Clinical trial NCT01994980
Conditions: Early Ventilator Associated Pneumonia
Sponsor: Denver Health and Hospital Authority
Start date: 2013-12-01; Completion date: 2021-11-05
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hypothesis: 4 days of antibiotic therapy, as compared to 8 days, is equally effective and results in decreased antibiotic exposure among surgical ICU patients with early VAP.

Detailed description:
The prevalence of multi-drug resistant (MDR) pathogens in intensive care units (ICUs) worldwide has reached epidemic proportions. In some cases, the choice of potential therapy is limited or even non-existent. Antibiotic prescription, through selection pressure, represents the main mechanism by which resistance emerges. Limitations in the development of new antibiotics underscores the importance of adherence to the principles of antibiotic stewardship.

Ventilator associated pneumonia (VAP) is the most common serious infection in mechanically ventilated, critically ill patients. Approximately one half of antibiotic prescription in the ICU is related to VAP, including prophylactic, empiric, and definitive therapy. The development of evidence-based algorithms for the rational use of antibiotics in the management of patients with both suspected and confirmed VAP is pivotal to decreasing the emergence of MDR pathogens.

Shortening the duration of antimicrobial therapy for VAP represents one strategy to curtail the emergence of MDR pathogens. Although current guidelines recommend a treatment course of 8-14 days, both clinical and microbiologic resolution (MR) of infection typically occur much sooner \[10, 11\]. In one study of ICU patients ventilated for \> 5 days who developed VAP, 8 days of antimicrobial therapy was equally as effective as 14 days, provided VAP was not caused by a non-lactose fermenting gram negative bacillus. Favorable results following shorter courses of therapy for VAP have been observed, albeit in small, uncontrolled series.

One subset of patients for whom a decreased duration of antimicrobial therapy may be particularly effective is those who develop VAP ≤ 5 days after intubation (early VAP). Early VAP comprises approximately one half of cases of pneumonia diagnosed in the ICU. Furthermore, as compared to patients who develop late VAP, patients who develop early VAP are more likely to be infected with community-acquired pathogens sensitive to narrow spectrum antibiotics. Finally, nearly all cases of early VAP caused by sensitive pathogens demonstrate MR after relatively short (3-5 days) courses of therapy.

Arms: arm 1: Default 4 days antibiotic therapy arm 2: Default 8 days antibiotic therapy
Interventions: intervention 1: Default 4 days antibiotic therapy
Intervention descriptions: intervention 1: The intervention for this trial involves a shorter duration of antibiotic therapy. Specifically, a default of 4 vs. 8 days.

Protocol documents:
Prot_SAP_000.pdf: 
page 1 of 13 
A Multicenter Randomized Clinical Trial of 4 vs. 8 Days of Definitive 
Antibiotic Therapy for Early Ventilator-Associated Pneumonia in the 
Surgical Intensive Care Unit: 
The Duration of Antibiotic Therapy for Early VAP (DATE) Trial 
(COMIRB 13-3062, NCT01994980)    
12.26.13 
Pieracci 
Jenkins 
Rodil 
Stovall 
Haenel 
Preslaski 
Johnson 
Price 
Burlew 
Moore 
 
Departments of Surgery, Medicine, Division of Infectious Disease, and Pharmacy 
Denver Health Medical Center/University of Colorado Health Sciences Center 


