A Phase III Multicenter, Open Label Randomized Controlled Trial of Cefoxitin Versus Piperacillin-Tazobactam as Surgical Antibiotic Prophylaxis in Patients Undergoing Pancreatoduodenectomy
Phase: PHASE3
Conditions: Pancreatic Cancer, Pancreas Cancer, Pancreatic Diseases
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 1 of 44 
 
 
A Phase III Multicenter, Open Label Randomized Controlled Trial of Cefoxitin 
versus Piperacillin-Tazobactam as Surgical Antibiotic Prophylaxis in Patients 
Undergoing Pancreatoduodenectomy 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal 
Investigator/Department: 
Michael D’Angelica, MD 
Surgery / Hepatopancreatobiliary 
Co-Principal 
Investigator(s)/Department: 
T. Peter Kingham, MD 
Surgery / Hepatopancreatobiliary 
Investigator(s)/Department: 
Susan Seo, MD 
Jeffrey Drebin, MD 
William Jarnagin, MD 
Vinod Balachandran, MD 
Alice Wei, MD 
Kevin Soares, MD 
Mithat Gonen, PhD 
Medicine / Infectious Disease 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Epidemiology & Biostatistics 
Consenting 
Professional(s)/Department: 
Jeffrey Drebin, MD 
Michael D’Angelica, MD 
William Jarnagin, MD 
T. Peter Kingham, MD 
Vinod Balachandran, MD 
Alice Wei, MD 
Kevin Soares, MD 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
Surgery / Hepatopancreatobiliary 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
All Protocol Activities 
Basking Ridge 
Consent Only 
Commack 
Consent Only 
Westchester 
Consent Only 
 
 
 
Participating Institutions: 
PI's Name 
Site's Role 
Advocate Illinois Masonic Medical Center 
Ajay Maker, MD 
Data Collection 
Albany Medical Center 
Ankesh Nigam, MD 
Data Collection 
Baptist Memorial Healthcare 
Stephen Behrman, MD 
Data Collection 
Baylor Scott & White Health 
Scott Celinski, MD 
Data Collection 
Cleveland Clinic 
Garreth Morris-Stiff, MD 
Data Collection 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 2 of 44 
 
 
 
Duke University 
Kevin Shah, MD 
Data Collection 
East Carolina University 
Rebecca Snyder, MD 
Data Collection 
Emory University 
Shishir Maithel, MD 
Data Collection 
Fox Chase Cancer Center 
Sanjay Reddy, MD 
Data Collection 
Gundersen Lutheran Medical Foundation 
Travis Smith, MD 
Data Collection 
Hackensack Meridian Health (Hackensack 
University Medical Center) 
Marson Davidson, MD 
Data Collection 
Hackensack Meridian Health (Jersey Shore 
University Medical Center) 
Ronald Matteotti, MD 
Data Collection 
Hamilton Health Sciences Center 
(Juravinski Hospital) 
Pablo Serrano, MD 
Data Collection 
Indiana University 
Michael House, MD 
Data Collection 
Intermountain Healthcare 
Mark Ott, MD 
Data Collection 
Johns Hopkins University 
William Burns, MD 
Data Collection 
Massachusetts General Hospital 
Carlos Fernandez del Castillo, 
MD 
Data Collection 
Montefiore Health System 
Peter Muscarella II, MD 
Data Collection 
Mount Sinai Hosp-NY 
Umut Sarpel, MD 
Data Collection 
Northshore University HealthSystem 
Mark Talamonti, MD 
Data Collection 
Northwestern University 
David Bentrem, MD 
Data Collection 
Penn State Hershey 
Chad Gonczy, MD 
Data Collection 
Providence Health & Services (Portland 
Med Ctr) 
Pippa Newell, MD 
Data Collection 
Rhode Island Hospital 
Rachel Beard, MD 
Data Collection 
SUNY Stony Brook 
Aaron Sasson, MD 
Data Collection 
Sunnybrook Health Sciences Centre, 
Canada 
Paul Karanicolas, MD 
Data Collection 
Temple University 
Andreas Karachristos, MD 
Data Collection 
Ohio State University 
Mary Dillhoff, MD 
Data Collection 
Ottawa Hospital 
Kimberly Bertens, MD 
Data Collection 
Thomas Jefferson University Hospital 
Harish Lavu, MD 
Data Collection 
UC Davis Cancer Center 
Sepideh Gholami, MD 
Data Collection 
University of Chicago 
Kevin Roggin, MD 
Data Collection 
University of Iowa 
Carlos Chan, MD 
Data Collection 
University of Mississippi Medical Center 
Christopher Anderson, MD 
Data Collection 
University of Nebraska Medical Center 
Bradley Reames, MD 
Data Collection 
University of Texas Southwestern 
Adam Yopp, MD 
Data Collection 
University of Utah 
Courtney Scaife, MD 
Data Collection 
University of Wisconsin 
Sharon Weber, MD 
Data Collection 
Washington University 
Dominic Sanford, MD 
Data Collection 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 3 of 44 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 4 of 44 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 8 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 9 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 20 
4.1 
Design ........................................................................................................................... 20 
4.2 
Intervention .................................................................................................................... 20 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 21 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 22 
6.1 
Subject Inclusion Criteria ................................................................................................ 22 
6.2 
Subject Exclusion Criteria .............................................................................................. 22 
7.0 
RECRUITMENT PLAN ...................................................................................................... 22 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 23 
9.0 
TREATMENT/INTERVENTION PLAN............................................................................... 23 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................... 25 
11.0 
TOXICITIES/SIDE EFFECTS ............................................................................................ 28 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 31 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 33 
14.0 
BIOSTATISTICS ............................................................................................................... 33 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
35 
15.1 
Research Participant Registration .................................................................................. 35 
15.2 
Randomization ............................................................................................................... 35 
16.0 
DAT A M ANAGEMENT ISSUES........................................................................................ 35 
16.1 
Quality Assurance .......................................................................................................... 37 
16.2 
Data and Safety Monitoring ............................................................................................ 37 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 38 
17.1 
Privacy ........................................................................................................................... 39 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 39 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................... 40 
19.0 
REFERENCES .................................................................................................................. 41 
20.0 
APPENDICES ................................................................................................................... 44 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 5 of 44 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This phase III multi-center, open-label randomized controlled study will determine the most 
appropriate surgical antibiotic prophylaxis for patients undergoing 
pancreatoduodenectomy (PD) for all indications. This trial will compare two cohorts of 
enrolled patients undergoing PD at institutions participating in the American College of 
Surgeons’ National Surgical Quality Improvement Program (ACS NSQIP) Hepato- 
Pancreato-Biliary (HPB) Collaborative. The conduct of this trial will utilize ongoing ACS 
NSQIP data collection processes. Cohort 1 will be comprised of patients who receive 
cefoxitin, a second generation cephalosporin, as surgical antibiotic prophylaxis. Cohort 2 
will be comprised of patients who receive piperacillan-tazobactam, a broad-spectrum 
penicillin, as surgical antibiotic prophylaxis. Both cohorts with successful procedures will 
be followed for 30 days after the index operation according to ACS NSQIP standard 
operating procedures, with the primary intent to observe differences in postoperative 
surgical site infection (SSI) rates between cohorts. 
 
Title 
A Randomized Controlled Trial of Cefoxitin vs. Piperacillin- 
Tazobactam as Surgical Antibiotic Prophylaxis in Patients 
Undergoing Pancreatoduodenectomy 
Protocol Number 
17-418 
Phase 
III 
Methodology 
Open label 
Study Duration 
24 months 
Study Center(s) 
Multi-center 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 6 of 44 
 
 
 
Objectives 
Primary objective: 
• 
To determine if administration of piperacillin-tazobactam as 
surgical antibiotic prophylaxis results in decreased rates of 30- 
day surgical site infection (SSI) as compared to the 
administration of cefoxitin in patients undergoing 
pancreatoduodenectomy (PD) for all indications. 
Secondary objective(s): 
• 
To determine rates of non-SSI morbidity within 30 days of the 
operation associated with use of piperacillin-tazobactam as 
surgical antibiotic prophylaxis as compared to cefoxitin including 
pneumonia, intraoperative or postoperative unplanned 
intubation, intraoperative or postoperative pulmonary embolism, 
ventilator dependence over 48 hours, progressive renal 
insufficiency or acute renal failure requiring dialysis, urinary 
tract infection, intraoperative or postoperative stroke or cerebral 
vascular accident, intraoperative or postoperative cardiac arrest 
requiring CPR, intraoperative or postoperative myocardial 
infarction, intraoperative or postoperative transfusion of red 
blood cells, vein thrombosis requiring therapy, postoperative 
clostridium difficile colitis, sepsis, sepsis shock, pancreatic 
fistula, delayed gastric emptying, intraoperative drain 
management, need for percutaneous drain placement, 
withdrawal of care, and death during operation or postoperative 
death within 30 days of procedure. To determine rates of 
healthcare utilization within 30 days of the operation associated 
with use of piperacillin-tazobactam as surgical antibiotic 
prophylaxis as compared to cefoxitin including hospital stay > 
30 days, hospital readmission, and unplanned reoperation. 
Correlative objectives: 
• 
To determine the bacterial isolates and their sensitivities from 
those with postoperative surgical site infections. 
• 
To determine the bacterial isolates and their sensitivities from 
intraoperative bile cultures obtained during PD. 
Number of 
Subjects 
Cohort 1: 445 patients 
Cohort 2: 445 patients 
Total: 890 patients 
Diagnosis and 
Main Inclusion 
Criteria 
1. Patients undergoing elective pancreatoduodenectomy for either 
benign or malignant indications. 
2. Age ≥18 years of age 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 7 of 44 
 
 
 
Study 
Product(s), 
Dose, Route, 
Regimen 
Cohort 1: cefoxitin 2 grams (gm) intravenous (IV) once within 60 
minutes prior to PD incision. Cefoxitin should be re-dosed every 
120-240 minutes (2-4 hours) for up to 3 doses. For cases >12 
hours, cefoxitin should be re-dosed every 120-240 minutes (2-4 
hours) for up to 3 doses, then every 6 hours until end of surgery. It 
will be discontinued within 24 hours after anesthesia end time. 
Cohort 2: piperacillin-tazobactam 3.375-4.5 gm IV once 60 minutes 
prior to PD incision. 
For centers that employ 3.375 gm doses of IV piperacillin- 
tazobactam: Piperacillin-tazobactam should be re-dosed every 120- 
240 minutes (2-4 hours) for up to 3 doses. For cases > 12 hours, 
piperacillin-tazobactam should be re-dosed every 120-240 minutes 
(2-4 hours) for up to 3 doses, then every 6 hours until end of 
surgery. It will be discontinued within 24 hours after anesthesia end 
time. 
For centers that employ 4.5 gm doses of IV piperacillin-tazobactam: 
Piperacillin-tazobactam should be re-dosed every 120-240 minutes 
(2-4 hours) for up to 3 doses. For cases > 12 hours, piperacillin- 
tazobactam should be re-dosed every 120-240 minutes (2-4 hours) 
for up to 3 doses, then every 8 hours until end of surgery. It will be 
discontinued within 24 hours after anesthesia end time. 
Duration of 
administration 
Cohort 1: No longer than 24 hours after anesthesia end time. 
Cohort 2: No longer than 24 hours after anesthesia end time. 
Statistical 
Methodology 
Patients undergoing elective PD will be randomized to receive 
either cefoxitin or piperacillin-tazobactam, and then will be followed 
for SSI occurrence for 30 days after the operation according to 
standard ACS NSQIP data collection processes. A two-sided type I 
error rate of 0.05 and a power of 0.8 will be used to detect a 
reduction in SSI rates from 0.2 in the cefoxitin group to 0.13 in the 
piperacillin-tazobactam group. An interim efficacy analysis will be 
conducted at 223 patients per group (446 total). If the p-value for a 
test of no difference was <0.005 then the trial would stop at that 
time. Otherwise, the trial will continue enrolling patients until 445 
patients per group have been accrued, for a total of 890 patients 
overall. At the final analysis, the null hypothesis of no difference 
between groups will be rejected if the p-value for the test was 
<0.048. The study is expected to be completed within 24 months. 
All analyses will be conducted among resected patients. For the 
primary endpoint, a logistic regression model will be fitted where the 
outcome is SSI yes or no, the primary predictor is the randomized 
treatment group, and additional adjustment is made for 
preoperative biliary stent presence. There are a number of 
secondary endpoints as well. For secondary endpoints, logistic 
regression models with the secondary endpoint as the outcome, 
randomization group as the primary predictor, and additional 
adjustment for preoperative biliary stent presence will be used. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 8 of 44 
 
