Multi-Drug Resistant Organism Network - MDRO Network
Conditions: Infections Resistant to Multiple Drugs, Bacterial Infections
Sponsor: Duke University

 
 
1  
Version date 31 August 2018 
 
 
 
 
 
Multi-Drug Resistant Organism Network (MDRO NETWORK) 
 
Protocol Name: MDRO Network 
 
Funding Sponsor: Antibiotic Resistance Leadership Group (ARLG) 
 
Trial Identifier and Registry Name:  NCT03646227 
 
 
Funding Mechanism: This project is funded by the National Institute of Allergy and 
Infectious Diseases of the National Institutes of Health under Award Number 
UM1AI104681 
 
 
 
Protocol Date: 
31 August 2018 
Protocol Version: 
Version 3.0 
Study Sponsor: 
 
Principal Investigator: 
 
ARLG 
 
 
 
David van Duin, MD, PhD 
Associate Professor of Medicine 
Division of Infectious Diseases 
University of North Carolina 
 
 
 
 

 Multi-Drug Resistant Organism Network (MDRO) 
2  
Version date 31 August 2018 
SIGNATURE PAGE 
 
 
The signature below documents the review and approval of this protocol and provides 
the necessary assurances that this study will be conducted according to the protocol, 
including all statements regarding confidentiality, and according to national, regional, 
and local legal and regulatory requirements. 
 
 
   
 
 
Site Principal Investigator Name (Print)  
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 

 Multi-Drug Resistant Organism Network (MDRO) 
3  
Version date 31 August 2018 
MDRO Network – Study Contact Information: 
 
Protocol Chair and Principal Investigator 
 
David van Duin, MD, PhD 
Associate Professor of Medicine 
Division of Infectious Diseases 
University of North Carolina 
 
 
Co-Principal Investigator 
 
Robert A. Bonomo, MD 
Professor of Medicine, Pharmacology, Molecular Biology and Microbiology 
Chief, Medical Service 
Louis Stokes Cleveland Department of Veterans Affairs Medical Center 
University Hospitals Case Medical Center 
 
 
Coordinating Center 
The coordinating center for the MDRO Network will be Duke Clinical Research Institute.  
Dr. van Duin is the Principal Investigator (PI) and will be directly overseeing all activities.   
 
ARLG Publication Committee 
The ARLG Publication Committee comprises representatives of the network cores, 
thought-leaders, and the ARLG Statistical and Data Management Center (SDMC), and 
is responsible for generation and coordination of the publications that report scientific 
findings of the network. 
 
 

 Multi-Drug Resistant Organism Network (MDRO) 
4  
Version date 31 August 2018 
List of Abbreviations 
ARLG 
Antibacterial Resistance Leadership Group 
BSI 
Bloodstream infection 
CDC 
Centers for Disease Control and Prevention 
DCRI 
Duke Clinical Research Institute 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
GEE 
Generalized estimating equation 
ICH 
International Council on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
IDES 
Internet Data Entry System 
MDRO 
Multi-Drug Resistant Organism  
IRB 
Institutional Review Board 
MALDI-TOF 
Matrix-assisted laser desorption ionization time of flight mass spectrometry 
MIC 
Minimum inhibitory concentration 
MLST 
Multilocus sequence typing 
NIAID 
National Institutes of Allergy and Infectious Disease 
NIH 
National Institutes of Health 
PBS 
Pitt bacteremia score 
PI 
Principal Investigator 
RIFLE 
Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease 
SDMC 
ARLG Statistical and Data Management Center 
SOP 
Standard operating procedures 
UTI 
Urinary tract infection 

 Multi-Drug Resistant Organism Network (MDRO) 
5  
Version date 31 August 2018 
Protocol Summary 
 
 
 
Protocol Title: 
Multi-Drug Resistant Organism Network - MDRO 
Study Design: 
Master protocol for prospective, multicenter, observational cohort studies 
Study Population: 
Hospitalized patients with multi-drug resistant organisms 
Number of subjects: 
To be specified in each study sub-protocol as outlined in Appendices 
Clinical Samples: 
Multi-drug resistant organism isolates from specimens obtained from any anatomic 
site 
Estimated Start of 
Enrollment: 
Second quarter of 2016  
Estimated Time to 
Completion: 
Second quarter of 2019 

 Multi-Drug Resistant Organism Network (MDRO) 
6  
Version date 31 August 2018 
  
1 
TABLE OF CONTENTS 
MDRO NETWORK – STUDY CONTACT INFORMATION: ............................................................ 3 
LIST OF ABBREVIATIONS ........................................................................................................ 4 
PROTOCOL SUMMARY ........................................................................................................... 5 
1 TABLE OF CONTENTS ........................................................................................................ 6 
2 BACKGROUND AND RATIONALE ....................................................................................... 8 
3 OBJECTIVE ....................................................................................................................... 9 
3.1 
AIM 1. IDENTIFICATION OF TARGET POPULATION AND HIGH VOLUME CENTERS .................................. 10 
3.2 
AIM 2. PROVIDE DATA ON IMPACT OF POTENTIAL INCLUSION/EXCLUSION CRITERIA ON ENROLLMENT IN 
FUTURE TRIALS ............................................................................................................................... 10 
3.3 
AIM 3. PROVIDE DATA ON EXPECTED OUTCOMES OF PATIENTS WITH MDRO INFECTIONS FOR POWER AND 
SAMPLE SIZE CALCULATIONS FOR FUTURE TRIALS ................................................................................... 10 
4 STUDY SETTING .............................................................................................................. 10 
5 STUDY POPULATION ...................................................................................................... 10 
5.1 
INCLUSION CRITERION ........................................................................................................... 10 
5.2 
EXCLUSION CRITERION ........................................................................................................... 10 
6 STUDY DESIGN ............................................................................................................... 11 
6.1 
OVERALL STRATEGY............................................................................................................... 11 
6.2 
CLINICAL VARIABLES .............................................................................................................. 11 
6.3 
CLINICAL DEFINITIONS ........................................................................................................... 11 
6.4 
PARTICIPANT ENROLLMENT AND FOLLOW-UP ............................................................................. 12 
7 STATISTICAL ANALYSIS ................................................................................................... 12 
7.1 
SAMPLE SIZE ESTIMATE .......................................................................................................... 12 
7.2 
PRIMARY ANALYSIS ............................................................................................................... 12 
7.3 
TIMING OF ANALYSES ............................................................................................................ 13 
8 ETHICS AND REGULATORY CONSIDERATIONS ................................................................. 13 
8.1 
ETHICAL STANDARDS ............................................................................................................. 13 
8.2 
DATA CONFIDENTIALITY ......................................................................................................... 14 
9 QUALITY CONTROL AND QUALITY ASSURANCE ............................................................... 14 
10 DATA COLLECTION, MANAGEMENT, AND ANALYSIS ....................................................... 14 
10.1 DATA MANAGEMENT RESPONSIBILITIES .................................................................................... 14 
10.2 DATA CAPTURE METHODS ..................................................................................................... 15 
10.3 STUDY RECORD RETENTION .................................................................................................... 15 
11 PUBLICATION POLICY ..................................................................................................... 15 
11.1 STUDY FINDINGS .................................................................................................................. 15 

