Rapid Diagnostic Testing to Guide Antibiotic Therapy in Drug Resistant Pneumonia
Phase: NA
Conditions: Pneumonia, Methicillin-Resistant Staphylococcus Aureus
Sponsor: Northwestern University

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PROTOCOL TITLE: 
Rapid diagnostic testing to guide antibiotic therapy in drug resistant pneumonia 
 
PRINCIPAL INVESTIGATOR: 
Richard G Wunderink, MD 
Arkes Pavilion Suite 1400 
676 N. Saint Clair Ave 
Chicago, IL 60611 
 
 
VERSION DATE: 9/9/2016 
 
 

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Table of Contents 
1.0 
Objectives ............................................................................................................. 3 
2.0 
Background .......................................................................................................... 3 
3.0 
Inclusion and Exclusion Criteria ............................................................................ 5 
4.0 
Study-Wide Number of Subjects ........................................................................... 5 
5.0  
Study-Wide Recruitment methods ........................................................................ 5 
6.0 
Multi-Site Research .............................................................................................. 6 
7.0 
Study Timelines .................................................................................................... 6 
8.0 
Study Endpoints ................................................................................................... 6 
9.0 
Procedures Involved ............................................................................................. 6 
10.0 Data and Specimen Banking ................................. Error! Bookmark not defined. 
11.0 Data and Specimen Management ......................................................................... 9 
12.0 Provisions to Monitor the Data to Ensure the Safety of Subjects......................... 10 
13.0 Withdrawal of Subjects* ...................................................................................... 10 
14.0 Risks to Subjects* ............................................................................................... 11 
15.0 Potential Benefits to Subjects ............................................................................. 11 
16.0 Vulnerable Populations ....................................................................................... 11 
17.0 Community-Based Participatory Research ......................................................... 12 
18.0 Sharing of Results with Subjects......................................................................... 12 
19.0 Setting ................................................................................................................ 12 
20.0 Resources Available ........................................................................................... 12 
21.0 Prior Approvals ................................................................................................... 13 
22.0 Recruitment Methods .......................................................................................... 13 
23.0 Local Number of Subjects ................................................................................... 13 
24.0 Confidentiality ................................................................................................... 133 
25.0 Provisions to Protect the Privacy Interests of Subjects ....................................... 14 
26.0 Compensation for Research-Related Injury ........................................................ 14 
27.0 Economic Burden to Subjects ............................................................................. 14 
28.0 Consent Process ................................................... Error! Bookmark not defined. 
29.0 Process to Document Consent in Writing ............................................................ 14 
30.0 Drugs or Devices .............................................................................................. 155 
31.0 Publication Plan .................................................................................................. 15 

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1.0 
Objectives 
1.1 
The purpose of this study is to conduct an open-label randomized 
pilot clinical trial to compare an antibiotic strategy based on a novel rapid 
diagnostic test, based on polymerase chain reaction (PCR), to usual care 
in critically ill adults with pneumonia suspected to be caused by methicillin 
resistant staphylococcus aureus (MRSA).  
1.2 
We hypothesize that when automated PCR is used to guide 
antibiotic therapy, antibiotic exposure will be reduced in critically ill 
subjects with pneumonia. 
 