 
 
Funding 
Sources 
No external-not-for-profit funds are available for the conduct of this 
trial. Specifically, participating institutions must provide, at their own 
cost, the trial drugs (cefoxitin, piperacillin-tazobactam). 
The Americas Hepatopancreatobiliary Association (AHPBA) Clinical 
Trials Committee will provide material support for data analysis of 
this trial only. The American College of Surgeons will not provide 
additional funding for the conduct of this trial as the trial will be 
conducted using already-in-place processes at eligible and 
participating institutions. 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
This study aims to compare the differences in surgical site infection (SSI) rates of patients 
who undergo pancreatoduodenectomy (PD) for any indication by the type of surgical 
antibiotic prophylaxis administered. This is a randomized, open-label, multi-institutional 
phase III therapeutic trial of cefoxitin vs. piperacillan-tazobactam in patients undergoing 
PD. Data collection processes are based on the ACS NSQIP framework and 
infrastructure. After randomization, patients will receive one dose of either cefoxitin or 
piperacillan-tazobactam within 1 hour of incision time, redosed every 2-4 hours in the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 9 of 44 
 
 
operating room until closure of the incision, and discontinued within 24 hours following 
anesthesia end time. Patients will be followed for determination of SSI occurrences for 30 
days following their index operation, unless they withdraw their consent. 
 
Primary Objective: 
To compare the effectiveness of cefoxitin, a second generation cephalosporin (Cohort 1), 
with piperacillin-tazobactam, a broad-spectrum penicillin (Cohort 2), as surgical antibiotic 
prophylaxis in decreasing the overall rate of postoperative SSIs in patients undergoing PD. 
The primary endpoint, overall SSI rate, is defined as superficial incisional SSI, deep 
incisional SSI, or organ/space SSI within the first 30 days after the operation, as defined 
according to the ACS NSQIP data collection operations manual (Appendix A1 and A2). 
 
Hypothesis: A broad-spectrum penicillin as surgical antibiotic prophylaxis, will result in 
lower rates of SSIs (i.e., superficial, deep incisional, and organ/space) within 30 days from 
the index operation as compared to a standard second generation cephalosporin. 
 
Secondary Objective(s): 
To measure and compare the occurrences of non-SSI morbidity and healthcare utilization 
occurring in patients given a second generation cephalosporin as surgical antibiotic 
prophylaxis (Cohort 1) versus a broad-spectrum penicillin (Cohort 2). Secondary endpoints 
will also be collected according to the ACS NSQIP data collection operations manual 
within the first 30 days following the operation (Appendix A1 and A2). Specifically, 
secondary endpoints related to non-SSI morbidity include pneumonia, intraoperative or 
postoperative unplanned intubation, intraoperative or postoperative pulmonary embolism, 
ventilator dependence over 48 hours, progressive renal insufficiency or acute renal failure 
requiring dialysis, urinary tract infection, intraoperative or postoperative stroke or cerebral 
vascular accident, intraoperative or postoperative cardiac arrest requiring CPR, 
intraoperative or postoperative myocardial infarction, intraoperative or postoperative 
transfusion of red blood cells, vein thrombosis requiring therapy, postoperative clostridium 
difficile colitis, sepsis, sepsis shock, pancreatic fistula, delayed gastric emptying, 
intraoperative drain management, need for percutaneous drain placement, and death 
during operation or postoperative death within 30 days of procedure. Secondary endpoints 
related to healthcare utilization include a hospital stay > 30 days, hospital readmission, 
and unplanned reoperation. 
 
Hypothesis: Use of a broad-spectrum antibiotic will result in lower non-SSI morbidity and 
healthcare utilization rates as compared to a standard second generation cephalosporin. 
 
Correlative Studies: 
To determine the bacterial isolates and sensitivities of SSIs that occur in patients in both 
cohorts. 
To determine the bacterial isolates and sensitivities of intraoperative bile cultures obtained 
from patients in both cohorts. 
 
 
3.0 
BACKGROUND AND RATIONALE 
PANCREATODUODENECTOMY 

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IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 10 of 44 
 
 
The first successful pancreatoduodenectomy (PD) was performed as a two-stage 
procedure by Walter Kausch in 1909. Later, Allen O. Whipple popularized this 
procedure in a one-step procedure with a case series of 37 operations performed 
during his lifetime. A PD is performed for benign or malignant lesions in the 
periampullary region and involves an en bloc resection of the head of the 
pancreas, duodenum, proximal jejunum, gallbladder, and oftentimes the distal 
stomach with subsequent reconstruction of the alimentary tract. 
Because of high mortality rates nearing 25% following PD, the operative approach 
was nearly abandoned in the 1970s. During the 1980s and 1990s, however, high- 
volume centers developed in which complex alimentary procedures were 
commonly performed and, as a result, the benchmark for operative mortality 
following PD in the current era is now below 5%.1, 2 
Despite improving mortality rates due to improvements in patient selection, surgical 
technique, and perioperative care, the incidence of perioperative morbidity after PD 
remains high and ranges from 40% to 58%.1, 3, 4 The most common postoperative 
complications from PD include delayed gastric emptying (15-20%), pancreatic 
fistula (10-20%), and surgical site infection (SSI) (11-48%). As the majority of PD 
procedures are performed for periampullary malignancies, such as pancreatic 
cancer, perioperative complications can significantly delay receipt of adjuvant 
chemotherapy potentially impacting cancer outcome and patient survival.5-8 
 
 
3.2 
AMERICAN COLLEGE OF SURGEONS NATIONAL SURGICAL QUALITY 
IMPROVEMENT PROGRAM (ACS NSQIP) 
The American College of Surgeons National Surgical Quality Improvement 
Program (ACS NSQIP) is a nationally validated, risk-adjusted, outcome-based 
approach to measure and improve surgical care. It employs a prospective data 
registry to quantify 30-day, risk-adjusted surgical outcomes, which provide a 
standardized comparison of outcomes among all hospitals in the program. ACS 
NSQIP has a rich history stemming from the mid-1990s.9 Peer-reviewed studies 
have shown that ACS NSQIP is effective in improving the quality of surgical care 
and reducing complications, which lead to lower costs. In addition, collaborations 
with the federal government and collaboratives among participating hospitals have 
advanced ACS NSQIP effectiveness in surgical quality improvement. 
More than 700 hospitals voluntarily participate in the ACS NSQIP to improve 
surgical care quality. Hospitals subscribing to the program are provided 
benchmarked performance reports on 30-day, risk-adjusted surgical outcomes in 
comparison to all hospitals in the program.10,11 Trained data abstractors, called 
Surgical Clinical Reviewers (SCRs), at each hospital collect patient information 
pertaining to demographics, operative details, and postoperative outcomes from 
the clinical record using standardized definitions up to 30 days from the index 
operations. Outcomes are determined directly from the medical record, by 
communicating with any involved providers, or from the patient directly via mail or 
telephone. Operations are recorded using Common Procedural Terminology 
(CPT®) codes. While outpatient operations are included, minor operations in free- 
standing surgery centers or in offices are not. Submitted data are periodically 

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IRB Number: 17-418 A(6) 
Approval date: 20-Dec-2019 
Page 11 of 44 
 
 
audited to ensure quality and reliability between abstractors.12 All patient 
information submitted to the ACS NSQIP for quality improvement are de-identified 
and compliant with the Health Information Portability and Accountability Act 
(HIPAA) of 1996. 
The ACS NSQIP offers three program options (Essentials, Procedure Targeted, 
Small & Rural) to their subscribing hospitals based upon the hospital’s size, 
operative volume, and quality improvement goals. Hospitals that participate in the 
Procedure Targeted program can select from 34 different procedure types to 
“focus” their quality improvement efforts. For example, hospitals that participate in 
the Procedure Targeted Pancreatectomy program increase the number of 
pancreatectomies accrued into the ACS NSQIP registry (usually 100%) and collect 
additional procedure-specific details and outcomes (e.g., pancreatic fistula, 
delayed gastric emptying, etc.) to evaluate their performance on pancreatectomies. 
While the central tenant of the ACS NSQIP is surgical quality improvement, it has 
served myriad other purposes. For example, secondary analyses of the rich data 
collected have also made considerable contributions to clinical practice and health 
policy. Furthermore, as a registry, it might also be ideal for conducting trials. To 
overcome some of the contemporary challenges facing traditional randomized 
controlled trials (RCTs), recent trialists have begun leveraging the abundance of 
clinical registries as platforms for conducting randomized trials. The registry-based 
randomized trial, or randomized registry trial (RRT), aims to approach the 
statistical rigor of randomization, while expediting patient enrollment, minimizing 
cost, and improving generalizability of findings.13-17 This study represents the first 
RRT in surgery. 
Through the ACS NSQIP, hospitals with similar quality improvement interests and 
focuses form collaboratives to network, share best practices, and learn from one 
another. The Hepato-Pancreato-Biliary (HPB) Collaborative, founded in late 2014, 
is one prominent example of a collaborative formed through the ACS NSQIP and 
currently comprises over 80 hospitals. Studies have demonstrated that 
collaboratives improve surgical quality, and statewide initiatives, such as those in 
Tennessee and Illinois, have formed using this framework.18 Specific to this study, 
all hospitals participating in the ACS NSQIP HPB Collaborative will be eligible for 
participation as long as they agree to capture all PDs performed at their institution 
during the trial study period. 
This pragmatic trial will utilize the ACS NSQIP for data collection according to ACS 
NSQIP standard operating procedures already in place at participating hospitals. 
The use of standard of care antibiotics will allow the trial to be conducted in a 
pragmatic and “standard of care” fashion with no extraneous data collection 
(except those data required to safely conduct the trial) or treatment. Among the 
many outcomes monitored and tracked through the ACS NSQIP (Appendix A1 and 
A2), surgical site infections (SSIs) have always been a primary focus to improve 
surgical quality. Hospital performance is benchmarked using SSI rates. 
Standardized definitions based upon the US Centers for Disease Control 
definitions are used (see below). Although SSI rates overall across all types of 
operations have decreased in hospitals in the ACS NSQIP, it appears that SSIs 
occurring after PD have remained high.19 
3.3 
SURGICAL SITE INFECTIONS BACKGROUND 

