Clinical trial NCT05102162
Conditions: Pneumonia
Sponsor: University of Florida
Start date: 2021-12-17; Completion date: 2023-02-28
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study plans to randomize a total of 240 patients infected with Gram-negative bacterial pneumonia to receive beta-lactam (meropenem, cefepime, or piperacillin/tazobactam) continuous or intermittent infusion and collect baseline and regular follow-up respiratory cultures to assess the development of new resistance. The investigators will measure beta-lactam concentration to assess the impact of drug exposure on the bacterial resistance.

Detailed description:

Arms: arm 1: Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose. arm 2: Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
Interventions: intervention 1: Cefepime, Meropenem, or Piperacillin/Tazobactam intervention 2: Cefepime, Meropenem, or Piperacillin/Tazobactam
Intervention descriptions: intervention 1: A 1:1 randomization scheme based on the infusion duration (continuous over 24 hours or intermittent over 30 minutes) with stratification based on the beta-lactam prescribed (cefepime, meropenem, or piperacillin/tazobactam) intervention 2: A 1:1 randomization scheme based on the infusion duration (continuous over 24 hours or intermittent over 30 minutes) with stratification based on the beta-lactam prescribed (cefepime, meropenem, or piperacillin/tazobactam)

Protocol documents:
Prot_SAP_000.pdf: 
 
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Project title 
Beta-lactam continuous versus intermittent infusion and associated bacterial 
resistance and therapy outcomes in critically ill patients with severe pneumonia 
 
Investigators 
 
Mohammad H. Alshaer 
Charles A. Peloquin 
Awewura Kwara 
Kenneth Rand 
Veena Venugopalan 
Cesar Trillo Alvarez 
Kartikeya Cherabuddi 
Kathryn DeSear 
Barbara Santevecchi 
Haya Kaseer 
Ada Jutba 
Arkaprava Roy 
Study coordinator (TBD: still to be hired) 
 
 
Abstract 
 
 
 
Infections caused by resistant microorganisms are affecting millions of people 
and causing thousands of deaths every year in the United States. This has created a 
problem along with the slow development of new antimicrobials which limited the 
treatment options for infected patients. In the intensive care unit (ICU), pneumonia is the 
most commonly encountered bacterial infection, which is associated with severe 
outcomes including longer ICU stay, mechanical ventilation, and high mortality rate. 
Such infection is usually treated with beta-lactams using standard doses which may be 
inadequate to treat serious infections in ICU patients. To date, no published clinical 
trials evaluated the impact of beta-lactam continuous vs. intermittent infusion on the 
bacterial resistance in patients with severe pneumonia. 
We plan to randomize a total of 240 patients infected with Gram-negative 
bacterial pneumonia to receive beta-lactam (meropenem, cefepime, or 
piperacillin/tazobactam) continuous or intermittent infusion and collect baseline and 
regular follow-up respiratory cultures to assess the development of new resistance. In 
addition, we will measure beta-lactam concentration to assess the impact of drug 
exposure on the bacterial resistance. The primary outcome in this trial will be the 
incidence of Gram-negative bacterial resistance, while the secondary outcomes will be 
the microbiologic eradication, clinical cure, length of stay, mortality, and incidence of 
adverse events. Given the sample size, the admission rate, and the multidisciplinary 
team involved, we expect to adequately describe the microbiologic and clinical 
outcomes associated with the beta-lactam continuous vs. intermittent infusion.  


 
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Background 
Being a worldwide problem, antimicrobial resistance is putting millions of 
people’s lives at risk (WHO, 2015). Resistant bacteria and fungi cause 3 million 
infections and >35,000 deaths every year in the United States. In their most recent 
Antibiotic Resistance threats report, the Centers for Disease Control and Prevention 
specified certain bacteria to be associated with great threat to people due to their 
resistance pattern and high mortality rates. These bacteria include carbapenem-
resistant and extended-spectrum beta-lactamase-producing Enterobacteriaceae and 
multidrug-resistant Pseudomonas aeruginosa (CDC, 2019). With the slow development 
of new antibiotics, the resistance problem has created a barrier to treating patients and 
limited the available options. 
 
Sepsis is considered a major problem in the intensive care unit (ICU). Globally, 
the sepsis-associated mortality is 25% (Kaukonen 2014, McPherson 2013, Fleischmann 
2016). One of the most common bacterial infections in the ICUs is pneumonia, which 
has been consistently associated with prolonged mechanical ventilation, ICU stay, and 
high mortality rate (Papazian 2020). Early antibiotic therapy is important in these 
infections and resistance may develop in this population if there is suboptimal 
antimicrobial exposure that is insufficient to eradicate the invading bacteria (Roberts 
2008, Tam 2005). Beta-lactams are frequently prescribed to treat these infections in the 
ICUs. The bacterial killing of beta-lactams is driven by the amount of time the free 
antibiotic concentration is above the minimum inhibitory concentration (fT>MIC). 
Currently suggested doses in the package inserts may be inadequate to treat the 
serious infections encountered in the critically ill patients, including pneumonia (Lipman 
1999, Crandon 2010, Koomanachai 2010, Al-Shaer 2020). 
 
To date, no published clinical trial evaluated the impact of beta-lactam 
continuous infusion on the emergence bacterial resistance in patients with severe 
pneumonia, which will be addressed in this project. 
 
 
Statement of Work 
 
Scope 
 
 
This randomized, controlled clinical trial aims to identify the benefits and risks of 
beta-lactams continuous vs. intermittent infusion in critically ill patients with Gram-
negative bacterial severe pneumonia, who will be admitted to the medical ICU at UF 
Health Shands from 2021 to 2023. We will compare the microbiologic, clinical, and 
safety outcomes between the two groups. 
 
Objectives 
 


 
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Primary objective 
 
• Compare the incidence of Gram-negative bacterial resistance between patients 
treated with continuous and intermittent infusion beta-lactam regimens. 
 
