Rapid Identification and Phenotypic Susceptibility Testing for Gram-Negative Bacteremia (RAPIDS-GN)
Phase: NA
Conditions: Gram-negative Bacteremia
Sponsor: Duke University

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Antibacterial Resistance Leadership Group (ARLG) 
Rapid Identification and Phenotypic Susceptibility Testing for Gram-Negative Bacteremia 
(RAPIDS-GN) 
Protocol Number ARLG_RAPIDS-GN-Y3 
NCT03218397
Funding Sponsor: 
National Institute of Allergy and Infectious Diseases (NIAID) 
Funding Mechanism: 1UM1AI104681-01 
Protocol Date: 
November 30, 2018 
Protocol Version: 
4.0 
Principal Investigator: 
Dr. Ritu Banerjee, M.D, PhD 
Vanderbilt University Medical Center 
Phone: 615-322-3157 
Email: Ritu.banerjee@vumc.org 

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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 

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ARLG RAPIDS-GN TEAM ROSTER 
All questions concerning this protocol should be sent via email to arlg.rapids@mc.duke.edu.  The 
appropriate team member will respond to questions via email, generally within 24 hours (Monday-Friday).
Principal Investigator (Protocol Chair) 
Ritu Banerjee, MD, PhD 
Vanderbilt University Medical Center 
1161 21st Avenue, D7229 MCN 
Nashville, TN 37232 
Phone: 615-322-3157 
Email: Ritu.banerjee@vumc.org 
 
 
Project Leader 
 
Maria Souli, M.D. 
Project Leader I 
Duke Clinical Research Institute 
300 West Morgan Street, Room 1188 
Durham, NC  27701 
Phone:  919-684-0562 
Email: Maria.Souli@duke.edu 
 
Protocol Statisticians 
 
Lauren Komarow, MS 
The George Washington University Biostatistics Center 
6110 Executive Boulevard 
Suite 750 
Rockville, MD 20852-3943 
Phone: 301-881-9260 
Email: lkomarow@bsc.gwu.edu 
 
Michelle Earley, MS 
The George Washington University Biostatistics Center 
6110 Executive Boulevard 
Suite 750 
Rockville, MD 20852-3943 
Phone: 301-881-9260 
Email: mearley@bsc.gwu.edu 
 
Protocol Clinicians 
 
Sarah Doernberg, MD, MAS 
University of California, San Francisco 
513 Parnassus Ave, Box 0645 
San Francisco, CA 94143 
Phone: 415-502-5548 
Email: sarah.doernberg@ucsf.edu 
 

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Protocol Data Manager 
 
Ginger Kessing 
300 West Morgan Street, Suite 800 
Durham, NC 27701 
Phone: (919) 660-2285 
Email: ginger.kessing@duke.edu 
  
 
 Co-investigators 
 
Robin Patel, MD(CM), D(ABMM), FIDSA, FACP, F(AAM)  
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Phone: 507-538-0579  
Email: patel.robin@mayo.edu  
 
Omai Garner, PhD (ABMM) 
UCLA Pathology & Laboratory Medicine 
10833 Le Conte Ave 
Brentwood Annex 
Los Angeles, CA 90095 
Phone: 310-794-8748 
Email: OGarner@mednet.ucla.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1.0 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................................................... 8 
1.1 
BACKGROUND INFORMATION ....................................................................................................................... 8 
1.2 
SCIENTIFIC RATIONALE ................................................................................................................................ 9 
2.0 
HYPOTHESES ...................................................................................................................................... 10 
3.0 
OBJECTIVES ........................................................................................................................................ 10 
3.1 
PRIMARY OBJECTIVES ............................................................................................................................... 10 
3.2 
SECONDARY OBJECTIVES .......................................................................................................................... 10 
4.0 
STUDY DESIGN ................................................................................................................................... 10 
4.1 
INCLUSION CRITERIA .................................................................................................................................. 10 
4.2 
EXCLUSION CRITERIA ................................................................................................................................ 10 
5.0 
STUDY PROCEDURES ....................................................................................................................... 11 
5.1 
SCREENING AND ENROLLMENT ................................................................................................................. 11 
5.2 
RANDOMIZATION ........................................................................................................................................ 11 
5.3 
INTERVENTIONS.......................................................................................................................................... 11 
5.4 
BLINDING .................................................................................................................................................... 13 
5.5 
ASSESSMENTS ........................................................................................................................................... 13 
6.0 
MONITORING ....................................................................................................................................... 14 
7.0 
STATISTICAL ANALYSIS PLAN ........................................................................................................ 15 
7.1 
DEFINITIONS ............................................................................................................................................... 15 
7.2 
OUTCOME MEASURES ............................................................................................................................... 16 
7.3 
SAMPLE SIZE .............................................................................................................................................. 17 
7.4 
ANALYSIS ................................................................................................................................................... 18 
8.0 
ETHICS AND REGULATORY ............................................................................................................. 19 
8.1 
ETHICAL STANDARDS................................................................................................................................. 19 
8.2 
DATA CONFIDENTIALITY ............................................................................................................................. 19 
8.3 
DATA HANDLING AND RECORD KEEPING .................................................................................................. 19 
9.0 
PUBLICATION POLICY ....................................................................................................................... 20 
10.0 
REFERENCES ...................................................................................................................................... 22 
APPENDIX I – SCHEDULE OF ASSESSMENTS .......................................................................................... 24 
 
 

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List of Abbreviations 
ANC 
Absolute neutrophil count 
ARLG 
Antibacterial Resistance Leadership Group 
AS  
Antimicrobial stewardship  
AST 
Antimicrobial susceptibility testing 
AXDX 
Accelerate PhenoTMSystem 
CDC 
Centers for Disease Control and Prevention 
CRF 
Case report form 
DCRI 
Duke Clinical Research Institute 
DOOR/RADAR 
Desirability of outcome response and response adjusted for days of antibiotic risk 
EMR 
Electronic medical record 
FDA 
Food and Drug Administration 
FISH 
Fluorescent in situ hybridization 
FSTRF 
Frontier Science Technology and Research Foundation 
GNB 
gram-negative bacilli 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive care unit 
ID 
Infectious diseases 
IRB 
Institutional review board 
IV 
By vein 
MALDI-TOF MS 
Matrix-assisted laser desorption/ionization mass spectrometry 
MDRO 
Multi-drug resistant organism 
NIAID 
National Institutes of Allergy and Infectious Disease 
NIH 
National Institutes of Health 
NHSN 
National Healthcare Safety Network 
PCR 
Polymerase chain reaction 
PO 
By mouth 
SD 
Standard deviation 
SDMC 
Statistics and data management center  
SOC  
Standard of care 
VAP 
Ventilator-associated pneumonia 
 

