Elliott bennett guerrero et al - JAMA cardiac sponge RCT

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. 2010;304(7):755-762 (doi:10.1001/jama.2010.1152)JAMA
Elliott Bennett-Guerrero; T. Bruce Ferguson, Jr; Min Lin; et al.
A Randomized Trial
Surgery:on Sternal Wound Infections Following Cardiac
Effect of an Implantable Gentamicin-Collagen Sponge
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ORIGINAL CONTRIBUTION
Effect of an Implantable Gentamicin-Collagen
Sponge on Sternal Wound Infections
Following Cardiac Surgery
A Randomized Trial
Elliott Bennett-Guerrero, MD
T. Bruce Ferguson Jr, MD
Min Lin, PhD
Jyotsna Garg, MS
Daniel B. Mark, MD, MPH
Vincent A. Scavo Jr, MD
Nicholas Kouchoukos, MD
John B. Richardson Jr, MD
Renee L. Pridgen, BS
G. R. Corey, MD
for the SWIPE-1 Trial Group
D
ESPITETHEUSEOFPROPHYLAC-
ticsystemicantibiotics,post-
operative sternal wound in-
fection continues to be a se-
rious problem after cardiac surgical
procedures,especiallyintheincreasing
populationofpatientswithdiabetesand/
orobesity.Sternalwoundinfectionisas-
sociated with significant suffering, ad-
ditionalexpense,1,2
lengthenedhospital
stay,3,4
and increased mortality. The
gentamicin-collagenspongewasdevel-
oped to prevent and/or treat wound in-
fections by providing high local genta-
micin concentrations without the high
systemicconcentrationsassociatedwith
nephotoxicity.5
The sponge’s collagen
matrixisbiodegradable.Thegentamicin-
collagensponge(InnocollTechnologies
Ltd,Roscommon,Ireland)receivedmar-
ketingapprovalinGermanyin1985,and
iscurrentlyapprovedforuseinanother
53 countries. To date, more than 2
millionspongeshavebeenusedtotreat
morethan1millionpatientsoutsidethe
United States across a broad range of
Author Affiliations and Members of the SWIPE-1 Trial
Group are listed at the end of this article.
CorrespondingAuthor:ElliottBennett-Guerrero,MD,Peri-
operativeClinicalResearch,DukeClinicalResearchInstitute,
DukeUniversityMedicalCenter,POBox3094,Durham,
NC 27710 (Elliott.BennettGuerrero@Duke.edu).
Context Despite the routine use of prophylactic systemic antibiotics, sternal wound in-
fection still occurs in 5% or more of cardiac surgical patients and is associated with signifi-
cant excess morbidity, mortality, and cost. The gentamicin-collagen sponge, a surgically
implantabletopicalantibiotic,iscurrentlyapprovedin54countries.Alarge,2-center,ran-
domized trial in Sweden reported in 2005 that the sponge reduced surgical site infection
by 50% in cardiac patients.
Objective To test the hypothesis that the sponge prevents infection in cardiac sur-
gical patients at increased risk for sternal wound infection.
Design, Setting, and Participants Phase 3 single-blind, prospective randomized
controlled trial, 1502 cardiac surgical patients at high risk for sternal wound infection
(diabetes, body mass index Ͼ30, or both) were enrolled at 48 US sites between De-
cember 21, 2007, and March 11, 2009.
Intervention Single-blind randomization to insertion of 2 gentamicin-collagen sponges
(total gentamicin of 260 mg) between the sternal halves at surgical closure (n=753)
vs no intervention (control group: n=749). All patients received standardized care in-
cluding prophylactic systemic antibiotics and rigid sternal fixation.
Main Outcome Measures The primary end point was sternal wound infection oc-
curring through 90 days postoperatively as adjudicated by a clinical events classification
committee blinded to study treatment group. The primary study comparison was done
in the intent-to-treat population. Secondary outcomes included (1) superficial wound in-
fection (involving subcutaneous tissue but not extending down to sternal fixation wires),
(2) deep wound infection (involving the sternal wires, sternal bone, and/or mediasti-
num), and (3) score for additional treatment, presence of serous discharge, erythema,
purulent exudate, separation of the deep tissues, isolation of bacteria, and duration of
inpatient stay (ASEPSIS; minimum score of 0 with no theoretical maximum).
Results Of 1502 patients, 1006 had diabetes (67%) and 1137 were obese (body mass
index Ͼ30) (76%). In the primary analysis, there was no significant difference in sternal
woundinfectionin63of753patientsrandomizedtothegentamicin-collagenspongegroup
(8.4%)comparedwith65of749patientsrandomizedtothecontrolgroup(8.7%)(P=.83).
Nosignificantdifferenceswereobservedbetweenthegentamicin-collagenspongegroup
and the control group, respectively, in superficial sternal wound infection (49/753 [6.5%]
vs46/749[6.1%];P=.77),deepsternalwoundinfection(14/753[1.9%]vs19/749[2.5%];
P=.37), ASEPSIS score (mean [SD], 1.9 [6.4] vs 2.0 [7.2]; P=.67), or rehospitalization for
sternal wound infection (23/753 [3.1%] vs 24/749 [3.2%]; P=.87).
Conclusion Among US patients with diabetes, high body mass index, or both un-
dergoing cardiac surgery, the use of 2 gentamicin-collagen sponges compared with
no intervention did not reduce the 90-day sternal wound infection rate.
Trial Registration clinicaltrials.gov Identifier: NCT00600483
JAMA. 2010;304(7):755-762 www.jama.com
©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, August 18, 2010—Vol 304, No. 7 755

clinicalindications(InnocollTechnologies
Ltd, unpublished data, October 2007).