 Multi-Drug Resistant Organism Network (MDRO) 
7  
Version date 31 August 2018 
12 REFERENCES: ................................................................................................................. 17 
APPENDIX I: ......................................................................................................................... 18 
LIST OF ABBREVIATIONS ...................................................................................................... 18 
1    BACKGROUND ................................................................................................................ 18 
2    OBJECTIVE AND PRIMARY AIMS ..................................................................................... 18 
2.1   AIM 1. IDENTIFICATION OF TARGET POPULATION AND HIGH VOLUME CENTERS .................................... 19 
2.2   AIM 2. PROVIDE DATA ON IMPACT OF POTENTIAL INCLUSION/EXCLUSION CRITERIA ON ENROLLMENT IN 
FUTURE TRIALS ............................................................................................................................... 19 
2.3   AIM 3. PROVIDE DATA ON EXPECTED OUTCOMES OF PATIENTS WITH CRE INFECTIONS FOR POWER AND 
SAMPLE SIZE CALCULATIONS FOR FUTURE TRIALS ................................................................................... 19 
3    LABORATORY ASSESSMENTS .......................................................................................... 19 
4    EXPLORATORY AIMS ...................................................................................................... 19 
4.1   EXPLORATORY AIM 1. THE ASSOCIATION BETWEEN BACTERIAL CHARACTERISTICS AND CLINICAL OUTCOMES IN 
PATIENTS WITH CRE ....................................................................................................................... 19 
4.2   EXPLORATORY AIM 2. THE ASSOCIATION BETWEEN TREATMENT MODALITIES AND CLINICAL OUTCOMES IN 
PATIENTS WITH CRE ....................................................................................................................... 19 
4.3   EXPLORATORY AIM 3. RISK FACTORS FOR BASELINE AND TREATMENT-EMERGENT RESISTANCE TO ANTI-CRE 
ANTIBACTERIALS IN PATIENTS WITH CRE ............................................................................................. 19 
5    STUDY POPULATION....................................................................................................... 20 
6    CLINICAL DEFINITIONS .................................................................................................... 20 
7    STATISTICAL ANALYSIS PLAN .......................................................................................... 21 
7.1   SAMPLE SIZE ESTIMATE ............................................................................................................ 21 
APPENDIX II: ........................................................................................................................ 22 
LIST OF ABBREVIATIONS ...................................................................................................... 22 
1 BACKGROUND ............................................................................................................... 22 
2 OBJECTIVE ..................................................................................................................... 22 
2.1 
AIM 1. IDENTIFICATION OF TARGET POPULATION AND HIGH VOLUME CENTERS .................................. 23 
2.2 
AIM 2. PROVIDE DATA ON IMPACT OF POTENTIAL INCLUSION/EXCLUSION CRITERIA ON    ENROLLMENT IN 
FUTURE TRIALS ............................................................................................................................... 23 
2.3 
AIM 3. PROVIDE DATA ON EXPECTED OUTCOMES OF PATIENTS WITH CRAB INFECTIONS FOR POWER AND 
SAMPLE SIZE CALCULATIONS FOR FUTURE TRIALS ................................................................................... 23 
3    EXPLORATORY AIMS: ..................................................................................................... 23 
4    ENROLLMENT TARGET .................................................................................................... 23 
5    STUDY POPULATION....................................................................................................... 23 
6    CLINICAL DEFINITIONS .................................................................................................... 24 
7    STATISTICAL ANALYSIS PLAN .......................................................................................... 24 

 Multi-Drug Resistant Organism Network (MDRO) 
8  
Version date 31 August 2018 
7.1 SAMPLE SIZE ESTIMATE ............................................................................................................. 24 
APPENDIX III: ....................................................................................................................... 25 
LIST OF ABBREVIATIONS ...................................................................................................... 25 
1 BACKGROUND ............................................................................................................... 25 
2 OBJECTIVE ..................................................................................................................... 25 
2.1 
AIM 1. TO ASSEMBLE A MULTICENTER PROSPECTIVE COHORT OF PATIENTS WITH VRE BSIS TO PROVIDE 
DATA ON OUTCOMES OF PATIENTS WITH VRE BSIS FOR SAMPLE SIZE CALCULATIONS FOR FUTURE TRIALS ......... 26 
2.2 
AIM 2. TO PROVIDE DATA ON THE IMPACT OF POTENTIAL INCLUSION/EXCLUSION CRITERIA ON ENROLLMENT 
IN FUTURE VRE TRIALS .................................................................................................................... 26 
3 EXPLORATORY AIM. TO COLLECT VRE ISOLATES CAUSING BSIS IN ORDER TO UNDERSTAND 
THE MOLECULAR EPIDEMIOLOGY OF INFECTING ORGANISMS FOR FUTURE STUDIES ............ 26 
4    ENROLLMENT TARGET .................................................................................................... 26 
5    STUDY POPULATION....................................................................................................... 26 
6  CLINICAL DEFINITIONS ................................................................................................... 26 
7    REFERENCES ................................................................................................................... 27 
APPENDIX IV: ...................................................................................................................... 28 
LIST OF ABBREVIATIONS ...................................................................................................... 28 
1 BACKGROUND ............................................................................................................... 28 
2 OBJECTIVES .................................................................................................................... 28 
2.1 
AIM 1 ................................................................................................................................ 28 
2.2 
AIM 2 ................................................................................................................................ 28 
3 ENROLLMENT TARGET ................................................................................................... 29 
4 STUDY POPULATION ...................................................................................................... 29 
4.1 
INCLUSION CRITERIA .............................................................................................................. 29 
4.2 
EXCLUSION CRITERIA .............................................................................................................. 29 
5 CLINICAL DEFINITIONS ................................................................................................... 29 
6 STATISTICAL ANALYSIS PLAN .......................................................................................... 29 
6.1  SAMPLE SIZE ESTIMATE ............................................................................................................. 29 
7 REFERENCES .................................................................................................................. 29 
2 
BACKGROUND AND RATIONALE 
Per the World Health Organization, antimicrobial resistance is “one of the greatest 
threats to human health worldwide”. In the US, infections caused by multi-drug resistant 
organisms (MDRO) add between $21 billion and $34 billion to health care costs 
annually, as compared to susceptible pathogens (2).  In many bacterial pathogens, 
resistance has been increasing over the last few decades and as a general rule 

 Multi-Drug Resistant Organism Network (MDRO) 
9  
Version date 31 August 2018 
clinically relevant resistance against any specific novel antibacterial either precedes or 
relatively quickly follows the introduction of the antibacterial for clinical use ((1), figure of 
timeline). 
 