2.0 
Background 
2.1 
Significance. 
Bacterial resistance to antibiotics is a major problem in intensive care units 
(ICUs). (4-6) The Centers for Disease Control (CDC) estimate drug resistant 
infections affect more than 2 million individuals nationwide and cause 23,000 
deaths annually. (7) In a recent executive order, the President of the United 
States (8) called for improved antibiotic stewardship and the development of 
rapid diagnostic tests to identify antibiotic resistant infections. (9) In ICU patients 
with pneumonia, guidelines (10, 11) advocate the routine use of broad spectrum 
antibiotics in most patients. In large part this is because diagnostic testing for 
pneumonia is too insensitive and too slow to inform decision making about 
appropriate antibiotics. Overuse of broad spectrum antibiotics promotes drug 
resistance by selecting for antibiotic resistant bacterial strains. (12-14) This 
proposal will apply a new diagnostic test, polymerase chain reaction (PCR), to 
rapidly identify a drug resistant pathogen, methicillin resistant staphylococcus 
aureus (MRSA) to reduce inappropriate antibiotics in ICU patients with suspected 
pneumonia.  
MRSA is an important cause of drug resistant pneumonia associated with high 
mortality. (15, 16) Methicillin resistance in Staphylococcus aureus (SA) results 
from acquisition of the mecA gene located in the mobile element staphylococcal 
cassette chromosome mec (SCCmec). (2) Risk factors for MRSA are shown in  
 Table 1. MRSA pneumonia requires specific antibiotic therapy, (17) treatment 
guidelines recommend addition of empiric antibiotics against MRSA in patients 
admitted to the ICU with 
risk factors for DRPs. 
(10, 11) Our prior work 
demonstrates that there 
is significant overlap of 
MRSA risk factors with 
risk factors for other 
DRPs, (18) which 
potentially leads to the 
overuse of anti-MRSA 
antibiotics. (19, 20)  
Globally, MRSA 
pneumonia occurs in an 
estimated 2-6% of ICU 
patients. (21, 22) By 
contrast, empiric anti-
MRSA therapy is 
prescribed in the 
Table 1. Risk factors for drug resistant pneumonia 
Nonspecific DRPs in CAP 
Chronic lung disease  
Immunosuppression 
Wound care  
Poor functional status  
Diabetes mellitus 
Tobacco use 
Gastric acid suppression  
Indwelling catheter 
MRSA specific risk factors  
Prior MRSA colonization  
Pulmonary necrosis  
Sputum gram stain with 
gram positive cocci 
Nonspecific DRPs in 
HCAP/HAP/VAP 
Hospitalization within 90 
days 
Antibiotics within 90 days 
Immunosuppression 
Non-ambulatory status 
Tube feedings  
Gastric acid suppression  
MRSA specific risk factors  
Prior MRSA colonization   
Hemodialysis  
Congestive heart failure 
Adapted from (1-3)) 
Key: CAP: Community acquired pneumonia, HCAP: 
Healthcare associated pneumonia HAP: hospital acquired 
pneumonia, VAP: Ventilator associated pneumonia 

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majority of ICU patients with suspected pneumonia. (23) We have shown that at 
our own institution, the prevalence of MRSA is 5.5%, but empiric anti-MRSA 
therapy is prescribed in 89.5% of ICU patients with pneumonia. (24, 25) The 
large gap between empiric antibiotic therapy for MRSA pneumonia and actual 
cases of MRSA pneumonia is due to the lack of specificity of DRP risk factors, 
and the time delay of bacterial cultures. Overuse of antibiotics against MRSA has 
adverse consequences for patients, including new hospital acquired infections 
(HAIs), increased hospital length of stay (LOS), and higher cost. (26-28) 
Faster and more accurate diagnostic tests for MRSA, such as PCR, have the 
potential to reduce antibiotic exposure and improve patient outcomes.  The time 
delay of bacterial cultures and the lack of specificity of DRP risk factors is a major 
limitation to the treatment of pneumonia, particularly in ICUs where the rapid 
delivery of appropriate antibiotics could be life saving. PCR has the potential to 
change the paradigm of empiric antibiotics by increasing diagnostic certainty and 
reducing the time to diagnosis or exclusion of a resistant pathogen. However, 
molecular diagnostic tests have not yet been validated for routine clinical 
practice. (29) 
2.2 Preliminary data. 
We will compare detection of MRSA in BAL samples obtained in 
intubated adult patients with suspected pneumonia using Cepheid Xpert® 
PCR to traditional microbiologic cultures.   
The Cepheid Xpert® system. The Cepheid Xpert® is an automated, self-
contained platform designed to detect S. aureus and MRSA in body fluids using 
PCR amplification. Two assays are available: Cepheid Xpert® SA Nasal 
Complete for nasopharyngeal samples and Cepheid Xpert ®MRSA/SA SSTI for 
use in skin and soft tissue samples. S. aureus (SA) is detected by the presence 
of the staphylococcal protein A (spa) gene, MRSA is identified by mecA gene 
and the SCCmec. Prior studies report detection of MRSA is possible in 58 
minutes. 
Three groups (30-32) have reported using Cepheid Xpert® to detect MRSA in 
lower respiratory tract samples. PCR exhibits a sensitivity of 80-100% and 
negative predictive value (NPV) of 96.3% - 100%. The range in sensitivity is likely 
related to variation in the prevalence of MRSA and inadequate power. One study, 
Leone et al (30), reported that 10.6% of the tests were not interpretable, and 
there was 1 false negative. All the non-interpretable results and the false 
negative came from a single center using the Nasal Complete assay. 
 