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Protocol Synopsis 
 
Protocol Title: 
Rapid Identification and Phenotypic Susceptibility Testing for Gram- 
Negative Bacteremia (RAPIDS-GN) 
Study Design: 
Multi-center, prospective, randomized, controlled trial to evaluate the following 
strategies for patients with confirmed gram-negative bacillus bacteremia: 
 
1) Standard culture and antimicrobial susceptibility testing (AST); or  
2) Rapid identification and AST using the Accelerate PhenoTest™ BC Kit, 
performed on the Accelerate Pheno™ System (AXDX) 
Primary Study 
Objectives: 
To evaluate the impact of rapid identification and AST on time to first antibiotic 
modification in the first 72 hours after randomization 
Secondary 
Objectives 
To evaluate the impact of rapid identification and AST on antimicrobial utilization 
and clinical outcomes. 
• 
30-day mortality 
• 
Length of stay in the hospital 
• 
Days in the ICU 
• 
Duration of broad-spectrum gram-negative coverage in the first 72 hours 
following randomization 
• 
Mean time to antibiotic escalation 
• 
Mean time to antibiotic de-escalation  
• 
Hospital-onset Clostridium difficile 
• 
Acquisition of new hospital-acquired infections (HAIs) and/or multidrug 
resistant organisms (MDROs)  
Study 
Population 
All patients with blood culture bottles growing gram-negative bacilli (GNB) 
detected on Gram staining will be eligible  
Number of 
subjects 
500 subjects 
Number of sites 
2 sites 
Clinical Samples 
Clinically collected blood cultures with growth of GNB detected by Gram stain 
Start of 
Enrollment: 
October 2017 
End of 
Enrollment: 
October 2018 

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1.0 
Background Information and Scientific Rationale  
 
1.1 
Background Information  
 
Novel molecular diagnostics to identify bacteria and determine antimicrobial susceptibility from 
clinical cultures are quickly entering the arsenal of tools used by clinical microbiology laboratories. 
However, the clinical benefit of these methods has not been well-quantified. 
 
The goal of this study is to determine the impact of rapid bacterial identification and phenotypic 
antimicrobial susceptibility testing (AST) on antimicrobial usage and clinical outcomes.  
 
The Accelerate PhenoTest™ BC Kit, performed on the Accelerate Pheno™ System (together 
termed AXDX) (Accelerate Diagnostics, Tucson, AZ) is an FDA-approved fully automated 
platform that performs rapid bacterial identification within 1.5 hours followed by determination of 
minimum inhibitory concentration (MIC)-based phenotypic susceptibility within approximately 7 
hours directly from positive blood cultures.1 This novel system uses fluorescence in situ 
hybridization (FISH) for rapid bacterial identification for a panel of organisms followed by time-
lapse microscopy for determining phenotypic AST directly from positive blood culture bottles (see 
Table 1). In a study of 1850 blood cultures with gram-positive, gram-negative, or yeast isolates, 
AXDX was found to have overall 97.4% sensitivity and 99.3% specificity for organism 
identification compared to conventional culture methods (see Table 2). Among 728 gram-negative 
isolates, AXDX had 97.6% sensitivity and 99.6% specificity for pathogen identification, and had 
excellent essential (device result agrees exactly with or within one two-fold dilution of the 
reference result) and categorical (the device and reference result interpretive categories agree)  
agreement with the gold-standard methods for drug susceptibility testing, according to Food and 
Drug Administration (FDA) and/or Clinical and Laboratory Standards Institute (CLSI) breakpoints 
(see Table 3)1. 
 
Table 1. FDA-approved gram-negative bacilli and antibiotic combinations available on AXDX  
 
Ampicillin-sulbactam 
Piperacillin-tazobactam 
Cefepime 
Ceftazidime 
Ceftriaxone 
Ertapenem 
Meropenem 
Amikacin 
Gentamicin 
Tobramycin 
Ciprofloxacin 
Aztreonam 
E coli 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Klebsiella spp.* 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Enterobacter spp.* 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Proteus spp.* 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Citrobacter spp.*  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
S. marescens 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
P. aeruginosa 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
A. baumannii 
 
x 
 
 
 
 
 
x 
 
 
 
 
*Klebsiella spp. includes pneumoniae and oxytoca; Enterobacter spp. includes cloacae and 
aerogenes; Proteus spp. includes mirabilis and vulgaris; Citrobacter spp. includes freundii and 
koseri 
 
 
 

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Table 2. Clinical trial results of AXDX performance for gram-negative bacilli identification (N = 728) 
Organism 
Sensitivity (%) 
Specificity (%) 
A. baumannii 
98.6 
99.7 
Citrobacter spp. 
96.8 
99.3 
E. coli 
97.3 
99.7 
Enterobacter spp. 
97.3 
99.5 
Klebsiella spp. 
96.1 
99.6 
P. aeruginosa 
100 
99.4 
Proteus spp. 
97.7 
99.6 
Serratia marcescens 
100 
99.9 
Gram-negative bacilli, total 
97.6 
99.6 
 
Table 3. Clinical trial results of AXDX performance for gram-negative bacilli antibiotic susceptibility. 
Antibiotic 
EA (%) 
CA (%) 
# of fresh isolates 
# of challenge isolates 
Amikacin 
93.8 
93.8 
202 
200 
Ampicillin-sulbactam 
91.0 
82.7 
174 
92 
Aztreonam 
96.4 
97.6 
198 
137 
Cefepime 
96.2 
95.5 
215 
209 
Ceftazidime 
92.4 
92.1 
203 
163 
Ceftriaxone 
94.7 
96.4 
180 
124 
Ciprofloxacin 
98.4 
98.4 
216 
209 
Ertapenem 
98.8 
98.5 
200 
139 
Gentamicin 
99.5 
98.7 
207 
165 
Meropenem 
96.7 
96.9 
215 
208 
Piperacillin-tazobactam 
91.0 
90.8 
207 
205 
Tobramycin 
96.3 
96.0 
210 
165 
EA, essential agreement; CA, categorical agreement; challenge isolates with key resistance phenotypes 
and genotypes were seeded into blood culture broths. 
 