Secondary objectives 
 
Compare the following outcomes and variables between the continuous and 
intermittent beta-lactam infusion groups: 
 
• Superinfection 
• Microbiologic eradication 
• Clinical cure 
• PK/PD target attainment (calculated fT>MIC and fT>4×MIC) 
• Length of stay 
• Mortality rate 
• Incidence of adverse events 
 
 
Definitions 
 
Bacterial resistance will be defined as new numeric increases (≥2-fold) in the 
bacterial MIC during the follow-up period compared to the baseline when starting beta-
lactam therapy. Superinfection will be defined as the growth of resistant Gram-negative 
bacteria during the follow-up period which was not isolated in baseline culture. 
Microbiologic eradication is the absence of bacterial growth during the follow-up period 
with no subsequent positive culture from any site. Clinical cure is the resolution of 
infection-related symptoms at the end of therapy, including normalization of body 
temperature and WBC count and taking the patient off mechanical ventilation or 
vasopressors, and non-initiation of a new antibiotic within 48 hours of stopping the 
original one. Adverse events include drop in platelets (<125×103 cells/mm3) or WBC 
(<2,500 cells/mm3), increase in serum creatinine (≥1.3 times of baseline) 
(HHS/NIH/NIAID/DAIDS 2017), Clostridioides difficile colitis, and neurotoxicity. Beta-
lactam neurotoxicity is defined as meeting ≥2 of the National Cancer Institute (NCI) 
criteria for neurological toxicity including symptoms such as presence of new onset 
confusion, delirium, and drowsiness (NCI CTCAE v5.0), electroencephalogram (EEG) 
findings consistent with beta-lactam toxicity as per the neurologist, and improvement of 
signs and symptoms of neurotoxicity after beta-lactam discontinuation. The EEG 
findings will be categorized based on the 2012 American Clinical Neurophysiology 
Society standardized EEG critical care terminology (Hirsch 2013). Patients who will 
develop neurotoxicity will be extensively reviewed by a neurologist to assess the cause 
of this event (beta-lactam therapy vs. other factors). Patients with serious adverse 
events will be assessed for stopping or changing therapy as per clinician discretion. 
 


 
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Specific aims and tasks 
 
Aim 1. To describe the incidence of Gram-negative bacterial resistance in the 
continuous and intermittent beta-lactam infusion groups 
 
Study design 
 
A randomized, open-label study of patients admitted to UF Health Shands 
Hospital in Gainesville, FL.  
 
Inclusion criteria 
 
• Admission to the medical ICU with severe pneumonia defined as per IDSA/ATS 
2019 criteria on mechanical ventilation: presence of signs, symptoms and 
confirmatory chest imaging consistent with pneumonia (e.g. fever, cough and 
pulmonary infiltrate by chest radiograph) requiring mechanical ventilation due to 
respiratory failure 
• Age ≥18 years 
• Positive rapid identification test and respiratory culture for Gram-negative 
bacteria including, but not limited to, P. aeruginosa, K. pneumoniae, E. coli, S. 
marcescens, H. influenzae, Enterobacter spp., M. catarrhalis, A. baumannii, 
Achromobacter spp., P. mirabilis, and/or B. cepacia 
• Received within the last 48 hours or will receive meropenem, cefepime, or 
piperacillin/tazobactam therapy 
 
Exclusion criteria 
 
• Pregnancy 
• Prisoners 
• Allergy to the beta-lactams to be administered in this study 
• On renal replacement therapy at the time of randomization 
• Gram-negative bacteria identified by rapid testing only with negative respiratory 
culture at baseline 
• COVID patients enrolled in other trials 
 
Patients who will develop renal impairment requiring renal replacement therapy 
after randomization will be included in the analysis and, in case they were on 
continuous infusion, will be switched to intermittent infusion (see intention to treat (ITT) 
and per protocol (PP) analyses under Statistical Analysis section below).  
 
Procedures and Intervention arms 
 
Patients will be identified from the medical ICU admission list by the study team. 
Once the patient is intubated, a bronchoalveolar lavage or endotracheal aspirate will be 


 
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sent for culture and susceptibility testing as per standard of care. As part of the 
screening process, the same specimen will be used for quick semi-quantitative 
pathogen identification using the BioFire® FilmArray® pneumonia panel (BioFire 
Diagnostics Salt Lake City, Utah, USA) that detects 15 common potential agents of 
pneumonia in intubated patients within 1 hour in the laboratory. If Gram-negative 
bacteria were identified, patient or their representative will be approached and provided 
with informed consent form, and if they agree to participate the patient will be enrolled in 
the study. 
 
Alternate Plan: The BioFire® FilmArray® pneumonia panel is expected to be 
available at UF Health starting Summer 2021. The availability and quantity offered may 
vary based on the supply. In case the panel will not be available for this study, the 
research team will use the positive respiratory cultures at baseline, using growth on 
MacConkey agar in the first 24 hours as a proxy for presumptive growth and 
identification of appropriate culture results for inclusion into the study. 
 
The beta-lactam agent and duration of therapy will be specified by the treating 
physician. A 1:1 randomization scheme based on the infusion duration (continuous over 
24 hours or intermittent over 30 minutes) with stratification based on the beta-lactam 
prescribed (cefepime, meropenem, or piperacillin/tazobactam) will be developed before 
starting the trial using a random number generator. Only the PI will have access to the 
randomization list. On recruitment, the study coordinator will contact the PI, who will 
assign a unique study identifier in sequential order and provide the team with the 
randomization arm. These identifiers correspond with entries in the randomization list, 
which indicates either starting/switching the patient to 24-hour continuous infusion beta-
lactam therapy (intervention group) or 30-minute intermittent infusion beta-lactam 
therapy (control group) as shown in Table 1. For continuous infusion regimens, 
piperacillin and cefepime will be provided by the pharmacy as one 24-hour-dose bag, 
whereas meropenem provided as two 12-hour-dose bags based on previous experience 
with its stability (Venugopalan 2018). In case the patient was randomized to an infusion 
group then the treating physician decided to switch the beta-lactam to another one in 
this study before completing therapy, the patient will remain in the study and their new 
beta-lactam will be infused based on the original randomization group the patient was 
assigned to. If the patient was switched to another agent not included in this study 
within the first 72 hours, the patient will be withdrawn from this study. If the switch to a 
different agent was after 72 hours of beta-lactam therapy, the patient will remain in the 
study and their respiratory samples will be collected for up to 4 weeks to assess the 
emergence of resistance. Patients in the ICU will have triple lumen IV line so they have 
a dedicated line for the beta-lactam infusion. Once the patient is transferred out of the 
ICU and still needs to continue the beta-lactam therapy, a dedicated peripheral line will 
be inserted if needed. 
 
 
 
 


 
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Table 1: Initial beta-lactam doses per infusion group and CrCl value 
 
Creatinine clearance 
Intermittent infusion arm 
Continuous infusion arm 
Cefepime 
>60 
2 g IV every 8 hr 
6 g IV daily 
30-60 
2g IV every 12 hr 
4 g IV daily 
10-30 
2g IV every 24 hr 
2 g IV daily 
<10 
1g IV every 24 hr 
1 g IV daily 
Meropenem 
>50 
2 g IV every 8 hr 
6 g IV daily 
25-50 
2g IV every 12 hr 
4 g IV daily 
10-25 
1g IV every 12 hr 
2 g IV daily 
<10 
1g IV every 24 hr 
1 g IV daily 
Piperacillin/tazobactam 
>40 
4.5 g IV every 6 hr 
18 g IV daily 
20-40 
3.375 g IV every 6 hr 
13.5 g IV daily 
<20 
2.25 g IV every 6 hr 
9 g IV daily 
 
Tracheal aspirate (intubated patients) or sputum samples (extubated patients) 
will be collected twice weekly and sent for culture and susceptibility testing for a 
maximum of 4 weeks from the initiation of beta-lactam therapy. More cultures may be 
drawn as per standard of care and clinicians discretion which will be included in the 
analysis. The MICs for the bacteria will be determined in the onsite UF Health Shands 
microbiology laboratory. Bacteria will be identified by standard microbiologic methods 
using VITEK® Mass Spectrometry and Vitek® II (AST GP 72, AST GP 78, AST GN 73, 
and AST XN06) (bioMérieux, Inc., Durham, NC, USA). MICs will be done by E-test. 
 