 
Table 2. Operating characteristics of Xpert platform for detection of MRSA in 
respiratory samples 
Study 
Platform 
Body fluid  
MRSA 
prevalence 
Sens 
Spec 
PPV 
NPV 
Cercenado, 
2012 (31) 
SSTI 
ETA 
High 
99.0% 
72.2% 
90.7% 
96.3% 
Oh 2013 (32) 
Not specified 
ETA and 
BAL 
Medium 
100% 
90.7% 
78.0% 
100% 
Leone 2013 
(30) 
Nasal / SSTI 
BAL 
Low 
80.0% 
99.5% 
66.7% 
99.8% 
Sens = sensitivity, Spec = specificity, PPV = positive predictive value, NPV = negative 
predictive value 

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We are currently prospectively validating automated PCR using BAL 
samples from intubated ICU patients with suspected pneumonia. 
Residual BAL samples obtained for the clinical care of ICU patients will 
be obtained for analysis. The methodology for this is described in our 
prior IRB submission: PCR to ID MRSA in BAL, STU00201397. 
2.3 
Innovation of the current proposal. 
In this proposal, we will use automated PCR to manage antibiotics in 
critically ill subjects with suspected MRSA pneumonia. This is a novel 
approach to pneumonia diagnosis and treatment. Automated PCR has 
not been used previously to withhold or stop empiric antibiotics to cover 
MRSA in critically ill patients with suspected pneumonia.  
 
3.0 
Inclusion and Exclusion Criteria 
3.1 Screening.  
Patients admitted to the medical intensive care unit (MICU) with suspected 
pneumonia will be screened for inclusion. Screening will be conducted by the 
principal investigator and MICU research staff by manual review of the MICU 
census. Screening will be done during working hours, Monday thru Saturday, 
excluding holidays.  
3.2 
Inclusion criteria 
1. Adults aged 18 years and older with known or suspected pneumonia who are 
endotracheally intubated and mechanically ventilated  
2. Have or are planned to have bronchoalveolar lavage (BAL) for suspected 
pneumonia 
3. Have received 48 hours or less of MRSA therapy (the antibiotics vancomycin 
or linezolid) prior to study enrollment but who are anticipated to continue MRSA 
therapy pending further workup    
3.3 Exclusion criteria. 
1. More than 48 hours of MRSA therapy  with either vancomycin or linezolid,  
2. Subjects with extra pulmonary infection requiring treatment with vancomycin or 
linezolid  
3. Neutropenic fever  
4. Chronic airway infection  
5. Patient/surrogate refusal 
6. Subjects in whom BAL is deemed unsafe by the treating physician 
7. Treating physician refusal to discontinue antibiotics to treat MRSA if PCR 
negative   
3.4 Special populations.  
1. Adults who are unable to consent are eligible for study enrollment if a 
surrogate decision maker is available to provided informed consent.  
2. Prisoners will be excluded. 
3. Vulnerable populations (pregnant women and children) will not be 
eligible for inclusion.  
  
4.0 
Study-Wide Number of Subjects 
The study will be a time-limited study but will aim to recruit at least 44 subjects in 
about a 12-month period of time from a single site, the medical intensive care 
unit (MICU) at Northwestern Memorial Hospital (NMH).  
 
5.0 
Study-Wide Recruitment Methods 
Not applicable  

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6.0 
Multi-Site Research 
Not applicable  
 
7.0 
Study Timelines 
7.1 Timeline for subject recruitment   
Subjects will be followed by the research staff from the time of screening 
(order or notification of a planned BAL in the MICU) until discharge from 
the hospital. The study intervention, randomization to PCR strategy 
versus usual care, will occur at the time of consent. Subjects who are 
randomized to PCR strategy will have BAL soon after enrollment if not 
already obtained, and PCR will be conducted within 1 hour of study 
enrollment and or receipt of sample. Subject in both the PCR arm and 
usual care arm will be followed until discharge from the hospital. Clinical 
data will be gathered using the Northwestern University Electronic Data 
Warehouse (NU-EDW) 
7.2 Timeline for subject enrollment  
The anticipated duration of the clinical trial to enroll subjects is January 
2016 to January 2017 
7.3 Timeline for study completion  
The estimated date for the investigators to complete the study, including 
the primary analysis, is targeted for April 2017  
 
8.0 
Study Endpoints 
8.1 Study outcomes  
The primary outcome measure is antibiotic-days of vancomycin or 
linezolid, defined as days on which at least one dose of antibiotic is 
given. For antibiotics dosed at > 24 hour intervals, any interval day will be 
included as an antibiotic day. Secondary outcomes are cost, subsequent 
hospital acquired infections (HAIs), ICU and hospital length of stay (LOS), 
and mortality. 
8.2 Safety outcomes  
The primary safety endpoint is concordance of MRSA PCR result to the 
results of respiratory cultures. In addition, clinical response subsequent to 
withdrawing/withholding MRSA drugs and subsequent documentation of 
MRSA infection(s) at other sites will be recorded.  
 