In addition to increased healthcare costs, infections with MDRO have been linked to 
worse patient outcomes including increased mortality (3).  The study of the treatment 
and diagnosis of patients with MDRO infections is limited by a number of factors.  First, 
patients with MDRO infections tend to be more chronically and acutely ill as compared 
to their counterparts infected with more susceptible organisms. This results in an added 
difficulty in prospective enrollment of these patients.  Second, evaluation of outcomes in 
patients with MDRO infections may be complicated by a high rate of poor clinical 
outcomes unrelated to the infection (4).  For instance, mortality unrelated to infection is 
unlikely to be impacted by a different antibiotic treatment strategy or an earlier 
diagnosis.  Third, use of concomitant antibiotics prior to diagnosis of the MDRO 
infection is extremely common in these populations which in turn further limits 
enrollment into trials with restrictions on such prior treatment. 
This study is specifically designed to provide data which can help in the design of future 
randomized clinical trials on both therapeutics and diagnostics, and describe, on the 
basis of observational data, patients with MDRO infections in hospitalized patients. 
These data will include a detailed clinical and epidemiological description of patients 
including potential barriers to enrollment in future trials. In addition, data will be collected 
on species, strain type, and mechanism of drug resistance of the causative organism. 
Knowing the molecular characteristics will further inform future trial design as not all 
diagnostics detect and not all therapeutics are active against the same mechanisms of 
resistance (5). 
3 
OBJECTIVE 
The objective of this study is to provide observational data that will aid in the design of 
randomized clinical trials on therapeutics and diagnostics for MDRO infections. To this 
end, clinical and epidemiological data will be collected on patients who have MDRO 
isolated from clinical cultures during hospitalization as well as descriptions of the 
outcomes of patients treated with various antimicrobial regimens.  Molecular and 
microbiological characterization will also be performed on MDRO isolates. 
Figure 1. 
Timeline of 
antibiotic 
deployment and 
resistance 
development (1) 

 Multi-Drug Resistant Organism Network (MDRO) 
10  
Version date 31 August 2018 
3.1 Aim 1. Identification of target population and high volume centers 
The prevalence of specific MDRO is extremely variable in various patient populations. In 
addition, over time, prevalence patterns for specific MDRO tend to change.  The data 
collection carried out under this protocol will provide real-time data on which patients 
are the target population for any trial directed against MDRO infection. Also, the data 
collected will indicate which geographic areas and which centers have the highest 
incidence of MDRO infections. This will facilitate rational site selection for future trials. 
3.2 Aim 2. Provide data on impact of potential inclusion/exclusion 
criteria on enrollment in future trials 
Detailed clinical data will be collected to guide the future development of clinical trials. 
The eCRF is designed to collect data on the most common barriers to enrollment in 
clinical trials. Data can then be used in the design of future trials to be presented to 
pharmaceutical companies, as well as to regulators from the FDA, to provide a rationale 
for requesting exceptions in inclusion/exclusion criteria. This will result in clinical trials 
that are more readily generalizable. 
3.3 Aim 3. Provide data on expected outcomes of patients with MDRO 
infections for power and sample size calculations for future trials 
In the MDRO network, detailed outcomes data will be collected. Data will include 
survival and microbiologic clearance outcomes when available. In addition, anatomical 
site specific clinical symptomatic outcomes, modeled on FDA guidance documents, will 
be documented. Data obtained will aid in guiding the design of future clinical trials by 
providing data needed for power and sample size calculations.  
4 
STUDY SETTING 
Study sites from across all five regions of the continental US and international sites from 
multiple countries will participate in the MDRO Network. 
5 
STUDY POPULATION 
Cohorts will be constructed for each MDRO of eligible patients by investigating 
hospitalized patients who have an MDRO isolated in clinical cultures from any 
anatomical site. This study will be conducted under a waiver of informed consent to 
facilitate universal inclusion. All patients who are admitted to one of the participating 
hospitals and who have a MDRO – as defined in the specific sub-study protocol 
(Appendices) – isolated in a clinical culture are targeted for inclusion.  
5.1 Inclusion Criterion 
All hospitalized patients, including pediatric patients, who have at least one MDRO – as 
defined in the MDRO specific Appendices – isolated from a clinical culture will be 
eligible for inclusion. 
5.2 Exclusion Criterion 
Patients who only have a positive culture for MDRO – as defined in the MDRO specific 
Appendices – that is obtained outside the hospital setting and do not have a positive 

 Multi-Drug Resistant Organism Network (MDRO) 
11  
Version date 31 August 2018 
culture for MDRO during hospitalization. 
6 
STUDY DESIGN  
6.1 Overall Strategy 
The MDRO Network will enroll at multiple sites globally. For each patient identified as 
having an MDRO, the data manager at the site will access the patient’s medical record 
and use web-based data entry to enter the relevant data into the electronic case report 
form (eCRF) for the study’s centralized database.  
All MDRO isolates will be sent to the central research laboratories for molecular and 
microbiologic analysis. Molecular and microbiologic analyses may include, but will not 
be limited to, antimicrobial susceptibility testing, determination of mechanisms of 
antibiotic resistance, and strain typing.  
6.2 Clinical Variables 
At both enrollment and then at 90 days after discharge from the index hospitalization 
during which MDRO was identified, a limited data set will be collected for each patient, 
and entered into a secure database. Patient demographics and co-morbid conditions; 
antibiotic allergies; length of hospital stay prior to first positive culture; ICU stay; reason 
for hospitalization; complications during hospitalization such as renal failure; 
components of the Pitt Bacteremia Score and Charlson comorbidity index; anatomic 
site-specific risk factors such as lines and devices; antibiotic use; and outcomes 
including all-cause and attributable mortality will be included. Specific data will be 
collected based on the anatomical site from which MDRO was isolated; data will include 
relevant symptomatology, radiographic imaging results, laboratory results, and specific 
interventions. Length of stay after isolation of MDRO, disposition, and readmission rates 
will also be collected. To specifically track the origin and spread of MDRO, detailed 
information regarding the origin and post-hospital disposition of each patient will be 
collected; for long term care facilities, the specific facility will be noted, for home origin 
or discharge, the first 3 digits of the international zip code will be used.  
6.3 Clinical Definitions 
MDRO: Specific Multi-Drug Resistant Organisms of interest are defined in the 
Appendices 
Culture episode:  A positive MDRO culture from any anatomical site marks the 
beginning of a culture episode that includes any subsequent cultures within 7 days from 
the same site and during the same hospital admission. If a period of more than 7 days 
elapses between positive cultures, this is considered the start of a new culture episode. 
A positive MDRO culture from a different anatomical site is considered a separate 
culture episode.  
Hospital Setting:  For the purposes of this protocol, patients are considered to be in a 
hospital setting during the first positive MDRO culture if they are admitted to a short-
term acute care hospital, or if they are in the emergency department awaiting admission 
with a subsequent admission. In addition, a stay in the emergency department of >24 