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SSIs remain the most common and costly of all hospital acquired infections (HAIs), 
accounting for nearly 20% of all HAIs.20 SSIs are associated with increased length 
of stay (LOS) and a 2-to-11-fold increase in mortality. Though most patients 
recover from an SSI without long-term adverse sequelae, 77% of postoperative 
mortalities in patients with an SSI can be attributed to the infection itself.20,21 
The financial burden of SSIs is considerable, ranking as the most costly of the 
HAIs. The annual cost of SSI in the United States is estimated at $3.5-10 billion.21 
Increased costs from SSIs are driven by increased LOS, emergency department 
visits, and readmission rates.22 On average, a SSI extends hospital length of stay 
by 9.7 days, and increases the cost of hospitalization by over $20,000 per 
admission. Over 90,000 readmissions annually are attributed to SSI, costing an 
additional $700 million per year.20,21,23,24 Because up to 60% of SSIs were 
estimated to be preventable with the use of evidence-based measures, the rate of 
SSIs has become a pay-for-performance metric, such as the Medicare Hospital 
Value-Based Purchasing program. Accordingly, the multiagency Surgical Care 
Improvement Project (SCIP) and the ACS NSQIP have emphasized reduction of 
SSIs in quality improvement efforts.21,25-27 
The detection and diagnosis of a SSI depends on a standardized definition. The 
Centers for Disease Control and Prevention’s (CDC’s) National Healthcare Safety 
Network (NHSN) classification of SSIs is the most widely used (Figure 1).28 This 
definition is used for research, quality improvement, public reporting, and pay-for- 
performance comparisons. According to this definition, SSIs are classified by depth 
and tissue spaces involved: (1) a superficial incisional SSI involves only the skin or 
subcutaneous tissue; (2) a deep incisional SSI involves the fascia and/or muscular 
layers; and (3) an organ/space SSI involves any part of the body opened or 
manipulated during a procedure excluding the previously mentioned layers. These 
definitions are also employed by the ACS NSQIP when identifying and tracking 
SSIs across their approximately 700 participating hospitals (see Appendix A1 and 
A2). Because an essential strength of the ACS NSQIP is standardized, audited 
data abstraction processes, SSIs are tracked with less variability and more 
reliability than methods required of NHSN.29 
 

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Figure 1. CDC classifications of surgical site infection 28. 
To aid decision making for surgical antibiotic prophylaxis administration, a surgeon 
can preoperatively determine whether administration of antibiotic prophylaxis is 
appropriate based upon the expected microbial contamination of the operation, so- 
called wound classification.28 Using this CDC wound classification schema, PD is 
categorized as either a clean-contaminated (Class II; in the absence of a 
preoperatively placed biliary stent) or a contaminated (Class III; in the presence of 
the stent or cholangitis) surgical wound. 
3.4 
SURGICAL SITE INFECTIONS AND PANCREATODUODENECTOMY 
 
Despite rates of SSIs in other complex abdominal operations decreasing, the rate 
of SSIs after PD has remained unchanged, ranging from 11% to 48%.4 An internal 
analysis of data from the approximately 70 institutions within the Hepato- 
Pancreato-Biliary (HPB) Collaborative of the ACS NSQIP detailing 3,592 PDs in 
2015 revealed the rate of postoperative combined superficial incisional, deep 
incisional, and organ/space SSIs to be 21.7% (n = 778), nearly three-fold the rate 
seen after colon resections, which was 8.9% in ACS NSQIP hospitals from 2015. 
Factors associated with the high rate of SSIs in patients undergoing PD include 
preoperative biliary stenting, malnutrition, receipt of neoadjuvant therapy, and 
prolonged operative duration.30,31 
Approximately 70% of patients present with obstructive jaundice due to malignant 
compression of the distal common bile duct from a periampullary tumor, 
particularly pancreatic cancer.1 Frequently, these patients undergo biliary 
decompression with stent placement during endoscopic retrograde 
cholangiopancreatography (ERCP) to alleviate symptoms of hyperbilirubinemia, to 
correct coagulopathy, and to prevent development of ascending cholangitis and 
malnutrition. However, biliary decompression with a stent via ERCP results in free 
flow of intestinal contents into the normally steril biliary tree and results in biliary 
contamination with intestinal flora. Other logistical reasons for biliary stent 
placement include initial diagnosis by a gastroenterologist or as a bridge to surgical 
therapy (e.g., when neoadjuvant therapy is indicated for patients with borderline 
resectable disease).31 
Common to all of these reported complications is a strong association between 
preoperative biliary drainage and postoperative SSIs.23,32-34 Barreto et al. compared 
the characteristics of patients who underwent PD and developed SSIs compared to 
those who did not.35 All patients were given ertapenem as surgical antibiotic 
prophylaxis. They found 4.6-times greater odds of SSI in those who had biliary 
stenting (95% confidence interval 2.0-10.4). However, one-third of those with SSIs 
in their study did not have biliary stenting. Similarly, Sahora et al. found a SSI rate 
of 19% in those with biliary stenting compared to 9% in those without (p = 0.001).36 
When they compared intraoperative bile cultures of stented patients with and 
without SSIs, they found the presence of Enterobacter spp. (OR 2.4, 95% CI 1.5- 
4.1) and Citrobacter spp. (OR 2.3, 95% CI 1.1-5.2) in the bile significantly 
increased the odds of a SSI. Cortes et al. performed a similar study in France 
where 79 patients undergoing PD for were given a first-generation cephalosporin 
(i.e., cefazolin) as the prophylactic antibiotic and intraoperative bile cultures were 
obtained.37 Postoperative infectious complications were more common in the 

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cohort with culture-positive bile (65% vs. 37%, p = 0.003) and isolated microbes 
were resistant to cefazolin in 97%. Notably, 37% of patients had a SSI despite 
having culture-negative bile. More than 60% of the microorganisms isolated from 
SSI cultures were sensitive to piperacillin-tazobactam. Also in France, Sourrouille 
et al. prospectively examined 175 patients and found positive bile cultures in 81% 
of cases with preoperative biliary stenting.38 When examining the sensitivities of 
the microorganisms isolated from SSIs, 0% were sensitive to a second-generation 
cephalosporin, while 90% were sensitive to piperacillin-tazobactam. Similarly, 
Gavazzi et al. reported positive bile cultures in 58.9% patients following 
preoperative biliary drainage before PD.39 The reported incidence of SSI in that 
cohort was 20.8%. Limongelli et al. reported a SSI rate of 29% after PD, of which 
69% occurred in patients who had preoperative biliary stenting.40 Recently, Fong et 
al. retrospectively analyzed the microbiology of post-PD SSI cultures and their 
association with the choice of antibiotic prophylaxis from three high-volume 
institutions.3,41 1,623 patients underwent PD with a superficial SSI rate of 8.2% (n = 
133); low as expected for those with superficial SSIs only. Preoperative biliary 
stenting was the strongest predictor of postoperative SSI (OR 2.5; 95% CI 1.58- 
3.88), and microbes isolated in intraoperative bile cultures were similar to those 
identified in the SSI cultures. 
The costs of SSIs following PD have been evaluated by Enestvedt et al. in a 
single-institution trial at a high-volume academic center.42 Additional hospital costs 
of a wound infection and intra-abdominal abscess in the postoperative period 
following PD were $18,184 and $46,166, respectively. Ceppa et al. examined the 
ACS NSQIP data of 895 hepatopancreatobiliary procedures at their institution and 
showed that increasing severity of SSI resulted in greater costs.23 Notably, they 
showed that their reduction in SSI rates from 2007 to 2009 resulted in a cost 
savings of $11,462 per infection totaling approximately $370,000 in 2009. 
3.5 
SURGICAL CARE IMPROVEMENT PROJECT (SCIP) MEASURES 
In 2003 the Centers for Medicare and Medicaid Services (CMS) initiated a program 
to reduce preventable surgical complications including SSIs.27,43,44 This resulted in 
the creation of the Surgical Care Improvement Project (SCIP) measures.21,28,45 The 
3 SCIP measures with regard to antibiotics and SSI prevention include 1) 
administration of antibiotics within 1 hours of incision time, 2) selection of 
appropriate antibiotic therapy, and 3) discontinuation of antibiotics within 24 hours 
after surgery end time (or 48 hours for cardiac procedures). The antibiotic 
recommendations for gastrointestinal and biliary tract operations are summarized 
in Table 1. The current SCIP guidelines recommend a one-time dose of cefazolin 
(first generation of cephalosporin) of 2-3 grams given every 4 hours in patients with 
no evidence of -lactam allergy as antimicrobial prophylaxis in PD. In patients with 
a contaminated biliary tree, as seen in preoperative placement of a biliary stent, 
cefazolin, cefoxitin (2 grams every 2 hours), cefotetan (second generation 
cephalosporins) (2 grams every 6 hours), or ceftriaxone (third generation 
cephalosporin) (2 grams once). Alternative agents in patients with a -lactam 
allergy include clindamycin or vancomycin plus aminoglycoside or aztreonam or 
fluoroquinolone. 
Table 1. Recommended antibiotics for surgical antibiotic prophylaxis.45 

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Type of Procedure 
Recommended Agents 
Alternative for β-lactam 
Allergy 
Gastroduodenal 
Procedures involving entry into lumen of 
gastrointestinal tract (bariatric, 
pancreatoduodenectomy) 
Procedures without entry into 
gastrointestinal tract (antireflux, highly 
selective vagotomy) for high-risk patients 
Cefazolin 
Cefazolin 
Clindamycin or vancomycin 
+ aminoglycoside or 
aztreonam or 
fluoroquinolone 
Clindamycin or vancomycin 
+ aminoglycoside or 
aztreonam or 
fluoroquinolone 
Biliary tract 
Open procedure 
Cefazolin, cefoxitin, 
cefotetan, ceftriaxone, 
ampicillin-sulbactam 
Clindamycin or vancomycin 
+ aminoglycoside or 
aztreonam or 
fluoroquinolone 
Metronidazole + 
aminoglycoside or 
fluoroquinolone 
Laparoscopic procedure 
Elective, low-risk 
None 
None 
Elective, high-risk 
Cefazolin, cefoxitin, 
cefotetan, ceftriaxone, 
ampicillin-sulbactam 
Clindamycin or vancomycin 
+ aminoglycoside or 
aztreonam or 
fluoroquinolone 
Metronidazole + 
aminoglycoside or 
fluoroquinolone 
 
3.6 
SCIP MEASURES AND PANCREATODUODENECTOMY 
 
It remains unknown whether the standard choice of SCIP recommended 
antimicrobial surgical prophylaxis (i.e., first or second generation cephalosporin) in 
patients undergoing PD is the most effective at reducing SSIs.45-49 Observational 
studies in the United States, Europe, and Japan have suggested that a second 
generation cephalosporin may provide inadequate coverage for the microbes 
encountered during PD, especially in patients who have had preoperative biliary 
stenting. The most common isolates from SSIs following PD include the following: 
Enterococcus spp. (50-60%), Escherichia coli (30-40%), Klebsiella spp. (20-30%), 
Enterobacter (15-20%), and other organisms (10-15%). Due to both intrinsic and 
extrinsic resistance mechanisms Enterococcus spp is not appropriately covered by 
first, second, or third generation cephalosporins. In addition, although Enterobacter 
spp is appropriately covered by cephalosporins, a high rate of institutional 
resistance to ampillicin-sulbactam has rendered this regimen insufficient. 
A small retrospective pilot study at UCLA compared the rate of SSI following PD 
when antimicrobial surgical prophylaxis was changed from the SCIP recommended 
cefoxitin (62%), cefazolin and metronidazole (15%), and clindamycin (8%) to a 
piperacillin-tazobactam regimen.50 Antibiotics were redosed according to guidelines 
based on the half-life of the antibiotic. During the time period administrating the 
SCIP-recommended antibiotics, SSIs were 32.4 per 100 cases with Enterobacter 