In a large (n=2000) investigator-
initiated, 2-center trial conducted in
Sweden, cardiac surgery patients ran-
domized to insertion of 2 sponges dem-
onstrated a 53% decrease in sternal
wound infection (4.3% vs 9.0%;
PϽ.001) and a 46% decrease in surgi-
cally treated sternal wound infection
(2.1% vs 3.9%; P=.02).6
The current
phase 3 trial was designed to confirm
these promising data and support regu-
latory approval in the United States.
METHODS
We conducted a phase 3, single-blind,
prospective,randomizedcontrolledtrial
of the gentamicin-collagen sponge in
patientsundergoingcardiacsurgery.Pa-
tients were enrolled at 48 sites through-
out the United States.
After institutional review board ap-
proval from each site, and individual
written informed consent, patients
meeting the following criteria were eli-
gible for enrollment: (1) male or fe-
male patients aged 18 years or older, (2)
scheduled to undergo nonemergent
coronary artery bypass graft and/or
valve repair or replacement surgery
through a full median sternotomy, and
(3) at higher risk for sternal wound in-
fection, defined as the presence of dia-
betes mellitus (treated with either oral
agent or insulin) and/or obesity, de-
fined as body mass index (calculated as
weight in kilograms divided by height
in meters squared) greater than 30.
The exclusion criteria were (1)
known history of hypersensitivity to
gentamicin or bovine collagen, (2)
emergency surgery, (3) significant con-
comitant surgical procedure, (4) mini-
mally invasive or thoracic surgical ap-
proach, (5) pregnancy, (6) preoperative
mechanical assist device or intraaortic
balloon pump if inserted for shock or
low output syndrome, (7) active and
significant systemic infection, (8) an-
tibiotic therapy within 2 weeks preop-
eratively, (9) preoperative serum cre-
atinine level greater than 3 mg/dL (to
convert to µmol/L, multiply by 88.4) or
renal failure requiring dialysis, (10) ma-
lignancy except for squamous or basal
cell carcinoma of the skin, (11) major
organ transplantation, (12) signifi-
cant drug or alcohol abuse, (13) receiv-
ing systemic immunosuppressive drugs,
including steroids (at a dose Ͼ10 mg
of oral prednisone daily), or current im-
munosuppressive condition (eg, symp-
tomatic human immunodeficiency vi-
rus infection), (14) scheduled to receive
stress doses of glucocorticoids, (15)
postsurgical life expectancy of 90 days
or less, (16) participation in another ex-
perimental drug or device study, and
(17) refusal to accept medically indi-
cated blood products.
Each 100 cm2
(5ϫ20 cm) sponge
contained 280 mg of collagen and 130
mg of gentamicin. Study patients re-
ceived 2 sponges inserted between the
sternal halves along the full length of the
sternum immediately before closure of
the sternum, as described previously.6
The control group did not receive gen-
tamicin-collagen sponges. The proto-
col called for patients randomized to the
gentamicin-collagen sponge group and
requiring reexploration (eg, due to
bleeding) within 1 week after surgery to
receive 2 new sponges inserted at the
time of closure of the reoperation. The
protocol required all surgeons to un-
dergo a training and certification pro-
cess that included viewing a video out-
lining proper handling and insertion of
the gentamicin-collagen sponge.
Randomization occurred after sur-
gical incision using a central random-
ization interactive voice response
system, thus providing complete allo-
cation concealment. The randomiza-
tion scheme was stratified by site and
random block sizes were used.
Patients and members of the clinical
events adjudication committee were
blinded to study group assignment.
Surgeons also were asked to deter-
mine the presence or absence of infec-
tion. To avoid possible bacterial
growth on an unimpregnated sponge,
patients in the control group did not
receive a placebo sponge. As a result,
surgeons were not blinded to study
group assignment.
Figure 1. Flow of Individuals From Randomization Through Analysis
753 Included in primary analysis
26 Excluded from per-protocol analysis
12 Eligibility criteria not met
9 Did not receive a sponge
3 Did not receive antibiotics
prior to incision
1 Received 4 sponges
1 Received 1 sponge
749 Included in primary analysis
727 Included in per-protocol analysis 733 Included in per-protocol analysis
16 Excluded from per-protocol analysis
1 Did not receive antibiotics
prior to incision
1 Unknown reason
753 Randomized to gentamicin-collagen
sponge intervention group
10 Did not receive a sponge
1 Received 1 sponge
749 Randomized to control group and
received control intervention
13 Lost to follow-up at 90 d 18 Lost to follow-up at 90 d
1502 Randomized
1544 Patients gave consent to
participate in study
42 Not randomized
17 Received antibiotics preoperatively
6 Unknown reason
3 Withdrew consent
3 Surgery canceled
2 Change in surgical procedure
1 Died prior to surgery
PREVENTION OF STERNAL WOUND INFECTIONS AFTER CARDIAC SURGERY
756 JAMA, August 18, 2010—Vol 304, No. 7 (Reprinted) ©2010 American Medical Association. All rights reserved.

Preoperatively, the use of nasal
mupirocin prophylaxis was allowed but
not required. Consistent with pub-
lished guidelines,7-9
the protocol called
for antibiotic regimens with cefazolin or
cefuroxime to be initiated 60 minutes
prior to skin incision. Vancomycin was
administeredtoindividualswhowereal-
lergic to cephalosporin or penicillin, or
those at increased risk of methicillin-
resistant Staphylococcus aureus coloni-
zation. It was permissible for ciprofloxa-
cin to be added to vancomycin if greater
gram-negative coverage was desired.
Dosing was weight based and was to be
continued for at least 24 hours, but not
more than 48 hours.7-9
The use of other
topicalantibioticswasprohibitedinboth
the gentamicin-collagen sponge group
and the control group.