 Multi-Drug Resistant Organism Network (MDRO) 
12  
Version date 31 August 2018 
hours will qualify as a hospital setting. 
Infection:  A patient is deemed to have an infection if a MDRO is isolated from blood or 
any other sterile source. For patients with positive respiratory cultures the criteria 
outlined by the American Thoracic Society (ATS) and the Infectious Diseases Society of 
America (IDSA) are used (6, 7).  For patients with positive cultures from urine or 
surgical wounds, the CDC/National Healthcare Safety Network (NHSN) criteria are used 
(8).  Patients with cultures from non-surgical wounds are considered infected only if the 
treating physician documents infection in the medical record and evidence of systemic 
inflammation on the day the positive culture is documented, defined as an abnormal 
systemic white cell count (either >10K cells/uL or <4K cells/uL), and/or abnormal body 
temperature (either >99.5 ºF or <96 ºF).  
Colonization:  All culture episodes that do not meet the preceding definitions of 
infection are designated as colonization (9). 
Renal failure:  Renal failure will be defined using the Risk, Injury and Failure 
components of the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney 
disease RIFLE criteria (10).  
Severity of acute illness:  The Pitt bacteremia score (PBS) is calculated using 
temperature, mental status, cardiac arrest, blood pressure, mechanical ventilation, as 
described (11). 
Chronic comorbidity: The Charlson Comorbidity Index will be calculated using 
documented history of myocardial infarct, congestive heart failure, peripheral vascular 
disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective 
tissue disease, ulcer disease, liver disease, diabetes, hemiplegia, renal failure, any 
tumor, leukemia, lymphoma, AIDS, as described (12). 
6.4 Participant Enrollment and Follow-up 
The demographic and hospitalization data will be entered in the eCRF once the patient 
is enrolled per eligibility criteria. The timing of the remaining data entry will be at 90 days 
after the conclusion of the index hospitalization.  If a patient is readmitted to a study 
hospital and again meets criteria for inclusion in the study, a new enrollment episode 
will be created in the database. 
7 
STATISTICAL ANALYSIS 
7.1 Sample Size Estimate   
The estimated sample size for each MDRO is documented in the MDRO specific 
section of the Appendices.   
7.2 Primary Analysis 
Data will be analyzed as outlined in each appendix.  Furthermore, comparative analyses 
between different organisms will be performed. 
The primary analysis will summarize the key clinical, epidemiologic, and molecular data 

 Multi-Drug Resistant Organism Network (MDRO) 
13  
Version date 31 August 2018 
on patients with MDRO isolated from clinical cultures during hospitalization. Data will 
serve to determine potential eligibility for future trials. Strain data and mechanism of 
resistance will aid in determining the likelihood of response to novel antibiotic options, 
based on other in vitro and animal studies. 95% confidence intervals will be provided on 
key outcomes. 
Data to be summarized include the following: 
• Demographics 
• Origin (skilled nursing facility, home, long term acute care facility, transfer from 
another hospital) 
• Disposition (skilled nursing facility, home, long term acute care facility, transfer to 
another hospital, death, hospice) 
• Charlson Score 
• Pitt Bacteremia Score 
• Source of positive culture (blood, respiratory, urine, wound, abdominal, other) 
• Outcome (length of stay, ICU admission, discharge location, death) 
• Antibiotic summary 
• Status at 90 days 
o Defined as 90 days after the index culture. However, data will be collected 
through 90 days after discharge from index hospitalization. 
7.3 Timing of Analyses 
Data will be analyzed approximately 3 times yearly in order to prepare data for reporting 
at annual meetings as well as for publication.  
8 
ETHICS AND REGULATORY CONSIDERATIONS 
8.1 Ethical Standards 
The procedures set forth in this study protocol are designed to ensure that the site 
investigators abide by International Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and Good Clinical Practice 
(GCP) guidelines in the conduct, evaluation, and documentation of this study. 
Site Investigators agree, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of GCP that it 
conforms to. 
The investigator will ensure that the study will be conducted in accordance with all 
applicable national, regional, and local regulations.  
This study will request a waiver of informed consent, consistent with country specific 
regulations. The study does not involve direct interaction with human subjects. The 
medical records of patients admitted to the hospital will be screened and data collected 
from those records according this protocol. The patients will not be approached to 
obtain information, no intervention is being tested nor are human specimens being 

 Multi-Drug Resistant Organism Network (MDRO) 
14  
Version date 31 August 2018 
collected. Only pathogen MDRO isolates will be collected and analyzed. 
8.2 Data Confidentiality 
Each participating site will prepare and maintain complete and accurate study 
documentation and research records for this study, in compliance with ICH E6 as well 
as applicable national, regulatory, and institutional requirements. The site investigator, 
in compliance with GCP standards, will for each participant in the study, promptly 
complete all eCRFs. The site investigator will comply with any other IRB or Ethics 
Committee requirements as stipulated by local regulations. 
The sponsor’s representative, Duke Clinical Research Institute (DCRI), will use a 
configured electronic data capture (EDC) RAVE database, to collect study data. Access 
will be limited to study personnel who are issued a unique user identification and 
password and are listed on the authorized study user list.  
By signing the protocol, the site investigator acknowledges that, within legal and 
regulatory restrictions and institutional and ethical considerations, study documentation 
will be promptly and fully disclosed to the sponsor or their representative by the site 
investigator upon request and also shall be made available at the site investigator’s site 
upon request for inspection, copying, review and audit at reasonable times by 
representatives of the sponsor or by responsible government agencies as required by 
law.  
9 
QUALITY CONTROL AND QUALITY ASSURANCE 
The DCRI will implement a Data Driven Trial Management Plan to ensure data quality. 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written procedures and standard 
operating procedures (SOPs) to ensure that the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, 
rules and regulations relating to the conduct of the study. 
10 DATA COLLECTION, MANAGEMENT, AND ANALYSIS 
The site investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. Data reported in the eCRF derived from source 
documents must be consistent; discrepancies should be explained in the comments 
field in the eCRF. The study team may provide guidance to site investigators on making 
corrections to the source documents and eCRF.  
10.1 Data Management Responsibilities 
All source documents must be reviewed by the site data entry staff, who will ensure that 
they are accurate and complete. Data collection is the responsibility of the clinical study 
staff at the site under the supervision of the site investigator. During the study, the site 
investigator must maintain complete and accurate documentation for the study. The 
ARLG Statistical and Data Management Center (SDMC) will serve as the statistical and 
data coordinating center for this study and will be responsible for data management, 
quality review, analysis, and reporting of the study data. 

 Multi-Drug Resistant Organism Network (MDRO) 
15  
Version date 31 August 2018 
10.2 Data Capture Methods 
Clinical and laboratory data will be entered into a Web-based Internet Electronic Data 
Capture System (EDC) that ensures data confidentiality. The data system includes 
individual user accounts with password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents.  
10.3 Study Record Retention 
Study documents should be retained per local regulations or 6 years after the end of the 
study, whichever is longer. No records will be destroyed without the written consent of 
the sponsor. It is the responsibility of the sponsor to inform the site investigator when 
these documents no longer need to be retained. 
11 PUBLICATION POLICY  
11.1 Study Findings 
The principal investigator may publish the results of this research in a scientific journal 
under the oversight of the MDRO Network and ARLG Publication Committees. 
The ARLG Publication Committee comprises representatives of the network cores, 
thought leaders, and the SDMC, and is responsible for generation and coordination of 
the publications that report scientific findings of the network. All public presentations 
(abstracts, manuscripts, slides and text of oral or other presentations, and text of any 
transmission through any electronic media) by participating investigators, participating 
institutions, the SDMC, and ARLG that use ARLG data and are intended to represent 
the ARLG or are supported by the ARLG will be reviewed by the Publication Committee 
per the Publication Committee charter and must include the following statement 
“Research reported in this publication was supported by the National Institute Of Allergy 
And Infectious Diseases of the National Institutes of Health under Award Number 
UM1AI104681 (The Antibacterial Resistance Leadership Group – ARLG). The content 
is solely the responsibility of the authors and does not necessarily represent the official 
views of the National Institutes of Health.” 
The Publication Committee guarantees that the study results are presented by experts 
in the field who have working knowledge of the study design, implementation, data 
synthesis/analysis, and interpretation. The committee goals are to ensure that any 
confidential or proprietary information is protected, and that all appropriate statistical 
analyses have been included. 
All investigators funded by the NIH must submit or have submitted for them to the 
National Library of Medicine’s PubMed Central an electronic version of their final, peer-
reviewed manuscripts upon acceptance for publication, to be made publicly available no 
later than 12 months after the official date of publication. The NIH Public Access Policy 
ensures the public has access to the published results of NIH-funded research. It 
requires investigators to submit final peer-reviewed journal manuscripts that arise from 
NIH funds to the digital archive PubMed Central upon acceptance for publication. 
Further, the policy stipulates that these papers must be accessible to the public on 
PubMed Central no later than 12 months after publication. Refer to: 

