Perioperative Antibiotic Therapy to Prevent Cardiac Implantable Electronic Device Infections.

1.0 Background

The number of cardiac implantable electronic devices (CIEDs) implanted each year has grown
rapidly over the past two decades, largely due to expanding use of implantable
cardioverter-defibrillators (ICDs) and devices capable of delivering cardiac
resynchronization therapy (CRT). CIEDs have increasingly been utilized in older patients with
multiple medical comorbidities. As a result CIED infections, defined as infections involving
the generator implant site (pocket) and/or intravascular leads, have become increasingly
prevalent, with the rate of growth in infections outpacing that of CIED procedures. The
increase in incidence of CIED infections has outpaced the growth in device implantation, in
large part due to the medical complexity of today's CIED patients. These devastating
complications are associated with significant cost, morbidity, and mortality. The odds of
both short term and long term mortality are at least doubled in patients who suffer CIED
infections, and long term survival is particularly poor in women.

Patient-specific risk factors for CIED infections have been examined in multiple registries
and case-control studies. For patients with at least two risk factors, the reported incidence
of CIED infection is 2-3%. Management of these infections is complex and expensive. The
cornerstone of management is the complete removal of all infected hardware whenever possible,
which in itself poses significant risks for patients. Therefore prevention of infections is
crucial.

Best practices for reducing CIED infections are an active area of research. Since most
infections occur as a result of bacterial seeding at the time of device implantation or
revision, careful attention to strict sterile technique is mandatory. Optimal skin
preparation and perioperative intravenous antibiotics have been associated with a reduced
rate of CIED infections in randomized controlled studies. Additionally, several recent
retrospective studies have suggested an important role of the minocycline and rifampin
impregnated TYRX antibacterial envelope in reducing infections. The device consists of 2
polypropylene mesh sheets joined on 3 sides with a 3mm seam and is available in 2 sizes to
accommodate pacemaker and ICD pulse generators. This polypropylene envelope releases
minocycline and rifampin from a bioresorbable polyarylate polymer over approximately 7 days,
directly into the CIED generator pocket.

Aside from optimal skin preparation and perioperative intravenous antibiotics, other
practices to reduce the risk of CIED infections vary widely. Many operators use an
antibacterial solution (e.g., polymyxin-B/bacitracin) to irrigate the pocket during device
implantation. Additionally, many centers have adopted the routine use of prophylactic
postoperative antibiotics to reduce the risk of CIED infections. However, neither of these
strategies has been evaluated in randomized clinical studies. Antibacterial irrigation
solution is expensive, and oral antibiotics are associated with a small yet clinically
important risk of adverse effects, including Clostridium difficile infection. Therefore,
prospective randomized studies are needed to evaluate the efficacy, safety, and
cost-effectiveness of intraoperative antibacterial rinse and postoperative oral antibiotics.

Summary of significance: CIED infections constitute major complications of device
implantations or revisions and are becoming increasingly prevalent. Infections are associated
with increased morbidity, mortality, and cost, and are very difficult to treat. Recent
studies have explored ways to reduce the incidence of CIED infections, and use of the TYRX
antibacterial envelope has emerged as a potential strategy for prevention. Other strategies
including intraoperative antibacterial irrigation and postoperative oral antibiotics are
commonly used despite the lack of prospective studies documenting efficacy, safety, and
cost-effectiveness. We and others have reported a very low incidence (<1%) of CIED infections
in high-risk patients receiving the TYRX antibacterial envelope. One intriguing possibility
is that the antibacterial envelope can be used instead of intraoperative antibacterial rinse
and postoperative oral antibiotics. Therefore, an important knowledge gap exists about the
best practices to prevent CIED infections in high-risk individuals.

2.0 Rationale and Specific Aims

SPECIFIC AIM: to test the hypothesis that the use of the TYRX antibacterial envelope alone is
noninferior to a strategy using the antibacterial envelope and intraoperative antibacterial
irrigant and postoperative oral antibiotics for the reduction of cardiac implantable device
infections in patients with ≥2 risk factors for infection.