 
As per standard of care, patients will have their beta-lactam plasma drug 
concentration measured in the first days of therapy, and repeated as needed. The 
ID/ICU pharmacist or physician will order a peak (1 hour after the end of the infusion) 
and a trough (before the start of next dose) sample for patients on intermittent infusion. 
We recommend two random samples, while the patient is on the same infusion bag, to 
be ordered for those on continuous infusion. A minimum of one sample will be 
considered acceptable for continuous infusion patients. Beta-lactam plasma 
concentration will be quantified at the IDPL using validated LCMS-MS assays. The IDPL 
is a CLIA-licensed clinical laboratory. All assays will be performed using standard 
operating procedures (SOPs) that have been reviewed and certified by the College of 
American Pathologists (CAP). The standard curve (calibrators) consists of 6 
concentrations of samples. A minimum of three quality control samples are assayed 
along with the standard curve samples. The calibration curves for meropenem, 
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ranges of the coefficient of variation for the plasma meropenem, cefepime, and 
piperacillin quality control samples are 3.7%–8.6%, 3.3%–9.8%, and 4.6%–6.3% for 
inter-day precision and the ranges are 1.4%–12.6%, 3.7%–11.0%, and 4.1%–7.3% for 
intra-day precision, respectively. Meropenem-d6, cefepime-d3, and piperacillin-d5 are 
used as internal standards. A Thermo Scientific Altis triple quadrupole mass 
spectrometer (Thermo Fisher, San Jose, CA), coupled with a Vanquish autosampler 
and pump (Thermo Fisher) will be used to analyze the samples. The fT>MIC will be 
calculated for each patient using BestDose™ software (LAPKB, University of Southern 
California) and therapy adjusted based on the clinician discretion (Table 2), while each 
patient remaining in their randomized infusion group. 
 
 
 
 
 
 
Table 2: Suggested therapy adjustment for patients above or below the target 
Therapy group 
<100% fT>MIC 
>100% fT>5×MIC 
Intermittent infusion 
25-50% increase in 
frequency of administration 
50% decrease in dose or 
25-50% decrease in 
frequency 
Continuous infusion 
25-50% increase in dose 
50% decrease in dose 
 
 
Data will be collected include patients’ age, sex, comorbidities, APACHE II and 
SOFA scores, vital signs, cultures and susceptibilities, bronchoalveolar lavage culture 
data and cell count, lab results including complete blood count, basic metabolic panel, 
C-reactive protein, erythrocyte sedimentation rate, and procalcitonin, antimicrobial 
regimens, vasopressors requirement, ventilation settings and requirements, and EEG 
findings if available. 
 
 
Outcomes 
 
 
Primary outcome, incidence of Gram-negative bacterial resistance, will be 
reported under this aim. Definitions were mentioned previously (see Definitions under 
Objectives). 
 
Statistical analysis 
 
Descriptive statistics of median and interquartile range or mean and standard 
deviation will be reported for the continuous variables, whereas counts and percentages 
will be reported for categorical variables. The primary outcome under this aim will be 
assessed using ITT analysis, and PP analysis including only those who finished their 
therapy on the randomized beta-lactam infusion. Multiple regression models will be built 


 
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to assess the incidence of resistance while controlling for beta-lactam infusion time, 
drug exposure (fT>MIC and trough/MIC), APACHE and SOFA scores, mono- vs. 
polymicrobial infections, administration of other antibacterial agents (fluoroquinolones, 
aminoglycosides, polymixins), and source of infection. Time-to-event analysis and log-
rank test will be used to compare the time to developing new resistance between 
groups. Data will be analyzed both individually for each beta-lactam and pooled since 
target exposure for resistance suppression in pre-clinical studies was similar for most 
beta-lactams (i.e. trough/MIC ≥4) (Sumi 2019). The study team will do their best to 
avoid missing any datapoint. In case there is missing data in certain outcomes or 
variables for a patient, that patient will be dropped from that specific analysis and the 
number of patients included in each analysis will be reported. Inability to provide sputum 
sample for culture for a patient who is improving clinically with no subsequent positive 
cultures will be considered as no new resistance developed. JMP Pro v15.0 (SAS) will 
be used for the statistical analysis. 
 
Assuming the incidence of new resistance will be 20% in the intermittent vs. 5% 
in the continuous infusion groups, with 80% power and 20% dropout rate, a sample size 
of 76 (one-sided test) or 96 (two-sided test) per group will be needed. We will aim to 
enroll a total of 240 patients (120 per group) based on the current rate of admissions 
and positive respiratory cultures in the medical ICU. 
 
Aim 2. To compare clinical outcomes, including microbiologic eradication, 
clinical cure, mortality rate, and length of stay, between the two infusion groups 
 
 
The protocol mentioned previously in Aim 1 will be followed for participant 
enrollment, treatments, and follow-up evaluations. 
 
Outcomes 
 
 
Secondary outcomes, including microbiologic eradication, clinical cure, mortality 
rate, and length of stay, will be reported under this aim. Definitions were mentioned 
previously (see Definitions under Objectives). 
 
Statistical analysis 
 
Descriptive statistics of median and interquartile range or mean and standard 
deviation will be reported for the continuous variables, whereas counts and percentages 
will be reported for categorical variables. Outcomes under this aim will be assessed 
using ITT analysis, and PP analysis including only those who finished their therapy on 
the randomized beta-lactam infusion. Multiple regression models will be built to assess 
the microbiologic eradication, clinical cure, mortality, length of stay, days on mechanical 
ventilation, and days on vasopressors while controlling for beta-lactam infusion time, 
drug exposure (fT>MIC and trough/MIC), APACHE and SOFA scores, mono- vs. 
polymicrobial infections, administration of other antibacterial agents (fluoroquinolones, 
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rank test will be used to compare the time to microbiologic eradication and transfer out 
of ICU and time on mechanical ventilation and vasopressors between groups. Data will 
be analyzed both individually for each beta-lactam and pooled while controlling for 
achieving the optimal PK/PD target for clinical efficacy (i.e. fT>MIC meropenem >40%, 
cefepime >70%, and piperacillin >50%) (Heffernan 2018). The study team will do their 
best to avoid missing any datapoint. In case there is missing data in certain outcomes or 
variables for a patient, that patient will be dropped from that specific analysis and the 
number of patients included in each analysis will be reported. Inability to provide sputum 
sample for culture for a patient who is improving clinically with no subsequent positive 
cultures will be considered as presumed microbiologic eradication. JMP Pro v15.0 
(SAS) will be used for the statistical analysis. 
 