A previous trial indicated that the ef-
fectiveness of the gentamicin-collagen
sponge was enhanced if rigid fixation of
thesternum,definedasuseofmorethan
6 wires, was achieved.10
Therefore, our
protocol called for the use of at least 7
sternal fixation wires. Standard preop-
erative demographics and intraopera-
tivevariableswerecollectedaswellasthe
following variables that were thought to
have a possible role in sternal wound in-
fection: diabetic control (level of hemo-
globin A1c), body mass index, adminis-
tration of insulin in the perioperative
period, perioperative serum glucose lev-
els, perioperative core temperature,
methodofsurgicalskinpreparation,and
durationofsurgery.Overallriskformor-
tality and morbidity was assessed using
the validated Parsonnet risk score.11
To comply with US Food and Drug
Administration regulations, informa-
tion regarding each individual’s race and
ethnicity was collected on the study case
reportform,whichwascompletedbysite
personnel from the individual’s medi-
cal record. The intent-to-treat popula-
tion included all randomized individu-
als. The per-protocol population, as
definedinthestatisticalanalysisplan,in-
cludedallrandomizedpatientswhocom-
pleted the study and had none of the fol-
lowing prespecified major protocol
deviations:(1)didnotmeeteligibilitycri-
teria unless waiver obtained prior to en-
rollment, (2) received treatment differ-
ent from that to which they were
randomized or received incorrect dos-
ingofgentamicin-collagensponge,or(3)
did not receive prophylactic antibiotics
prior to skin incision.
The primary study outcome was the
incidenceofsternalwoundinfectionoc-
curring within the period from surgery
through postoperative day 90. Key sec-
ondary efficacy end points included the
incidence of deep sternal wound infec-
tions,superficialsternalwoundinfections,
surgicallytreatedsternalwoundinfections
(definedasanytypeofsurgicalinterven-
tionforsternalwoundinfectioninclud-
ing opening the wound), postoperative
hospital length of stay, and score for
additionaltreatment,presenceofserous
discharge,erythema,purulentexudate,
separation of the deep tissues, isolation
of bacteria, and duration of inpatient
stay (ASEPSIS) through 90 days post-
operatively.12-14
The validated ASEPSIS
scoreassignspointsfor9variablesinclud-
ing antibiotics, drainage of pus under
localanesthesia,debridementofwound
undergeneralanesthesia,isolationofbac-
teria,durationofhospitalstaylongerthan
14days,anddailyassessmentsinvolving
theportionofwoundaffectedfor4sepa-
ratevariables(serousdischarge,erythema,
purulentexudate,andseparationofdeep
tissues).12-14
The minimum score is 0,
higher scores are worse, and there is no
theoreticalmaximumscore.Wealsoas-
sessed(1)changeinserumcreatininelevel
frombaselinetopeakthroughpostopera-
tiveday7orhospitaldischargeifearlier,
(2)assessmentofpainandwoundheal-
Table 1. Patient Demographics and Baseline Characteristics
Characteristic
No. (%) of Patientsa
Gentamicin-Collagen
Sponge (n = 753)
Control
(n = 749)
Patient demographics
Age, median (IQR), y 64.2 (58.0-71.5) 64.9 (57.2-72.1)
White race 688 (91.4) 683 (91.2)
Weight, median (IQR), kg 98.0 (86.1-113.0) 98.8 (85.0-111.1)
Body mass index, median (IQR) 33.1 (30.2-37.2) 32.8 (30.0-36.2)
Body mass index Ͼ30 574 (76.2) 563 (75.2)
Male sex 530 (70.4) 530 (70.8)
Medical history
History of hypertension 659 (87.5) 659 (88.0)
History of diabetes 493 (65.5) 513 (68.5)
Current or history of smoking 458 (60.8) 450 (60.1)
Current smoking 136 (29.7) 123 (27.3)
History of chronic obstructive pulmonary disease 117 (15.5) 107 (14.3)
History of peripheral vascular disease 105 (13.9) 89 (11.9)
Previous median sternotomy 52 (6.9) 42 (5.6)
History of TIA or stroke 77 (10.2) 81 (10.8)
History of myocardial infarction 233 (31.0) 245 (32.7)
History of congestive heart failure 89 (11.8) 90 (12.0)
History of hyperlipidemia 619 (82.2) 607 (81.0)
Steroid use Յ1 mo prior to surgery 28 (3.7) 33 (4.4)
Receiving dialysis preoperatively 4 (0.5) 2 (0.3)
Preoperative diagnostic values
Left ventricular ejection fraction, median (IQR), % 55 (45-60) 55 (45-60)
Serum glucose, median (IQR), mg/dL 125 (101-160) 124 (103-167)
Serum hemoglobin A1c, median (IQR), % 6.5 (5.9-7.6) 6.6 (5.9-7.7)
Hematocrit, median (IQR), % 39 (36-42) 39 (36-42)
Serum creatinine, median (IQR), mg/dL 1.0 (0.9-1.3) 1.0 (0.9-1.2)
Preoperative core temperature, median (IQR), °C 97.6 (97.0-98.2) 97.7 (97.0-98.2)
Preoperative hospital stay, median (IQR), d 1.0 (0-3.0) 1.0 (0-3.0)
Parsonnet risk score, median (IQR)b 9.0 (6.0-14.5) 9.0 (6.0-16.0)
Abbreviations: IQR, interquartile range; TIA, transient ischemic attack.
SI conversion factors: To convert creatinine to µmol/L, multiply by 88.4; glucose to mmol/L, multiply by 0.0555.
aUnless otherwise indicated.
bTheoretical range is 0 to 148; 50% in Parsonnet et al11
had a score between 0 and 9.