 Multi-Drug Resistant Organism Network (MDRO) 
16  
Version date 31 August 2018 
http://publicaccess.nih.gov 

 Multi-Drug Resistant Organism Network (MDRO) 
17  
Version date 31 August 2018 
12 REFERENCES: 
1. 
Clatworthy AE, Pierson E, Hung DT. 2007. Targeting virulence: a new paradigm for antimicrobial 
therapy. Nat Chem Biol 3:541-548. 
2. 
Spellberg B, Blaser M, Guidos RJ, Boucher HW, Bradley JS, Eisenstein BI, Gerding D, 
Lynfield R, Reller LB, Rex J, Schwartz D, Septimus E, Tenover FC, Gilbert DN. 2011. 
Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis 
52(Suppl 5):S397-428. 
3. 
Vardakas KZ, Rafailidis PI, Konstantelias AA, Falagas ME. 2013. Predictors of mortality in 
patients with infections due to multi-drug resistant Gram negative bacteria: the study, the patient, 
the bug or the drug? J Infect 66:401-414. 
4. 
Hauck C, Cober E, Richter SS, Perez F, Salata RA, Kalayjian RC, Watkins RR, Scalera NM, 
Doi Y, Kaye KS, Evans S, Fowler VG, Jr., Bonomo RA, van Duin D, Antibacterial Resistance 
Leadership G. 2016. Spectrum of excess mortality due to carbapenem-resistant Klebsiella 
pneumoniae infections. Clin Microbiol Infect 22:513-519. 
5. 
Zasowski EJ, Rybak JM, Rybak MJ. 2015. The beta-Lactams Strike Back: Ceftazidime-
Avibactam. Pharmacotherapy 35:755-770. 
6. 
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File 
TM, Jr., Musher DM, Niederman MS, Torres A, Whitney CG. 2007. Infectious Diseases Society 
of America/American Thoracic Society consensus guidelines on the management of community-
acquired pneumonia in adults. Clin Infect Dis 44 Suppl 2:S27-72. 
7. 
American Thoracic Society and Infectious Diseases Society of America. 2005. Guidelines for 
the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated 
pneumonia. Am J Respir Crit Care Med 171:388-416. 
8. 
Centers for Disease Control and Prevention.  January 2014 2014.  CDC/NHSN Surveillance 
Definitions for Specific Types of Infections. www.cdc.gov/nhsn. Accessed  
9. 
van Duin D, Perez F, Rudin SD, Cober E, Hanrahan J, Ziegler J, Webber R, Fox J, Mason P, 
Richter SS, Cline M, Hall GS, Kaye KS, Jacobs MR, Kalayjian RC, Salata RA, Segre JA, 
Conlan S, Evans S, Fowler VG, Jr., Bonomo RA. 2014. Surveillance of Carbapenem-Resistant 
Klebsiella pneumoniae: Tracking Molecular Epidemiology and Outcomes through a Regional 
Network. Antimicrob Agents Chemother 58:4035-4041. 
10. 
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative w. 
2004. Acute renal failure - definition, outcome measures, animal models, fluid therapy and 
information technology needs: the Second International Consensus Conference of the Acute 
Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204-212. 
11. 
Chow JW, Yu VL. 1999. Combination antibiotic therapy versus monotherapy for gram-negative 
bacteraemia: a commentary. Int J Antimicrob Agents 11:7-12. 
12. 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. 1987. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373-383. 
 

 Multi-Drug Resistant Organism Network (MDRO) 
18  
Version date 31 August 2018 
Appendix I: 
 
CRACKLE II:  Consortium on Resistance Against Carbapenems in Klebsiella 
pneumoniae and Other Enterobacteriaceae (CRACKLE) : a Prospective, Observational 
Cohort Study 
 
List of Abbreviations 
CRACKLE 
Consortium on Resistance Against Carbapenems in Klebsiella 
pneumoniae and other Enterobacteriaceae 
CRE 
Carbapenem-resistant Enterobacteriaceae 
CRKP 
Carbapenem-resistant Klebsiella pneumoniae 
K. pneumoniae 
Klebsiella pneumoniae 
PCR 
Polymerase Chain Reaction 
rep-PCR 
Repetitive extragenic palindromic polymerase chain reaction 
ST258 
Sequence type 258 
 
1    Background 
Carbapenem resistance is increasingly common in Enterobacteriaceae (CRE), 
especially Klebsiella pneumoniae (K. pneumoniae) isolates, and represents a major 
threat to our global population. Since the first reported carbapenem-resistant K. 
pneumoniae (CRKP) was identified in 1996, the incidence of infections due to this 
multidrug-resistant (MDR) pathogen has increased dramatically. According to data from 
the Centers of Disease Control (CDC), 11% of K. pneumoniae that cause healthcare-
associated infections are carbapenem resistant. Regrettably, outcomes after CRKP 
bloodstream infections are generally poor. All-cause mortality rates of 42-72% have 
been reported. The globally endemic CRKP strain type 258 (ST258) is responsible for 
the majority of infections in the US. The mechanism of resistance for most ST258 
isolates in the US is the Klebsiella pneumoniae carbapenemase (KPC) family.  
2    Objective and Primary Aims 
The objective of this study is to provide observational data that will aid in the design of 
randomized clinical trials on therapeutics and diagnostics for CRE infections. To this 
end, clinical and epidemiological data will be collected on patients who have CRE 
isolated from clinical cultures during hospitalization as well as descriptions of the 
outcomes of patients treated with various antimicrobial regimens.  Molecular and 
microbiological characterization will also be performed on CRE isolates. 