9.0 
Procedures Involved 
9.1 Study goals  
Whether rapid automated PCR can safely replace the traditional approach that 
relies on DRP risk factors and bacterial cultures to choose appropriate 
antimicrobial therapy in the ICU is unknown. Therefore we will conduct a clinical 
trial to compare a PCR guided approach to MRSA therapy to usual care. 
Goals of the clinical trial are:  
1) To determine if an antibiotic strategy that utilizes rapid automated PCR 
reduces antibiotic-days in ICU subject with suspected pneumonia,  
2) To compare the safety of an antibiotic strategy that relies on rapid automated 
PCR to usual care,  
3) To compare costs of the rapid automated PCR based strategy to routine 
microbiologic cultures,  

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4) To determine if an antibiotic strategy based on rapid automated PCR will 
reduce subsequent HAIs.  
9.2. Study site.  
This study will be conducted in the medical ICU (MICU) at NMH, a 33-bed unit 
staffed by critical care physicians, trainees, and respiratory therapists (RTs). In 
intubated patients with suspected pneumonia, BALs are obtained by the MICU 
physician or qualified trainee for bronchoscopic BALs, or trained RTs for 
nonbronchoscopic BALs (NBBALs). About 60 total BALs are collected monthly in 
the MICU. 
9.3. Study design.  
An overview of the clinical trial is shown in Figure 1. Patients admitted to 
the MICU with suspected pneumonia will be screened for inclusion. 
Subjects with suspected pneumonia will be randomized to antibiotic 
management with automated PCR compared to usual care in a 1:1 
fashion. In the usual care arm, MRSA therapy will be given at the 
discretion of the care team. If bacterial cultures are negative for MRSA at 
72 hours, the care team will be prompted to discontinue MRSA therapy. 
In subjects randomized to the automated PCR arm who are clinically 
stable, results from the PCR must be available prior to the administration 
of MRSA therapy. Subjects with a positive MRSA PCR will be 
administered MRSA therapy. In subjects with a negative MRSA PCR, 
MRSA therapy will be withheld. In subjects randomized to the automated 
PCR arm who are clinically unstable, as defined by hypotension requiring 
vasopressors, lactic acidosis, or intubation within the previous 12 hours, 
empiric MRSA therapy will be allowed until the PCR is completed. In 
these cases of unstable subjects, empiric MRSA therapy will be 
discontinued if the PCR is negative. 
 
 
 

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9.4 
Bronchoalveolar lavage (BAL)  
Bronchoalveolar lavage specimens will be gathered from all study subjects by a 
respiratory therapist (RT) nonbronchoscopically (NB-BAL) or by a qualified 
physician bronchoscopically (B-BAL). BAL is routinely preformed for clinical care 
of patients with pneumonia in ICU settings, and all subjects enrolled in this study 
will have had a BAL done for clinical care rather than for the study. The most 
common risk is transient hypoxia which typically resolves within 15 minutes of the 
procedure without the need for any specific intervention other than an increase in 
the fraction of inspired oxygen.  There is a very small risk of other procedural 
complications including bronchospasm, airway bleeding, and pneumothorax.  
These are seen rarely and occur in <1% of all non-bronchoscopic BALs 
performed.  
9.5 
Sample processing and Study device  
Following collection, BAL samples gathered from subjects in the PCR arm will be 
transferred immediately to the molecular epidemiology laboratory at NMH where 
the BAL will tested for the presence of MRSA using PCR by a qualified laboratory 
technician. Testing will be done using the Cepheid Xpert® Assay, performed on 
the GeneXpert® Instrument Systems, a qualitative in vitro diagnostic test 
designed for rapid detection and differentiation of Staphylococcus aureus (SA) 
and methicillin resistant Staphylococcus aureus MRSA in body fluids using the 
Cepheid Xpert ® MRSA/SA SSTI developed for use in skin and soft tissue 
samples. SA is detected by the presence of the staphylococcal protein A (spa) 
gene, MRSA is identified by the mecA gene and staphylococcal cassette 
chromosome mec (SCCmec). Prior studies report detection of MRSA is possible 
in 58 minutes. (30) the GeneXpert® Instrument is already available in the NMH 
Microbiology laboratory.  
Once the PCR is completed, the results will be relayed to the study 
physician who will communicate with the treating physician regarding whether 
MRSA antibiotic therapy (vancomycin or linezolid) will be started or stopped 
based on the study protocol. All BAL samples will be sent for routine bacterial 
cultures based on routine clinical care. If there bacterial culture result and the 
PCR result are discordant, the treating physician will be notified immediately.  
9.6 
Safety 
The major safety concern is a false negative PCR result, which would 
result in withholding MRSA therapy in a subject with MRSA pneumonia. 
However, PCR is a sensitive diagnostic test, and based on prior work the 
rate of false negative is approximately 0.1%. In subjects who are clinically 
unstable, as defined above, MRSA coverage will be provided until the 
results of the PCR are available. Our prior study, PCR to ID MRSA in 
BAL, STU00201397, is designed to confirm there is high concordance of 
the two tests. In the unlikely event that the PCR yields a false negative 
test for MRSA, the treating team will be informed immediately and 
appropriate antibiotic therapy will be started.   
9.7 
Patient data collection  
All relevant patient data will be collected using the Northwestern University 
Enterprise Data Warehouse (NU-EDW) from Cerner Powerchart and EPIC 
electronic health records. A program will be written using NU-EDW to extract 
clinical variables (see Appendix for data collection form and coded identifier list).  
Patient data will be removed and subjects will be identified based a unique study 
identifier. A separate password protected file will map the study identifier to the 
subject’s medical record number. All patient data will be kept on a password 