1.2 
Scientific Rationale  
 
Bacteremia due to gram-negative bacilli (GNB) poses a dangerous threat due to increasing rates 
of resistance and high mortality with ineffective antibiotic therapy.2-6 Conversely, treatment with 
overly broad antibiotics increases risks of adverse drug events and drives further development of 
resistance.7,8  An important solution to address this conundrum is development of methods for 
rapid detection of drug resistant GNB, which would allow for rapid de-escalation or escalation of 
antibiotics to appropriate definitive therapy.9  Standard turn-around-time for clinical microbiology 
laboratories to isolate, identify, and perform antimicrobial susceptibility testing (AST) of bacterial 
isolates is 48-96 hours from the time a blood culture turns positive, while rapid testing methods 
can provide results within 6-24 hours. Strategies for rapid phenotypic AST of GNB are preferred 
over methods for genotypic resistance detection, which cannot reliably predict the numerous 
antibiotic resistance mechanisms in GNB.2,10,11   
 
Prior single-center, observational studies have demonstrated decreased time to appropriate 
antibiotics, lower mortality, shorter durations of hospital and ICU stay, and reduced costs when 
rapid identification and AST methods are coupled with antimicrobial stewardship.12-14  Limitations 
to these studies include the fact that they were retrospective, subject to temporal trends, single-
center, and uncontrolled. A previous single-center, randomized, controlled trial demonstrated that 
rapid polymerase chain reaction (PCR)-based identification paired with antimicrobial stewardship 
intervention was associated with more rapid antibiotic de-escalation, shorter time to appropriate 
antibiotic therapy, and less use of broad-spectrum antibiotics.15 However, the diagnostic test 
evaluated in that study had limited impact on management of patients with GNB bacteremia 

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because the test detected only a single GNB resistance determinant (blaKPC), and did not provide 
rapid phenotypic susceptibility information for a full panel of antibiotics.  
 
Accelerate’s AXDX is the first FDA-approved platform to provide both identification and rapid 
phenotypic antibiotic susceptibility testing of organisms directly from positive blood cultures.  We 
will evaluate the clinical impact of AXDX testing for GNB bacteremia in a multicenter, prospective, 
randomized, controlled clinical trial. This study will evaluate the impact of AXDX testing in the 
setting of baseline antimicrobial stewardship activities, because current regulations mandate that 
all acute care settings have antimicrobial stewardship programs,16,17 and several prior studies 
demonstrate benefit of combining rapid testing with antimicrobial stewardship. Results from this 
study will inform strategies to improve diagnostic testing for GNB bacteremia. 
 
 
2.0 
Hypotheses 
 
We hypothesize that subjects with GNB bacteremia who receive rapid testing of blood cultures 
using AXDX will have faster time to antibiotic modification within the first 72 hours following 
randomization compared to subjects who receive standard bacterial culture and AST.  
 
3.0 
Objectives 
 
3.1 
Primary Objectives 
 
The primary objective is to evaluate the impact of rapid identification and AST on time to 
first antibiotic modification in the first 72 hours after randomization. 
 
3.2 
Secondary Objectives 
 
Secondary objectives will be to evaluate the impact of rapid identification and AST on 
antibiotic utilization and clinical outcomes. 
 
4.0 
Study Design 
 
This study will be a multicenter, prospective, randomized, controlled trial evaluating antimicrobial 
utilization and clinical outcomes among patients with GNB bacteremia.  Patients will be 
randomized to one of the following arms:  
 
1. Standard culture and AST 
2. Rapid identification and AST using AXDX 
 
Baseline antimicrobial stewardship will occur in both arms. The blood sample for arm 2 will also 
undergo standard culture and AST in addition to the rapid testing. 
 
4.1 
Inclusion Criteria 
 
Patients who meet the following inclusion criteria, and none of the exclusion criteria, will 
be included in the study:   
• 
Positive blood culture with Gram stain showing GNB identified during local laboratory 
business hours. 
 
4.2 
Exclusion Criteria 
 
 
Patients who meet any of the following criteria will be excluded from the study:   

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• 
Identification of GNB outside of local laboratory business hours (e.g. whenever 
laboratories are staffed to perform both rapid testing and routine testing)  
• 
Positive blood culture for GNB at the same institution within prior 7 days (if 
known at the time of randomization).  
• 
Deceased at the time of randomization.  
 
GNB plus gram-positive organism, gram-negative cocci, and/or yeast detected 
on Gram stain 
 
Previous enrollment in this study 
• 
No Minnesota research authorization (Rochester site only)  
 
If the patient does not meet any of the above exclusion criteria, he/she will be 
randomized, and laboratory testing will be performed according to group assigment. 
 
5.0 
Study Procedures 
 
5.1 
Screening and Enrollment 
 
Eligible patients will be identified based on positive blood culture bottles with Gram stain 
showing GNB. The Microbiology Laboratory Technologists will screen for exclusion 
criteria and then will enroll patients who do not meet any exclusion criteria.  
 
This study will not require informed consent because this FDA approved test is being 
used for its approved indication, in addition to standard of care. Furthermore, the rapid 
test is not being evaluated for its diagnostic accuracy (which has been determined by 
studies used to gain FDA approval), but rather to determine whether its use in the clinical 
setting can improve quality of patient care. 
 
5.2 
Randomization  
 
Patients meeting enrollment criteria will be assigned, in a 1:1 ratio using permuted 
blocks, to one of the two arms outlined in Section 4.0. The randomization scheme will be 
stratified by site. Randomization will occur at the time the Gram stain detecting GNB is 
identified by the lab. Randomization will be performed by the Laboratory Technologists, 
using an electronic system.  
 