Assuming the absolute difference in clinical cure will be 15% between the 
intermittent and the continuous infusion groups (Dulhunty 2013), with 80% power and 
5% level of significance, a total sample size of 60 (two-sided test) will be needed. 
Aiming to enroll a total of 240 patients (120 per group) for our Aim 1 (detection of new 
resistance), our study will have enough power to detect a difference in clinical cure. 
 
Aim 3. To compare safety of both infusion strategies 
 
 
The protocol mentioned previously in Aim 1 will be followed for participant 
enrollment, treatments, and follow-up evaluations. 
 
Data collection for this aim includes platelets and WBC count, serum creatinine, 
Clostridioides difficile colitis, and EEG reports for neurotoxicity. Neurotoxicity has been 
defined previously. Patients who will develop neurotoxicity will be extensively reviewed 
by a neurologist to assess the cause of this event (beta-lactam therapy vs. other 
factors). Patients with serious adverse events will be assessed regularly for stopping or 
changing therapy as per clinician discretion and the Safety Officer will review all safety 
data on a regular basis (see Data Safety Monitoring Plan). 
 
Outcomes 
 
 
Secondary outcome, incidence of adverse events, will be reported under this 
aim. Definitions were mentioned previously (see Definitions under Objectives). 
 
Statistical analysis 
 
Descriptive statistics of median and interquartile range or mean and standard 
deviation will be reported for the continuous variables, whereas counts and percentages 
will be reported for categorical variables. Outcomes under this aim will be assessed 
using ITT analysis, and PP analysis including only those who finished their therapy on 
the randomized beta-lactam infusion. Multiple regression models will be built to assess 
the incidence of adverse events while controlling for beta-lactam infusion time, drug 
exposure (fT>MIC, area under the concentration-time curve, trough/MIC), APACHE and 


 
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SOFA scores. Time to event analysis and log-rank test will be used to compare the time 
to developing the adverse event between groups. Data will be analyzed for each beta-
lactam individually. The study team will do their best to avoid missing any datapoint. In 
case there is missing data in certain outcomes or variables for a patient, that patient will 
be dropped from that specific analysis and the number of patients included in each 
analysis will be reported. JMP Pro v15.0 (SAS) will be used for the statistical analysis. 
 
Given that no previous clear data on the toxicity associated with different 
infusions of beta-lactams, the analysis in this aim will be exploratory and hypothesis 
generating. 
 
Tasks 
 
We are dividing our deliverables into pilot, proof-of-concept, and final groups of 
patients. As a result, the tasks and subtasks will be the same for all aims as we will be 
assessing the three aims above (Aim 1 – 3) for every group of patients.  
 
 Task 1 (Base period): Pilot group (first 60 patients) (timeframe: months 0 to 6): 
o Subtask 1. Screening 100 patients using BioFire pneumonia panel: 
 Study coordinator will be available on a daily basis for reviewing 
admission list and identifying the eligible patients. Dr. Trillo will 
oversee the admission to the medical ICU and help identify the 
patients who may be eligible  at the time of intubation. If a patient 
fulfills the inclusion criteria, Dr Trillo or his clinical team (including 
Drs. Kaseer and Jutba) will ask the patient or their representative if 
they are interested to enroll in this study. If yes, Dr. Trillo's clinical 
team will inform the study coordinator who will approach the eligible 
patient’s family or representative for consenting. If informed 
consent was obtained from an authorized representative, it will be 
obtained from the patient again once they are able to provide one 
and still enrolled in the study. Dr. Rand will oversee the respiratory 
samples coming to the microbiology lab for pneumonia panel 
screening and assess the quality of the results. The results will be 
available for the study team and clinicians through the secured 
EMR. 
o Subtask 2. Randomizing 60 patients to continuous or intermittent infusion 
beta-lactam therapy after confirming the result of the pneumonia panel: 
 The study coordinator will be in touch with the microbiology lab for 
the final results of the pneumonia panel. Dr. Alshaer will provide the 
study coordinator with the randomization code and oversee the 
randomization process. Dr. Venugopalan, along with ID and ICU 
pharmacists, will oversee the adherence to the randomization 
protocol in terms of beta-lactam infusion time and order beta-lactam 
plasma samples to quantify the drug exposure. Dr. Peloquin will 
oversee the samples received at the IDPL, assess the quality of the 


 
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results generated by the assay, and make sure the results are 
released in a timely manner to EMR. Drs. Trillo, Kwara, and 
Venugopalan will evaluate the clinical status of the patients on a 
regular basis and determine the clinical cure and incidence of 
adverse events with the help of the assigned nurses. 
o Subtask 3. Obtaining and sending respiratory cultures for randomized 
patients twice weekly for a total of 4 weeks: 
 Dr. Trillo or designate and Dr. Kwara will order regular respiratory 
cultures (twice per week) for up to 4 weeks from randomization. 
Respiratory therapist will obtain the samples and the study 
coordinator will take them to the microbiology lab. Dr. Rand will 
oversee the respiratory samples coming to the microbiology lab for 
Gram-negative bacteria identification and MIC testing, and assess 
the quality of the results. The results will be available for the study 
team through the secured EMR. 
o Subtask 4. Calculating beta-lactam target attainment and drug exposure 
for randomized patients using plasma concentration and BestDose™: 
 As the beta-lactam plasma concentrations become available, Dr. 
Alshaer will use BestDose™ to calculate the PK and PK/PD 
parameters for each patient, using their plasma concentration and 
dosing info, to be included later in the analysis. BestDose™ will use 
the entire discrete joint distribution of PK parameters (i.e. support 
points) generated in a PK model to identify each patient’s total drug 
exposure using Multiple Model Bayesian adaptive control, in which 
the most probable support point, the one with the best fit, for each 
patient will be used to generate the full PK exposure. Dr. Alshaer 
will assess the model fit to the patient’s data and evaluate the bias 
and imprecision of the predictions. 
o Deliverables: Number of patients screened, distribution of Gram-negative 
bacteria identified using pneumonia panel, number of patients randomized 
to each arm and their initial beta-lactams regimens, distribution of Gram-
negative bacteria identified using respiratory cultures and their MICs, 
number of patients for each objective (new resistance [primary], 
microbiologic eradication, clinical cure, days on mechanical ventilation and 
vasopressors, days in ICU and hospital, mortality rate, and PK/PD target 
attainment [secondary]) along with statistical analysis to compare the two 
infusion groups. 
 Task 2 (Option 1): Proof-of-concept group (second 60 patients) (timeframe: 
months 6 to 12): 
o Subtask 1. Screening the next 100 patients using BioFire pneumonia 
panel: details above. 
o Subtask 2. Consenting and randomizing the next 60 patients to 
continuous or intermittent infusion beta-lactam therapy after confirming the 
result of the pneumonia panel: details above. 