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protected computer. Only the study personnel will be allowed to access patient 
data.  
 
10.0 
Data and Specimen Banking  
10.1 
Data storage  
Patient data will be kept on a single, encrypted, Northwestern University issued 
password protected computer. Only the study investigators will have access to 
the data. In the event that the data has to be transported to another computer, it 
will be done using a password protected USB drive. Patient data will be available 
for the duration of the study and publication of the manuscript, which is 
anticipated to be 1 year from study completion.  
10.2 
Specimen storage  
BAL specimens will be stored in a refrigerator contained in a locked room only 
accessible to the study staff and microbiology lab personnel. The specimens will 
be stored at 2-8°C for up to 96 hours. Following testing, the specimens will be 
disposed of in accordance to NMH policies.  
10.3 
Optional Sample Banking 
Subject and/or LAR will have the option of participating to have any left over BAL 
speciman and their collected clinical information stored in a de-identied manner 
for use in other not directly related research.  These samples will be stored in a -
80°C freezer in the Wunderink lab for up to 1 year from study completion. 
 
11.0 
Data and Specimen Management 
11.1 Data analysis plan. 
Main Outcomes. The primary outcome measure is antibiotic-days of vancomycin 
or linezolid, defined as days on which at least one dose of antibiotic is given. (37, 
38) For antibiotics dosed at > 24 hour intervals, any interval day will be included 
as an antibiotic day. Secondary outcomes are cost, subsequent hospital acquired 
infections (HAIs), ICU and hospital LOS, and mortality. Disease adjusted 
mortality will be calculated using the Acute Physiology and Chronic Health 
Evaluate (APACHE) IV score. (39, 40) Patient information will be collected using 
the NU-EDW.  Categorical outcomes will be analyzed using logistic regression, 
continuous outcomes will be analyzed using linear regression. Statistical analysis 
will be conducted with SPSS (IBM corporation) and STATA.  We have budgeted 
statistical support to 
conduct the analyses for 
this Aim.  
11.2 Power  
calculation.  
Based on our prior work, 
89.5% of intubated 
subjects with suspected 
pneumonia in the MICU 
will receive empiric vancomycin or linezolid therapy; however the prevalence 
MRSA pneumonia is approximately 5.5%. In patients with no evidence of MRSA, 
only 32.1% had antibiotics discontinued appropriately (24, 25) Therefore the 
potential reduction in antibiotics-days of vancomycin or linezolid with a rapid 
diagnostic test based on current practices is 65.7%. With a conservative estimate 
that all subjects will have received up to 3 doses of vancomycin or linezolid prior 
to randomization, and that up to 94% of vancomycin or linezolid therapy can be 
discontinued at 72 hours in the usual care arm, we anticipate PCR will be able to 
Table 4. Power calculation for clinical trial 
Usual care group anti- 
MRSA antibiotic utilization 
(% antibiotic days) 
Effect size of 
intervention 
N  
(for each 
group) 
94% 
88.5% 
3 
57.1% 
33.6% 
22 
46% 
25% 
35 
36% 
15% 
109 
26% 
5% 
861 

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reduce antibiotic exposure by 33.6%. Based on these estimates, 22 subjects in 
each group would be needed to detect a clinically relevant difference in antibiotic 
days between the intervention and control groups, with 80% power (β=0.20) and 
two-sided α=0.05, see also Table 3. The average cost per dose of vancomycin is 
$43.45, whereas the cost of PCR is $72.75; 33.6% reduction in empiric antibiotic 
use would result in an average cost savings of $121.75 per subject.  
 