5.3 
Interventions 
 
5.3.1 
Notifications 
 
Once study group is assigned, the Laboratory Technologists will immediately notify the 
Study Coordinator via electronic or telephone page. The Study Coordinator will then 
notify the Antimicrobial Stewardship (AS) team that a subject has been randomized to 
either arm. Each subject’s medical record number, group assignment and subject ID will 
be recorded in an electronic log. 
 
For subjects in both arms, the Laboratory Technologists will notify ordering clinicians by 
telephone when the Gram stain results are available, as is done in routine clinical 
practice. 
 
Sites are responsible for notifying appropriate agencies of reportable infectious diseases 
per institutional policy.  
 
5.3.2 
Standard Subculture and AST 
 

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For all patients, the local standard of care for identification and AST of GNB from positive 
blood cultures will be performed, including standard subculture and AST as well as 
matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS). If the 
primary or AS teams desire to have additional drug susceptibility information that is not 
routinely reported, they may request this information from the Microbiology Laboratory.  
 
If standard culture methods detect a gram-positive organism, gram-negative cocci, and/or 
yeast instead of a gram-negative organism (as was originally detected on Gram stain), 
the culture result will be reported in the medical record, as per standard of care, and the 
subject will be considered unevaluable as he or she will not have GNB bacteremia.  
 
5.3.3 
Rapid identification and AST  
 
For patients randomized to the rapid testing arm, testing will be performed during local 
laboratory business hours, using the AXDX system. Several milliliters of material from the 
positive bottle will be used to perform the testing, while the remainder will be used for 
standard of care testing. If no targets are identified using the rapid testing panel (see 
Table 1, Section 1.1), then identification and AST will be done through standard methods 
only. Combinations of bacteria/antibiotics that are reported by AXDX but not routinely 
reported by each laboratory will be suppressed for study patients. GNB/antibiotic 
combinations that are not reported by AXDX, but are routinely reported by the lab using 
standard of care testing, will be added to the final AST report for study patients. 
 
If there is disagreement between the rapid AST and the standard AST results, any 
“intermediate” or “resistant” result will be reported, regardless of testing method. The 
primary team caring for the patient will be notified by phone of discrepant results, and 
additional susceptibility testing will be performed as needed and determined by the site 
Laboratory Director. Discrepant results will be reviewed by the Microbiology Laboratory 
Director as detailed in section 6.0. If the primary or AS teams desire to have additional 
drug susceptibility information that is not reported by AXDX or standard of care testing, 
they may request this information from the Microbiology Laboratory.  
 
If the AXDX assay detects a gram-positive organism, gram-negative cocci, and/or yeast 
(that was not originally noted on Gram stain) in addition to GNB, the laboratory 
technologist will review the Gram stain. If the gram-positive organism or yeast is seen 
upon review, the following FDA-approved gram-positive or yeast organism identifications 
along with AST will be reported in the medical record: Staphylococcus aureus, 
Staphylococcus lugdunensis, Enterococcus faecalis, Candida albicans, Candida glabrata, 
coagulase-negative staphylococci, Enterococcus species, Streptococcus species. If the 
gram-positive bacteria or yeast is not seen upon review of the Gram stain, the AXDX 
result will not be reported, as this test is not FDA approved for clinical use if organisms 
are not visualized by Gram stain. If the AXDX assay detects a gram-positive organism, 
gram-negative cocci, and/or yeast instead of GNB (as was originally detected on Gram 
stain), the AXDX result will not be reported. In these cases, if standard culture methods 
detect other organisms instead of GNB, the standard culture result will be reported in the 
medical record, and the subject will be considered unevaluable as he or she will not have 
GNB bacteremia.  
 
5.3.4 
Antimicrobial Stewardship 
 
All patients in both arms of the study will undergo prospective audit and feedback by the 
institutional AS programs. The AS physician or pharmacist will review the subject’s 
microbiology results and medical records. The AS provider will contact the primary 
service (or the consulting infectious diseases (ID) physician, if applicable) if modifications 

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to therapy are indicated, at any time following notification of positive Gram stain result, 
organism identification, and/or AST results. If the ID service is consulting on the subject, 
the AS team will contact the ID service rather than the primary service. If the rapid test 
result is ready when the AS team is unavailable (i.e. in the evening or weekend), the AS 
team will review the record and make recommendations at the beginning of the following 
working day. Local institutional treatment guidelines will be followed. Recommendations 
will be communicated to the treating teams via telephone or pager and documented per 
institutional standards. Recommendation types and acceptance rates will be recorded in 
the study database. Categories of recommendations include: intravenous to oral 
conversion, de-escalation of gram negative coverage, de-escalation of gram positive 
coverage, escalation of gram negative coverage, escalation of gram positive coverage, 
dose optimization, discontinuation of therapy, therapeutic drug monitoring, reduce/define 
duration of therapy, ID consultation, and other. More than one stewardship 
recommendation category may be chosen. 
 
In addition to prospective audit and feedback, other routine institutional AS activities will 
continue, such as implementation of institutional treatment guidelines, prior authorization 
of restricted antibiotics, review of all patients on selected antibiotics with feedback to 
clinicians, and daily review of specific culture results. 
 
5.4       Blinding 
 
Primary service/provider: The primary service, including the prescribing provider, will be 
unaware of group assignment at the time of randomization, so initial antibiotic choice will 
not be affected by group assignment. Once rapid results become available and/or AS 
interventions are made, treating providers may become aware of group assignment.  
 
The AS team and laboratory technologists will not be blinded. 
 
5.5 
Assessments 
 
 
For this study, all measurements and assessments will be taken from the electronic medical 
record (EMR) and are done as routine standard of care practice. 
 
5.5.1 
Baseline Assessment 
 
 
 
Once a patient is randomized, information about the patient’s demographics, comorbid 
conditions, severity of illness (e.g. components of the Pitt Bacteremia Score18-20), and 
microbiology and antimicrobial susceptibility results will be recorded. Whether a patient is 
on comfort care will be recorded, as determined by review of the primary physician team 
notes and any relevant consultations (e.g. Palliative Care). 
 
5.5.2 
Daily Evaluations 
 
Information about additional microbiology results and antibiotic treatment will be gathered 
from the EMR during the three days following randomization. Suspected source and site 
of infection will be recorded by the AS providers. 
 