ing in individuals based on a structured
wound healing questionnaire adminis-
tered at 30, 60, and 90 days postopera-
tively,(3)emergencydepartmentorsur-
gical office visits secondary to wound
complaints, (4) rehospitalization and
mortalityrates,(5)painassessmentsfrom
surgerythroughpostoperativeday7and
amountofpainmedicationadministered
inthefirst3dayspostoperatively,and(6)
serum gentamicin levels in a subset of
sites. Blood was withdrawn at baseline
(Յ2 hours before implantation of 2
sponges), and then at of 2±0.5 hours,
4±0.5hours,8±0.5hours,12±1hours,
and24±2hoursafterclosureofthesur-
gicalwoundforcorelaboratorydetermi-
nationofserumgentamicinlevels.Acost
analysis was planned, but was not
performed due to the study’s negative
results.
Clinical Events Committee
The independent clinical events classi-
fication committee was composed of 3
infectious disease experts blinded to the
treatment assignments. Possible infec-
tions were identified by triggered events
in the electronic case report form, in-
cluding signs or symptoms of possible
infection, administration of postopera-
tive antibiotics, rehospitalization, and
death. Afterreview of all pertinentmedi-
cal records, the clinical events classifi-
cation committee determined the pres-
ence or absence, extent, and severity of
all possible infections using standard-
ized criteria including those from the
Centers for Disease Control and Preven-
tion12,13,15,16
andtheASEPSISscoringsys-
tem.12-14
The clinical events classifica-
tion committee also adjudicated the
followingsecondaryendpointsof(1)re-
hospitalization for sternal wound infec-
tion within 90 days postoperatively, (2)
presence of superficial or deep inci-
sional sternal wound infection, and (3)
presence of surgically treated sternal
wound infection. Infections not related
to the sternum (eg, infection at saphe-
nous vein harvesting sites, intravenous
catheter, or pneumonia) were not in-
cluded.
Statistical Analysis
Allstatisticalanalyseswereconductedby
the independent Duke University statis-
tical trial team. Sample size calculation
during the planning stage indicated that
a total of 1450 patients (randomized at
a ratio of 1:1) would be required to de-
tect a 50% relative reduction of sternal
wound infections occurring within the
period from surgery through postopera-
tive day 90 in the gentamicin-collagen
sponge group compared with the con-
trol group, with a power of 85% and a
2-sided type I error rate of .05. Based on
previous trials, we assumed a 7% ster-
nal wound infection rate in the control
group.
Table 2. Surgical Preparation and Intraoperative Characteristics
Characteristic
No. (%) of Patientsa
Gentamicin-
Collagen Sponge
(n = 753)
Control
(n = 749)
Preoperative
Nasal mupirocin 363 (48.2) 361 (48.2)
Shower with chlorhexadine soap 677 (90.0) 661 (88.3)
Oral mouthwash 228 (30.3) 228 (30.4)
Hair at operative site not removed 170 (22.6) 193 (25.8)
Preincision skin prep
Povidone-iodine 433 (57.5) 436 (58.2)
Alcohol 396 (52.6) 390 (52.1)
Chlorhexidine based 358 (47.5) 354 (47.3)
Intravenous antibiotics administered Յ60 min prior to incision 734 (97.5) 737 (98.4)
Type of antibiotic administered prior to incision
Cefazolin 403 (53.5) 394 (52.6)
Cefuroxime 176 (23.4) 191 (25.5)
Ciprofloxacin 14 (1.9) 17 (2.3)
Vancomycin 230 (30.5) 223 (29.8)
Prophylactic intravenous antibiotics discontinued Յ48 h 659 (87.5) 667 (89.1)
Surgical procedure performed
Isolated CABG 601 (80.0) 595 (79.4)
Isolated valve repair or replacement 68 (9.0) 79 (10.6)
Combined CABG plus valve surgery 79 (10.5) 73 (9.8)
No. of internal mammary arteries used
0 130 (17.3) 139 (18.6)
1 598 (79.4) 585 (78.1)
2 24 (3.2) 23 (3.1)
No. of wires used to close body of sternum
0-3 12 (1.6) 10 (1.3)
4-6 640 (85.0) 644 (86.0)
Ͼ6 99 (13.2) 92 (12.3)
No. of wires used to close manubrium
1 2 (0.3) 1 (0.1)
2 390 (51.8) 407 (54.3)
3 306 (40.6) 292 (39.0)
Ͼ3 53 (7.0) 46 (6.1)
Duration, median (IQR)
Aortic cross clamp, min 60 (43-86) 61 (42-86)
Cardiopulmonary bypass, min 88 (64-121) 90 (64-124)
Surgery, h 3.5 (2.9-4.4) 3.6 (2.9-4.5)
Peak serum glucose in first 24 h postoperatively, median (IQR),
mg/dL
163 (136-205) 161 (137-201)
Insulin, units administered in operating room plus first 24 h
postoperatively, median (IQR)
89 (49-132) 89 (51-133)
Perioperative allogeneic red blood cell transfusion given 442 (58.7) 438 (58.5)
Core temperature at end of surgery, median (IQR), °C 36.1 (35.7-36.6) 36.1 (35.7-36.6)
Required postoperative surgical reexploration 21 (2.8) 28 (3.7)
Intensive care unit postoperative duration of stay, median (IQR), d 2.0 (1.0-3.0) 2.0 (1.0-3.0)
Abbreviations: CABG, coronary artery bypass graft; IQR, interquartile range.
SI conversion factor: To convert glucose to mmol/L, multiply by 0.0555.
aUnless otherwise indicated.