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(50%) and Enterococcus (42%) the most common culture isolates. Following the 
change to the piperacillan-tazobactam regimen the SSI rate was 6.6 per 100 
cases, p=0.004). A similar study by Kondo et al. examined their single-institution 
experience in 116 patients undergoing PD following a change from second- 
generation cephalosporin antimicrobial surgical prophylaxis to a regimen with 
piperacillan-tazobactam in β-lactam tolerant patients.51 Following the change in 
antibiotic regimen, the incidence of SSI decreased from 46.6% to 24.1 (p=0.0116). 
In both studies, there was no significant difference in preoperative biliary stenting 
between the two antibiotic regimens. The efficacy of the piperacillan-tazobactam 
regimen in decreasing the rate of SSIs is not surprising, as this regimen is highly 
sensitive to all of the aforementioned common bacterial isolates in post-PD SSI. 
Currently, based on reported case series on PD and SSI, the most common 
surgical antibiotic prophylaxis is a second-generation cephalosporin, which may be 
inadequate based upon the microorganisms isolated from SSI cultures. A summary 
of the studies is presented in Table 2. 
3.7 
INTRODUCTION OF INVESTIGATIONAL TREATMENTS AND OTHER STUDY 
TREATMENTS 
3.7.1 
Overview of cephalosporins 
Cephalosporins, as a type of β-lactam antibiotic, inactivate the enzymes involved in 
bacterial cell wall synthesis and result in bactericidal activity. Clinically, they are 
frequently grouped into five “generations” based upon their spectrum of activity 
against aerobic, facultative gram-negative bacilli, and gram-positive bacteria.52 The 
most commonly utilized cephalosporins for surgical antibiotic prophylaxis are first- 
and second-generation.28,45-47 
Cefazolin is the only parenteral first-generation cephalosporin available in the 
United States, and is widely recommended and used for surgical antibiotic 
prophylaxis including pancreatic resections. Cefazolin has activity against the most 
common surgical-site microbes including methicillin-sensitive S. aureus and 
coagulase-negative staphylococci. However, for operations that involve entry into 
the lumen of the intestinal tract, such as in PD, cefazolin has limited to no activity 
against gram-negative bacilli. 
Cefoxitin is a second-generation cephalosporin with broadened activity against E. 
coli, Proteus species, Klebsiella species, and many strains of Bacteroides. Notably, 
it has less activity against Staphylococcus. It is therefore more appropriate and 
recommended as surgical antibiotic prophylaxis for operations involving entry into 
the lumen of the intestinal tract, biliary operations, and vaginal operations. As 
prophylaxis, 2g of cefoxitin is administered 30-60 minutes prior to surgical incision 
followed by re-dosing of 2g every 2-4 hours while the incision is open, and for no 
longer than 24 hours after the incision is closed.28,45 
Cefoxitin remains the only cephalosporin with antimicrobial activity suitable for 
gastrointestinal flora, specifically because of its activity against Bacteroides fragilis 
group. In addition to surgical antibiotic prophylaxis, cefoxitin is frequently used 
following penetrating trauma, uncomplicated acute appendicitis, perforated 
duodenal ulcers and other less severe intra-abdominal infections. 

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Adverse reactions to the cephalosporins are rare with the most common being 
diarrhea occurring 1-10% of the time. Severe life-threatening reactions occur <1% 
of the time. As a β-lactam, type I hypersensitivity reactions to cephalosporins can 
occur in 30% of patients with type I hypersensitivity reactions to penicillins.53,54 
However, 98% of penicillin skin test-positive patients are able to tolerate 
cephalosporins.55 Among patients who report penicillin reactions but do not 
undergo testing, between 0.2 and 8% will react if given a cephalosporin.53,56 

 
cephalosporin 
cephalosporin 
cephalosporin 
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Table 2. Summary of observation studies examining surgical site infections and surgical antibiotic prophylaxis in PD. 
 
Author(s), year 
Country 
Breadth 
N 
PBD 
Rate, % 
SSI 
Rate, 
% 
Surgical antibiotic 
prophylaxis (β-lactam 
tolerant) 
Most common bacterial isolates from 
SSI 
 
Cortes 2006 37 
France 
Single institution 
79 
43 
32 
First-generation 
Enterococcus spp., E. coli, and Klebsiella 
spp. 
 
Fong 2016 41 
USA, 
Italy 
Multi-institution 
1623 
52 
8* 
First- or second- 
generation cephalosporin 
Enterococcus spp., Enterobacter spp., S. 
aureus 
 
Howard 2006 33 
USA 
Single institution 
138 
62 
14 
Second- or third- 
generation cephalosporin, 
ampicillin- 
sulbactam 
 
Enterococcus spp., Klebsiella spp., yeast 
 
Kondo 2013 51 
Japan 
Single institution 
116 
71 
47 
Second-generation 
Enterococcus spp., E. coli, Klebsiella spp. 
 
 
Okano 2015 57 
Japan 
Multi-institution 
4147 
47 
27 
Second-generation 
cephalosporin 
Enteroccocus spp., Enterobacter spp., 
Klebsiella spp. 
 
Sourrouille 2013 38 
France 
Single institution 
175 
57 
21 
Second-generation 
Enterococcus spp., E. coli, Klebsiella spp. 
 
 
Sugiura 2012 58 
Japan 
Single institution 
408 
59 
51 
First-generation 
cephalosporin 
PBD: preoperative biliary drainage/stenting; SSI: surgical site infection; * superficial SSI only 
Enteroccocus spp., Enterobacter spp., 
Klebsiella spp. 
 
 
Page 18 of 44 
Barreto 2014 35 
India 
Single institution 
277 
39 
13 
Ertapenem 
Not reported 
Donald 2013 50 
USA 
Single institution 
176 
30 
32 
First- or second- 
Enterobacter spp., Enterococcus spp., 
generation cephalosporin 
coagulase-negative Staphylococcus 
Gavazzi 2016 39 
Italy 
Single institution 
180 
49 
25 
First-generation 
cephalosporin 
Enterococcus spp., E. coli, Klebsiella spp. 
Kent 2013 2 
USA 
Single institution 
550 
17 
First-generation 
31 
cephalosporin + 
metronidazole 
Staphylococcus spp., Enterococcus spp., 
E. coli 
Limongelli 2007 40 
UK 
Single institution 
220 
46 
45 
Second-generation 
cephalosoporin + 
metronidazole 
Enterococcus spp., lactose-fermenting 
coliform (e.g., Enterobacteriaceae spp.), 
non-lactose-fermenting coliform (e.g., 
Pseudomonas spp.) 
Sahora 2016 36 
USA 
Single institution 
1000 
50 
24 
Second-generation 
cephalosporin 
Enterococcus spp., Streptococcus spp., 
Klebsiella spp 
Sudo 2014 34 
Japan 
Single institution 
254 
54 
3* 
First- or fourth-generation 
Enterococcus spp., Klebsiella spp., 
cephalosporin 
Enterobacter spp. 

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3.7.2 
Overview of piperacillin-tazobactam 
 
Penicillins are another type of β-lactam antibiotic.59,60 As such, they have antimicrobial 
properties against gram-positive bacteria. Gram-negative bacteria frequently produce 
β-lactamases, enzymes that degrade β-lactam antibiotics, and confer antibiotic 
resistance. β-lactamase inhibitors are frequently administered in combination with 
penicillins to extend the antimicrobial activity of penicillins. Examples of β-lactamase 
inhibitors include clavulanate, sulbactam, and tazobactam. Adding tazobactam to 
piperacillin extends the activity of piperacillin against S. aureus, H. influenza, 
Neisseria gonorrhoeae, some Enterobacteriaceae, and anaerobes. Most importantly, 
it has greater activity against streptococci and enterococci. Nevertheless, it does not 
provide coverage for methicillin-resistant staphylococci (e.g., methicillin-resistant S. 
aureus [MRSA]), strains of enterococci that are resistant to both β-lactams and 
aminoglycosides, and certain gram-negative bacilli, such as resistant strains of 
Pseudomonas. As surgical antibiotic prophylaxis, piperacillin-tazobactam is 
administered at a dose of 3.375-4.5 g within 60 minutes prior to surgery and 
readministered during the surgical procedure based on half-life.28,45 
Serious adverse events from piperacillin-tazobactam are relatively infrequent.60 
Analysis of adverse events and laboratory tests performed during clinical trials 
revealed no unusual or unanticipated toxicity. Liver function tests may become 
abnormal, but these have almost always been transient and of little clinical 
consequence. Piperacillin-tazobactam possesses a safety profile characteristic of 
other β-lactam agents. Rates of reactions are comparable to those reported in the 
literature for piperacillin alone, ticarcillin-clavulanate, ampicillin-sulbactam, and 
imipenem-cilastatin. Among 1,111 patients enrolled in phase III trials of piperacillin- 
tazobactam, 174 (16%) had one or more adverse events, and this was no different 
compared to imipenem/cilastatin.59,60 Drug-related gastrointestinal disturbances were 
most common, occurring in 4.6% of patients given piperacillin-tazobactam. Diarrhea 
is the most common side effect experienced by patients, but often it does not impede 
completion of therapy. Furthermore, it is relatively free of adverse effects in a variety 
of dosages and clinical settings. Clearance of piperacillin-tazobactam may be 
impaired in patients with advanced renal disease, but compensatory dosage 
adjustment guidelines are standard and not complicated. This study does not include 
patients with renal failure. Allergy may be a limiting factor, but it appears to occur no 
more commonly than with other β-lactam agents, including cephalosporins.61 
3.8 
STUDY RATIONALE 
 
This study aims to leverage the ACS NSQIP data collection processes and 
infrastructure in collaboration with the AHPBA to prospectively compare two FDA 
approved antibiotics used as surgical antibiotic prophylaxis in patients undergoing 
PD. Specifically, this is a pragmatic, multi-center randomized controlled trial 
comparing the SCIP-recommended antimicrobial prophylaxis of a second generation 
cephalosporin, cefoxitin (which is FDA approved for use as a surgical antibiotic 
prophylaxis), with piperacillin-tazobactam (which is not FDA approved for surgical 
antibiotic prophylaxis, but is often used in this way off label) in patients undergoing 
elective PD. The scientific question and study design are attractive for the following 
reasons: 

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• 
Although the mortality rates following PD have decreased dramatically over 
the past three decades, perioperative morbidity rates remain high and are 
driven mainly by infectious complications from SSIs. 
• 
The implementation of SCIP measures has influenced the culture of quality 
improvement; however, adherence to performance measures alone in the 
absence of randomized controlled trials demonstrating improvement in patient 
outcomes is insufficient and is contrary to the spirit of continuous quality 
improvement. 
• 
Based upon abundant retrospective studies, institutional common bacterial 
isolates indicate that SCIP recommended antimicrobial prophylaxis with 
second generation cephalosporins does not adequately cover the organisms 
in SSIs occurring after PD. 
• 
Administration of piperacillan-tazobactam in preliminary studies has 
demonstrated improved efficacy compared to SCIP recommended 
antimicrobial prophylaxis in patients undergoing PD irrespective of 
preoperative biliary stenting. 
• 
For surgical quality improvement purposes, SSI rates are monitored and 
tracked as part of the ACS NSQIP in addition to many other relevant 
outcomes. Therefore, it is reasonable to utilize the ACS NSQIP quality 
improvement platform in collaboration with the AHPBA to assess the 
endpoints in this study. 
• 
This study represents the first randomized registry trial (RRT) in surgery, and 
can serve as proof of concept for other RRTs in the future. 
It is our primary hypothesis that the piperacillan-tazobactam regimen as antimicrobial 
prophylaxis will be associated with decreased rates of SSIs within 30 days compared 
to the SCIP-recommended antimicrobial prophylaxis with a second generation 
cephalosporin, cefoxitin, in patients undergoing elective PD for any indication. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a non-blinded, randomized, open-label, multi-institutional phase III therapeutic 
trial of cefoxitin vs. piperacillan-tazobactam as surgical antibiotic prophylaxis in 
patients undergoing elective PD for any indication. 
4.2 
Intervention 
After informed consent and randomization, patients will receive one dose of either 
cefoxitin or piperacillin-tazobactam within 1 hour of incision time, redosed every 2-4 
hours in the operating room until closure of the incision, and discontinued within 24 
hours after anesthesia end time. The half-lives of piperacillan-tazobactam and 
cefoxitin are 0.7-1.2 hours and 0.7-1.1 hours, respectively, in adults with normal renal 
function; therefore, American Society of Health-System Pharmacists (ASHP) 
therapeutic guidelines45 recommend redosing antibiotics two times the half life, or 
every 2-4 hours for both antibiotics until skin closure. Surgical antibiotic prophylaxis 
must be discontinued within 24 hours after anesthesia end time according to the 

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same guidelines. Patients will be followed for determination of SSI occurrences for 30 
days following their index operation, unless they withdraw their consent, using the 
ACS NSQIP standard operating procedures. 
 