5.5.3 
Antibiotic spectrum and antibiotic intensity score 
 
The antibiotic intensity score will be determined as follows: Each antibiotic is assigned an 
antibiotic spectrum rank from 1-5 (see Table 4). The antibiotic rank will be multipled by 
the duration each antibiotic is received (in hours) within the first 72 hours following 
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score will be the summation of the rank x duration product for each antibiotic. If a single 
dose of antibiotic is administered, duration will be considered 1 hour. For all antibiotics 
given for more than one dose, the duration will be the time of administration of the last 
dose minus the time of administration of the first dose (or time of randomization, if subject 
was receiving antibiotic at randomization) plus one hour. Patients who die before 72 
hours will be assigned the highest intensity score among patients in the study who were 
alive at 72 hours. 
 
Table 4. Antibiotic spectrum rank, categorized by clinical use and spectrum  
Intensity score 
Rank 
Antibiotics 
1 
Narrowest 
Amoxicillin, ampicillin, first-generation cephalosporins, 
clindamycin, dalbavancin, daptomycin, dicloxacillin, 
linezolid, macrolides, metronidazole, nafcillin, 
oritavancin, oxacillin, penicillin, 
quinupristin/dalfopristin, rifampin, tedizolid, 
vancomycin 
2 
Medium narrow 
Amoxicillin/clavulanic acid, ampicillin/sulbactam, 2nd-
generation cephalosporins, 3rd generation 
cephalosporins (except ceftazidime), PO 
fluoroquinolones (ciprofloxacin, moxifloxacin, 
levofloxacin), tetracyclines, trimethoprim-
sulfamethoxazole,  
3 
Medium  
Aminoglycosides (amikacin, gentamicin, tobramycin), 
ceftaroline, ceftazidime, IV fluoroquinolones 
(ciprofloxacin, moxifloxacin, levofloxacin), fosfomycin  
4 
Medium broad 
Anti-Pseudomonal penicillin/penicillinase 
combinations, aztreonam, cefepime, ertapenem 
5 
Broadest 
Anti-Pseudomonal carbapenems, 
ceftazidime/avibactam, ceftolozane/tazobactam, 
polymyxins, tigecycline 
 
5.5.4 
Outcomes 
 
Final outcomes for each enrolled patient will be gathered retrospectively from the EMR. 
Patients will be followed for the duration of their hospitalization, or up to 30 days if they 
remain hospitalized. 
 
Inpatient hospitalization cost data will be obtained from Vizient/University Health 
Consortium (UHC). 
 
 
6.0 
Monitoring 
 
The site Microbiology Laboratory Director is responsible for monitoring and reviewing discordant results 
between the rapid and standard test methods for subjects in arm 2. AST discrepancies will be categorized 
as follows: 
 
• 
Very major errors: susceptible by rapid test method and resistant by standard culture/AST.  
• 
Major errors: resistant by rapid test method and susceptible by standard culture/AST 
• 
Minor errors: intermediate by one method and susceptible or resistant by the other method 
 
Sites will record all errors. 
 
Discrepancies between the rapid and standard results will be handled as noted in section 5.3.3. 

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15 
 
The proportion of discrepancies between testing methods for individual bacteria-drug combinations 
classified as very major errors, major errors, or minor errors will be calculated. Acceptable performance 
will be categorical agreement ≥90%, very major errors ≤3% and major errors ≤3%.21. 
 
 
7.0 
Statistical Analysis Plan 
 
7.1 
Definitions 
 
7.1.1 
Escalation: Changing to a broader spectrum antibiotic (higher number category in 
Tables 5 and 6), addition of one or more antibiotics, or conversion of oral (PO) to 
intravenous (IV) route. 
 
7.1.2 
De-escalation: Changing to a narrower spectrum antibiotic (lower number 
category in Tables 5 and 6) cessation of one or more antibiotics, or changing 
from an IV to PO route of appropriate drug (i.e. PO ciprofloxacin or levofloxacin). 
 
Table 5. Gram negative agents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6. Gram positive agents 
 
Category 
Spectrum 
Antibiotics 
1 
Narrow 
Ampicillin, cefazolin, clindamycin, erythromycin, 
nafcillin, oxacillin, trimethoprim-sulfamethoxazole, 
tetracycline, azithromycin  
2 
Medium  
Dalbavancin, IV vancomycin  
3 
Broad 
Ceftaroline, daptomycin, IV/PO linezolid, oritavancin, 
quinupristin/dalfopristin, IV/PO tedizolid  
 
 
 
 
 
Category 
Spectrum 
Antibiotics 
1  
Narrowest 
Ampicillin, cefazolin 
2 
Narrow 
Amoxicillin/clavulanic acid, ampicillin/sulbactam, 2nd-
generation cephalosporins, 3rd generation 
cephalosporins (except ceftazidime), PO 
fluoroquinolones (ciprofloxacin, moxifloxacin, 
levofloxacin), metronidazole, tetracyclines, 
trimethoprim-sulfamethoxazole,  
3 
Medium  
Aminoglycosides (amikacin, gentamicin, tobramycin), 
ceftaroline, ceftazidime, IV fluoroquinolones 
(ciprofloxacin, moxifloxacin, levofloxacin), fosfomycin  
4 
Medium broad 
Anti-Pseudomonal penicillin/penicillinase 
combinations, aztreonam, cefepime, ertapenem 
5 
Broadest 
Anti-Pseudomonal carbapenems, 
ceftazidime/avibactam, ceftolozane/tazobactam, 
polymyxins, tigecycline 

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7.2 
Outcome Measures 
 
7.2.1 
Primary Outcome Measures 
 
• 
Mean time until first modification of antibiotic therapy (in hours) within 72 hours post 
randomization 
 