The primary statistical analysis was
performed using standard intention-
to-treat methods. Unless otherwise in-
dicated, all results in the text, tables, and
figures reflect the intent-to-treat popu-
lation. As a prespecified secondary
analysis, we also performed a per-
protocol analysis, which included all
randomizedpatientswhocompletedthe
study and had no prespecified major
protocol deviations. Comparisons of the
primary end point (incidence of ster-
nal wound infections) between the 2
study groups were analyzed with
2-sided ␹2
testing that used data from
across all sites after checking for
treatmentϫsite interaction. For all sec-
ondary efficacy and subgroup analy-
ses, a nominal P value of less than .05
(2-sided) was adopted to indicate sta-
tistical significance, and the results were
considered descriptive.
Descriptive statistical comparisons
between the treatment groups were per-
formed using the ␹2
test or the Fisher
exact test as appropriate for the cat-
egorical secondary efficacy end points.
The t test or Wilcoxon rank sum test
were used as appropriate for compari-
son of continuous secondary efficacy
end points. The log-rank tests were used
to compare the time to first sternal
wound infection between the 2 study
groups. Kaplan-Meier survival curves
of time to first sternal wound infec-
tion also were presented.
Noformalinterimanalysiswasplanned
in this study. An independent data and
safetymonitoringcommitteemonitored
the trial on an ongoing basis. All statis-
ticalanalyseswereperformedusingSAS
software version 9.2 (SAS Institute Inc,
Cary, North Carolina).
RESULTS
Overall, 1502 individuals were en-
rolled at 48 US sites between December
21, 2007, and March 11, 2009. FIGURE 1
shows the flow of individuals from en-
rollment through randomization, to 90-
day follow-up. Of 753 patients random-
ized to receive 2 gentamicin-collagen
sponges, 741 received 2 sponges
(98.5%), 1 received 1 sponge (0.1%),
and 10 did not receive any sponges
(1.3%). One individual (0.1%) random-
ized to the gentamicin-collagen sponge
group received 4 sponges intraopera-
tively; 2 were inserted and then the sur-
geon needed to reevaluate the bypass
grafts and enough time had elapsed so
he removed the 2 sponges and in-
serted 2 new gentamicin-collagen
sponges prior to closing the sternum.
Of note, only 31 individuals (2.1%)
were lost to follow-up at 90 days (13
in the gentamicin-collagen sponge
group and 18 in the control group).
Only 12 of 1502 individuals did not
contribute information to the primary
end point. Due to the small effect made
by these 12 patients (0.8%), in the fi-
nal primary analysis with the intent-
to-treat population we treated them as
not having sternal wound infection.
Of the 1502 individuals in the study
population, there were 1060 men
(70.6%). Patients had a median body
mass index of 32.9 and 1006 had dia-
betes (67.0%). The control group
(n=749) and the gentamicin-collagen
sponge group (n=753) were balanced
with regard to baseline characteristics
including age, weight, diabetes, and
smoking history (TABLE 1). Periopera-
tive variables including preincision an-
tibiotics, type and duration of sur-
gery, and number of internal mammary
arteries used were also well balanced by
treatment group (TABLE 2).
Table 3. Sternal Wound Infection (SWI) and Other Postoperative End Points Through Postoperative Day 90
Characteristic
No. (%) of Patients [95% CI]a
P ValueGentamicin-Collagen Sponge (n = 753) Control (n = 749)
Intent-to-treat analysis
Any SWI (primary end point) 63 (8.4) [6.4-10.3] 65 (8.7) [6.7-10.7] .83
Surgically treated SWI 25 (3.3) [2.0-4.6] 37 (4.9) [3.4-6.5] .12
Superficial SWI 49 (6.5) [4.8-8.3] 46 (6.1) [4.4-7.9] .77
Deep SWI 14 (1.9) [0.9-2.8] 19 (2.5) [1.4-3.7] .37
ASEPSIS score, mean (SD)b 1.9 (6.4) 2.0 (7.2) .67
Rehospitalization for SWI 23 (3.1) [1.8-4.3] 24 (3.2) [1.9-4.5] .87
Visit to ED or physician office due to wound complaint 48 (6.4) [5.0-8.7] 52 (6.9) [5.7-9.7] .55
Postoperative hospital length of stay, median (IQR), d 6.0 (5.0-8.0) 6.0 (5.0-8.0) .88
Per-protocol analysis (n = 727) (n = 733)
Any SWI 61 (8.4) [6.4-10.4] 63 (8.6) [6.6-10.6] .89
Surgically treated SWI 23 (3.2) [1.9-4.4] 36 (4.9) [3.4-6.5] .09
Superficial SWI 48 (6.6) [4.8-8.4] 45 (6.1) [4.4-7.9] .72
Deep SWI 13 (1.8) [0.8-2.8] 18 (2.5) [1.3-3.6] .38
ASEPSIS score, mean (SD)b 1.8 (6.1) 1.9 (7.0) .85
Rehospitalization for SWI 22 (3.0) [1.8-4.3] 24 (3.3) [2.0-4.6] .79
Visit to ED or physician office due to wound complaint 46 (6.3) [4.9-8.7] 51 (7.0) [5.7-9.8] .52
Postoperative hospital length of stay, median (IQR), d 6.0 (5.0-8.0) 6.0 (5.0-8.0) .92
Abbreviations: ASEPSIS, additional treatment, the presence of serous discharge, erythema, purulent exudate, and separation of the deep tissues, the isolation of bacteria, and the
duration of inpatient stay; CI, confidence interval; ED, emergency department; IQR, interquartile range.
aUnless otherwise indicated. The 95% CIs for binary variables are calculated based on the Wald asymptotic confidence limits.
bThe median (IQR) was 0 (0-0) for both groups.