 
We do not anticipate that statistical significance will be obtained for any 
secondary endpoint. This pilot is designed to provide preliminary data for a larger 
multicenter trial which would address these more difficult endpoints. However, 
the preliminary data will be important for powering that study. 
11.3 
Data storage  
Patient data will be kept on a single, encrypted, Northwestern University issued 
password protected computer. Only the study investigators will have access to 
the data. In the event that the data has to be transported to another computer, it 
will be done using a password protected USB drive. Patient data will be available 
for the duration of the study and publication of the manuscript, which is 
anticipated to be 1 year.  
 
12.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects 
Patients will be monitored daily for evidence of adverse events, 
particularly in the first 72 hours when results of BAL cultures become 
available. Safety data collection will begin at the start of the clinical trial. 
Safety data will be collected with case report forms. 
The principle investigator and other members of the research 
team will meet on a bi-monthly basis to review the interim data including 
main outcome measures. Safety information will be collected by review of 
the medical record and maintained by the MICU research staff.  
Untoward events will be defined as mortality of subjects and 
discordant results between the PCR test and routine bacterial cultures. 
Standardized mortality rate using APACHE IV disease adjusted mortality 
and Chi-square tests will be used to determine difference in mortality and 
discordance between the two diagnostic tests of pneumonia. An interim 
analysis will be conducted when half of the target subjects are enrolled. If 
a significant trend in increased mortality in the PCR arm (P < 0.10) is 
seen, the study will be immediately suspended. If a greater than 5% false 
negative rate with PCR compared to routine bacterial cultures for the 
detection of MRSA, the study will be immediately terminated.    
 
13.0 
Withdrawal of Subjects* 
13.1 
Subjects who withdraw consent  
Subjects who withdraw their consent at any time for any reason will be 
allowed to exit the study. In that event, antibiotic prescription will be left 
up to the treating physician. If a subject or his/her surrogate withdraws 
consent after randomization, the subject will continue to be followed by 
the MICU research team and their results will be included in the final 
analysis. 
13.2 
Subjects with indeterminate PCR results  
Subjects in whom PCR test on BAL yields an indeterminate result will be 
allowed to start empiric antibiotic therapy with either vancomycin or 
linezolid while the PCR is repeated. If the PCR on BAL is indeterminate a 
second time, the subject will be withdrawn from the study. Any subject 

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withdrawn from the study will be followed by the research team, but 
outcomes will not be included in the final analysis. 
13.3 
Subjects with a new indication for vancomycin or linezolid  
Subjects who develop a new or suspected extrapulmonary infection due to 
MRSA following randomization will be allowed to start vancomycin or linezolid 
per the treating physician’s discretion. Outcomes of subjects who start 
vancomycin or linezolid for an extrapulmonary indication following randomization 
will be included in the final analysis.  
 
14.0 
Risks to Subjects* 
14.1 Risks to subjects 
The main intervention of this clinical trial is the decision to start or stop 
specific antibiotic therapy for MRSA pneumonia (the antibiotics 
vancomycin or linezolid) based on the results of the PCR. All PCR results 
will be followed up with bacterial culture, the current gold standard test. 
The primary risk to subjects is an inaccurate PCR test. The time delay 
between the PCR test and bacterial cultures is between 48 to 72 hours.  
14.1a In the case of a false positive PCR test, the risk to subjects is 
continuing antibiotic therapy for MRSA (either vancomycin or 
linezolid per the treating physician’s discretion) until the results of 
the bacterial culture. This is consistent with usual care of ICU 
patients of pneumonia, and therefore adds no added risk to 
subjects.  
14.1b In the case of the false negative PCR test, the risk to subjects 
is stopping appropriate antibiotic therapy. The probability of this 
occurring is extremely low based on weighted average of the 
negative predictive value (NPV) of prior work listed in Table 1: 
approximately 0.3%. The duration of stopping appropriate antibiotic 
therapy would last approximately 48 to 72 hours, until bacterial 
cultures result. The physical risk of withholding appropriate antibiotic 
therapy includes worsening infection, sepsis, and death.   
14.2 There are no unforeseeable risks to subjects.  
14.3 This trial does not include pregnant women.  
14.4 There are no foreseeable risk to others who are not subjects, e.g., 
risks to ethnic or cultural groups, risks to sexual partners of 
subjects, etc. 
 