7.2.2 
Secondary Outcome Measures 
 
• 
In-hospital mortality within 30 days of randomization  
• 
Length of stay in the hospital after randomization, up to 30 days, for those 
patients alive at 30 days. Length of stay will be date of discharge minus date of 
randomization. 
• 
< 72 hours or ≥72 hours in the ICU after randomization.    
• 
Mean time to antibiotic escalation in those who have antibiotic escalation within 
72 hours from randomization. This will be further broken down by whether the 
escalation was in gram positive coverage, gram negative coverage, or both.  
• 
Mean time to antibiotic de-escalation in those who have antibiotic de-escalation 
within 72 hours from randomization. This will be further broken down by whether 
the de-escalation was in gram positive coverage, gram negative coverage, or 
both.  
• 
Hospital-onset Clostridium difficile within 30 days, as defined by the National 
Healthcare Safety Network (NHSN). This will be normalized to patient-days.22 
• 
Acquisition of new hospital-acquired infections (HAIs) and/or multidrug resistant 
organisms (MDROs) within 30 days during index hospitalization identified on 
routine clinical or surveillance samples. This will be normalized to patient-days. 
Cultures that will be tracked include the following, from any specimen source, 
unless otherwise indicated: 
o 
Methicillin-resistant Staphylococcus aureus  
o 
Vancomycin-resistant Enterococcus  
o 
3rd generation cephalosporin non-susceptible Enterobacteriaceae  
o 
Carbapenem-resistant Enterobacteriaceae, as defined by the CDC: 
resistant to imipenem, meropenem, doripenem, or ertapenem OR 
documentation that the isolate possesses a carbapenemase 23  
o 
Multidrug-resistant Pseudomonas aeruginosa (resistant to 
aminoglycosides, cephalosporins, fluoroquinolones, and carbapenems)24  
o 
Carbapenem-resistant Acinetobacter 
o 
Candida species (isolated from blood cultures only) 
 
7.2.3 
Exploratory Analyses 
 
• 
Standardized costs, obtained from the UHC/Vizient database 
• 
The primary endpoint will be analyzed comparing patients who are: 
o 
in the ICU at baseline versus not in the ICU at baseline 
o 
neutropenic at baseline versus not neutropenic at baseline 
• 
The primary endpoint will be analyzed excluding antibiotic modifications made within 
the first hour after randomization, as these changes may be in response to Gram 
stain result rather than AXDX result 
• 
30-day readmission to the index hospital 
• 
The proportion of discrepancies (as detailed in 6.0) between rapid testing and 
standard of care testing among subjects who receive rapid testing (arm 2) 
• 
Antibiotic intensity score (as detailed in 5.5.3) in the first 72 hours post randomization 

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• 
Desirability of outcome response and response adjusted for antibiotic risk within 72 
hours (DOOR-RADAR) score (see Table 7 below) 
 
Table7. Desirability of outcome response (DOOR) ranking table. 
DOOR Rank 
30-day 
mortality 
In ICU at 72h post- 
randomization 
HO-CDI* 
New resistant 
or hospital-
acquired 
organism** 
1 
Alive 
No 
No 
No 
2 
Alive 
No 
Yes 
No 
3 
Alive 
No 
No 
Yes 
4 
Alive 
No 
Yes 
Yes 
5 
Alive 
Yes 
No 
No 
6 
Alive 
Yes 
Yes 
No 
7 
Alive 
Yes 
No 
Yes 
8 
Alive 
Yes 
Yes 
Yes 
9 
Dead 
-- 
-- 
-- 
*HO-CDI, Hospital onset C. difficile infection 
**Newly acquired within 30 days post-randomization, from clinically collected or surveillance 
cultures 
 
7.3 Sample Size 
 
The study is designed to detect a difference in primary outcome, mean time to first antibiotic 
modification in the first 72 hours after randomization.  We plan to enroll 500 unique participants 
(250 in each arm) in order to have at least 200 evaluable participants in each arm. Participants 
who died prior to randomization, were on comfort care at time of randomization, had GNB 
bacteremia at same or different institution within 7 days prior to randomization, or who were 
erroneously randomized due to laboratory issues such as spurious Gram stain result, will be 
considered unevaluable. This will provide 80% power with a 2-sided alpha=0.05 test, to detect a 
difference in the time to first modification of antibiotic therapy between the two arms of at least 9 
hours, with a standard deviation (SD) of 32 hours. With 500 participants, if the SD is larger than 
32 hours, there will still be sufficient power to detect a difference between the arms of 10 or more 
hours (see Table 8).   
 
We assume that differences in the primary outcome will be due to the rapid testing results. We 
anticipate that most subjects will be receiving empiric broad-spectrum antibiotic therapy at 
randomization, and a difference between the arms of 9 hours or more in time to antibiotic 
escalation or de-escalation would be reasonable based on the turn-around-time of the rapid test, 
and clinically relevant with regards to risks of ineffective therapy or prolonged exposure to broad-
spectrum agents. Estimates for the SD for time to first modification of antibiotic therapy are based 
on data from subjects with GNB bacteremia from the BCID trial15. We assume that the arm 
including stewardship in the BCID trial (BCID test plus AS), is a reasonable surrogate for the 
RAPIDS standard testing arm. This is because the BCID test provided minimal susceptibility 
results for GNB, and did not impact time to antibiotic modifications for subjects with GNB 
bacteremia15. Based on the BCID trial data, in the RAPIDS standard testing arm, we expect 63% 
will have antibiotic de-escalation with mean time of 31 hours (SD 27), 23% will have antibiotic 
escalation with mean time of 18 hours (SD 21), and 14% will have no antibiotic change. 
Incorporating the participants with no change, we expect the overall mean time to change in the 
standard testing arm will be 33.75 hours (SD 28.8).  We anticipate that the rapid testing arm will 
have similar frequencies of antibiotic de-escalation, escalation, and no change. Based on the 
turn-around-time of the rapid test, we estimate that mean time to antibiotic de-escalation and 
escalation will be approximately 12 hours (SD 24). Incorporating subjects with no antibiotic 
change, we expect the overall mean time to antibiotic modification in the rapid testing arm will be 

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20.4 hours (SD 30.5). The sample size was selected to allow the study to be well powered if this 
is an optimistic estimate of the standard deviation.  
 