There was no significant difference
in sternal wound infections in pa-
tients randomized to the gentamicin-
collagen sponge group (63/753; 8.4%
[95% confidence interval {CI}, 6.4%-
10.3%]) compared with patients in the
control group (65/749; 8.7% [95% CI,
6.7%-10.7%]; P=.83) (TABLE 3). No sig-
nificant differences were observed be-
tween the sponge group and the con-
trol group, respectively, in superficial
sternalwoundinfections(49/753[6.5%;
95% CI, 4.8%-8.3%] vs 46/749 [6.1%;
95% CI, 4.4%-7.9%]) and deep sternal
wound infections (14/753 [1.9%; 95%
CI, 0.9%-2.8%] vs 19/749 [2.5%; 95%
CI, 1.4%-3.7%). Kaplan-Meier curves
for adjudicated sternal wound infec-
tion in the intent-to-treat population ap-
pear in FIGURE 2. Analysis using the
principal investigator’s assessment of
sternal wound infection for each indi-
vidual US site demonstrated results
similar to the clinical events classifica-
tion committee’s adjudicated events for
sternal wound infection within 90 days
postoperatively for the gentamicin-
collagen sponge group (148/753
[19.7%] compared with the control
group (150/749 [20.0%]; P=.86). In ad-
dition, analyses performed in the per-
protocol population (n=1460) revealed
similar results to the intent-to-treat
population (Table 3).
Exploratory analyses for the pri-
mary end point (adjudicated sternal
wound infection in the intent-to-treat
population) were conducted in sev-
eral subgroups related to our pre-
defined eligibility criteria for the sponge
group vs the control group, respec-
tively, of patients who were obese and
had diabetes (35/316 [11.1%] vs 45/
327 [13.8%]; P=.30), patients who had
diabetes but were not obese (7/177
[4.0%] vs 10/186 [5.4%]; P=.52), and
patients who were obese but did not
have diabetes (21/258 [8.1%] vs 10/
236 [4.2%]; P=.07).
Potential pathogens were isolated
with equal frequency from patients
with sternal wound infections in the
sponge group (27/753 [3.6%]) and in
the control group (32/749 [4.3%];
eTable 1 at http://www.jama.com).
Except for coagulase negative staphy-
lococci (involving 10 patients in the
controlgroupvs3patientsinthesponge
group), all pathogens were similarly
distributed in the 2 groups. This in-
cluded both sensitive and resistant
S aureus, gram-negative bacilli, and
streptococci including enterococcus.
Only 3 organisms from each group were
found to be resistant to gentamicin; 4 of
the 6 were Staphylococcus epidermidis
(eTable 2).
Peak serum gentamicin levels in 68
individuals ranged from 0.7 µg/mL to
4.6 µg/mL (mean, 2.3 µg/mL) and
decreased to a mean (SD) level of 1.0
(0.8) µg/mL by 24 hours after sponge
insertion (FIGURE 3). The percentage
increase in serum creatinine from
baseline to peak level through post-
operative day 7 or hospital discharge
was similar in both groups (mean
[SD] change of 34.0% [47.7%] for
the gentamicin-collagen sponge
group vs 33.3% [57.6%] for the con-
trol group).
Overall, 49 individuals required
reexploration of their surgical wound
(21 in the sponge group and 28 in the
control group). There were 46 deaths
observed from randomization through
90 days postoperatively (19 in the
sponge group [2.6%] and 27 in the
control group [3.6%]). There was no
difference in the frequency of adverse
events (eTable 3). No overt differences
were observed in wound healing be-
tween the 2 groups at 30, 60, or 90 days
postoperatively based on data from a
structuredsubjectquestionnaire(eTable
4). The median opioid equianalgesic
dosing17
in the first 3 days postopera-
tivelywassimilarinbothgroups(sponge
group: 34.3 mg; control group: 35 mg)
as were daily pain scores (data not
shown).
COMMENT
Our primary finding in this phase 3 ran-
domized controlled trial is that the gen-
tamicin-impregnated collagen sponge
did not reduce the rate of sternal wound
Figure 2. Kaplan-Meier Curve for Days From Surgery to Surgical Wound Infection (SWI)
0.15
0.10
0.5
Sponge intervention
Control
No. at risk
0
752
749
10
740
732
20
717
700
30
695
677
40
679
668
50
674
663
60
671
658
70
669
652
80
667
650
90
665
650
Period From Surgery to SWI, d
ProbabilityofSWI
Gentamicin-collagen sponge group
Control group
Log-rank P=.77
One patient in the sponge intervention had a missing value for SWI, so this person is not included in the at-risk
analysis.
Figure 3. Serum Gentamicin Levels Prior to
and 2, 4, 8, 12, and 24 Hours After Insertion
of 2 Gentamicin-Collagen Sponges
1.6
0.8
1.2
2.8
2.0
2.4
3.6
3.2
4.8
4.0
4.4
0.4
0
Baseline 2 h 4 h 8 h 12 h 24 h
Timepoints
GentamicinConcentration,µg/mL
These data were collected in 68 individuals at a sub-
set of study sites to confirm published findings of low
serum gentamicin levels after insertion of 2 sponges.
The box and whisker plot shows minimum, 25th per-
centile, median, 75th percentile, and maximum val-
ues. The solid dot represents the mean value.

infections in patients undergoing car-
diac surgery. These findings directly
contradict the data previously avail-
able on the efficacy of this technology
in wound infection prevention.6
Thegentamicin-collagensponge,de-
veloped to deliver a high concentration
of gentamicin to the skin and soft tissue
surroundingpostoperativewounds,has
undergonetestingforuseincardiacsur-
gery throughout northern Europe. Ini-
tially, in a single center trial in Finland,
542cardiacsurgerypatientsrandomized
toinsertionof1sponge(130mgofgen-
tamicin) during sternal closure vs con-
trolexhibitedanonsignificantreduction
insternalwoundinfection(4.0%vs5.9%;
P=.20).18
In a larger (n=2000) inves-
tigator-initiatedtrialconductedin2cen-
ters in Sweden, cardiac surgery patients
randomized to insertion of 2 sponges
(total of 260 mg of gentamicin) showed
a 53% decrease in sternal wound infec-
tion(4.3%vs9.0%;PϽ.001)anda46%
decrease in surgically treated sternal
woundinfection(2.1%vs3.9%;P=.02).6
This study served as strong preliminary
data for our trial.
