The Avisa BreathTest
The Avisa BreathTest (ABT) is a simple, quantitative, point-of-care test for rapidly detecting pulmonary infections due to certain virulent pathogens without the need to collect and culture sputum or other biological samples. The ABT is intended for use in pediatric and adult pneumonia patients. The test is based on the presence of the urease enzyme found in certain bacterial species that cause pneumonia, such as S. aureus, P. aeruginosa, Klebsiella, Acinetobacter, and H. influenza. Urease activity can be detected using inhaled, nebulized 13C-urea which is converted by these bacteria to labeled carbon dioxide (13CO2) and ammonia. The non-radioactive, isotopic ratio of 13CO2 to naturally occurring 12CO2 is measured in the exhaled breath and large differences in this isotopic ratio (δ13CO2) indicate an active pulmonary infection with a urease pathogen. In combination with clinical signs and symptoms, the ABT will aid clinical decision making as to use and choice of antibiotics for patients diagnosed with pneumonia in the Emergency Department and for Intensive Care Unit (ICU) patients on mechanical ventilation at risk for or suspected of having ventilator associated respiratory infections.
The anticipated value of the ABT is the decreased use of powerful, broad spectrum antibiotics in the Emergency Department and corresponding decrease in hospital admissions because of its high negative predictive value for certain urease bacterial pneumonias. In addition, the ABT will find application in ventilated patients for early detection of and antibiotic decision guidance for ventilator associated respiratory infections to decrease length of stay, morbidity and mortality.
Previous Clinical Studies
Cystic Fibrosis (CF): In 2014 Avisa collaborated with the University of New Mexico (UNM) to conduct a proof-of-concept study in human subjects to determine whether inhalation of 13C-urea can be safely used to detect the presence of urease producing bacteria in the lungs. The study cohort consisted of three subjects with cystic fibrosis and known to be colonized with P. aeruginosa but otherwise healthy, and three healthy control subjects. The study subjects were administered nebulized 20 mg and 50 mg doses of 13C-urea on different days and the resulting exhaled δ13CO2 (DOB) was measured at 5, 10 and 15 minutes after completion of the dose. Both doses of the nebulized 13C-urea were well tolerated by all study subjects and there were no adverse events. The CF subjects colonized with P. aeruginosa had significantly higher DOB levels than the controls at both the 5 and 10 minute breath collection time points and the 50 mg dose of 13C-urea produced better separation between the groups. Details of this study can be found in a recent journal article (H. Raissy, G. Timmins, L Davies, T. Heynekamp, M. Harkins, Z. Sharp, H. W. Kelly, A Proof of Concept Study to Detect Urease Producing Bacteria in Lungs Using Aerosolized 13C Urea. Pediatric Allergy, Immunology, and Pulmonary, 29:68-73, 2016).
Pneumonia in the Emergency Department (CAP): Avisa collaborated with the Emergency Departments at University of New Mexico and Henry Ford Hospital who conducted an investigator sponsored pilot evaluation of an inhaled 13C-urea breath test in the identification of urease positive bacteria in patients diagnosed with pneumonia in the emergency department (ED). This study enrolled 75 adult male and female subjects.
Adult subjects were screened for participation in two cohorts that were enrolled sequentially. Cohort A, a safety evaluation of the inhaled Urea 13C-urea breath test, enrolled 15 subjects (men or women ages 18-70) presenting to the study sites with pneumonia symptomatology and who were planned for outpatient treatment. The initial safety arm of the study was completed successfully and the results were reviewed by the FDA and local Investigational Review Boards, who approved continuation of the study in a second cohort of 60 subjects (men and women ages 18-85). Cohort B subjects received a diagnosis of suspected bacterial pneumonia on presentation to the study sites based on findings of a positive chest x-ray or advanced radiology and clinical signs and symptoms. These findings showed good correlations between the breath test results and the “gold standard” sputum cultures where sputums could be collected successfully. This Phase I trial has provided critical efficacy and safety information for the planning of the pivotal clinical trial for the detection of urease pathogens in patients suspected of Community Acquired Pneumonia and Hospital Associated Pneumonia.
Planned Clinical Studies
Ventilator Associated Pneumonia (VAP): Avisa is planning a pilot study of the ABT’s ability to detect and monitor urease pathogens in 40 mechanically ventilated ICU subjects who are suspected of having a lower respiratory tract infection. The primary study endpoint is the safety and feasibility of performing the Avisa BreathTest (ABT) in mechanically ventilated patients with a suspected lower respiratory tract infection. This trial is expected to inform additional studies of the ABT in mechanically ventilated subjects who are at risk for developing lower respiratory tract infections while in the hospital. Results of this study will be used in the planning of the pivotal PMA clinical trial.
Chronic Obstructive Pulmonary Disease (COPD): A study is planned to use the Avisa BreathTest to look at urease activity in the lung of COPD patients experiencing exacerbations, and test its utility as a biomarker of respiratory symptoms in these patients. The Avisa BreathTest results will be compared with Bronchoalveolar Lavage (BAL) study results. The results of preliminary study of oral urease activity in COPD patients were presented at the 2018 annual American Thoracic Society conference.
Community Acquired and Hospital Associated Pneumonia: Avisa is planning a Pivotal Study of the use of the AV BreathTest™ in CAP/HAP patients. The study will focus on understanding the ability of a 13C-urea (AV-U13) breath test to detect urease producing pathogens (Pseudomonas Aerginosa, Methicillin Resistant Staphylcoccus aureus, Klebsiella pneumoniae, Hemophilus influenzae, Acineobacter baumannii, Proteus spp.) in patients with CAP and HAP as confirmed by sputum culture microbiology results. Additional objectives of this study will include the evaluation of the safety and tolerability of the 13C-urea (AV-U13) breath test in patients with pneumonia.