Table 8: Power to detect a difference in means over a range of SD for a sample size of 250 per 
arm/500 total (200 per arm inflated 20% for death at randomization, comfort care at 
randomization, GNB bacteremia at same or different institution within 7 days, laboratory errors) 
for a 2-sided alpha=0.05 test 
Difference in 
means (hours) 
SD = 27 h 
SD = 30 h 
SD = 32 h 
SD = 33 h 
SD = 34 h 
8  
84% 
76% 
70% 
68% 
65% 
9  
91% 
85% 
80% 
78% 
75% 
10  
96% 
91% 
88% 
86% 
84% 
12  
99% 
98% 
96% 
95% 
94% 
 
 
 
7.4 Analysis 
 
7.4.1 
Analysis of primary outcome 
 
We will calculate the mean difference in time to first antibiotic modification within 72 hours 
post randomization in both treatment arms, together with a 95% confidence interval. 
Patients who do not have antibiotic modifications will be assigned a time of 72 hours. The 
primary test will be a t-test (relying on a normal approximation, allowing for unequal 
variances in the treatment groups) for whether the mean of the primary outcome is 
different between the arms. We will also carry out a Wilcoxon rank-sum test, to compare 
the distribution of the time to first antibiotic modification between the arms without the 
assumption of normality. We will estimate the probability of having an escalation or de-
escalation of antibiotics between 0 and 72 hours after randomization using the empirical 
cumulative distribution function with pointwise 95% confidence intervals. 
 
The primary analysis will be a modified intention to treat analysis (ITT). Participants who 
died prior to randomization, were on comfort care at randomization as assessed by the 
study coordinator, had GNB bacteremia at same or different institution within 7 days prior 
to randomization, or whose blood culture had erroneous Gram stain results in the 
laboratory will be considered unevaluable. These are all issues which may not be known 
to the laboratory technologist at the time of randomization and would otherwise be 
exclusion criteria.  Participants randomized to the rapid testing arm will be analyzed as 
randomized, including cases where the rapid test does not return a result.  
 
 
7.4.2 
Analysis of secondary and exploratory outcomes 
 
We will compare all secondary and exploratory outcomes between the rapid testing and 
standard testing arms. Where interest lies in mean differences, we will follow the same 
approach as for the primary outcome. The DOORs will be compared between arms to 
estimate the probability (with 95% CI) that a randomly selected participant will have a 
better DOOR outcome if assigned to rapid testing. We will determine the proportion of 
very major errors and very major or major errors among patients who receive rapid 
testing. 
 
 
 

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8.0 
Ethics and Regulatory  
 
8.1 
Ethical Standards 
 
The investigator will ensure that the study will be conducted in accordance with all 
applicable national, regional, and local regulations. The study does not involve direct 
interaction with human subjects, and all outcome data will be obtained as part of routine 
clinical care.  
 
The purpose of this study is not to test the rapid assay’s performance characteristics but 
rather to evaluate whether the use of this assay along with bacteremia-focused AS 
program will lead to improvement in the quality of care for patients. Because this study is 
considered a quality improvement initiative, we will request an exemption from IRB 
review at all sites, along with a waiver of informed consent.  
 
8.2 
Data Confidentiality 
 
The study protocol, documentation, data, and all other information generated by this 
study will be maintained in a secure manner and will be kept confidential as required by 
law.  
 
Database access will be limited to study personnel who are issued a unique user 
identification and password.  Data will be entered at each site by study personnel.  No 
information concerning the study or the data will be released to any third party without 
prior written approval of the sponsor.  Study records may be reviewed in order to meet 
federal or state regulations.  Reviewers may include the IRBs, the DCRI or the NIH. 
 
Quality Control and Quality Assurance  
 
The DCRI will provide direct access to the dataset for the purposes of monitoring, 
auditing and statistical analysis by ARLG staff and their affiliates and inspection by local 
and regulatory authorities. The local site principal investigator will ensure that study 
personnel are appropriately trained and applicable documentations are maintained.   
 
The DCRI will implement a quality plan described in the Project Management Plan to 
ensure protocol training, data quality and data security are being undertaken. 
 
Source Documents and Access to Source Data 
 
Source documents will be stored at the sites. Redacted source documents may be 
requested by DCRI as needed to ensure data quality.  Study monitoring is planned to be 
performed remotely, but may occur at the local site. 
 
8.3 
Data Handling and Record Keeping 
 
Data Capture Methods 
 
This study will use the REDCap data collection tool, which is HIPAA compliant.  The site 
staff who will be entering data will receive training on the system, after which each person 
will be issued a unique user identification and password. 
 
For security reasons, and in compliance with regulatory guidelines, it is imperative that 
only the persons who own the user identification and passwords access the system using 
their own unique access codes. Access codes are nontransferable. Site personnel who 

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have not undergone training may not use the system and will not be issued user 
identification and password until appropriate training is completed. 
 
 
Study Records Retention 
 
Applicable records and documents pertaining to the conduct of this study will be kept for 
a minimum of 6 years after final reporting or publication. Sites will remove medical record 
numbers from the electronic subject logs when notified by principal investigator (PI), after 
database lock. 
 
 
8.4 
Study Discontinuation 
 
This study may be terminated at any time by the PI in consultation with the ARLG and/or 
NIH. 
 
 
9.0 
Publication Policy  
 
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal under the oversight of the Publication Committee of the ARLG.  
 
The ARLG Publication Committee comprises representatives of the network cores, thought-
leaders, statistics and data management center (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, 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 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 
that 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.  
 
The ARLG Publication Committee will adhere to the trials registration policy adopted by the 
International Committee of Medical Journal Editors (ICMJE) member journals. This policy 
requires that all applicable clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other biomedical 
journals are considering adopting similar policies.  
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship between 
a medical intervention and a health outcome. Studies designed for other purposes, such as to 
study pharmacokinetics or major toxicity (e.g., phase I trials), would be exempt from this policy.  
 