 
 
 
4.3 
Correlative Studies 
4.3.1 
Postoperative SSI bacterial cultures 
Investigators will be encouraged to collect bacterial cultures and isolates obtained 
from postoperative SSIs whenever feasible. These data will not be collected by the 
standard ACS NSQIP mechanism, but instead will be studied in a retrospective 
fashion by participating institutions where surgeons routinely perform these cultures 
via chart review. Specifically, these correlative studies will be performed by 
institutions whose surgeons routinely culture bile and/or their postoperative SSIs. 
4.3.2 
Intraoperative bile bacterial cultures 
Investigators will be encouraged to collect bacterial cultures obtained intraoperatively 
from the biliary system in patients undergoing PD at the time of biliary duct 
transection whenever feasible. These data will not be collected by the standard ACS 
NSQIP mechanism, but instead will be studied in a retrospective fashion from 
institutions where surgeons routinely perform these cultures via chart review. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Each participating institution will supply the therapeutic drugs, cefoxitin and piperacillin- 
tazobactam, as part of institutional standard processes. No additional special instructions for 
maintaining, tracking, and monitoring of the therapeutic agents is necessary as part of this 
study and will be dependent on each participating institution’s standard processes , such as 
pharmacy oversight, antimicrobial stewardship program, etc. These agents are currently 
used in practice and are neither novel nor require additional approval from regulatory bodies 
for use in this study’s capacity. See Section 3.6 for additional details regarding each 
individual agent. 
In the rare event of national drug shortages affecting the therapeutic agents used in this trial, 
we will substitute cefoxitin (Mefoxin®) for cefotetan (Cefotan®).62 In this rare event, a dose of 
2 g administered within 60 minutes prior to skin incision will be administered. Doses are not 
adjusted for weight. Following the ASHP Clinical Guidelines,45 cefotetan, if used, will be 
redosed at 2 g every 6 hours until the skin incision is closed. The duration of cefotetan 
administration after incision close will be at the discretion of the treating surgeon as long as 
the antibiotic prophylaxis is discontinued, according to guidelines, within 24 hours of 
anesthesia end time. Continuation of cefotetan for longer than 24 hours as prophylactic 
purpose will constitute a protocol violation. However, administration of antibiotics 
postoperatively for non-prophylactic purposes (e.g. treatment for infection) should not be 
considered a protocol deviation. The time of administration and composition of the solvent 
will be at the discretion of the participating institution. 
National drug shortages for piperacillin-tazobactam (Zosyn®) are incredibly rare. Because 
there are no other available drugs of the same class with the same antimicrobial properties, 

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there will be no substitution for piperacillin-tazobactam in the event of a national shortage. In 
this circumstance, patient accrual will be halted until appropriate supplies can be obtained. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion 
criteria to be registered and enrolled to the study. Randomization of the patient to one of the 
two treatment arms may not occur until a subject is registered (see Section 15.0). 
6.1 
Subject Inclusion Criteria 
• 
Age ≥ 18 years 
• 
Patients undergoing elective pancreatoduodenectomy (PD) for any 
diagnosis/indication 
6.2 
Subject Exclusion Criteria 
• 
Patients undergoing a minimally invasive PD, such as laparoscopic or robotic PD 
• 
Patients with known and documented allergies to any of the penicillins, 
cephalosporins, or β-lactamase inhibitors 
• 
Patients who are otherwise ineligible to receive the antibiotics in this study 
• 
Patients highly unlikely to undergo PD according to the surgeon’s judgment, such 
as conditions amenable to pancreas enucleation, ampullectomy, etc. 
• 
Patients with long-term glucocorticosteroid use. The following uses of 
corticosteroids are permitted: single doses, topical applications (e.g., for rash), 
inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular) 
• 
Patients unable to provide informed consent 
• 
Creatinine clearance (CrCl) ≤ 40 mL/min 
• 
Patients receiving hemodialysis or peritoneal dialysis 
• 
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test 
• 
Patients with a known bacterial infection present at the time of surgery or who 
received antimicrobial therapy within 7 days prior to surgery 
7.0 
RECRUITMENT PLAN 
The study will be open to all patients seen at the participating (ACS NSQIP) Hepato- 
Pancreato-Biliary (HPB) Collaborative institutions who meet the eligibility criteria outlined in 
Section 6.0. Furthermore, to be a participating institution, the institution must be part of the 
ACS NSQIP Procedure Targeted Pancreatectomy program and agree to collect all PDs 
performed at their institution during the study period. 
Patients will be identified from surgical clinics for treatment of their disease. After a 
discussion of the patient’s disease and a formulation of the initial treatment plan, the 
physician-investigator will describe the study to the patient. The protocol will be discussed in 
a private clinic room or office. Details including the risks and obligations of the subjects will 
be explained. For non-English speaking patients, an independent translator will be available 

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to communicate the details of the protocol. A research coordinator or appropriate designee 
will be available either in the clinic or by phone to answer any additional questions. 
The investigators take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. There will be no limitation to access with regard to 
race or gender. Patients will be required to read, agree to, and sign an IRB-approved 
informed consent form prior to registration on this trial. The registration procedure will be 
conducted as described above. Patients will not receive payment for their participation on 
this study. 
8.0 
PRETREATMENT EVALUATION 
Following determination of patient eligibility, patients will undergo preparations for PD 
according to the operating surgeon’s standard of practice. No specific laboratory or radiologic 
examinations are necessary for this study beyond standard of practice. 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
OVERVIEW 
Study subjects who agree and are eligible to participate in this study will sign an 
informed consent at the time the treating surgeon recommends PD for their medical 
condition. Once informed consent is obtained and all eligibility criteria are met as 
detailed in Section 6.0, patients will undergo PD at the discretion of the treating 
surgeon. 
9.2 
STUDY TREATMENT 
For this study, the term “study treatment” refers to either cefoxitin or piperacillan- 
tazobactam administered as surgical antibiotic prophylaxis. The procedure, 
pancreatoduodenectomy (PD), is standard of care for both benign and malignant 
conditions of the periampullary region (i.e., the area around and including the head of 
the pancreas). 
Cefoxitin or piperacillan-tazobactam are drug products, administrated intravenously, 
and supplied by each participating institution. The trial drugs, cefoxitin and 
piperacillin-tazobactam, will be supplied by each participating institution and no 
external-not-for-profit funding will be used to obtain these trial drugs for participating 
institutions. Storage conditions are standard and described in the medication labels. 
PD will be performed in usual standard of care practice by the treating surgeon as 
described in Section 9.5. 
Administration and dosing are based on published national guidelines, specifically 
those of the American Society of Health-System Pharmacists (ASHP).28,45 As a 
pragmatic trial, the administration and dosing are also based upon currently in-place 
measures as defined by the SCIP and the US CDC on surgical antibiotic 
prophylaxis.21,28 
9.3 
CEFOXITIN ADMINISTRATION SCHEDULE AND DOSE ADJUSTMENT 
 
Cefoxitin will be administered intravenously within 60 minutes (1 hour) of incision of 
the PD. Doses are not adjusted based on weight. No adjustments are necessary 
based upon renal function (i.e., glomerular filtration rate [GFR]) as patients requiring 

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dialysis are excluded. Cefoxitin will be re-administered during the operation every 
120-240 minutes (2 hours) up to 3 doses until close of incision. For cases >12 hours, 
cefoxitin should be re-dosed every 120-240 minutes (2-4 hours) for up to 3 doses, 
then every 6 hours until end of surgery. As a pragmatic trial, the duration of cefoxitin 
administration after incision close will be at the discretion of the treating surgeon as 
long as the antibiotic prophylaxis is discontinued, according to guidelines, within 24 
hours of anesthesia end time. Continuation of cefoxitin for longer than 24 hours as 
prophylactic purpose will constitute a protocol violation. However, administration of 
antibiotics postoperatively for non-prophylactic purposes (e.g. treatment for infection) 
should not be considered a protocol violation. The time of administration and 
composition of the solvent will be at the discretion of the participating institution. 
In the rare event of national drug shortages affecting the therapeutic agents used in 
this trial, we will substitute cefoxitin (Mefoxin®) for cefotetan (Cefotan®).62 In this rare 
event, a dose of 2 g administered within 60 minutes prior to skin incision will be 
administered. Doses are not adjusted for weight. Following the ASHP Clinical 
Guidelines,45 cefotetan, if used, will be redosed at 2 g every 6 hours until the skin 
incision is closed. The duration of cefotetan administration after incision close will be 
at the discretion of the treating surgeon as long as the antibiotic prophylaxis is 
discontinued, according to guidelines, within 24 hours of anesthesia end time. 
Continuation of cefotetan for longer than 24 hours as prophylactic purpose will 
constitute a protocol violation. However, administration of antibiotics postoperatively 
for non-prophylactic purposes (e.g. treatment for infection) should not be considered 
a protocol violation. The time of administration and composition of the solvent will be 
at the discretion of the participating institution. 
9.4 
PIPERACILLAN-TAZOBACTAM ADMINISTRATION SCHEDULE AND DOSE 
ADJUSTMENT 
A single dose of 3.375-4.5 gm of piperacillan-tazobactam will be given intravenously 
within 60 minutes (1 hour) of incision of the PD. Additional doses of 3.375-4.5 grams 
of piperacillan-tazobactam will be given every 120-240 minutes (2-4 hours) until 
closure of skin incision following national guidelines.45 For centers that employ 
3.375 gm doses of IV piperacillin-tazobactam: Piperacillin-tazobactam should be 
re-dosed every 120-240 minutes (2-4 hours) for up to 3 doses. For cases > 12 hours, 
piperacillin-tazobactam should be re-dosed every 120-240 minutes (2-4 hours) for up 
to 3 doses, then every 6 hours until end of surgery. For centers that employ 4.5 gm 
doses of IV piperacillin-tazobactam: Piperacillin-tazobactam should be re-dosed 
every 120-240 minutes (2-4 hours) for up to 3 doses. For cases > 12 hours, 
piperacillin-tazobactam should be re-dosed every 120-240 minutes (2-4 hours) for up 
to 3 doses, then every 8 hours until end of surgery. As a pragmatic trial, the duration 
of piperacillin-tazobactam administration after incision close will be at the discretion of 
the treating surgeon as long as the antibiotic prophylaxis is discontinued, according to 
guidelines, within 24 hours of anesthesia end time. Continuation of piperacillin- 
tazobactam for longer than 24 hours as prophylactic purpose will constitute a protocol 
violation. However, administration of antibiotics postoperatively for non-prophylactic 
purposes (e.g. treatment for infection) should not be considered a protocol violation. 
The time of administration and composition of the solvent will be at the discretion of 
the participating institution. There will be no adjustment of dosage. Note specifically 
that doses of 3.375 and 4.5 grams are allowed in this protocol because these two 
dosages have equivalent concentrations and pharmacokinetics are similar (see 
Appendix C). 

