Combination antibiotic therapy for pseudomonas VAP (combat pseudo VAP): a pragmatic trial

The National Institute of Allergy and Infectious Diseases awarded a $1.478 million cooperative agreement to Northwestern University on July 10, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct a Phase 2 pragmatic, stratified, randomized, double-blind, multi-center clinical trial comparing tobramycin/beta-lactam combination antibiotic therapy to beta-lactam monotherapy for treating Pseudomonas aeruginosa ventilator-associated pneumonia. The trial will enroll patients across four participating centers and use bronchoalveolar lavage with quantitative cultures supplemented by multiplex bacterial PCR panels for diagnosis and management. The primary endpoint is demonstrating equivalence of acute kidney injury rates in patients randomized to combination therapy treated with five days of dose-optimized tobramycin, using the RIFLE (Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease) criteria for AKI diagnosis. Place of performance is Chicago, Illinois. The period of performance runs through May 31, 2031. Northwestern University's Sponsored Research Division serves as the recipient.

Abstract

The primary objective of this proposal is to perform a phase 2, pragmatic, stratified, randomized, double-blind, multi-center clinical trial of tobramycin/β-lactam combination antibiotic therapy (combat) compared to β-lactam monotherapy for treatment of pseudomonas aeruginosa (PSA) ventilated hospital-acquired/ventilator-associated pneumonia (vhap/VAP). PSA-vhap/VAP, particularly when due to multidrug-resistant isolates, is associated with increased mortality and length of stay, high clinical failure rates, and high recurrence rates compared to other pathogens, especially when treated with a single β-lactam antibiotic. With a paucity of high-quality data, current professional society guidelines for treatment of vhap/VAP equivocate on the need for combat; recommending against IT for definitive therapy in most cases of PSA-habp but offering a "weak recommendation" in favor of definitive combat for severely ILL patients or those with secondary bacteremia. However, concerns about acute kidney injury (AKI), the most significant adverse side effect of aminoglycosides, limit clinical aminoglycoside use, even in situations where use is recommended by guidelines. Because of this major concern, the primary endpoint of this phase 2 trial will be to demonstrate equivalence of rates of AKI in patients randomized to combat treated with 5-days of dose-optimized tobramycin. We will use the risk, injury, failure, loss of kidney function, and end-stage kidney disease (rifle) criteria, which are sensitive criteria for AKI diagnosis based on laboratory tests (creatinine) and urine volume. For diagnosis and management of vhap/VAP, the four participating centers routinely use bronchoalveolar lavage (BAL) with quantitative cultures supplemented with multiplex bacterial PCR panels. This cutting-edge approach of BAL combined with rapid diagnostic testing will enable prompt, accurate identification of PSA-vhap/VAP, facilitating enrollment of subjects early in their pneumonia course when the impact of therapeutic interventions is likely to be greatest. Open-label dose-optimized standard-of-care anti-pseudomonal β-lactams will be utilized for both arms, with choice of β- lactam individualized based on multiplex PCR resistance markers, prior antibiotic and pathogen history, and individual center standards. The pragmatic flexibility in β-lactam choice increases the generalizability of results. As a secondary analysis (AIM2), we will determine whether tobramycin/β-lactam combat for PSA-vhap/VAP is associated with improved clinical efficacy, as assessed by win ratio analysis, compared to β-lactam monotherapy. The win ratio methodology is a novel analytic approach that incorporates multiple hierarchical endpoints while accounting for the clinical and patient-oriented priority of each component endpoint. While we are committed to utilizing the win ratio, the optimal endpoint composition for inclusion in a pneumonia win ratio algorithm is unclear. As the first vhap/VAP RCT to use the win ratio analysis, this trial is ideal to optimize endpoint alternatives. Thus, in AIM3 we will investigate variations to the hierarchical endpoint composition that best reflect clinical and patient priorities and provide parsimonious differentiation of treatment efficacy.