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 

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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: http://publicaccess.nih.gov/     
 
 

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10.0 
References 
1 
Accelerate Diagnostics, Inc. Accelerate PhenoTest™ BC kit instructions for use [product 
label]. (2017). 
2 
Paterson, D. L. Resistance in gram-negative bacteria: Enterobacteriaceae. Am J Med 
119, S62-70 (2006). 
3 
Kang, C. I. et al. Bloodstream infections caused by antibiotic-resistant gram-negative 
bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on 
outcome. Antimicrob Agents Chemother 49, 760-766 (2005). 
4 
Raymond, D. P. et al. Impact of antibiotic-resistant gram-negative bacilli infections on 
outcome in hospitalized patients. Crit Care Med 31, 1035-1041 (2003). 
5 
Kollef, M. H., Sherman, G., Ward, S. & Fraser, V. J. Inadequate antimicrobial treatment 
of infections: a risk factor for hospital mortality among critically ill patients. Chest 115, 
462-474 (1999). 
6 
Ibrahim, E. H., Sherman, G., Ward, S., Fraser, V. J. & Kollef, M. H. The influence of 
inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the 
ICU setting. Chest 118, 146-155 (2000). 
7 
Paterson, D. L. "Collateral damage" from cephalosporin or quinolone antibiotic therapy. 
Clin Infect Dis 15, S341-345 (2004). 
8 
Safdar, N. & Maki, D. G. The commonality of risk factors for nosocomial colonization and 
infection with antimicrobial-resistant Staphylococcus aureus, Enterococcus, gram-
negative bacilli, Clostridium difficile, and Candida. Ann Intern Med 136, 834-844 (2002). 
9 
Spellberg, B., Srinivasn, A. & Chambers, H. F. New societal approaches to empowering 
antibiotic stewardship. JAMA 25 (2016). 
10 
Paterson, D. L. & Bonomo, R. A. Extended-spectrum β-lactamases: A clinical update. 
Clin Microbiol Rev 18, 657-686 (2005). 
11 
Thomson, J. M. & Bonomo, R. A. The threat of antibiotic resistance in gram-negative 
pathogenic bacteria: β-lactams in peril! Curr Opin Microbiol 8, 518-524 (2005). 
12 
Perez, K. K. et al. Integrating rapid diagnostics and antimicrobial stewardship improves 
outcomes in patients with antibiotic-resistant gram-negative bacteremia. J Infect 69, 216-
225 (2014). 
13 
Perez, K. K. et al. Integrating rapid pathogen identification and antimicrobial stewardship 
significantly decreases hospital costs. Arch Pathol Lab Med 137, 1247-1254 (2013). 
14 
Huang, A. M. et al. Impact of rapid organism identification via matrix-assisted laser 
desorption/ionization time-of-flight combined with antimicrobial stewardship team 
intervention in adult patients with bacteremia and candidemia. Clin Infect Dis 57, 1237-
1245 (2013). 
15 
Banerjee, R. et al. Randomized trial of rapid multiplex polymerase chain reaction-based 
blood culture identification and susceptibility testing. Clin Infect Dis 61, 1071-1080 
(2015). 
16 
Centers for Medicare and Medicaid Services. Medicare and Medicaid programs; Hospital 
and critical access hospital (CAH) changes to promote innovation, flexibility, and 
improvement in patient care. Federal Register 81, 39447-39460 (2016). 
17 
Joint Commission. Approved: New antimicrobial stewardship standard. Joint 
Commission Perspectives 36, 1-8 (2016). 
18 
Paterson, D. L., Ko, W., Gottberg, A. & et al. International prospective study of Klebsiella 
pneumoniae bacteremia: Implications of extended-spectrum β-lactamase production in 
nosocomial infections. Annals of Internal Medicine 140, 26-32, doi:10.7326/0003-4819-
140-1-200401060-00008 (2004). 

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19 
Chow, J. W., Fine, M. J., Shlaes, D. M. & et al. Enterobacter bacteremia: Clinical 
features and emergence of antibiotic resistance during therapy. Annals of Internal 
Medicine 115, 585-590, doi:10.7326/0003-4819-115-8-585 (1991). 
20 
Hilf, M. et al. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: Outcome 
correlations in a prospective study of 200 patients. The American Journal of Medicine 
87, 540-546, doi:10.1016/S0002-9343(89)80611-4. 
21 
CLSI. Verification of commercial microbial identification and antimicrobial susceptibility 
testing systems.  1st ed. CLSI guideline M52.  Wayne, PA:  Clinical and Laboratory 
Standards Institute; 2015.  
22 
Cohen, S. H. et al. Clinical practice guidelines for Clostridium difficile infection in adults: 
2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the 
Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 31, 431-
455 (2010). 
23 
Centers for Disease Control and Prevention. FAQs about choosing and implementing a 
CRE definition, <https://www.cdc.gov/hai/organisms/cre/definition.html> (2015). 
24 
Centers for Disease Control and Prevention. Antibiotic resistance threats in the United 
States, <https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-
508.pdf#page=69> (2013). 
 
 
 

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APPENDIX I – Schedule of Assessments 
 
Screening 
Enrollment/baseline 
24 hours 
48 hours 
72 hours 
30 days 
Close of study 
Time of blood culture 
x 
 
 
 
 
 
 
Evaluation of exclusion criteria 
x 
 
 
 
 
 
 
Randomization  
 
x 
 
 
 
 
 
Demographics 
 
x 
 
 
 
 
 
Medical history 
 
x 
 
 
 
 
 
Components of Pitt Bacteremia 
Score18 
 
x 
 
 
 
 
 
Comfort care 
 
x 
 
 
 
 
 
Antibiotic administration 
 
x 
x 
x 
x 
 
 
Admission information 
 
x 
 
 
 
 
 
Vital signs 
 
x 
 
 
 
 
 
Source of bacteremia 
 
 
 
 
X[2] 
 
 
Results of microbial identification 
 
 
 
 
x 
 
 
Results of AST 
 
 
 
 
x 
 
 
Evaluation of whether stewardship 
recommendation made and, if so, 
whether accepted[1] 
 
 
x 
x 
x 
 
 
Date of discharge 
 
 
 
 
 
x 
 
Clostridium difficile testing results 
 
 
 
 
 
x 
 
Acquisition of new target HAI or 
MDRO 
 
 
 
 
 
x 
 
Readmission 
 
 
 
 
 
x 
 
Death status through 30 days 
 
 
 
 
 
 
x 
Cost data through 30 days 
 
 
 
 
 
 
x 
Footnotes: 
1. 
Stewardship recommendations may occur at any time between randomization and 72h post randomization. 
2. 
As assessed by the stewardship team within 72 hours of randomization