 
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o Subtask 3. Obtaining and sending respiratory cultures for randomized 
patients twice weekly for a total of 4 weeks: details above. 
o Subtask 4. Calculating beta-lactam target attainment and drug exposure 
for randomized patients using plasma concentration and BestDose™: 
details above. 
o Deliverables: Number of patients screened from month 6 to 12, 
distribution of Gram-negative bacteria identified using pneumonia panel, 
number of patients randomized to each arm and their initial beta-lactams 
regimens, distribution of Gram-negative bacteria identified using 
respiratory cultures and their MICs, number of patients for each objective 
(new resistance [primary], microbiologic eradication, clinical cure, days on 
mechanical ventilation and vasopressors, days in ICU and hospital, 
mortality rate, and PK/PD target attainment [secondary]) along with 
statistical analysis, updated analysis for all patients randomized in the first 
year of the study (target 120 patients). 
 Task 3 (Option 2): Final group (last 120 patients) (timeframe: months 12 to 24): 
o Subtask 1. Screening the next 200 patients using BioFire pneumonia 
panel: details above. 
o Subtask 2. Consenting and randomizing the last 120 patients to 
continuous or intermittent infusion beta-lactam therapy after confirming the 
result of the pneumonia panel: details above. 
o Subtask 3. Obtaining and sending respiratory cultures for randomized 
patients twice weekly for a total of 4 weeks: details above. 
o Subtask 4. Calculating beta-lactam target attainment and drug exposure 
for randomized patients using plasma concentration and BestDose™: 
details above. 
o Deliverables: Number of patients screened from month 12 to 24, 
distribution of Gram-negative bacteria identified using pneumonia panel, 
number of patients randomized to each arm and their initial beta-lactams 
regimens, distribution of Gram-negative bacteria identified using 
respiratory cultures and their MICs, number of patients for each objective 
(new resistance [primary], microbiologic eradication, clinical cure, days on 
mechanical ventilation and vasopressors, days in ICU and hospital, 
mortality rate, and PK/PD target attainment [secondary]) along with 
statistical analysis, updated analysis for all patients randomized in the 
whole study period (target 240 patients). 
 
Protection of Human Subjects 
 
This study is considered an ‘Applicable Clinical Trial.’ At University of Florida, all 
clinical studies will need to be reviewed by the Institutional Review Board (IRB) once 
funded and before enrollment of participants. As part of the IRB review, the study will be 
directed to specialized staff for registration at ClinicalTrials.gov registry. 
 


 
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This study will enroll both men and women equally as well as elderly patients 
fulfilling the inclusion criteria. Given the current practice in the adult medical ICU, use of 
beta-lactams of interest (meropenem, cefepime, and piperacillin), and the study scope 
(isolated Gram-negative bacteria from respiratory specimens), pediatrics will not be 
included in this study. 
 
1. Risk to the subjects 
 
a. Human subject involvement and characteristics 
 
The Statement of Work provides a detailed description of the participation 
of human subjects in this project, including participant characteristics, 
numbers, age and inclusion/exclusion criteria. To summarize, this study 
will enroll 240 patients hospitalized at UF Health Shands in Gainesville, 
Florida with severe pneumonia who are 18 years or older and on (or will 
be on) meropenem, cefepime, or piperacillin. Potential subjects will be 
excluded if they are pregnant, allergic to beta-lactam therapy in the study, 
on renal replacement therapy, and/or COVID patients enrolled in other 
trials. The IRB of University of Florida will review the protocol and 
informed consent, and approve the study before enrollment begins. All 
subjects or surrogate will provide signed written informed consent. The 
informed consent will describe the purpose of the study, the procedures to 
be followed, the risk and benefits of participation. A copy of the consent 
forms will be given to the subject. Dr. Alshaer is responsible for 
overseeing the conduct of the clinical trial. 
 
b. Sources of Materials 
 
Potential participants will be screened in the medical ICU to ensure that 
they meet the inclusion criteria. As part of the screening process, eligible 
patients will have their respiratory samples sent to the microbiology lab for 
bacterial cultures and MIC determination at the time of intubation as per 
standard of care. To limit the study-related invasive procedures, the same 
sample will be used for rapid identification of bacteria. Screening 
evaluation will be recorded on electronic sheet and will be stored on the 
secured server of the University of Florida, which is only accessible to staff 
involved in this study. 
 
Once the participant is enrolled and the study has started, regular 
respiratory samples (from regular suctioning in intubated patients [usual 
care practice] or sputum samples in extubated patients) will be obtained 
for research purposes. Respiratory samples will be handled like other 
clinical samples within the closed hospital system. Blood samples for drug 
concentrations will be drawn as per standard of care and sent to the IDPL 
for quantification within 24 hours on weekdays. 


 
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Routinely collected antibiotic side effects data will be extracted and 
entered into the research database for the purposes of research analysis. 
Drug concentration data will be made available to the clinicians for routine 
care. All patients’ data including laboratory specimens, evaluation forms, 
reports and other records extracted from EPIC will be assigned a coded 
number to maintain subject confidentiality; only research staff will be able 
to identify the subject from the code. All records will be kept in a secured 
server at University of Florida. 
 
c. Potential Risks 
 
All the study medications are approved for clinical use and prescribed by 
the treating physicians of participants. Both the continuous and 
intermittent beta-lactam infusion regimens are administered on daily basis 
to the medical ICU patients. As a result, both the clinicians and study team 
have long experience with these regimens. Antibiotic dose adjustments 
will be based on recommendations by ID and ICU pharmacists and 
physicians as per usual care. Close clinical and laboratory monitoring is 
routinely done for hospitalized patients. The patient-to-nurse ratio is 1:1 to 
2:1 in the medical ICU, and 4:1 to 5:1 in the floors. The patients will be 
under continuous observation by their clinical nurse during the study 
period. In the event of a serious medical emergency related to the study, 
treatment will be provided. Adverse events related to the beta-lactam 
infusion or respiratory sampling for research are reported to the 
appropriate University of Florida IRB according to existing regulations. 
 