For our trial, we enrolled individu-
als with diabetes, obesity, or both, to
study patients at higher risk for ster-
nal wound infection because the un-
met medical need is greatest in these in-
dividuals. Indeed, using these criteria
we observed an event rate of 8.7% in
the control group, which was slightly
higher than the 7% rate assumed in our
sample size and power calculation and
demonstrates that the lack of effective-
ness observed was not due to a defi-
ciency of treatable outcome events. Our
data do not allow us to identify with cer-
tainty the cause of the lack of efficacy
we observed. One potential explana-
tion that does not appear to apply in this
trial is that sternal infections were due
to gentamicin-resistant organisms.
However, we can speculate that genta-
micin may elute too rapidly to add ef-
ficacy to systemic preoperative antibi-
otics. In support of this theory is the
data from Friberg et al5
demonstrating
low wound and local levels of genta-
micin 12 hours after insertion of 2
sponges (total of 260 mg of gentami-
cin) between the sternal halves. Argu-
ing against this explanation, however,
is the fact that these data were ob-
tained in a subset of patients enrolled
in the trial with very positive results,6
so it appears that gentamicin levels were
indeed adequate to prevent 53% of all
sternal wound infections in that trial.6
Because the collagen-gentamicin
sponge was not effective in our trial, one
may ask why an earlier large study sug-
gested such a strong treatment benefit,6
especially because the dosing of the
sponge was the same in both studies and
our protocol mandated use of rigid ster-
nal fixation, identified by the previous
trial as an important factor associated
with sponge efficacy.10
Important differ-
encesbetweentheSwedishstudyandour
studyincludeseveralofthefollowingim-
portant quality-control measures that
were not incorporated in the previous
study:onsitemonitoringandsourcedata
verification, central adjudication of out-
comes by an independent blinded com-
mittee, and the inclusion of a large num-
ber of hospitals (48 vs 2).
Theimportanceoflargevalidationtrials
is evident from our results and from the
observation that findings from positive
single-centertrialsareoftennotconfirmed
inlargermulticentertrials.19
Furthermore,
ethnicandregionaldifferencesmayhave
produced differing results between this
US-basedtrialandthepreviousstudycon-
ductedinSweden.20
Forexample,thedis-
tributionofbacterialpathogenscanvary
betweencountries.21
IntheSwedishtrial
therewerenocasesofmethicillin-resistant
Saureus,22
whereasinourtrialsomepa-
tients, albeit a small percentage (6.3%),
hadmethicillin-resistantSaureusgrowth
from sternal wound infection (eTable 1
at http://www.jama.com), which may
not be sensitive to gentamicin even at
high levels. Thus, variations in the dis-
tribution of bacterial pathogens among
countries could affect efficacy in a trial
of infection prevention such as the pre-
sent one.
In conclusion, despite approval of the
gentamicin-collagen sponge in 54 coun-
tries outside of the United States and
positive results from a large Swedish
trial, our large multicenter US trial did
notfindthegentamicin-collagensponge
to be effective at preventing sternal
wound infection in the setting of car-
diac surgery.
Author Affiliations: Divisions of Perioperative Clini-
cal Research (Dr Bennett-Guerrero), Biostatistics and
Bioinformatics (Dr Lin and Ms Garg), Outcomes Re-
search (Dr Mark), Project Leadership (Ms Pridgen), and
Infectious Disease (Dr Corey), Duke Clinical Re-
search Institute, Duke University, Durham, North Caro-
lina; Department of Cardiovascular Sciences, East Caro-
lina Heart Institute, Greenville (Dr Ferguson); Indiana
Ohio Heart, Fort Wayne, Indiana (Dr Scavo); Mis-
souri Baptist Medical Center, St Louis (Dr Kouchou-
kos); and Saint Vincent’s Hospital, Birmingham, Ala-
bama (Dr Richardson).
Author Contributions: Dr Bennett-Guerrero had full
access to all of the data in the study and takes re-
sponsibility for the integrity of the data and the ac-
curacy of the data analysis.
Study concept and design: Bennett-Guerrero, Ferguson,
Lin, Mark, Corey.
Acquisition of data: Lin, Scavo, Kouchoukos,
Richardson, Pridgen, Corey.
Analysis and interpretation of data: Bennett-Guerrero,
Lin, Garg, Mark, Kouchoukos, Corey.
Drafting of the manuscript: Bennett-Guerrero, Lin,
Corey.
Critical revision of the manuscript for important in-
tellectual content: Ferguson, Lin, Garg, Mark, Scavo,
Kouchoukos, Richardson, Pridgen, Corey.
Statistical analysis: Lin, Garg.
Administrative, technical, or material support:
Ferguson, Mark, Kouchoukos, Richardson, Pridgen.
Study supervision: Bennett-Guerrero, Ferguson,
Kouchoukos, Corey.
Financial Disclosures: Dr Bennett-Guerrero reported
that he is in discussions with Excited States LLC re-
garding entering into a consulting agreement to ad-
vise on a clinical trial involving surgical wound infec-
tion prevention. Dr Ferguson reported receiving
honoraria from Innocoll Technologies Ltd (the study’s
sponsor) for participating on the steering committee.
Funding/Support: The study was sponsored by Inno-
coll Technologies Ltd and coordinated by the Duke
Clinical Research Institute, a department of Duke Uni-
versity, Durham, North Carolina. Each coauthor re-
ceived research funding and support from the Inno-
coll Technologies Ltd. None of the coauthors is or has
been employed by Innocoll Technologies Ltd.