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National drug shortages for piperacillin-tazobactam (Zosyn®) are incredibly rare. 
Because there are no other available drugs of the same class with the same 
antimicrobial properties, there will be no substitution for piperacillin-tazobactam in the 
event of a national shortage. In this circumstance, patient accrual will be halted until 
appropriate supplies can be obtained. 
9.5 
PANCREATODUODENECTOMY 
Pancreatoduodenectomy is considered standard of care for benign and malignant 
conditions of the periampullary anatomical region (i.e., the area around and including 
the head of the pancreas). Following determination of patient eligibility, patients will 
undergo PD according to the operating surgeon’s standard of practice. The 
perioperative care provided to both study treatment groups, including hair removal 
technique and skin preparation, will follow the standard practice of the operating 
surgeon in accordance with any standard operating procedures of the institution. 
Type of surgical incision, intraoperative use of sponges to contain contamination, 
glove and instant changes and saline irrigation of the surgical site, use and 
management of surgical drains, and closure of the incision at the end of surgery will 
be administered according to the preference of the surgeon. Additionally, use of 
wound protectors, topical antibiotics, and external wound vacuum dressings will be at 
the discretion of the surgeon. Use of nasogastric, gastrostomy or jejunostomy tubes 
as well as enteral or parenteral nutrition also will be at the discretion of the surgeon. 
Surgical antimicrobial prophylaxis will be continued following closure of the incision at 
the discretion of the treating surgeon so long as the antimicrobial prophylaxis is 
discontinued according to guidelines within 24 hours of anesthesia end time. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
SCREENING/PREOPERATIVE PHASE 
 
Patients must provide a signed informed consent prior to any study-specific 
evaluations including screening. Eligibility will be determined according to the 
inclusion/exclusion criteria as described in Section 6.0. Patients must meet all 
eligibility criteria to be considered for enrollment in the study. All screening 
procedures must be performed within 21 days prior to PD unless otherwise stated. All 
data will be collected as part of American College of Surgeon National Surgical 
Quality Improvement Program (ACS NSQIP) by trained data collectors according to 
standard operating procedures and definitions (see Section 3 for description; 
Appendix A1 and A2 for data collection definitions). 
10.1.1 Patient demographics and other baseline characteristics 
The data that will be collected on patient characteristics prior to PD include: 
• 
Date of birth 
• 
Gender 
• 
Race 
• 
Hispanic ethnicity 
• 
Preferred language 
• 
Hospital admission date 
• 
Operation date 
• 
Common Procedural Terminology (CPT) code for operation 

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• 
In/Out patient status 
• 
Origin status 
• 
Principal anesthetic technique 
• 
Surgeon specialty 
• 
Surgeon National Provider Identification (NPI) number 
• 
Height 
• 
Weight 
• 
Diabetes mellitus requiring therapy with non-insulin agents or insulin 
• 
Current smoker within one year of operation 
• 
Dyspnea 
• 
Functional health status 
• 
Ventilator dependent 
• 
Chronic obstructive pulmonary disease (COPD) 
• 
Ascites within 30 days prior to surgery 
• 
Congestive heart failure (CHF) within 30 days prior to surgery 
• 
Hypertension requiring medication 
• 
Acute renal failure 
• 
Currently requiring or on dialysis 
• 
Disseminated cancer 
• 
Open wound (with or without infection) 
• 
Steroid/Immunosuppressant use for a chronic condition 
• 
>10% loss of body weight in the 6 months prior to surgery 
• 
Bleeding disorders 
• 
Blood transfusions within 72 hours prior to surgery start time 
• 
Sepsis within 48 hours prior to surgery 
• 
Preoperative laboratory values (within 90 days of the operation) 
o Serum sodium 
o Blood urea nitrogen 
o Serum creatinine 
o Albumin 
o Total bilirubin 
o Aspartate transaminase (AST)/serum glutamin-oxaloacetic 
transaminase (SGOT) 
o Alkpaline phosphatase 
o White blood cell count (WBC) 
o Hematocrit 
o Platelets 
o International normalized ratio (INR) 
o Partial Thromboplastin Time (PTT) 
• 
American Society of Anesthesiology (ASA) Classification 
• 
Presence of preoperative jaundice 
• 
Presence of a preoperative biliary stent 
• 
Receipt of chemotherapy within 90 days of the operation 
• 
Receipt of radiation therapy within 90 days of the operation 
10.2 
TREATMENT PHASE 
 
Patients will be randomized after informed consent to either receive cefoxitin or 
piperacillan-tazobactam according to the following process: 

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After informed consent is obtained, patients will be randomized 1:1 and stratified 
based upon preoperative biliary stent presence. Site investigators will contact the trial 
coordinating center for randomization (see Section 14.0 for details). Randomization 
will occur before the day of the operation (see Section 15.2 for details). 
Following randomization and administration of the assigned surgical antibiotic 
prophylaxis, the following perioperative data will be collected according to standard 
ACS NSQIP operating procedures and definitions (see Appendices A1 and A2 for 
additional details): 
• 
Emergency operation status 
• 
Wound classification 
• 
Surgical wound closure 
• 
Operation start and end times 
• 
Additional operations/procedures performed simultaneously on the same patient 
• 
Need for intraoperative blood transfusion within 72 hours of surgery start time 
• 
Operative approach 
• 
Type of surgical incision 
• 
Use of a wound protector 
• 
Pancreatic duct size at the time of the operation 
• 
Pancreatic gland texture at the time of the operation 
• 
Type of pancreatic reconstruction performed, if any 
• 
Presence and type, if appropriate, of surgical drains 
• 
If surgical drains are placed, whether they are placed to suction 
• 
Need for vascular resection 
10.3 
POSTOPERATIVE PHASE 
Following PD and administration of the assigned surgical antibiotic prophylaxis, 
patients will be followed for 30 days. The following data will be collected during this 
time period according to standard ACS NSQIP operating procedures and definitions 
(details in Section 12.0; Appendices A1 and A2): 
• 
Superficial incisional surgical site infection (SSI) 
• 
Deep incisional SSI 
• 
Organ/space SSI 
• 
Wound disruption 
• 
Pneumonia 
• 
Intraoperative or postoperative unplanned intubation 
• 
Intraoperative or postoperative pulmonary embolism 
• 
On ventilator >48 hours 
• 
Progressive renal insufficiency 
• 
Acute renal failure requiring dialysis 
• 
Urinary tract infection 
• 
Intraoperative or postoperative stroke/cerebral vascular accident (CVA) 
• 
Intraoperative or postoperative cardiac arrest requiring CPR 
• 
Intraoperative or postoperative myocardial infarction 
• 
Venous thrombosis requiring therapy 
• 
Sepsis 
• 
Clostridium difficile infection 
• 
Need for postoperative blood transfusion within 72 hours of surgery start time 

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• 
Acute hospital discharge date 
• 
Hospital discharge destination 
• 
Death during operation or postoperative death within 30 days of procedure 
• 
Date of death 
• 
Hospital readmission 
• 
Unplanned reoperation 
• 
Drain amylase, specifically on postoperative day #1 and highest drain amylase 
from postoperative days #2-30, if surgical drain was placed at the time of the 
operation, and still present for drain amylase level assessment 
• 
Date of removal of last surgical drain, if surgical drain(s) placed at the time of the 
operation 
• 
Presence of pancreatic fistula 
• 
Presence of delayed gastric emptying 
• 
Placement of percutaneous drain 
• 
Malignancy versus benign pathology 
• 
If malignant, pathologic American Joint Committee on Cancer stage 
• 
If benign, tumor size 
For the purposes of this study, the ACS NSQIP must collect additional data to ensure 
patient safety and the integrity of this study. These are listed below and additional 
details can be found in Appendix A3: 
• 
Whether the patient is a participant in this study 
• 
To which treatment arm the patient was randomized 
• 
The type of protocol violation, if any 
• 
Grade of drug reaction due to the therapeutic treatment, if any 
ACS NSQIP will provide additional fields for these data to be stored in the same database that will 
house all other data collected for this study. 
11.0 
TOXICITIES/SIDE EFFECTS 
Measures taken to ensure the safety of patients participating in this trial are based upon 
routine monitoring at each participating institution for drug reactions. Specifically, patients 
enrolled in this study will be evaluated by the study team at each participating institution 
clinically after administration of the therapeutic drugs, cefoxitin or piperacillin-tazobactam, as 
surgical antibiotic prophylaxis. Because the drugs of study are currently routinely and widely 
used, we do not anticipate uncovering additional adverse events beyond those already 
known of cefoxitin and piperacillin-tazobactam. 
11.1 
CEFOXITIN TOXICITY 
11.1.1 Significant Adverse Reactions 
 
1% to 10%: Gastrointestinal: Diarrhea 
<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, bone 
marrow depression, dyspnea, eosinophilia, exacerbation of myasthenia gravis, 
exfoliative dermatitis, fever, hemolytic anemia, hypotension, increased blood urea 
nitrogen, increased serum creatinine, increased serum transaminases, interstitial 
nephritis, jaundice, leukopenia, nausea, nephrotoxicity (increased; with 
aminoglycosides), phlebitis, prolonged prothrombin time, pruritus, 

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pseudomembranous colitis, skin rash, thrombocytopenia, thrombophlebitis, toxic 
epidermal necrolysis, urticaria, vomiting 
11.1.2 Other Adverse Reactions 
 
Hypersensitivity: Use with caution in patients with a history of penicillin allergy, 
especially IgE-mediated hypersensitivity reactions (e.g., anaphylaxis, angioedema, 
urticaria). If a hypersensitivity reaction occurs, discontinue immediately. 
Superinfection: Prolonged use may result in fungal or bacterial superinfection, 
including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; 
CDAD has been observed >2 months after antibiotic treatment. 
GI disease: Use with caution in patients with a history of gastrointestinal disease, 
particularly colitis. 
Renal impairment: Use with caution in patients with renal impairment; modify dosage 
in severe impairment. 
Seizure disorders: Use with caution in patients with a history of seizure disorder; high 
levels, particularly in the presence of renal impairment, may increase risk of seizures. 
Elderly population: cefoxitin is known to be substantially excreted by the kidney, and 
the risk of toxic reactions to this drug may be greater in patients with impaired renal 
function. Elderly patients are more likely to have decreased renal function; use care in 
dose selection and monitor renal function. 
11.2 PIPERACILLIN-TAZOBACTAM TOXICITY 
11.2.1 Significant Adverse Reactions 
 
Cardiovascular: Phlebitis (1%), flushing (≤1%), hypotension (≤1%), thrombophlebitis 
(≤1%) 
Central nervous system: Headache (8%), insomnia (7%), rigors (≤1%) 
Dermatologic: Skin rash (4%), pruritus (3%), purpura (≤1%) 
Endocrine & metabolic: Hypoglycemia (≤1%), decreased serum albumin, decreased 
serum glucose, decreased serum total protein, electrolyte disturbance (increases and 
decreases in sodium, potassium, and calcium), hyperglycemia, hypokalemia, 
increased gamma-glutamyl transferase 
Gastrointestinal: Diarrhea (11%), constipation (8%), nausea (7%), dyspepsia (3%), 
vomiting (3%), abdominal pain (1%), pseudomembranous colitis (≤1%) 
Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin, 
eosinophilia, leukopenia, neutropenia, positive direct Coombs test, prolonged 
bleeding time, prolonged partial thromboplastin time, prolonged prothrombin time, 
thrombocythemia, thrombocytopenia 
Hepatic: Increased serum alkaline phosphatase, increased serum ALT, increased 
serum AST, increased serum bilirubin 
Hypersensitivity: Anaphylaxis (≤1%) 