2. Adequacy of protection against risks 
 
a. Recruitment and Informed Consent 
 
All protocols, consent forms, and recruitment materials and procedures 
will be reviewed and approved by University of Florida IRB. Since 
participants will be intubated and sedated, a patient’s representative will 
receive a complete description of the study procedures, including risks 
and benefits, from one of the study investigators or a designate. Informed 
consent also includes alternatives and principal investigator’s phone 
numbers. When the explanation is completed and subjects’ 
representatives indicate that all of their questions have been answered, 
they will sign the consent document, with an understanding that 
participation is voluntary. There are no waivers or modifications of the 
consent process. Subjects (or their representatives) will receive a copy of 
the consent form, and details of medical records or other patient data will 
be kept confidential except as required by law. If informed consent was 
provided initially by an authorized representative, the study coordinator will 


 
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obtain another informed consent from the patient once they are able to 
provide one and still enrolled in the study. 
 
b. Protection Against Risk 
 
The treating physicians will take responsibility for medical coverage, and 
for assuring the safety of study participants. All medications are given with 
ongoing monitoring and supervision by nurses and treating physicians. 
Medical coverage, including resuscitation coverage, is available at all 
times, and a physician is responsible for overseeing patient care. Should 
participants or representative have study related questions or problems 
that arise during the course of the study, it will be addressed by the 
research team in person or by phone. The numbers are listed on each 
consent form, a copy of which is provided to each subject. 
 
Every effort is made to protect the confidentiality of study-related data. All 
paper documents are stored under lock and key in a secure area, while 
electronic data kept on a secured server only accessible to the study 
team. All patients data are coded, with only the PI and designated 
research associates having access to the code. 
 
3. Potential benefits of the proposed research to the subjects and others 
 
There are no immediate direct benefits to individual subjects. However, the risks 
are considered acceptable based on the known adverse event profile associated 
with respiratory samples through suctioning or sputum samples. Also, patients in 
both groups will receive the same beta-lactam total daily dose based on their 
renal function initially and will have their beta-lactam drug concentration 
measured to make sure they are not having very high or toxic concentration. On 
the other hand, there may be substantial benefits to the society in general in 
further optimizing beta-lactam regimens to prevent the emergence of resistance 
in Gram-negative bacterial pneumonia. 
 
 
4. Importance of the knowledge to be gained from this work 
 
Gram-negative bacterial resistance represents a major worldwide problem. 
Robust clinical trials are needed to prove the efficacy of different beta-lactam 
dosing strategies against the emergence of resistance. Meropenem, cefepime, 
and piperacillin are used very often in the ICUs but there is currently limited data 
to support the suppression of new resistance with certain infusion strategy. This 
study helps answering this question in patients with severe pneumonia, the most 
common infection in the ICUs, coupled with measuring the drug exposure. Thus, 
the proposed work would provide applicable data that could inform the future 
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5. Data and Safety Monitoring Plan 
 
Typically, a data safety monitoring board would regularly review the safety of 
study and the data generated. Given that it is a relatively small, single-center, 2-
year study of fairly safe approved antibiotics at clinically used dosages, no 
experimental dosages or drugs administered, and the only research component 
is the administration modality (i.e. continuous versus intermittent), we propose an 
independent Safety Officer instead. The independent Safety Officer will be from a 
different clinical team, as free of conflict of interest as possible, and have 
experience with clinical research and clinical expertise relevant to this study (Dr. 
Bethany Shoulders, Clinical Assistant Professor, UF and ICU Pharmacy 
Specialist, Surgical ICU, UF Health). A Safety Officer charter will be developed to 
define the role of the Safety Officer, describe the reviews and meetings, define 
the data to be reviewed, and outline the content of the Safety Officer reports. The 
study investigators will meet with the Safety Officer through conference calls and 
present progress, interim analyses, and safety data to them every 6 months and 
as needed to ensure that the study continues to be safe for participants. The 
interim analyses will be performed after enrolling the first 60 patients (6 months 
from starting the study), second 60 patients (12 months from starting the study), 
and last 120 patients (24 months from starting the study). Should there be any 
unusual adverse outcomes or breaches in confidentiality, this will be reported 
immediately to the responsible IRB and the Safety Officer for the necessary 
corrective actions. Given that the amount of risk in this study might be minimal, 
there is no specific safety stopping criteria for this study and the Safety Officer 
will evaluate the data as they become available. The Safety Officer will check the 
data for any adverse events trends along with the statistical analysis for 
comparison. The same procedure will be followed for efficacy endpoint and the 
Safety Officer will review the data with the statistical analysis. 
 
Conflict of Interest 
 
 
The investigators have no conflict of interest to disclose. 
 
 

ICF_001.pdf: 
IRB Project #: IRB2021019769
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INFORMED CONSENT FORM
to Participate in Research, and
AUTHORIZATION 
to Collect, Use, and Disclose Protected Health Information (PHI)
INTRODUCTION
Name of person seeking your consent:
Place of employment & position: 
GENERAL INFORMATION ABOUT THIS STUDY
1. Name of Participant ("Study Subject")
___________________________________________________________________ 
2. What is the Title of this research study (this “Research Study”)?
Beta-lactam continuous versus intermittent infusion and associated bacterial resistance 
and therapy outcomes in critically ill patients with severe pneumonia
3. Whom do you call if you have questions about this Research Study (the “Study 
Team”)?
Principal Investigator: Dr. Charles Peloquin (352) 273-6266
Other research staff:  Drs. Awewura Kwara, Kenneth Rand, Veena Venugopalan, and 
Cesar Trillo.
4.  Who is paying for this Research Study?
 