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Background: 
The prevalence of multi-drug resistant (MDR) pathogens in intensive care units (ICUs) worldwide 
has reached epidemic proportions [1, 2]. In some cases, the choice of potential therapy is limited or 
even non-existent [3]. Antibiotic prescription, through selection pressure, represents the main 
mechanism by which resistance emerges [4]. Limitations in the development of new antibiotics [5] 
underscores the importance of adherence to the principles of antibiotic stewardship [6]. 
Ventilator associated pneumonia (VAP) is the most common serious infection in mechanically 
ventilated, critically ill patients [7]. Approximately one half of antibiotic prescription in the ICU is related 
to VAP, including prophylactic, empiric, and definitive therapy [8]. The development of evidence-based 
algorithms for the rational use of antibiotics in the management of patients with both suspected and 
confirmed VAP is pivotal to decreasing the emergence of MDR pathogens.   
Shortening the duration of antimicrobial therapy for VAP represents one strategy to curtail the 
emergence of MDR pathogens. Although current guidelines recommend a treatment course of 8-14 days 
[9], both clinical and microbiologic resolution (MR) of infection typically occur much sooner [10, 11]. In 
one study of ICU patients ventilated for > 5 days who developed VAP, 8 days of antimicrobial therapy 
was equally as effective as 15 days, provided VAP was not caused by a non-lactose fermenting gram 
negative bacillus [12]. Favorable results following courses of therapy < 8 days have been reported, albeit 
in small, uncontrolled series [13].  
One subset of patients for whom a decreased duration of antimicrobial therapy may be 
particularly effective is those who develop VAP ≤ 7 days after intubation (early VAP). Early VAP 
comprises the majority of cases of pneumonia diagnosed in the ICU[14] . Furthermore, as compared to 
patients who develop late VAP, patients who develop early VAP are more likely to be infected with 
community-acquired pathogens sensitive to narrow spectrum antibiotics [14]. Finally, nearly all cases of 


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early VAP caused by sensitive pathogens demonstrate MR after relatively short (3-5 days) courses of 
therapy [10].   
The hypothesis of this randomized clinical trial (RCT) is that 4 days of antibiotic therapy, as 
compared to 8 days, is equally effective and results in decreased antibiotic exposure among surgical ICU 
patients with early VAP.  
 
 Methods: 
 
Study Design: Randomized, double-blind (until treatment day 5) clinical trial.  
 
Intervention: Default 4 vs. 8 days of antibiotic therapy. 
 
Screening Pool: Trauma-Surgical ICUs. 
 
Inclusion Criteria: 
1) Surgical patient 
2) Early VAP, defined as:  
a. Duration of Intubation: 2-7 days [9] (via endotracheal or tracheostomy tube). 


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b. Clinical suspicion of pneumonia: New or progressing infiltrate on chest radiograph (CXR) 
along with ≥ 1 of the following: Temperature ≥ 38.5°C or < 36.5°C; blood leukocytes 
>11,000 mm3 or <4,000 mm3; purulent tracheal secretions; or PaO2:FiO2 < 200 [15].  
c. Quantitative microbiologic confirmation: Bronchoalveolar lavage (BAL) culture showing 
≥105 cfu/mL of at least one pathogen [16]. The quantitative microbiology threshold will 
be lowered to ≥104 cfu/mL if the patient was being treated with antibiotics to which the 
pathogen is sensitive at the time of the BAL. 
3) Hospital LOS ≤ 10 days at the time that the BAL was obtained. 
 
Exclusion Criteria: 
1) Age < 18 years. 
2) Prior episode of VAP for the index admission (the patient may have had prior BALs sent for 
culture, but these cannot have met the above mentioned diagnostic criteria for VAP). 
3) VAP caused by a MDR pathogen: Early VAP is rarely caused by MDR pathogens; in a recent 
analysis of our surgical ICU, 94% of cases of early VAP were caused by highly sensitive pathogens 
(Methicillin-sensitive staphylococcus aureus 39%, Haemophilus influenza 35%, Streptococcus 
pneumoniae 16%, Esterichia coli 9%) [14]. Patients with early VAP caused by the following MDR 
pathogens will be excluded: Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-
intermediate Staphylococcus aureus (VISA), pseudomonas aeruginosa, Vancomycin-resistant 
enterococcus (VRE), Acinetobacter baumannii, Stenotrophomonas maltophilia, carbapenem-