15.0 
Potential Benefits to Subjects 
Subjects who are randomized to the PCR arm who have MRSA pneumonia may 
benefit due to early recognition and treatment of the infection. Subjects who are 
randomized the PCR arm who do not have MRSA pneumonia may benefit from 
earlier tailored antibiotic therapy and therefore reduced antibiotic exposure; 
however, the impact of these benefits are not known. Otherwise, we not 
anticipate any direct benefit to subjects for participation in the trial.  
 
16.0 
Vulnerable Populations 
This study will not involve pregnant women.  
 
 This study will be enrolling critically ill subjects. Many of the individuals will lack 
decision-making capacity. In addition, the critical condition of these subjects 
limits their autonomy. Thus, all of these subjects must be considered vulnerable 

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research subjects. This study cannot be accomplished without enrollment of 
these subjects. 
 
17.0 
Community-Based Participatory Research 
Not applicable.  
 
18.0 
Sharing of Results with Subjects 
The results of the PCR test will be shared with the subject or surrogate decision 
maker verbally by the research team. Results of the study will not be shared with 
subjects. 
 
19.0 
Setting 
19.1 Clinical trial  
Patients who was admitted to the medical ICU (MICU) at Northwestern 
Memorial Hospital (NMH) will be screened for inclusion in this trial. The 
NMH MICU is a 33-bed unit staffed by critical care physicians, trainees, 
and respiratory therapists (RTs). In intubated patients with suspected 
pneumonia, BALs are obtained by the MICU physician, qualified trainee, 
or RT. About 60 BALs are collected monthly. 
19.2 
Research procedure 
PCR will be conducted in the molecular epidemiology laboratory at NMH 
under the direction of Chao Qi, PhD. PCR will be conducted using the 
GeneXpert® Instrument Systems (Cephaid Inc, Sunnyvale, CA). using 
the The Cepheid Xpert® Skin and Soft Tissue (SSTI) Assay. The PCR is 
a is a qualitative in vitro diagnostic test designed for rapid detection and 
differentiation of Staphylococcus aureus (SA) and methicillin resistant 
Staphylococcus aureus  (MRSA) in body fluids using PCR amplification. 
SA is detected by the presence of the staphylococcal protein A (spa) 
gene, MRSA is identified by the mecA gene and staphylococcal cassette 
chromosome mec (SCCmec). Prior studies report detection of MRSA is 
possible in 58 minutes. PCR analysis will be conducted by the 
investigators or a qualified laboratory technician.  
 
20.0 
Resources Available 
20.1 Clinical research team  
Screening and enrollment will be conducted by research team already in place in 
the MICU at NMH. This group is made up of physicians, a registered nurse, a 
pharmacist, and two research assistants. This group will screen all intubated 
patients who are receiving antibiotics therapy admitted to the MICU for 
enrollment into the clinical trial. Screening will be done using the daily census 
data of the MICU. Our research group has extensive experience conducting 
clinically oriented research in drug resistant pneumonia and critical care. BAL is 
routinely done at our ICU in patients with suspected pneumonia, which will 
provide us with patient samples and potential research subjects. We have 
scheduled monthly in person team meetings to ensure that all persons assisting 
with the research are adequately informed about the protocol, the research 
procedures, and their duties and functions. 
20.2 Laboratory research team  
The analysis of BAL using PCR will be conducted in the clinical 
epidemiology laboratory at NMH using the research instrument described 
above. BAL will be received by the laboratory within 1 hour of collection 

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by physician or RT. The PCR assay will be conducted by a qualified 
laboratory technician once the sample is received. The GeneXpert® 
Instrument is designed to require minimal laboratory expertise and 
laboratory technician qualified to perform the assay will be routinely 
available.  
20.3 
Feasibility and time frame  
Approximately 60 to 80 patients monthly had a BAL collected in the MICU 
due to suspicion for pneumonia. We estimate approximately 50 patients 
per month will be eligible to enroll this study. Our goal is to enroll at least 
44 subjects over 12 months, or 3-4 subjects per month. The principal 
investigator devotes 75% of time to clinical research, and the MICU 
research team devotes 75-100% of effort to clinical research.  
 
21.0 
Prior Approvals 
Not applicable.  
 
22.0 
Recruitment Methods 
Patients will be recruited from the Medical Intensive Care Unit at NMH.  
Potentially eligible patients will be identified during a daily screen of 
admissions to the medical intensive care unit and/or RT orders for NBBAL 
by authorized study personnel.    
No materials will be used to recruit subjects and no payments will be 
made to subjects. 
23.0 
Local Number of Subjects 
As noted above, we anticipate enrolling at least 44 patients during the first 
year.  Our minimum enrollment goal is 44 patients which we anticipate will 
take anywhere from 6 to 12 months.   
 