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Infection: Candidiasis (2%) 
Local: Injection site reaction (≤1%) 
Neuromuscular & skeletal: Arthralgia (≤1%), myalgia (≤1%) 
Renal: Increased blood urea nitrogen, increased serum creatinine 
Respiratory: Epistaxis (≤1%) 
<1%, postmarketing, and/or case reports (Limited to important and life-threatening): 
Acute generalized exanthemous pustulosis, agranulocytosis, Clostridium difficile 
associated diarrhea, convulsions, drug reaction with eosinophilia and systemic 
symptoms (DRESS) syndrome, eosinophilic pneumonitis, erythema multiforme, 
exfoliative dermatitis, hemolytic anemia, hypersensitivity reaction, jaundice, 
pancytopenia, shock, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis 
(TEN) 
11.2.2 Other Adverse Reactions 
 
Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal 
hypersensitivity (anaphylactic/anaphylactoid) reactions have been reported in patients 
on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history 
of sensitivity to multiple allergens, or previous IgE-mediated reactions (e.g., 
anaphylaxis, angioedema, urticaria). 
Dermatologic effects: Serious skin reactions, including TEN and SJS, acute 
exanthematous pustulosis, and DRESS have been reported. If a skin rash develops, 
monitor closely. Discontinue if lesions progress. 
Electrolyte abnormalities: Sodium content (2.84 mEq per gram of piperacillin) should 
be considered in patients requiring sodium restriction. Assess electrolytes periodically 
in patients with low potassium reserves, especially those receiving cytotoxic therapy 
or diuretics. 
Hematologic effects: Prothrombin time, platelet aggregation, and clotting time 
abnormalities have been reported with piperacillin and particularly in patients with 
renal impairment. Discontinue if thrombocytopenia or bleeding occurs. 
Leukopenia/neutropenia may occur; appears to be reversible and most frequently 
associated with prolonged administration. Assess hematologic parameters 
periodically, especially with prolonged (≥21 days) use. 
Superinfection: Use may result in fungal or bacterial superinfection, including C. 
difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been 
observed >2 months after antibiotic treatment. 
Cystic fibrosis: An increased frequency of fever and rash has been reported in 
patients with cystic fibrosis receiving piperacillin. 
Renal impairment: Use with caution in patients with renal impairment or 
underdeveloped kidneys; due to sodium load and to the adverse effects of high 
serum concentrations of penicillins. 

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Seizure disorders: Use with caution in patients with a history of seizure disorder; high 
levels, particularly in the presence of renal impairment, may increase risk of seizures. 
Drug-drug interactions: Potentially significant interactions may exist, requiring dose or 
frequency adjustment, additional monitoring, and/or selection of alternative therapy. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
AMERICAN COLLEGE OF SURGEONS NATIONAL SURGICAL QUALITY 
IMPROVEMENT PROGRAM (ACS NSQIP) 
The American College of Surgeon National Surgical Quality Improvement Program 
(ACS NSQIP) is a nationally validated program that measures risk-adjusted surgical 
outcomes from participating hospitals to benchmark performance in the name of 
improving the surgical care provided to patients. This quality improvement program 
collects prospective, standardized, clinically meaningful data to assess outcomes. 
ACS NSQIP has a rich history and currently has more than 700 participating hospitals 
both nationally and internationally. Peer-reviewed studies have shown ACS NSQIP is 
effective at improving the quality of surgical care and reducing complications thereby 
leading to lower costs.19 Because the study institutions participate in the ACS NSQIP 
and because the primary outcome is one central to surgical quality improvement, this 
study will utilize the standard operating procedures of the ACS NSQIP to assess its 
primary and secondary outcomes. Again, only patients treated at institutions 
participating in the ACS NSQIP, active in the ACS NSQIP HPB Collaborative, 
subscribe to the Procedure Targeted Pancreatectomy program option, and agree to 
accrue all 100% of their institution’s PDs into the ACS NSQIP will be eligible for this 
study. This will ensure that the measurement of outcomes at all institutions 
participating in this study is standardized and consistent thereby preserving the 
integrity of this study. See Section 3.2 for other details. 
12.2 
DEFINITION OF OUTCOMES 
Primary and secondary outcomes will be measured in this study using ACS NSQIP 
standard operating procedures and definitions. This ensures that the measurement of 
primary and secondary outcomes is consistent between each participating institution. 
The following reproduce a selection of the current definitions employed by the ACS 
NSQIP to monitor only this study’s primary and secondary outcomes. Additional 
details and definitions may be found within Appendices A1 and A2. 
The primary endpoint of this study is overall SSI rate, defined, according to the ACS 
NSQIP, as a composite of superficial SSI, deep incisional SSI, and organ/space SSI. 
12.2.1 Superficial Surgical Site Infection 
 
Superficial incisional surgical site infection (SSI) is an infection that involves only skin 
or subcutaneous tissue of the surgical incision. 
An infection occurs within 30 days after the index operation and the infection involves 
only skin or subcutaneous tissue of the incision and at least one of the following: 
a. Purulent drainage, with or without laboratory confirmation, from the 
superficial incision; or, 

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b. Organisms isolated from an aseptically obtained culture of fluid or 
tissue from the superficial incision; or, 
c. At least one of the following signs or symptoms of infection: pain or 
tenderness, localized swelling, redness, or heat and superficial incision 
that is deliberately opened by the surgeon, unless incision is culture 
negative; or 
d. Diagnosis of superficial incisional SSI by the surgeon or attending 
physician 
12.2.2 Deep Incisional SSI 
 
Deep incisional SSI is an infection which involves deep soft tissues. Deep soft tissues 
are typically any tissue beneath skin and immediate subcutaneous fat, for example, 
fascial and muscle layers. 
It is an infection that occurs at the surgical site within 30 days after the principal 
operative procedure and involves deep soft tissues and at least one of the following: 
a. Purulent drainage from the deep incision but not from the organ/space 
component of the surgical site 
b. A deep incision spontaneously dehisces or is deliberately opened by a 
surgeon when the patient has at least one of the following signs or 
symptoms: fever (>38.0° C, localized pain, or tenderness, unless the 
site is culture-negative 
c. An abscess or other evidence of infection involving the deep incision is 
found on direct examination, during reoperation, or by histopathologic 
or radiologic examination 
d. Diagnosis of a deep incision SSI by a surgeon or attending physician 
12.2.3 Organ/Space SSI 
Organ/space SSI is an infection that involves any part of the anatomy (e.g., organs or 
spaces), other than the incision, which was opened or manipulated during an 
operation. 
It is an infection that occurs within 30 days after the principal operative procedure and 
involves any of the anatomy (e.g., organs or spaces), other than the incision, which 
was opened or manipulated during the operation and at least one of the following: 
a. Purulent drainage from a drain that is placed through a stab wound 
into the organ/space. This does not apply to drains placed during the 
principal operative procedure, which are continually in place, with 
continual evidence of drainage/infection since the time of the principal 
operative procedure 
b. Organisms isolated from an aseptically obtained culture of fluid or 
tissue in the organ/space 

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c. An abscess or other evidence of infection involving the organ/space 
that is found on direct examination, during reoperation, or by 
histopathologic or radiologic examination 
d. Diagnosis of an organ/space SSI by a surgeon or attending physician 
12.2.4 Secondary Endpoints 
Secondary endpoints based on the ACS NSQIP data include the following: 
pneumonia, intraoperative or postoperative unplanned intubation, intraoperative or 
postoperative pulmonary embolism, ventilator dependence over 48 hours, 
progressive renal insufficiency or acute renal failure requiring dialysis, urinary tract 
infection, intraoperative or postoperative stroke or cerebral vascular accident, 
intraoperative or postoperative cardiac arrest requiring CPR, intraoperative or 
postoperative myocardial infarction, intraoperative or postoperative transfusion of red 
blood cells, vein thrombosis requiring therapy, postoperative clostridium difficile 
colitis, sepsis, sepsis shock, pancreatic fistula, delayed gastric emptying, 
intraoperative drain management, need for percutaneous drain placement, withdrawal 
of care, death during operation or postoperative death within 30 days of procedure, 
hospital stay > 30 days, hospital readmission, and unplanned reoperation. . All of 
these outcomes are assessed within 30 days after the PD. Please see Appendix A1 
and A2 for more details. 
Correlative studies will be conducted on bacterial isolates from any SSIs that do occur 
and from routine intraoperative bile duct cultures. Specifically, these data include 
whether bacterial cultures were positive, and if positive, which bacterial species are 
present and their antibiotic sensitivities. These correlative studies are not collected by 
the ACS NSQIP mechanism, and thus will be conducted retrospectively via chart 
review at participating institutions that routinely collect these data. 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
1. If prior to the administration of either therapeutic agent, the patient experiences a severe 
adverse event related to the anesthetic and does not undergo the planned PD 
2. If prior to the administration of either therapeutic agent, the patient no longer has the 
capacity to make medical decisions 
3. If, at any time, protocol ineligibility is identified, as designated in the section on Criteria for 
Patient/Subject Eligibility (i.e., a change in diagnosis), the patient will be removed from 
the study 
4. If, at any time, progressive disease is found and the planned operation, 
pancreatoduodenectomy, does not occur (e.g., metastatic disease at the time of 
operation requiring aborting the procedure) 
5. Determination by the investigator that it is no longer safe for the subject to continue 
therapy 
6. Changes in a patient’s condition which render the patient unacceptable for further 
treatment in the judgment of the investigator 
If a patient is removed from the study before undergoing and receiving study drug, safety monitoring 
will end on the date the patient is taken off study. 
14.0 
BIOSTATISTICS 

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The primary aim of this study is to determine if administration of piperacillin-tazobactam as 
surgical antibiotic prophylaxis results in decreased rates of surgical site infection (SSI) as 
compared to the administration of cefoxitin. To accomplish this aim, patients undergoing 
elective pancreatoduodenectomy will be randomized to receive one of the two treatments 
and then will be followed for SSI occurrence for 30 days. Interest is in detecting a reduction 
in SSI rate from 0.20 in the cefoxitin group to 0.13 in the piperacillin-tazobactam group. An 
internal analysis of data from the approximately 70 institutions within the Hepato-Pancreato- 
Biliary (HPB) Collaborative of the ACS NSQIP detailing 3,592 PDs in 2015 revealed the rate 
of postoperative combined superficial incisional, deep incisional, and organ/space SSIs to be 
21.7% (n = 778). Additional internal analysis of ACS NSQIP data that included additional 
hospitals revealed the overall SSI rate to be 20.4%. Therefore, these data represent the 
basis for the baseline rate of 20% used in this trial. The alternative rate of 13% represents a 
clinically meaningful reduction in SSIs in this patient population. This study will use a two- 
sided type I error rate of 0.05 and a power of 0.8. There will be one planned interim analysis 
when half of the patients have been accrued. The interim analysis is based on the O'Brien- 
Fleming spending function. We will accrue 223 patients per group for a total of 446 patients 
in total for interim analysis. At interim analysis, we would reject the null hypothesis of no 
difference between groups if the p-value for the test was <0.005, and the trial would stop at 
that time. Otherwise, the trial will continue enrolling patients until 445 patients per group have 
been accrued, for a total of 890 patients overall. At the final analysis, we would reject the null 
hypothesis of no difference between groups if the p-value for the test was <0.048. 
 
The planned sample size of 890 is for resectable patients. Randomization is done pre- 
surgery but it is expected that approximately 10% of patients who are taken to the operating 
room will be deemed unresectable. These patients will be ineligible. Enrollment will continue 
until the planned sample size has been reached. In 2015, 2,210 pancreatoduodenectomies 
were conducted at 48 institutions where HPB surgeons have expressed interest in 
participating and meet this study’s eligibility criteria. Accounting for recruitment and eligibility 
considerations, we expect to be able to complete the study within 24 months. 
 