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resistant enterobacteriaceae (CRE), and extended-spectrum beta lactamase producing gram 
negative bacilli. 
4) Causative pathogen not sensitive to choice of initial empiric antibiotic.  
5) Antibiotic therapy for ≥ 5 of the last 10 days preceding the BAL. 
6) Septic shock, defined as evidence of tissue hypoperfusion after adequate volume expansion, 
due to infection, and requiring ≥ 1 vasopressor [17]. 
7)  Current or recent (within 30 days) use of immunosuppressive medications. 
8) Length of stay ≥ 72 hours in a transferring facility.  
9) Pregnancy or lactation. 
10) Legal arrest or incarceration. 
11) Moribund state in which death is imminent. 
 
Outcomes: 
The two main outcomes will be effectiveness of treatment and antibiotic exposure. 
Effectiveness of treatment will be assessed in three ways: 1) Clinical response, 2) MR, and 3) biomarker 
response. 
Clinical Response: Current guidelines state that appropriately treated patients with VAP should have a 
favorable clinical response by day 3, and a substantial improvement by day 6 [9]. Clinical variables used 
to access for treatment response are organized into the Clinical Pulmonary Infection Score (CPIS). The 
original CPIS, as described by Pugin et al. [18], included five clinical variables [temperature, white blood 


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cell count (WBC), tracheal secretions, ratio of PaO2 to FiO2 (P:F), and chest radiograph findings) and one 
microbiologic variable (culture of tracheal aspirate and its relationship to the gram stain). Several 
authors have since modified the score to exclude the microbiologic variable in order to both screen for 
VAP and monitor efficacy of treatment [11, 19]. This modified score, herein referred to as CPISclinical, 
omits the microbiologic variable and ranges from 0-10.   
 
The CPISclinical will be calculated at baseline and daily thereafter during the study period. In the 
case that certain individual variables are not available for abstraction, they will be left blank rather than 
obtained solely for the purpose of the study. The worst values (those associated with the highest 
number of points) for each variable over the 24 hours prior to the BAL will be used. Tracheal secretions 
will be scored based on daily progress notes from the respiratory therapist. Chest radiograph findings 
will be scored based on attending final radiologist reads.  
It is important to note that CPISclinical possesses limited accuracy for monitoring VAP resolution in 
surgical ICU patients [20, 21]. Furthermore, a multicenter RCT reported decreased organ failure, 
mortality, and antibiotic use for patients with suspected VAP managed using a microbiologic endpoint as 
compared to a clinical one [22]. For these reasons, efficacy of treatment will also be assessed both 
microbiologically and using a biomarker of infection (see below).  
Microbiologic Response: The definition of microbiologic response for VAP reported most commonly 
ranges from <102 cfu/mL [23] to <103 cfu/mL [10] from a repeat BAL culture obtained the day after the 
end of therapy. For the purposes of this trial, microbiologic response will be defined as growth of the 
original pathogen of <103 cfu/mL from a BAL culture obtained the day after the end of treatment. 
Repeat BALs will thus be obtained on day 5 for the 4-days of antibiotics group and day 9 for the 8 days of 
antibiotics group. If the patient is no longer intubated at this time, a repeat BAL will not be obtained and 
MR will be inferred. The treatment team will have access to the results of the repeat BAL. 