24.0 
Confidentiality 
Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPPA).  Those regulations require a signed 
subject authorization (included in the informed consent document) 
informing the subject of the following 
• 
What protected health information (PHI) will be collected 
from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their 
authorization for user of their PHI 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information 
collected prior to the revocation of subject authorization 
As noted above, patient data will be kept on a single, encrypted, Northwestern 
University issued password protected computer on servers maintained by 
Feinberg Information Technology in compliance with NUFSM policies outlined in 

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their “Data Security Plans for Identifiable Information Used in Clinical Research.”  
Only the study investigators will have access to the data. In the event that the 
data has to be transported to another computer, it will be done using a password 
protected USB drive.  Patient data will be available for the duration of the study.   
 
25.0 
Provisions to Protect the Privacy Interests of Subjects 
25.1 
Once informed consent has been obtained, subjects will be given 
a study number.  This number will be used to link the subject to the data.  
The subject name and number will be kept separate.  Only the study team 
will have access to this information  
 
25.2 
The study team will access the subject’s eMR to obtain study specific 
information.  This data will be directly input into a secure database 
 
26.0 
Compensation for Research-Related Injury 
In the event the subject becomes ill or injured as a result of this study 
(medications or procedures), the hospital [university, researchers] will not pay for 
medical care required because of a bad outcome resulting from participation. 
 
27.0 
Economic Burden to Subjects 
The subjects will not accrue costs related to participation in this research 
 
28.0 
Consent Process 
28.1 
We anticipate that the majority, if not all, subjects in this trial will 
not be able to provide informed consent because of their critical illness. 
Therefor, after identification, a member of the study team will discuss 
participation in the study with the patient’s legally authorized 
representative (LAR).  The LAR will be identified in the subject’s eMR via 
the advanced directives tab in accordance to the hospital and Illinois law 
28.2 
Informed consent will be administered and the patient’s LAR will 
be asked to sign and date the approved informed consent document.  
The subject is not obligated to take part in research, and this will be made 
clear to their LAR.  Furthermore, LARs are not obligated to sign an 
informed consent document the same day in which they learn about the 
study.  If the patient’s surrogate decision maker does decide to take part 
in the study and reads, understands, and decides to sign the informed 
consent, all of his/her questions must be answered prior to the consent 
being signed.  Once the consenting form is signed and dated, it will be 
copied and the volunteer will receive a copy.  If at any point during the 
course of the study, a subject who was previously dependent on a LAR 
for consent regains the ability to provide informed consent, the study will 
be reviewed with the subject and consent obtained.  A signature block at 
the end of the consent document is available for appropriate 
documentation should this situation arise.  In situations where the LAR is 
not immediately available in person a copy of the informed consent will be 
faxed or emailed for their review.  A member of the study team will review 
the consent with signee over the telephone.  The LAR may fax back 
and/or scan email back the signed consent.  They will be instructed to 
return the original signed document at their next visit to the hospital. 
 
 
29.0 
Process to Document Consent in Writing 

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Written consent will be obtained following the procedures for documentation of 
informed consent outlined in HRP-091.  A consent documented is attached in this 
application. 
 
30.0 
Drugs or Devices 
30.1 
PCR will be conducted in the molecular epidemiology laboratory at 
NMH under the direction of Chao Qi, PhD. PCR will be conducted using 
the GeneXpert® Instrument Systems (Cephaid Inc, Sunnyvale, CA). 
using the The Cepheid Xpert® Skin and Soft Tissue (SSTI) Assay. The 
PCR is a is a qualitative in vitro diagnostic test designed for rapid 
detection and differentiation of Staphylococcus aureus (SA) and 
methicillin resistant Staphylococcus aureus  (MRSA) in body fluids using 
PCR amplification. SA is detected by the presence of the staphylococcal 
protein A (spa) gene, MRSA is identified by the mecA gene and 
staphylococcal cassette chromosome mec (SCCmec). Prior studies 
report detection of MRSA is possible in 58 minutes.. 
 
30.2 
After obtaining informed consent, the study team will obtain the 
study sample from leftover BAL fluid collected as standard of care.  For 
subjects randomized to PCR analysis this sample tested will be 
conducted by the investigators or a qualified laboratory technician.   
  
31.0 
Publication plan  
It is anticipated that the investigators will submit abstracts and research articles 
to major journals based on the data from this study.  In addition, the results of 
this study may also be used for teaching, publications, and/or presentations at 
scientific meetings.  If a subject’s individual results are discussed, their identity 
and all personal information will be protected.