemakers. Pacing Clin Electrophysiol Sep 1986;9:720-726. Glieca F, Luciani N, Di Giammarco G, Romolo M, Falcone F, Di Nardo E, Maddestra N, Alberico G, Possati F. [The role of antibiotic prophylaxis in the implantation of pacemakers]. Minerva Cardioangiol Oct 1987;35:549-552. Jacobson B, Bluhm G, Julander I, Nord CE. Coagulase-negative staphylococci and cloxacillin prophylaxis in pacemaker surgery. Acta Pathol Microbiol Immunol Scand B Apr 1983;91:97-99. Lüninghake F, Gottschalk A, Stierle U, Potratz J, Sack K, Diederich KW. Antibiotic prophylaxis for pacemaker implantation: a prospective randomized trial in 302 patients. . Pacing and Clinical Electrophysiology 1993;16:1138. Muers MF, Arnold AG, Sleight P. Prophylactic antibiotics for cardiac pacemaker implantation. A prospective trail. Br Heart J Nov 1981;46:539-544. Ramsdale DR, Charles RG, Rowlands DB, Singh SS, Gautam PC, Faragher EB. Antibiotic prophylaxis for pacemaker implantation: a prospective randomized trial. Pacing Clin Electrophysiol Sep 1984;7:844-849. Bluhm G, Jacobson B, Ransjo U. Antibiotic prophylaxis in pacemaker surgery: a prospective trial with local or systemic administration of antibiotics at generator replacements. Pacing Clin Electrophysiol Sep 1985;8:661-670. Dwivedi SK, Saran RK, Khera P, Tripathi N, Kochar AK, Narain VS, Puri VK. Short-term (48 hours) versus long-term (7 days) antibiotic prophylaxis for permanent pacemaker implantation. Indian Heart J Nov-Dec 2001;53:740-742. Lakkireddy D, Valasareddi S, Ryschon K, Basarkodu K, Rovang K, Mohiuddin SM, Hee T, Schweikert R, Tchou P, Wilkoff B, Natale A, Li H. The impact of povidone-iodine pocket irrigation use on pacemaker and defibrillator infections. Pacing Clin Electrophysiol Aug 2005;28:789-794. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation Jan 26 2010;121:458-477. Jan E, Camou F, Texier-Maugein J, Whinnett Z, Caubet O, Ploux S, Pellegrin JL, Ritter P, Metayer PL, Roudaut R, Haissaguerre M, Bordachar P. Microbiologic characteristics and in vitro susceptibility to antimicrobials in a large population of patients with cardiovascular implantable electronic device infection. J Cardiovasc Electrophysiol Apr 2012;23:375-381. Connolly SJ, Philippon F, Longtin Y, Casanova A, Birnie DH, Exner DV, Dorian P, Prakash R, Alings M, Krahn AD. Randomized cluster crossover trials for reliable, efficient, comparative effectiveness testing: design of the

35

100.

101.

102.

103.

104.

105. 106.

107.

108.

109.

110.

111.

112.

113.

Prevention of Arrhythmia Device Infection Trial (PADIT). Can J Cardiol Jun 2013;29:652-658. Raad I, Hanna H, Jiang Y, Dvorak T, Reitzel R, Chaiban G, Sherertz R, Hachem R. Comparative activities of daptomycin, linezolid, and tigecycline against catheter-related methicillin-resistant Staphylococcus bacteremic isolates embedded in biofilm. Antimicrob Agents Chemother May 2007;51:1656-1660. Stewart PS, Davison WM, Steenbergen JN. Daptomycin rapidly penetrates a Staphylococcus epidermidis biofilm. Antimicrob Agents Chemother Aug 2009;53:3505-3507. Fowler VG, Jr., Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med Aug 17 2006;355:653-665. Smith K, Perez A, Ramage G, Gemmell CG, Lang S. Comparison of biofilmassociated cell survival following in vitro exposure of meticillin-resistant Staphylococcus aureus biofilms to the antibiotics clindamycin, daptomycin, linezolid, tigecycline and vancomycin. Int J Antimicrob Agents Apr 2009;33:374-378. Rein MF, Westervelt FB, Sande MA. Pharmacodynamics of cefazolin in the presence of normal and impaired renal function. Antimicrob Agents Chemother Sep 1973;4:366-371. Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis Jan 1 2006;42 Suppl 1:S35-39. Kolek MJ, Dresen WF, Wells QS, Ellis CR. Use of an antibacterial envelope is associated with reduced cardiac implantable electronic device infections in high-risk patients. Pacing Clin Electrophysiol Mar 2013;36:354-361. Bloom HL, Constantin L, Dan D, et al. Implantation success and infection in cardiovascular implantable electronic device procedures utilizing an antibacterial envelope. Pacing Clin Electrophysiol Feb 2011;34:133-142. Wilkoff B, Tarakji K. World-wide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT). http://clinicaltrialsgov/show/NCT02277990 Last accessed 2015 Feb 09th. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG, Jr., Ryan T, Bashore T, Corey GR. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis Apr 2000;30:633-638. Smith PN, Vidaillet HJ, Hayes JJ, Wethington PJ, Stahl L, Hull M, Broste SK. Infections with nonthoracotomy implantable cardioverter defibrillators: can these be prevented? Endotak Lead Clinical Investigators. Pacing Clin Electrophysiol Jan 1998;21:42-55. Mela T, McGovern BA, Garan H, Vlahakes GJ, Torchiana DF, Ruskin J, Galvin JM. Long-term infection rates associated with the pectoral versus abdominal approach to cardioverter- defibrillator implants. Am J Cardiol Oct 1 2001;88:750-753. Margey R, McCann H, Blake G, Keelan E, Galvin J, Lynch M, Mahon N, Sugrue D, O'Neill J. Contemporary management of and outcomes from cardiac device related infections. Europace Jan 2009;12:64-70. Gould PA, Gula LJ, Champagne J, et al. Outcome of Advisory Implantable Cardioverter Defibrillator Replacement: One-year Follow-up. Heart Rhythm 2008;5:1635-1640.

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Figure 1

Figure 2