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Biomarker Response: Circulating levels of calcitonin precursors, including procalcitonin, are elevated in 
bacterial infections [24, 25]. Normalization of procalcitonin concentration in patients receiving therapy 
for VAP has been shown to both correlate with clinical response and guide discontinuation of antibiotics 
[26]. The relationship between clinical response, MR, and procalcitonin concentration has not been 
evaluated prospectively in critically ill patients being treated for VAP and will be the focus of a sub-
analysis.   
Currently, procalcitonin concentration is measured in all surgical ICU patients for whom a BAL is 
sent on the day of the BAL as part of a separate non-interventional study. For the purposes of the 
current trial, procalcitonin concentration will also be measured during treatment in order to assess 
response, as well as following treatment in order to assess for recurrence. Because study entry will 
occur at the time that VAP is confirmed microbiologically (approximately 72 hours following the BAL and 
initiation of empiric antibiotics), these measurements will begin after three days of antibiotic therapy. 
Procalcitonin concentration will then be measured daily for the remainder of treatment, as well as daily 
for 72 hours following treatment. Thus, the 4 day group will have procalcitonin concentration measured 
at baseline, treatment days 3 and 4, and post treatment days 1-3. The 8 day group will have 
procalcitonin measured at baseline, treatment days 3-8, and post-treatment days 1-3. The treatment 
team will have access to the results of these measurements. For the purposes of the trial, biomarker 
resolution will be defined as a procalcitonin concentration < 0.5 µg/L or a decrease of ≥ 80% relative to 
the day of the BAL [26].  
Additional Outcomes: Days of antibiotics, antibiotic days (defined as the product of days of antibiotics 
and number of antibiotics per day), recurrence, ventilator days, empyema, need for tracheostomy, non-
pulmonary infections, ICU length of stay (LOS), hospital LOS, and mortality. Recurrence is defined using 
the same clinical and microbiologic criteria as the initial episode of VAP, and occurring 2-14 days 


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following completion of initial therapy. Relapse is defined as recurrent VAP caused by the initial 
pathogen; super-infection is defined as recurrent VAP caused by ≥ 1 new pathogen. VAP occurring > 14 
days following completion of initial therapy will be considered a second episode of pneumonia as 
opposed to a recurrence. The incidence of recurrent VAP due to a MDR pathogen, as well as any other 
infection caused by a MDR pathogen, will also be abstracted.  
 
Baseline Variables: Age (years), gender, admission diagnosis, associated diagnoses, admission APACHE II 
score, comorbidity index [27], prior and current antibiotic exposure,  base deficit, serum lactate 
concentration, time from ICU admission to BAL, presence of organisms on gram stain, and presence of 
polymorphonuclear lymphocytes on gram stain.  
 
Study Flow & Stop Criteria: The trial will be reported in accordance with the recommendations of the 
CONSORT Statement [28]. IRB approval will be obtained. All subjects or their legally authorized 
representative will provide written consent for study participation. The trial is registered with the US 
National Institutes of Health (ClinicalTrials.gov Identifier NCT01994980).    
Screening will occur daily by study personnel. Eligible patients will be approached as soon as 
possible after inclusion criteria are met (i.e., 1-3 days prior to randomization). Randomization will occur 
using a computer-generated block pattern on the morning following the fourth day of appropriate 
antibiotic therapy. 
Empiric antibiotic therapy will be instituted as soon as possible following BAL acquisition. The 
default antibiotic will be ceftriaxone 2 gram IV q24 hours. Patients with potential allergies to 
cephalosporins will receive levofloxacin 750 mg IV q24hours. Pre-existing treatment for a non-


page 9 of 13 
pulmonary infection with at least one antibiotic that has appropriate activity against the VAP pathogen 
may be substituted for the default antibiotic. Once sensitivity data become available (approximately 72 
hours after BAL acquisition), therapy may be de-escalated to a more narrow-spectrum agent (e.g., 
cefazolin) as indicated. 
The default duration of antibiotic therapy will be determined by study group assignment; the 
treatment team will be asked to adhere to study group assignment whenever possible. However, the 
treatment team may choose to extend the duration of antibiotic therapy based on clinical 
circumstances, such as deterioration in hemodynamic or respiratory status that is believed to be related 
to incompletely treated VAP, or continued treatment of a non-pulmonary infection. The treatment team 
may also decide to extend the duration of antibiotic therapy based on the results of serial procalcitonin 
measurements. Finally, the treatment team may decide to extend the duration of antibiotic therapy 
based on the results of the BAL obtained the day after completion of therapy. These clinical decisions 
will take precedence over study group assignment. 
Patients will be followed for 28 days or until hospital discharge, whichever occurs first. Please 
see attached data collection tool for detailed information.  
 