Role of the Sponsor: The sponsor, Innocoll Technolo-
gies Ltd, designed the study and wrote the protocol
in conjunction with the Duke Clinical Research Insti-
tute and an external member of the steering commit-
tee (Dr Ferguson, East Carolina Heart Institute). The
sponsor was not involved in collection or manage-
ment of the data. The sponsor did not conduct any
statistical analyses, but did assist in analyzing and in-
terpreting the data. The sponsor did not prepare the
manuscript. Drs Bennett-Guerrero and Corey wrote
the first draft of the manuscript. The sponsor re-
viewed the manuscript and provided minor com-
ments. The study agreement provided Duke Univer-
sity freedom to publish the trial results without sponsor
approval; therefore, the sponsor did not formally ap-
prove the manuscript. The Duke Clinical Research In-
stitute wrote the protocol, gathered the data,
maintained and controlled the database, analyzed
the data, vouches for the data and analysis, wrote
the manuscript, and decided to publish the manu-
script.
Independent Statistical Analysis: Dr Lin, a Duke Uni-
versity faculty member and a coauthor, analyzed the
data and has verified that the results presented in this
article were provided by her.
SWIPE-1 Trial Group: Norbert E. Baumgartner, MD,

FACS (Michigan Cardiovascular Institute), William
Brinkman, MD, FAAP (Medical City Dallas Hospital),
Clay M. Burnett, MD (Olathe Medical Center), John
B. Casterline, MD (Cardio-Thoracic Surgeons, PC),
Manuel R. Castresana, MD, FCCM (Medical College
of Georgia Research Institute), Ramesh B. Cherukuri,
MD (Michigan Cardiovascular Institute), Thomas Chris-
topher, MD (Chippenham Medical Center), Allonso
Collar, MD, FACS (Thoracic and Cardiovascular Health-
care Foundation), Charles Cousar, MD (Jacksonville
Center for Clinical Research), Tracy Dorheim, MD (Ne-
braska Medical Center/Heart Consultants, PC), David
Duncan, MD (Forsyth Medical Center), Richard En-
gelman, MD (Baystate Medical Center), N. Martin Gie-
secke, MD (Texas Heart Institute), Allen Graeve, MD
(Multicare Health System), Chiwon Hahn, MD, FACS
(Henrico Doctors Hospital), Stephen Hazelrigg, MD
(Southern Illinois University School of Medicine), Rob-
ert Holmes, MD, FACS (Michigan Cardiovascular In-
stitute), Robert Kamienski, MD (Akron General Medi-
cal Center), Marc Kanchuger, MD (New York University
Medical Center), Gregory Keagy, DO (Genesis Health
Care System), Dean Kereiakes, MD, FACC (Lindner
Clinical Trial Center), William Killinger Jr, MD (Caro-
lina Cardiovascular Surgical Associates), Nicholas
Kouchoukos, MD (Missouri Baptist Medical Center),
Alan Kypson, MD (Brody School of Medicine, East
Carolina University), John Laschinger, MD, FACS (Mi-
datlantic Cardiovascular Associates), Stanley Lo-
chridge, MD (Medical Center East), George Maier, MD
(Gaston Memorial Hospital), Joseph Mathew, MD,
FASE (Duke University Medical Center), Charles
McCoy, MD (Wesley Medical Center), Thomas Mili-
tano, MD (Washington Adventist Hospital), Diane
Miller, MD (Portland VA Medical Center), Harold
Minkowitz, MD (Memorial Hermann Healthcare Sys-
tem), Stephen Olenchock Jr, DO (Saint Luke’s Hospital-
Allentown), Timothy Osborn, MD (Tomball Regional
Hospital), Ganga Prabhakar, MD (Iowa Heart Cen-
ter), Michael J. Reardon, MD (The Methodist Hospi-
tal), John Richardson Jr, MD (Saint Vincent’s Hospi-
tal), Gary Roach, MD (Kaiser Foundation Hospital),
Ronald Roddy, PhD (Duke Clinical Research Insti-
tute), Russell Ronson, MD (Brookwood Ambulatory
Care Center), Chittoor B. Sai-Sudhakar, MBBS, FACS,
FRCS (Ohio State University Medical Center), Vin-
cent Scavo, MD (Indiana/Ohio Heart), Alvaro Segura-
Vasi, MD (Eliza Coffee Memorial Hospital), Ravi
Sharma, MD (Regional Medical Center-Bayonet Point),
Linda M. Sundt, MD (Thomas Jefferson University Hos-
pital), Terrill E. Theman, MD (Saint Luke’s Hospital and
Health Network), James C. Todd III, MD (CV Surgi-
cal Associates, PA), Joseph T. Wingard, MD (Jack-
sonville Center for Clinical Research), and Hongqiu
Yang, PhD (Duke Clinical Research Institute).
Online-Only Material: eTables 1-4 are available at http:
//www.jama.com.
Additional Contributions: We thank the Duke Clini-
cal Research Institute coordinating center and staff,
Susan Cusack, BSN (regulator for Premier Research),
and the following members of the data and safety
monitoring board: Daniel Sexton, MD (chairman, De-
partment of Medicine, Division of Infectious Disease,
Duke University, Durham, North Carolina), John W.
Hammon Jr, MD (Department of Cardiothoracic Sur-
gery, Wake Forest University School of Medicine, Win-
ston-Salem, North Carolina), Shein Chung Chow, PhD
(Duke University, Department of Biostatistics and Bio-
informatics, Durham, North Carolina). Members of the
data and safety monitoring board received financial
compensation from Innocoll Technologies Ltd for their
contributions.
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