CIED infections are devastating yet potentially preventable complications. We previously
conducted a retrospective study of the TYRX antibacterial envelope and found that use of the
device in patients with ≥2 risk factors for CIED infection was associated with a markedly
decreased infection rate (0.4% with the device versus 3% without, adjusted odds ratio [95%
confidence interval]: 0.09 [0.01 to 0.73], P =0.02). All patients in our previous study had
intraoperative irrigation of the device pocket with polymyxin-B/bacitracin solution and
received routine postoperative oral antibiotics consistent with local practices. However,
whether use of intraoperative irrigant and postoperative antibiotics reduces the risk of
infection has not been evaluated in prospective, randomized trials. Moreover, it is unknown
whether these treatments offer any incremental benefit over the use of the TYRX antibacterial
envelope alone.

Given the significant cost of polymyxin-B/bacitracin solution and concerns over unnecessary
use of oral antibiotics and emerging resistant microorganisms, it is critically important to
establish whether these treatments offer any incremental benefit for patients at high risk
for a CIED infection who are receiving the TYRX antibacterial envelope. The Specific Aim of
this study will be to prospectively test the hypothesis that an infection risk-reduction
strategy using the TYRX antibacterial envelope alone is noninferior to a strategy using the
envelope with intraoperative antibacterial irrigant and postoperative oral antibiotics in
patients undergoing a CIED procedure who have at least 2 CIED infection risk factors.

3.0 Previous Animal and Human Studies

The TYRX antibacterial envelope effectively prevented CIED infections in an animal model. In
an animal model of direct bacterial inoculation into the device pocket, the TYRX
antibacterial envelope showed excellent activity against Staphylococcus epidermidis,
Staphylococcus capitis, Escherichia coli, and Acinetobacter baumannii. Importantly, systemic
levels of minocycline and rifampin were undetectable.

Use of the TYRX antibacterial envelope has been associated with a reduced incidence of CIED
infections in retrospective studies of high-risk patients. In a multi-center trial, use of
the TYRX antibacterial envelope was associated with a low risk of CIED infections (0.5%).
However, the relatively short follow-up period (mean: 1.9 months) and lack of a control arm
limited the interpretation of the study's results. We conducted a retrospective controlled
study of the TYRX antibacterial envelope in patients with at least 2 CIED infection risk
factors at our institution. Among 260 TYRX envelope recipients, the incidence of CIED
infection after a mean 18.7 month follow-up period was 0.4%, compared with 3% in 639
high-risk controls who did not receive the envelope (adjusted odds ratio: 0.09, 95%
confidence interval 0.01 to 0.73, P =0.02). Another retrospective study at a high-volume
center found that the prevalence of CIED infections decreased from 1.5% to 0.6% after the
TYRX antibacterial envelope was instituted into practice (P =0.03).

Based on these and other studies, the Worldwide Randomized Antibiotic Envelope CIED Infection
Prevention Trial (WRAP-IT) was conceived. This landmark trial will prospectively evaluate the
efficacy of the TYRX-A antibacterial envelope. However, our proposed study will be
complementary to the WRAP-IT trial because we will specifically evaluate whether the TYRX-A
antibacterial envelope alone offers ample protection against CIED infections without the use
of intraoperative antibacterial solution and postoperative oral antibiotics.

6.0 Study Procedures

Device implantation and follow-up. CIED procedures will be performed in accordance with
established practice guidelines. Perioperative procedures to reduce the risk of CIED
infection including optimal skin preparation and intravenous antibiotics (cefazolin or
vancomycin) will be applied to all patients. All patients will receive the TYRX absorbable
antibacterial envelope. Patients randomized to the intraoperative antibacterial
irrigant/postoperative oral antibiotic (control) arm will undergo irrigation of the device
pocket with up to 1 liter polymyxin-B/bacitracin solution. Patients in the control arm will
also receive 3 days of postoperative oral antibiotics (cephalexin 500mg 3 times daily,
clindamycin 300mg 3 times daily, or levofloxacin 500mg once daily) as per investigator
routine ordering practice with discretion per each individual patient. Patients randomized to
the experimental arm will not receive intraoperative antibacterial irrigation (will be
allowed up to 1 liter sterile saline irrigation), nor post-operative oral antibiotics.