Sample acquisition and processing: The default method for BAL specimen acquisition will be via the blind 
or “mini” BAL technique [18], using an 85 mm by 4 mm bronchial diagnostic catheter (Combicath, ® 
Prodimed, Neuilly-en-Thelle, France). The catheter is passed through the artificial airway until resistance 
is met. It is then withdrawn approximately 1 cm and the inner lavage catheter is deployed. Lavage is 
then performed with 20 – 40 mL of sterile saline. 


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The BAL will be obtained bronchoscopically if bronchoscopy is being performed for another 
indication (e.g., pulmonary toilet, percutaneous dilational tracheostomy). Lavage is performed using 20-
40 mL of normal saline lavage into the lobar bronchus that appears most abnormal on CXR.  
Using a 0.001 calibrated loop, vortexed BAL specimens will be plated onto sheep blood, 
MacConkey, and Chocolate agar at 35°C - 37°C in CO2. Plates will be examined after 24, 48, and 72 hours 
prior to issuing a final negative report. 100 or more colonies per plate is considered significant and 
represents ≥ 105 cfu/mL. 
 
Statistical Analyses:  
Power analysis: Power analysis was performed using SAS Version 9.1 (SAS, Inc., Carey, NC, proc power). 
The Analysis was based on a non-inferiority study design, defined as a difference in outcomes between 
the 4 day and 8 day groups of < 10%. Furthermore, as the intention was to show non-inferiority, tests 
were one-sided using an alpha error level of 0.10. The beta error level was set at 0.20 for 80% power. 
Analysis for the outcome of VAP recurrence returned the largest sample size. From 2010-2012, during 
which time VAP was treated with ≥ 8 days of therapy, the incidence of recurrent VAP in the DHMC 
surgical ICU was approximately 25%. Projecting a recurrence rate after 4 days of treatment of 35% 
returns a total sample size of 103..  
Interim Analysis: An interim analysis will be conducted for all outcomes after 50% accrual (ntotal=50).  
Data Analysis: Data analyses will be performed using SAS Version 9.1 (SAS, Inc., Carey, NC). Data will be 
analyzed using an intention-to-treat strategy (i.e., patients randomized to receive 4 days of antibiotic 
therapy will be analyzed with this group even if they receive longer courses). Data will be expressed as 
median (range) or number (%). Normality of continuous variables will be assessed using the 


page 11 of 13 
Kolmogorov-Smirnov test. Differences in the means of continuous variables that are distributed 
normally will be assessing using the Student’s t-test. Differences in the medians of continuous variables 
that are not distributed normally will be assessed using the Wilcoxon Rank Test. Proportions of 
categorical variables will be compared using the chi-squared test. When expected cell counts are < 5, 
Fischer’s exact test will be used. Univariate analysis of categorical outcomes will be expressed as the 
relative risk with 95% confidence intervals. A logistic regression model will be fit to address possible 
confounding by differences in baseline parameters between groups. Baseline variables associated with 
randomization status at the p<0.25 level by univariate analysis will be added to the model using a 
forward selection method. The overall contribution of the fitted model to predicting variability in the 
outcome of interest will be assessed using the likelihood ratio chi-squared test. The independent 
contribution of individual variables will be assessed using the Wald chi-squared test. Model fit was will 
be assessed using the Hosmer-Lemeshow goodness-of-fit chi-squared statistic, with p>0.05 indicating 
acceptable model calibration. The alpha error level is defined at 0.05, with statistical significance set at 
p<0.05.  
 
Adverse Event Monitoring and Reporting: Adverse event monitoring will occur daily. The safety of the 
study will be monitored by an independent, external Data Safety Monitoring Board, consisting of a 
medical intensivist, and an infectious disease physician. The committee will meet biannually and submit 
written reports to the IRB. 
 


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