The sponsor of this study is the Food and Drug Administration (FDA). 
5. In general, what do you need to know about this Research Study?
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
to which you are entitled. If you have questions about your rights as a research 
subject, please call the University of Florida Institutional Review Board (IRB) office at 
(352) 273-9600.    
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a) In general, what is the purpose of the research, how long will you be 
involved?  
As part of your normal care, your physician has prescribed an antibiotic to be given 
to you through a vein in your arm. The purpose of this research is to study if there 
is any difference in your health and safety if this antibiotic is given either as a 
continuous (never stops) infusion vs an infusion that starts and stops a few times a 
day, also called an intermittent infusion. Individuals who participate in this study will 
be involved for up to 4 weeks. This includes receiving the antibiotic prescribed by 
your doctor for the duration your doctor determines and the collection of saliva or 
sputum samples twice per week during and after finishing the antibiotic therapy for 
up to 4 weeks of starting therapy. The monitoring and follow up are all included in 
the 4-week study participation period. There are no study activities outside of the 
4-week study period.
b) What is involved with your participation, and what are the procedures to be 
followed in the research? 
If you participate in this research we will collect samples from your respiratory 
system that is normally collected as part of your care.  We will use the sample to 
screen for the type of bacteria that is in your body.  If a certain type of bacteria, 
called Gram-negative, is found in your body we will ask you to enroll in this study.  
If you decide to take part in this study, you will be randomly assigned (much like 
the flip of a coin) to receive either a continuous antibiotic dose group or an 
intermittent antibiotic dose group. You will have a 50% chance of receiving 
continuous antibiotic infusion and a 50% chance of receiving intermittent antibiotic 
infusion. The antibiotic is already prescribed by your doctor who will also decide 
the number of days you will need to receive the antibiotic. If you are in the 
continuous group, you will receive a 24-hour continuous dose of antibiotics.  If you 
are in the intermittent group, you will receive a 30-minute dose of antibiotics either 
every six, eight, twelve, or twenty-four hours depending on how your body 
responds. All doses are given as infusions which means they are given directly into 
your bloodstream to fight the bacteria in your body. You will receive the same 
antibiotic total daily dose regardless of whether you are in the intermittent or 
continuous dose group. Afterward we will collect a respiratory sample twice a week 
for up to 4 weeks to determine how much bacteria are left in your body after the 
antibiotic treatment. You will be on the antibiotic therapy for the duration specified 
by your doctor, but the respiratory samples collection will continue for up to 4 
weeks from starting therapy.
c) What are the likely risks or discomforts to you? 
There might be some brief discomfort associated with the line insertion (if not already 
in place) and the collection of the respiratory samples from the breathing tubes (in 
case you are on the ventilator), however, the respiratory samples will be collected 
by removing the excess secretions from your respiratory system and this process is 
done as part of your routine care to prevent the blockage of the breathing tubes. 
Giving the antibiotic by continuous infusion will need a dedicated line to be infused 
in blood over 24 hours. The clinical team will need to insert a separate line to 
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minimize other therapies interruption. The intermittent infusion may introduce the 
antibiotic amount to your blood quickly and then the amount will start to go down. 
Both of these infusions are used every day in the hospital and there is no information 
currently that one infusion may cause more side effects compared to the other.
d) What are the likely benefits to you or to others from the research?
The continuous infusion will keep the amount of antibiotic in your blood almost 
constant without fluctuations compared to the intermittent infusion. On the other 
hand, the intermittent infusion might be more convenient as it is infused over a 
short period of time (30 minutes) and so will not occupy the line for 24 hours. 
However, there is no enough information currently proving that the continuous 
infusion is more effective than the intermittent infusion or vice versa.
e) What are the appropriate alternative procedures or courses of treatment, if 
any, that might be helpful to you? 
In case you’re off the ventilator, we will collect your sputum samples instead of 
using the ventilator’s tubes. There are no other treatment alternatives.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results. You can search this Web 
site at any time.
Additional and more detailed information is provided within the remainder of 
this Informed Consent form, please read before deciding if you wish to 
participate in this study
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY?
6. What will be done as part of your normal clinical care (even if you did not 
participate in this Research Study)? 
If you are intubated, a sample from your airway or your saliva will be sent for testing as 
per standard of care. More samples may be drawn as per standard of care at the 
clinician’s discretion. Your doctor will start you on intravenous antibiotic to fight the 
suspected bacteria in your body. You will have your antibiotic blood concentration 
measured in the first days of therapy, and repeated as needed. 
7.  What will be done only because you are in this Research Study? 
You will be assigned to either a continuous antibiotic dose group or an intermittent 
antibiotic dose group. If you are in the continuous group, you will receive a 24-hour 
continuous dose of antibiotics.  If you are in the intermittent group, you will receive a 30-
minute dose of antibiotics either every six, eight, twelve, or twenty-four hours depending 
on how your body responds.  All doses are given as infusions which means they are 
given directly into your bloodstream. You will receive the same antibiotic total daily dose 
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regardless of whether you are in the intermittent or continuous dose group. Afterward, 
we will collect a respiratory sample from your airway or sputum twice a week for up to 
4 weeks to determine how much bacteria is left in your body after the antibiotic 
treatment. We will continue to monitor your health and any side effects of treatment.
Once this research study is completed, any information that could identify you might 
be removed from any identifiable private information or identifiable biospecimens 
collected and that, after such removal, the information or biospecimens could be used 
for future research studies or distributed to another investigator for future research 
studies without additional informed consent from you or your legally authorized 
representative.
If you have any questions now or at any time during this Research Study, please 
contact one of the Research Team members listed in question 3 of this form.
8. What identifiable health information will be collected about you and how will it be 
used?
The Research Team will collect data including your age, sex, chronic illness, your health 
status including but not limited to: blood pressure, body temperature, breathing rate, 
tests for infections or organisms that could cause infection, tests done on the secretions 
collected from the breathing tubes that carries air from the windpipe to the lung, lab 
results including blood cell counts, and amount of minerals in the blood, medications 
doses, how much you need the ventilator during the treatment, and report for picture of 
brain wave activity if done.
The Research Team may collect this information from other healthcare providers, 
such as laboratories, which are a part of this research, as well as healthcare providers 
that are not part of this research (other doctors, hospitals or clinics). Other 
professionals at the University of Florida or Shands Hospital who provide study-related 
care, and the University of Florida Institutional Review Board (IRB), may also collect 
your health information. 
The Research Team listed in question 3 above will use or share your health 
information as described below to carry out this research study. 
9. With whom will this health information be shared?
This health information may be shared with:

United States governmental agencies which are responsible for overseeing 
research, such as the Department of Health and Human Services and the Office 
of Human Research Protections;

Government agencies which are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments.
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
Your insurance company for purposes of obtaining payment as per usual care

The IRB that reviewed this Research Study and ensures your rights as a Study 
Subject are protected 
Otherwise, your identifiable health information will not be shared without your 
permission unless required by law or a court order. Once your health information is 
shared with those listed above, it is possible that they could share it without your 
permission because it would no longer be protected by the federal privacy law. 
Identifiable health information will not be shared with the study sponsor. 
 