All patients will be followed after their procedures according to established practice
guidelines. At a minimum, patients will be seen 4 weeks after the procedure for a wound
check, at 6 months, and then every year or more frequently as dictated by each patient's
clinical status. A digital photograph of the device pocket will be captured at the 4-week
postoperative visit. In addition, the study nurse will telephone each patient 3 months after
implantation to assess for symptoms and signs of infection. For the purposes of the study,
patients will continue to be followed for a minimum of 6 months after the procedure, but
additional follow-up data after six months may be collected continuously until the study
closes.

Ascertainment of the primary endpoint: CIED infection after a minimum 6-month follow-up
period. The primary study endpoint will be CIED infection resulting in complete CIED system
removal, antibiotic therapy in patients who are not candidates for system removal, or death
due to CIED infection. To avoid detection bias we will prospectively apply criteria for
definition of the primary endpoint and ask treating physicians to thoroughly document
objective findings.

Examples of objective signs of CIED infection.

Objective findings of CIED infection

- Fever or leukocytosis without an alternative explanation (e.g., urinary tract infection
or pneumonia)

- Tenderness, erythema, or warmth at the pulse generator site

- Purulent discharge from the pulse generator site (from incision or fistula)

- Positive blood or pulse generator site cultures

- Vegetation adherent to CIED hardware

- Purulent material within pulse generator pocket upon reoperation

A digital photograph of the device pocket will be captured routinely at the postoperative
visit and whenever CIED infection is a consideration. In case of a suspected CIED infection,
treating physicians will be strongly encouraged to obtain peripheral blood cultures prior to
initiation of antibiotic therapy and intraoperative cultures during CIED system removal. A
panel of 3 physicians at the coordinating center who are blinded to study assignment
(experimental versus control) will independently adjudicate outcomes in "real time" and will
vote whether or not the criteria for CIED infection have been met. A minor superficial
infection of the incision that does not involve the generator pocket, does not result in any
systemic symptoms or signs, and is treated with either observation or a short course of oral
antibiotics, will not be counted as a CIED infection but will be considered a secondary
endpoint.

Study oversight: The principal investigator at each study sight will be responsible for all
aspects of the study at their respective sites. To ensure fidelity with the study protocol,
an independent study coordinator at Vanderbilt University who is not directly involved with
the study will review upon initiation of the study and first patient enrolled at each site,
and then a random selection (10%) of patient records at each site (including Vanderbilt
University) on a continuous basis set out by the monitoring agreement throughout the duration
of the study, and quarterly prepare a report for the study's principal investigator.

Inclusion Criteria:

- Age ≥18 years old

- Able to give informed consent

- At least 2 of the following risk factors for infection:

- Diabetes mellitus

- Chronic kidney disease (estimated creatinine clearance <30 ml/min

- Therapeutic anticoagulation

- Chronic heart failure

- Chronic use of corticosteroids

- Fever ≥38° C or leukocytois (≥11,000 cells/mm3) within 24 hrs of implant

- Device revision (including generator change, or extraction)

- ≥3 leads in situ (CRT system or abandoned leads)

- Early reoperation (pocket re-entry <2 weeks)

- Previous CIED infection

Exclusion Criteria:

- Medical condition that is likely to be fatal in less than one year

- Emergent CIED procedure

- Allergy to rifampin or minocycline, Allergy to polymyxin-B or bacitracin

- Enrollment in WRAP-IT trial

- Current CIED pocket infection