 Multi-Drug Resistant Organism Network (MDRO) 
19  
Version date 31 August 2018 
2.1   Aim 1. Identification of target population and high volume centers 
The prevalence of specific CRE is extremely variable in various patient populations. In 
addition, over time, prevalence patterns for specific CRE tend to change.  The data 
collection carried out under this protocol will provide real-time data on which patients 
who are the target population for any trial directed against CRE infection. Also, the data 
collected will indicate which geographic areas and which centers have the highest 
incidence of CRE infections. This will facilitate rational site selection for future trials. 
2.2   Aim 2. Provide data on impact of potential inclusion/exclusion criteria 
on enrollment in future trials 
Detailed clinical data will be collected to guide the future development of clinical trials. 
The eCRF is designed to collect data on the most common barriers to enrollment in 
clinical trials. Data can then be used in the design of future trials to be presented to 
pharmaceutical companies, as well as to regulators from the FDA, to provide a rationale 
for requesting exceptions in inclusion/exclusion criteria. This will result in clinical trials 
that are more readily generalizable (see 3.2 in main MDRO protocol). 
2.3   Aim 3. Provide data on expected outcomes of patients with CRE 
infections for power and sample size calculations for future trials 
Detailed outcomes data will be collected. Data will include survival and microbiologic 
clearance outcomes when available. In addition, anatomical site specific clinical 
symptomatic outcomes, modeled on FDA guidance documents, will be documented. 
Data obtained will aid in guiding the design of future clinical trials by providing data 
needed for power and sample size calculations (see 3.3 in main MDRO protocol). 
3    Laboratory Assessments 
As novel antibiotics directed against CRE may have differential efficacy based on the 
mechanism of resistance, molecular characterization for strain type and mechanism of 
carbapenem resistance will be performed on CRE isolates, including whole genome 
sequencing, single gene PCR, multilocus sequence typing (MLST) and/or rep-PCR (6). 
Furthermore, phenotypic characteristics such as in vitro susceptibility testing will be 
performed in the central research laboratories.  
4    Exploratory Aims 
4.1   Exploratory Aim 1. The association between bacterial characteristics 
and clinical outcomes in patients with CRE  
4.2   Exploratory Aim 2. The association between treatment modalities and 
clinical outcomes in patients with CRE 
4.3   Exploratory Aim 3. Risk factors for baseline and treatment-emergent 
resistance to anti-CRE antibacterials in patients with CRE 
 

 Multi-Drug Resistant Organism Network (MDRO) 
20  
Version date 31 August 2018 
5   Study Population 
All patients who are admitted to one of the participating hospitals and who have a CRE  
isolated from bloodstream infection source in a clinical culture will be included.  
 
In addition, all participating hospitals in China will also enroll patients who meet the below 
criteria:  
a. have a CRE isolated from respiratory source in a clinical culture 
b. AND have a clinical diagnosis of pneumonia, per diagnosis criteria in Table 1 
 
Table 1. 
At least one criterion from each section must be present to meet definition of pneumonia 
diagnosis 
1 
Radiographic 
Criteria 
• 
Chest radiograph showing the presence of new or progressive 
infiltrate(s) suggestive of bacterial pneumonia within 48 hours of all 
other diagnostic criteria being present 
2 
Respiratory 
Signs/Symptoms 
• 
New onset or worsening: cough, dyspnea, tachypnea (respiratory rate 
>= 25 breaths per minute for patients >18 years,  >60 breaths per 
minute for children <1 year, >40 breaths per minute for children ages 1-
3 years, >30 breaths per minute for children ages 4-12 years, >20 
breaths per minute for children 12-18 years), or expectorated sputum 
production 
 
• 
Hypoxemia, defined as any of the following:  
 
A partial pressure of oxygen <60 millimeters of mercury 
measured by arterial blood gas (ABG) 
 
A worsening (decrease >10%) of the ratio of arterial partial 
pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2)  
 
Pulse oximetry reading of <90%  
 
New supplemental oxygen requirement 
 
Greater than 2LPM increase in amount of  supplemental 
oxygen required for patients on chronic supplemental oxygen 
therapy 
 
Need for acute changes, after 2 days stability, in ventilator 
support system to enhance oxygenation, as determined by 
worsening oxygenation (ABG or PaO2/FiO2) or needed 
changes in the amount of positive end-expiratory pressure 
 
3 
Systemic 
Inflammation 
• 
Documented body temperature ≥38 degrees Celsius or ≤ 35 degrees 
Celsius (core body temperature) 
• 
Leukocytosis, defined as total peripheral white blood cell count 
≥10,000 cells/cubic millimeter 
• 
Leukopenia, defined as total peripheral white blood cell count ≤4,500 
cells/cubic millimeter 
• 
Greater than 15% immature neutrophils (bands) noted on peripheral 
blood film 
6    Clinical Definitions 
CRE: For the purposes of this study, CRE are defined as any Enterobacteriaceae 
displaying in vitro resistance to any of the carbapenems as per CDC guidelines, i.e. 
Enterobacteriaceae that are resistant to any carbapenem antimicrobial (i.e., minimum 
inhibitory concentrations of ≥4 mcg/ml for doripenem, meropenem, or imipenem OR ≥2 

 Multi-Drug Resistant Organism Network (MDRO) 
21  
Version date 31 August 2018 
mcg/ml for ertapenem)  OR Documented to produce carbapenemase. 
 
In addition:  
• For bacteria that have intrinsic imipenem nonsusceptibility (i.e., Morganella morganii, 
Proteus spp., Providencia spp.), resistance to carbapenems other than imipenem is 
required.  
7    Statistical Analysis Plan 
7.1   Sample Size Estimate 
The sample size is estimated to be between 3,000-5,000 unique admissions.  

 Multi-Drug Resistant Organism Network (MDRO) 
22  
Version date 31 August 2018 
 
Appendix II: 
 
SNAP:  Study Network of Acinetobacter baumannii as Carbapenem-Resistant Pathogen  
 
List of Abbreviations 
SNAP 
Study Network of Acinetobacter baumannii as Carbapenem-
Resistant Pathogen 
CRAb 
Carbapenem-resistant Acinetobacter baumannii 
PCR 
Polymerase Chain Reaction 
rep-PCR 
Repetitive extragenic palindromic polymerase chain reaction 
 
1 
Background 
Acinetobacter baumannii has emerged as one of the most highly antimicrobial-resistant 
pathogens causing hospital-acquired infections globally. In the U.S., an estimated 
45,000 cases of A. baumannii infections occur per year. The most common 
presentations of invasive infection include bacteremia and pneumonia. A. baumannii 
has an extraordinary ability to develop resistance to even the most potent antimicrobial 
agents. In particular, carbapenem resistance among A. baumannii has dramatically 
increased in the last decade, with rates increasing from 21% in 2003-2005 to 48% in 
2009-2012. According to recent CDC data, 55% of A. baumannii causing ventilator-
associated pneumonia in the U.S. are resistant to carbapenems. Treatment options for 
carbapenem-resistant A. baumannii (CRAb) infections are extremely limited and include 
agents such as colistin, tigecycline and minocycline, which have uncertain efficacy and 
considerable toxicity. Risk factors for acquiring CRAb include exposure to antimicrobial 
agents, presence of indwelling catheters, severity of illness, and length of hospital stay 
especially in intensive care units. In-hospital and 30-day all-cause mortality from CRAb 
infections are estimated to be 42%-62% and 16%-58%, respectively. Despite this 
significant disease burden, prospective multicenter studies that evaluate microbiological 
factors that impact patient outcome – while carefully controlling for clinical co-variables 
– have not yet been conducted in the U.S. 
2 
Objective 
The objective of this study is to provide observational data that will aid in the design of 
randomized clinical trials on therapeutics and diagnostics for CRAb infections. To this 
end, clinical and epidemiological data will be collected on patients who have CRAb 
isolated from clinical cultures during hospitalization as well as descriptions of the 
outcomes of patients treated with various antimicrobial regimens.  Molecular and 