10. How long will you be in this Research Study?
Up to 4 weeks. This includes receiving the antibiotic prescribed by your doctor for the 
duration they choose and the collection of respiratory samples twice per week during 
and after finishing the antibiotic therapy for up to 4 weeks of starting therapy. The 
monitoring and follow up are all included in the 4-week study participation period. There 
are no study activities outside of the 4-week study period.
This Authorization to use and share your health information expires at the end of the 
study, unless you revoke it (take it back) sooner.
11.How many people are expected to take part in this Research Study?
240
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND 
WHAT ARE YOUR OPTIONS?
12.What are the possible discomforts and risks from taking part in this Research 
Study?
There might be some brief discomfort associated with the line insertion (if not already 
in place) and the collection of the respiratory samples from the tubes (in case you are 
on the ventilator), however, the samples will be collected by removing the excess 
secretions from your respiratory system and this process is done as part of your routine 
care to prevent the blockage of the breathing tubes.
If you were randomized to the continuous infusion group, the antibiotic will need a 
dedicated line to be infused in blood over 24 hours. If the line is not in place and in order 
not to interrupt other infusions you have as prescribed by your doctor, the clinical team 
will need to insert a separate line through the vein which might be associated with minor 
discomfort. If you were randomized to the intermittent infusion group, the amount of 
antibiotic in your blood may go up quickly and then starts to go down. Both of these 
infusions are used every day in the hospital and there is no information currently that 
one infusion may cause more side effects compared to the other. The clinical team will 
be following you and monitoring your results all the time during your stay.
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This Research Study may also include risks that are unknown at this time.
Please note, participating in more than one research study or project may further 
increase the risks to you.  If you are already enrolled in a research study, please inform 
one of the Research Team members listed in question 3 of this form or the person 
reviewing this consent with you before enrolling in this or any other research study or 
project.
During the study, the Research Team will notify you of new information that may 
become available and might affect your decision to remain in the study. 
The University of Florida is required by law to protect your health information. Your 
health information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices, as required by University 
policy. However, there is a slight risk that information about you could be released 
inappropriately or accidentally. Depending on the type of information, a release could 
upset or embarrass you, or possibly affect your ability to get insurance or a job. 
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the Research Team members listed in question 
3 in this form.
13a. What are the potential benefits to you for taking part in this Research Study?
Some potential benefits associated with the continuous infusion is that the amount of 
antibiotic in your blood will remain almost constant without fluctuations compared to the 
intermittent infusion. On the other hand, the intermittent infusion might be more 
convenient as it is infused over a short period of time (30 minutes) and so will not occupy 
the line for 24 hours. However, there is no enough information currently proving that the 
continuous infusion is more effective than the intermittent infusion or vice versa.
13b. How could others possibly benefit from this Research Study?
There may be substantial benefits to the society in general in further optimizing antibiotic 
doses to prevent the emergence of treatment-resistant bacteria in the future.
13c. How could the Research Team members benefit from this Research Study?
In general, presenting research results helps the career of a researcher. Therefore, the 
Research Team listed in question 3 of this form may benefit if the results of this 
Research Study are presented at scientific meetings or in scientific journals.
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14.What other choices do you have if you do not want to be in this study? 
Taking part in this research study is voluntary. Your alternative is to not take part in the 
study. If you choose to not take part, your Healthcare at the University of Florida will not 
be affected.
You may also refuse to authorize the use of your health information, but if you refuse, 
you may not be allowed to be in this research study or receive any research-related 
treatment that is only available in this research study. However, your decision not to 
sign this Authorization will not affect any other treatment you may be eligible to receive.
15a. Can you withdraw from this study?
You may withdraw your consent and stop participating in this Research Study at any 
time.  If you do withdraw your consent, there will be no penalty to you, and you will not 
lose any benefits to which you are otherwise entitled. If you decide to withdraw your 
consent to participate in this Research Study for any reason, please contact the 
Research Team listed in question 3 of this form. They will tell you how to safely stop 
your participation.
You can also change your mind and take back this Authorization at any time by sending 
a written notice to the Research Team listed in question 3 of this form to let them know 
your decision. If you take back this Authorization, the Research Team may only use and 
disclose your health information already collected for this research study. No additional 
health information about you will be collected or disclosed to the Research Team. 
However, if you take back this Authorization, you may not be able to continue in this 
study. Please discuss this with a member of the Research Team listed in question #3.
15b.Can the Principal Investigator withdraw you from this Research Study? 
You may be withdrawn from this Research Study without your consent for the following 
reasons:
1. You have a serious or unexpected adverse event.
2. You become pregnant.
3. Study doctors decide it is not in your best interest to continue the study.
4. You do not or cannot adhere to the instructions provided to you.
5. The IRB decides to stop the study early.
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE?
16. If you choose to take part in this Research Study, will it cost you anything?
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There may be costs associated with the healthcare you receive while you are 
participating in this study. At least one of the protocol-required items, services or 
procedures that will generate charges at UF Health are considered to be conventional 
care that you would have received even if you chose not to participate in this study.  
In addition, one or more protocol-required items, services or procedures will be 
provided by the sponsor at no charge to you. 
If you receive any healthcare at University of Florida Health that is not related to this 
study, this care will be billed as usual. If you feel you have received a bill related to 
this study in error, please contact the Principal Investigator.
17.Will you be paid for taking part in this Research Study?
There is no compensation for participating in this research study.
18.What if you are injured while in this Research Study?
  
If you are injured as a direct result of your participation in this study, only the 
professional services that you receive from any University of Florida Health Science 
Center healthcare provider will be provided without charge.  These healthcare 
providers include physicians, physician assistants, nurse practitioners, dentists or 
psychologists. Any other expenses, including Shands hospital expenses, will be 
billed to you or your insurance provider. 
You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
research-related injuries. Please contact your insurance company for additional 
information. 
The Principal Investigator will determine whether your injury is related to your 
participation in this study. 
No additional compensation is routinely offered. The Principal Investigator and others 
involved in this study may be University of Florida employees. As employees of the 
University, they are protected under state law, which limits financial recovery for 
negligence.
Please contact one of the research team members listed in question 3 of this form if you 
experience an injury or have questions about any discomforts that you experience while 
participating in this study.
 
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SIGNATURES
As an investigator or the investigator’s representative, I have explained to the participant the 
purpose, the procedures, the possible benefits, and the risks of this research study; the alternative 
to being in the study; and how the participant’s protected health information will be collected, 
used, and shared with others: 
___________________________________________________________________
Signature of Person Obtaining Consent & Authorization 
Date
Consenting Adults.  You have been informed about this study’s purpose, procedures, possible 
benefits, and risks; the alternatives to being in the study; and how your protected health 
information will be collected, used and shared with others.  You have received a copy of this 
Form.  You have been given the opportunity to ask questions before you sign, and you have been 
told that you can ask other questions at any time.  
Adult Consenting for Self.  By signing this form, you voluntarily agree to participate in this study. 
You hereby authorize the collection, use and sharing of your protected health information as 
described above.  By signing this form, you are not waiving any of your legal rights.
___________________________________________________________________
Signature of Adult Consenting & Authorizing for Self
Date
Parent/Adult Legally Representing the Subject.  By signing this form, you voluntarily give your 
permission for the person named below to participate in this study.  You hereby authorize the 
collection, use and sharing of protected health information for the person named below as 
described above.  You are not waiving any legal rights for yourself or the person you are legally 
representing.  After your signature, please print your name and your relationship to the subject.
___________________________________________________________________
Consent & Authorization Signature 
Date
of Parent/Legal Representative
____________________________________
___________________________________
Print:  Name of Legal Representative 
Print:  Relationship to Participant:  
______________________________________________
Print:  Name of Subject:  
Participants Who Cannot Consent But Can Read and/or Understand about the Study.  
Although legally you cannot "consent" to be in this study, we need to know if you want to take 
part.  If you decide to take part in this study, and your parent or the person legally responsible for 
you gives permission, you both need to sign.  Your signing below means that you agree to take 
part (assent).  The signature of your parent/legal representative above means he or she gives 
permission (consent) for you to take part.
_________________________________________________ __________________
Assent Signature of Participant
Date
Study ID:IRB202101979   Date Approved: 11/11/2022