All analyses will be conducted among resected patients. This is an intention-to-treat analysis, 
such that all patients deemed eligible who undergo PD will be analyzed in the treatment arm 
to which they were randomized. If a patient who underwent treatment and PD dies or is lost 
to follow-up within 30 days of their surgery, this patient will count as a failure toward the 
primary endpoint, though the rate of such losses to follow-up is expected to be very low (~1- 
2%). For the primary endpoint, we will fit a logistic regression model where the outcome is 
SSI yes or no, the primary predictor is the randomized treatment group, and additional 
adjustment is made for preoperative biliary stent presence. 
 
There are a number of secondary endpoints as well. All secondary endpoints are binary and 
will be analyzed using logistic regression models with the secondary endpoint as the 
outcome, randomization group as the primary predictor, and adjustment for preoperative 
biliary stent presence. 
 
Finally, there are several exploratory objectives. Data will be collected on intraoperative 
bacterial cultures and isolates from the cut-edge of the biliary tree, and from any SSIs that 
occur postoperatively. These bacterial cultures and isolates from certain participating 
institutions will be summarized. Specifically, these data include whether bacterial cultures 
were positive, and if positive, which bacterial species are present and their antibiotic 
sensitivities. This will allow us to determine whether the type of antibiotic given as surgical 
antibiotic prophylaxis correlates with intraoperatively obtained bile cultures and SSIs that 
occurred. 

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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
 
MSKCC ONLY 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. During the registration process registering individuals will be required 
to complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
Research participant registration at the Participating Institutions is described in Appendix D, 
Multicenter Therapeutic Protocol Addendum. 
 
 
15.2 
Randomization 
 
Patients will be randomized 1:1 to cefoxitin or piperacillin-tazobactam for prophylactic 
management of surgical site infection. After eligibility is established and immediately after 
consent is obtained, patients will be registered in the Clinical Trials Management System 
(CTMS) and randomized using the Clinical Research Database (CRDB). Randomization will 
be accomplished by the method of random permuted block, and patients will be stratified by 
preoperative biliary stent presence. Randomization will occur prior to the day of surgery to 
ensure availability of institutional antibiotic. 
For participating institutions other than MSKCC, randomization will be conducted using the 
same method for MSKCC patients as noted above. Confirmation of the randomization 
assignment, along with the participant ID will be sent by the MSKCC study coordinator via e- 
mail to the participating site study coordinator and the site Principal Investigator within 1 
business day of receiving all completed required enrollment documents. 
Randomization will only occur after all completed registration documentation is received by 
MSK. Due to the different timezones, randomization will only occur during the following 
timeframe: 
Weekdays: Monday – Friday 
Time: 9:00 AM – 5:00 PM Eastern Standard Time (EST) 
16.0 
DATA MANAGEMENT ISSUES 
 
Data will be managed by the American College of Surgeons National Surgical Quality 
Improvement Program (ACS NSQIP) as currently established at participating institutions. All 
data are managed at the ACS NSQIP in a de-identified fashion. No change to the current 
data management strategy as it exists between participating institution and the American 
College of Surgeons as specified under the Business Associate Agreements (BAAs) 

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between these entities will be necessary. Additional data that are not routinely collected by 
the ACS NSQIP are needed for the conduct of this trial. Please see Appendix A3 for details. 
REDCap, Research Electronic Data Capture, is an open source platform that allows for the 
collection of research data in a secure manner over a web based interface. Usage of the 
platform is contingent on an open source license. The platform was developed by Vanderbilt 
University which MSK has a standing agreement with to allow the usage of REDCap for 
academic/research purposes. 
 
For this protocol, REDCap will be only used as a notification platform. It will serve as a 
second notification to remind investigators of the randomization information. MSK study 
coordinator will email the following information to ACS: patient’s first and last name (or first 
and last initials), MRN (or CTMS generated MRN), site/hospital, treating physician/surgeon, 
DOB (or birth month and year), date of treatment, treatment arm (randomization information). 
The ACS fellow will input this information in REDCap. The ACS fellow will be responsible for 
emailing the randomization reminders to the sites. An email will be sent to the investigators 
and the study staff a day prior to the patient’s surgery date. If the email is sent and 
rescheduling of the surgery occurs, the investigator/staff will be able to notify the MSK staff 
via the link in the email notification. The non-MSK site is responsible for immediately notifying 
MSK staff of any surgery scheduling changes, even prior to receiving the notification email. 
Only the MSK study coordinator(s), PI, and ACS fellow will be given access to REDCap. 
 
Data will be housed in the Memorial Sloan Kettering Cancer Center’s (MSKCC) Jersey data 
center. REDCap has been approved by MSKCC’s Information Security to store PHI. The 
MSKCC Information Systems group is responsible for applying all operating system patches 
and security updates to the REDCap servers. All connections to REDCap utilize encrypted 
(SSL-based) connections to ensure data is protected. The server is backed up nightly in the 
event that disaster recovery would be necessary and system would need to be rolled back. 
Members of the Clinical Research Administration supporting the REDCap software will have 
access to REDCap projects for the purpose to ensuring the proper functioning of the 
database and the overall software system. 
 
Permissions to the database for both internal and external users will be managed by the 
REDCap project manager or study staff. User access to the data is contingent on those a 
part of the study team and data sharing agreements in place with third party entities if 
applicable. Project managers are responsible for regularly auditing these permissions to 
ensure changes in staff are reflected appropriately. 
 
REDCap has the ability maintain an audit trail of changes to the database providing a 
timestamp as well as the user making the update. In addition, a data resolution module 
offers the ability of opening and closing queries optionally requiring justification when data is 
being updated. Permission roles for data resolution are integrated in REDCap. 
Comprehensive system logs are also maintained of user activity and when changes to the 
database are made. 

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After the patient’s surgery, the antibiotic drug used will be documented in the study tracker. 
This is to track cases in which the wrong randomized drug was given to the patient. 
 
16.1 
Quality Assurance 
Trained data abstractors, called Surgical Clinical Reviewers (SCRs), at each hospital 
collect patient information pertaining to demographics, operative details, and 
postoperative outcomes from the clinical record using standardized definitions up to 
30 days from the index operations. Outcomes are determined directly from the 
medical record, by communicating with any involved providers, or from the patient 
directly via mail or telephone. Operations are recorded using Common Procedural 
Terminology (CPT®) codes. While outpatient operations are included, minor 
operations in free-standing surgery centers or in offices are not. Submitted data are 
periodically audited to ensure quality and reliability between abstractors.12 All patient 
information submitted to the ACS NSQIP for quality improvement are de-identified 
and compliant with the Health Information Portability and Accountability Act (HIPAA) 
of 1996. 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can 
be found at: 
https://cancercenters.cancer.gov/documents/DSMPReviewCriteria508.pdf. The DSM 
Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the 
MSKCC Intranet at: 
https://one.mskcc.org/sites/pub/clinresearch/Documents/MSKCC%20Data%20and%2 
0Safety%20Monitoring%20Plans.pdf 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance 
(e.g., protocol monitoring, compliance and data verification audits, therapeutic 
response, and staff education on clinical research QA) and departmental procedures 
for quality control, plus there are two institutional committees that are responsible for 
monitoring the activities of our clinical trials programs. The committees: Data and 
Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data 
and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center’s 
Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed 
for its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) 
will be addressed and the monitoring procedures will be established at the time of 
protocol activation. 
Additionally, quarterly teleconferences for participating hospitals will be arranged for 
the duration of the trial. Investigators participating in this study will be in attendance to 

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discuss issues related to patient safety and trial conduction. Because this study is 
dependent on the ACS NSQIP mechanism, Surgical Clinical Reviewers (data 
abstractors) will also be in attendance at these teleconferences to ensure that all 
variable definitions and data collected ensure patient safety and the integrity of the 
study. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. The study will protect the rights of 
all human subjects, and an informed consent will clearly define the risks, benefits, toxicities 
and side effects of treatment. The patients will also be informed of the alternative options for 
treatment. In this study, the alternative would be to proceed with national guidelines on 
choice of surgical antibiotic prophylaxis. 
Patient data will be managed by the ACS NSQIP. The ACS NSQIP is a HIPAA-compliant 
registry whose data is managed by Outcome Sciences LLC, a IQVIA company. All patient 
data are identifiable at each hospital. However, data submitted to the ACS NSQIP for quality 
improvement purposes, and for the purposes of this study, are de-identified. The data privacy 
and security policies can be found in Appendix B. 
Inclusion of Women and Minorities: Memorial Sloan Kettering Cancer Center has filed forms 
HHS 441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), and 680 
(age discrimination); we also take due notice of the NIH policy concerning inclusion of 
women and minorities in clinical research populations. Patients of all races, both male and 
female, will be accepted into the protocol. The proposed study population is as described in 
Section 6.0. 
Exclusion of Lactating or Pregnant Women: Children have been excluded from this study. 
Lactating and pregnant women are also excluded because pancreatoduodenectomy is rarely 
performed for conditions that require management during lactation or pregnancy. The only 
clinical scenario would be a traumatic injury requiring pancreatoduodenectomy. This scenario 
is excluded from this study because it is not elective. 
Benefits: It is possible that treatment with piperacillin-tazobactam will result in better 
prevention of postoperative surgical site infection as compared to cefoxitin. It is not known, of 
course, whether these or any other favorable events will occur. It is not known whether this 
treatment will actually decrease the incidence of postoperative surgical site infections of 
patients undergoing pancreatoduodenectomy. 
Incentives: No incentives will be offered to patients/subjects for participation in the study. 
Alternatives: All patients undergoing surgical procedures involving the gastrointestinal tract 
will receive some form of surgical antibiotic prophylaxis following national guidelines. 
Currently, the guideline recommends cefoxitin, used in the control arm of this study. The only 
alternative, therefore, is to receive the antibiotic based on national guidelines, which in this 
study, is the control arm. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Indeed, patients 
abstracted into the ACS NSQIP registry are de-identified, and measures are already in place 
at each participating institution and at the American College of Surgeons headquarters in 
Chicago, IL to maintain and preserve patient privacy. Data collected by the ACS NSQIP are 
compliant with the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 

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Page 39 of 44 
 
 
Research and hospital records are confidential. Patient names or any other personally 
identifying information will not be used in reports or publications resulting from this study. 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with others at 
the time of study publication. 
Patient data will be managed by the ACS NSQIP. The ACS NSQIP is a HIPAA-compliant 
registry whose data is managed by Outcome Sciences LLC, a IQVIA company. All patient 
data are identifiable at each hospital. However, data submitted to the ACS NSQIP for quality 
improvement purposes, and for the purposes of this study, are de-identified. The data privacy 
and security policies can be found in Appendix B. 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered 
an SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
PD is a major operation that is associated with a 1.6% mortality and a 30-40% morbidity in 
ACS NSQIP-HPB Collaborative institutions. Mortality and morbidity related to PD will not be 
considered an SAE. Hospital admission for a planned procedure/disease treatment is not 
considered an SAE. If a participant does not undergo a successful pancreatoduodenectomy 

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Page 40 of 44 
 
 
(PD) but received study drug will be followed for 48 hours after the procedure considering the 
clinical pharmacology and half-life of study drugs for participants with normal renal function. 
Only grade 4-5 SAEs that are related (possible, probable, definite) to the antibiotic must be 
reported. 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
17.2.1 SAE Reporting for the Participating Sites is described in Appendix D Multicenter 
Therapeutic Protocol Addendum. 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 

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20.0 
APPENDICES 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
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and metronidazole. Tex Heart Inst J. 1990;17(2):77-85. 
20.0 
APPENDICES 
Appendix A1: ACS NSQIP Standard Data Definitions 
Appendix A2: ACS NSQIP Pancreatectomy Data Definitions 
Appendix A3: Additional Data To Be Collected by the ACS NSQIP for this study 
Appendix B: Data Privacy and Security Policy 
Appendix C: Package Insert for piperacillin-tazobactam (Zosyn®) 
Appendix D: Multicenter Therapeutic Protocol Addendum