 Multi-Drug Resistant Organism Network (MDRO) 
23  
Version date 31 August 2018 
microbiological characterization will also be performed on CRAb isolates. 
2.1 Aim 1. Identification of target population and high volume centers 
The prevalence of specific CRAb is extremely variable in various patient populations. In 
addition, over time, prevalence patterns for specific CRAb tend to change.  The data 
collection carried out under this protocol will provide real-time data on which patients 
are the target population for any trial directed against CRAb infection. Also, the data 
collected will indicate which geographic areas and which centers have the highest 
incidence of CRAb infections. This will facilitate rational site selection for future trials. 
2.2 Aim 2. Provide data on impact of potential inclusion/exclusion criteria on    
enrollment in future trials 
Detailed clinical data will be collected to guide the future development of clinical trials. 
The eCRF is designed to collect data on the most common barriers to enrollment in 
clinical trials. Data can then be used in the design of future trials to be presented to 
pharmaceutical companies, as well as to regulators from the FDA, to provide a rationale 
for requesting exceptions in inclusion/exclusion criteria. This will result in clinical trials 
that are more readily generalizable (see 3.2 in main MDRO protocol). 
2.3 Aim 3. Provide data on expected outcomes of patients with CRAb 
infections for power and sample size calculations for future trials 
Detailed outcomes data will be collected. Data will include survival and microbiologic 
clearance outcomes when available. In addition, anatomical site specific clinical 
symptomatic outcomes, modeled on FDA guidance documents, will be documented. 
Data obtained will aid in guiding the design of future clinical trials by providing data 
needed for power and sample size calculations (see 3.3 in main MDRO protocol).  
3    Exploratory Aims: 
-To establish a prospective cohort of subjects with carbapenem-resistant Acinetobacter 
baumannii infection or colonization 
-To describe the demographics, natural history and clinical outcome of patients with 
CRAb 
-To collect the associated A. baumannii strains of patients with CRAb for future studies 
4    Enrollment Target 
The study will enroll up to 2000 unique admissions. This will be a global competitive 
enrollment.  
5    Study Population 
All patients who are admitted to one of the participating hospitals and who have a CRAb 
isolated in a clinical culture will be included.  
 

 Multi-Drug Resistant Organism Network (MDRO) 
24  
Version date 31 August 2018 
6    Clinical Definitions 
CRAb:  Acinetobacter baumannii isolates that are resistant (minimum inhibitory 
concentrations of  ≥8 mcg/ml ) to at least one of the following three carbapenems: 
doripenem, imipenem, meropenem. 
7    Statistical Analysis Plan 
7.1 Sample Size Estimate 
The sample size will be approximately 2000 unique admissions.   
 
 
 

 Multi-Drug Resistant Organism Network (MDRO) 
25  
Version date 31 August 2018 
 
 
Appendix III:  
 
VENOUS II:  Vancomycin-Resistant Enterococci Outcomes Study II  
List of Abbreviations 
VENOUS II 
Vancomycin-Resistant Enterococci Outcomes Study II 
VRE 
Vancomycin-Resistant Enterococci 
BSI 
Blood Stream Infection 
 
1 
Background 
Vancomycin-resistant enterococci (VRE) are one of the leading causes of health-care 
associated infections, causing approximately 20,000 infections and 1,300 deaths per 
year in the US alone (1). Moreover, VRE are a major cause of bloodstream infections 
(BSI) and preferentially affect patients who are severely ill and have an impaired 
immune system, such as cancer patients and subjects in the intensive care setting (2). 
Currently, there is only one FDA-approved drug to treat VRE (linezolid). However, 
linezolid has major limitations for the treatment of severe VRE infections and its use in 
patients that need prolonged therapy is discouraged due to an unfavorable toxicity 
profile. Although several new drugs have been approved for the management of other 
important drug-resistant gram-positives (e.g. methicillin-resistant Staphylococcus 
aureus), the majority of these new compounds lack bactericidal activity against VRE. 
The most common anti-VRE used drug is daptomycin (off-label), a lipopeptide antibiotic 
with in vitro bactericidal activity against these organisms (3). However, the emergence 
of resistance during daptomycin therapy is a serious concern and uncertainty in the best 
dose regimen to treat severe VRE infections remains (4). Thus, robust clinical data to 
determine the best treatment approaches for these multi-drug resistant organisms are 
urgently needed. Indeed, despite the significant burden of disease caused by VRE, 
prospective multicenter studies evaluating clinical and microbiological factors that 
impact patient outcomes have not yet been conducted in the U.S. 
2 
Objective 
The objective of this study is to establish a large multicenter prospective cohort of 
patients with VRE BSIs to provide solid observational data that will aid in the design of 
randomized clinical trials on therapeutics and diagnostics for deep-seated VRE 
infections. To this end, clinical and epidemiological data will be collected on patients 
who have VRE isolated from the bloodstream during hospitalization, as well as 
descriptions of the outcomes of patients treated with various antimicrobial regimens. 
VRE isolates will also be collected to perform molecular and genomic characterization. 

 Multi-Drug Resistant Organism Network (MDRO) 
26  
Version date 31 August 2018 
2.1 Aim 1. To assemble a multicenter prospective cohort of patients with 
VRE BSIs to provide data on outcomes of patients with VRE BSIs for sample 
size calculations for future trials 
We will leverage from an ongoing effort (VENOUS I) that has prospectively collected 
data from ca. 200 patients with enterococcal infections from three active centers to 
assemble a large multicenter cohort of patients with VRE BSIs. The data collected 
under this protocol will provide valuable information regarding outcomes and prognostic 
factors (both from the patient and isolate perspective), along with real-life data on which 
patients are the target population for any trial directed against invasive VRE infections. 
Also, we expect this cohort to help pinpoint specific geographic areas and/or centers 
with high incidence of VRE infections, facilitating the rational selection of sites for future 
trials. Data on outcomes (i.e. survival and microbiologic clearance) will aid in guiding the 
design of future clinical trials by providing reliable information needed for power and 
sample size calculations (see 3.3 in main MDRO protocol).  
2.2 Aim 2. To provide data on the impact of potential inclusion/exclusion 
criteria on enrollment in future VRE trials 
Detailed clinical data will be collected to guide the future development of clinical trials. 
The eCRF is designed to collect data on the most common barriers to enrollment in 
clinical trials. Data can then be used in the design of future trials to be presented to 
pharmaceutical companies, as well as to regulators from the FDA. The information will 
also be used to provide a rationale for requesting exceptions in inclusion/exclusion 
criteria. This valuable data will result in the design of clinical trials that are more readily 
generalizable (see 3.2 in main MDRO protocol). 
3 
Exploratory Aim. To collect VRE isolates causing BSIs in order to understand 
the molecular epidemiology of infecting organisms for future studies 
All infecting VRE isolates will be collected for further microbiological, molecular and 
genomic characterization, as part of future studies. Bacterial genomic information will be 
analyzed in order to find possible genetic factors that correlate with clinical outcomes in 
deep-seated VRE infections. 
4    Enrollment Target 
200 unique admissions. This will be a competitive enrollment.  
5    Study Population 
All patients admitted to one of the participating hospitals who develop a confirmed blood 
stream infection due to VRE will be included in the study. In order to enroll a patient, the 
VRE isolate should be available for further characterization. 
6  Clinical Definitions 
VRE BSI:  At least one blood culture positive for vancomycin-resistant enterococci 
(resistance to vancomcyin will be defined by current CLSI guidelines), regardless of the 
Enterococcal species and of the susceptibility method used by the microbiology 

 Multi-Drug Resistant Organism Network (MDRO) 
27  
Version date 31 August 2018 
laboratory. 
7    References 
 
1. Agudelo Higuita, N.I. and M.M. Huycke, Enterococcal Disease, Epidemiology, and 
Implications for Treatment, in Enterococci: From Commensals to Leading Causes of 
Drug Resistant Infection, M.S. Gilmore, et al., Editors. 2014: Boston. 
 
2. Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, Young JA. 
Enterococcal bacteremia is associated with increased risk of mortality in recipients of 
allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55(6):764-70. 
 
3. Britt NS, Potter EM, Patel N, Steed ME. Comparison of the Effectiveness and Safety 
of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream 
Infection: A National Cohort Study of Veterans Affairs Patients. Clin Infect Dis. 
2015;61(6):871-8. 
 
4. Britt, N.S., et al., Comparative Effectiveness and Safety of Standard-, Medium-, and 
High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant 
Enterococcal Bacteremia Among Veterans Affairs Patients. Clin Infect Dis, 2017. 64(5): 
p. 605-613. 
 
 

 Multi-Drug Resistant Organism Network (MDRO) 
28  
Version date 31 August 2018 
 
 
Appendix IV:  
 
POP:  Prospective Observational Pseudomonas study 
List of Abbreviations 
 
POP 
Prospective Observational Pseudomonas study 
CRPA 
carbapenem-resistant P. aeruginosa 
BSI 
Blood Stream Infection 
 
1 
Background 
Pseudomonas aeruginosa infections are common in immunocompromised patients, are 
a leading cause of hospital-acquired infection, and are associated with poor outcomes. 
Treatment of P. aeruginosa infections is complicated by antimicrobial resistance, 
including resistance to carbapenems. Carbapenem resistance is especially challenging 
because it is often associated with resistance to multiple classes of antibiotics, leaving 
few therapeutic options. Novel technologies and drugs are needed to better diagnose 
and treat P. aeruginosa infections, but designing the clinical trials necessary to address 
this demand is challenging given the lack of detailed data on P. aeruginosa resistance 
mechanisms, clinical and molecular epidemiology, treatment, and outcomes. This 
proposal aims to fill this gap by providing detailed clinical and microbiologic data in 
carbapenem-resistant P. aeruginosa (CRPA) pulmonary and bloodstream infections. 
We believe that this study is ideal for the ARLG, as it will utilize the existing the MDRO 
Network, which already has similar ongoing studies in patients with carbapenem-
resistant Enterobacteriaceae and carbapenem-resistant Acinetobacter infections. 
2 
Objectives 
2.1 Aim 1  
Define antibiotic resistance determinants and molecular epidemiology of CRPA 
pulmonary and bloodstream infections within the ARLG MDRO network. 
2.2 Aim 2 
Facilitate future interventional and diagnostic studies involving CRPA by detailing 
current epidemiology, treatment, and outcomes of CRPA pulmonary and bloodstream 
infections at potential clinical trial sites within the ARLG MDRO Network. 

 Multi-Drug Resistant Organism Network (MDRO) 
29  
Version date 31 August 2018 
3 
Enrollment Target 
The study will enroll up to 2000 unique admissions. This will be a global competitive 
enrollment.  
4 
Study population 
4.1 Inclusion criteria 
All patients at participating sites, including pediatric patients, with CRPA isolated from 
any clinical culture during hospitalization or within 3 days prior to hospitalization will be 
included in the study.  
4.2 Exclusion criteria 
1. Outpatient status at the time of collection of cultures that yield CRPA 
and patient not admitted to the hospital for CRPA infection within 3 days 
of collection of the culture 
2. Cystic fibrosis 
5 
Clinical Definitions 
CRPA:  Pseudomonas aeruginosa isolates that are resistant in vitro to at least one of 
the following carbapenems: doripenem, imipenem, meropenem. 
6 
Statistical Analysis Plan 
6.1 Sample Size Estimate 
The sample size will be approximately 2000 unique admissions.  
7 
References  
 
1. 
Que YA, Lazar H, Wolff M, Francois B, Laterre PF, Mercier E, Garbino J, Pagani JL, Revelly JP, 
Mus E et al: Assessment of panobacumab as adjunctive immunotherapy for the treatment of 
nosocomial Pseudomonas aeruginosa pneumonia. Eur J Clin Microbiol Infect Dis 2014, 
33(10):1861-1867. 
2. 
Lu Q, Rouby JJ, Laterre PF, Eggimann P, Dugard A, Giamarellos-Bourboulis EJ, Mercier E, 
Garbino J, Luyt CE, Chastre J et al: Pharmacokinetics and safety of panobacumab: specific 
adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa 
O11 pneumonia. J Antimicrob Chemother 2011, 66(5):1110-1116. 
3. 
Forestier C, Guelon D, Cluytens V, Gillart T, Sirot J, De Champs C: Oral probiotic and 
prevention of Pseudomonas aeruginosa infections: a randomized, double-blind, placebo-
controlled pilot study in intensive care unit patients. Crit Care 2008, 12(3):R69. 
4. 
Nichols L, Gudmundsson S, Maki DG: Experience with cefsulodin therapy for lower 
respiratory tract infections caused by Pseudomonas aeruginosa in adults without cystic 
fibrosis or granulocytopenia. Rev Infect Dis 1984, 6 Suppl 3:S711-720. 
5. 
Deal EN, Micek ST, Reichley RM, Ritchie DJ: Effects of an alternative cefepime dosing 
strategy in pulmonary and bloodstream infections caused by Enterobacter spp, Citrobacter 

 Multi-Drug Resistant Organism Network (MDRO) 
30  
Version date 31 August 2018 
freundii, and Pseudomonas aeruginosa: a single-center, open-label, prospective, 
observational study. Clin Ther 2009, 31(2):299-310. 
6. 
Luyt CE, Aubry A, Lu Q, Micaelo M, Brechot N, Brossier F, Brisson H, Rouby JJ, Trouillet JL, 
Combes A et al: Imipenem, meropenem, or doripenem to treat patients with Pseudomonas 
aeruginosa ventilator-associated pneumonia. Antimicrobial agents and chemotherapy 2014, 
58(3):1372-1380. 
7. 
Lu Q, Yang J, Liu Z, Gutierrez C, Aymard G, Rouby JJ, Nebulized Antibiotics Study G: Nebulized 
ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas 
aeruginosa. Am J Respir Crit Care Med 2011, 184(1):106-115. 
8. 
Chow JW, Yu VL: Combination antibiotic therapy versus monotherapy for gram-negative 
bacteraemia: a commentary. Int J Antimicrob Agents 1999, 11(1):7-12. 
9. 
Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987, 
40(5):373-383. 
10. 
van Duin D, Perez F, Rudin SD, Cober E, Hanrahan J, Ziegler J, Webber R, Fox J, Mason P, 
Richter SS et al: Surveillance of carbapenem-resistant Klebsiella pneumoniae: tracking 
molecular epidemiology and outcomes through a regional network. Antimicrobial agents and 
chemotherapy 2014, 58(7):4035-4041.