The MASTERMIND-Pneumonia Study (also known as Pneumonia Direct Pilot Study) is designed to assess whether combining molecular diagnostics for bacteria and AMR markers with host-response profiling improves agreement and predictive value for the diagnosis of VAP versus an adjudicated clinical reference standard. The feasibility design is intended to inform future interventional studies that will investigate the clinical impact of combined pathogen- and host-directed testing approaches.

This is a prospective, observational, diagnostic, feasibility study to determine the accuracy of pathogen- and host-directed testing for the diagnosis of VAP. Newly intubated adult patients admitted to the ICU will be assessed for eligibility around the time of intubation according to the inclusion/exclusion criteria. Screening and consent can occur any time within 48 hours of a patient being intubated. Between 48 and 60 hours after intubation, eligible participants will have blood drawn and dedicated research aliquots from SOC ETS samples retrieved. The dedicated research aliquots from SOC ETS samples will be obtained simultaneously with routine sampling for microbiologic testing or, when this is not possible, during routine suctioning as a part of standard airway care. Collection of other clinical data may occur 24 to 72 hours after intubation.

Participants will be followed daily for a clinical change for up to 14 days from the time of intubation. Clinical change is defined as a clinical suspicion of new-onset VAP that prompts the collection of lower respiratory tract secretions for routine microbiologic testing and initiation, continuation, or modification of antibiotic therapy for a pneumonia indication.

Participants who experience a clinical change will have additional blood samples drawn and dedicated aliquots of the sample retrieved from standard-of-care ETS procedures. Additionally, if available, leftover bronchoalveolar lavage (BAL) will be reclaimed, and respiratory and blood bacterial isolates will be obtained from SOC cultures. Participants will be followed through the diagnosis of clinical change and finalization of all local microbiological and radiological results obtained as a part of usual care. Clinical data will be recorded through medical record review.

Participants who do not experience a clinical change will be followed through extubation, ICU discharge, death, or for up to 14 days after intubation - whichever comes first. Participants who do not have a clinical change will not undergo additional sample collection.

Clinical change events will be used to assess whether the participant meets the clinical case definition (FDA criteria) for VAP: VAP-positive (VAP+) or VAP-negative (VAP-) categories will be obtained by an algorithm linked to the eCRF data. The VAP clinical case definition will be adjudicated against the participants' clinical data and microbiological evidence and the certainty of the VAP diagnosis will be classified as follows: Prove, Probable, Possible VAP, or No VAP. Every participant with a clinical change will be assessed for the presence of an extrapulmonary infection. Extrapulmonary infection will be classified as follows: Proven, Possible, or No Infection.

Evaluable participant specimens will be sent to a central laboratory for distribution to the testing centers that will perform the index testing. This study will compare pathogen-directed tests and host biomarker tests. Pathogen-directed tests detect and identify the most common causes of bacterial pneumonia, while host biomarker tests assess the host's immune response to infection. Testing centers will be blinded to whether the samples were collected at baseline or clinical change. Neither the study sites, participants, nor adjudicators will receive the results from the index testing.

Inclusion Criteria:

1. Are ≥18 years old
2. Are newly intubated for less than 48 hours and for reasons other than suspected bacterial pneumonia or suspected acute bacterial infection
3. Are expected to require intubation for at least 48 hours, per the discretion of the treating clinician
4. Are able to provide protocol-accepted consent (legally authorized representative [LAR] is acceptable)
5. Are expected to live long enough to receive a VAP diagnosis, at the discretion of the treating clinician
6. Are able to provide study-required biological samples

Exclusion Criteria:

1. Have a witnessed or suspected aspiration event prompting the need for current, new intubation
2. Have known active lung cancer or metastatic disease to a lung
3. Received a lung transplant
4. Have cystic fibrosis
5. Are receiving comfort care
6. Are receiving antibiotic treatment for suspected or proven active acute bacterial infection (eg, pneumonia, tracheobronchitis, sepsis)
7. Have a current or within-the-last-30-days diagnosis of active bacterial pneumonia
8. Were previously enrolled in this trial
9. Require long-term ventilator support
10. Have a tracheostomy tube in place
11. Are currently participating in an interventional drug or device study.

Intubated adult patients (≥18 years of age) admitted to the ICU will be assessed for eligibility around the time of intubation according to the inclusion/exclusion criteria. Screening and consent may occur at any time within 48 hours of patients being intubated. The target sample size is 250 participants in order to observe approximately 30 clinical VAP-positive cases. Vulnerable patients, including women and minorities, will be included in this study.

During the analysis process, diagnostic companies will support the testing of some specimens and will provide the resulting data back to the Duke Clinical Research Institute.

Once clinical and laboratory data have been analyzed and the primary manuscript has been published, investigators may apply to the Antibacterial Resistance Leadership Group (ARLG) for use of data. Continued regulatory oversight, Data Use Agreements, and Material Transfer agreements may apply.

Once the primary manuscript has been published

Application to the ARLG for use