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Background Bacteriophages (phages) are a promising anti-infective option for human disease. Major gaps remain in understanding their potential utility. Methods This is a randomized, placebo-controlled, double-blind study of a single dose of intravenous phage in approximately 72 clinically stable adult cystic fibrosis volunteers recruited from up to 20 US sites with Pseudomonas aeruginosa airway colonization. The single dose of phage consists of a mixture of four anti-pseudomonal phages. Six sentinel participants will be sequentially enrolled with dose escalation of the phage mixture by one log 10 beginning with 4 × 10 7 plaque-forming units in an unblinded stage 1. If no serious adverse events related to the study product are identified, the trial will proceed to a double-blinded stage 2. In stage 2a, 32 participants will be randomly assigned to one of three phage dosages or placebo in a 1:1:1:1 allocation. An interim analysis will be performed to determine the phage dosage with the most favorable safety and microbiological activity profile to inform phage dosing in stage 2b. During stage 2b, up to 32 additional volunteers will be randomized 1:1 to the phage or placebo arm. Primary outcomes include (1) the number of grade 2 or higher treatment-emergent adverse events, (2) change in log 10 P. aeruginosa total colony counts in sputum, and (3) the probability of a randomly selected subject having a more favorable outcome ranking if assigned to receive phage therapy versus placebo. Exploratory outcomes include (1) sputum and serum phage pharmacokinetics, (2) the impact of phage on lung function, (3) the proportion of P. aeruginosa isolates susceptible to the phage mixture before and after study product administration, and (4) changes in quality of life. Discussion This trial will investigate the activity of phages in reducing P. aeruginosa colony counts and provide insights into the safety profile of phage therapy. Trial registration ClinicalTrials.gov NCT05453578. Registered on 12 July 2022.

Background Novel, rapid blood culture diagnostics can provide faster antibiotic susceptibility results (AST) compared to standard methods but their impact on clinical outcomes is unclear and not assessed in many prospective clinical trials. Methods This study is a two-arm, multicenter, multinational, prospective randomized controlled clinical trial conducted in countries with high antibiotic resistance rates including Greece, India, Israel, and Spain. Nine hundred hospitalized subjects who have blood cultures collected as part of routine clinical care with growth of Gram-negative bacilli (GNB) will be randomized 1:1 to blood culture evaluation using standard of care (SOC) AST vs. a rapid phenotypic AST method, VITEK REVEAL™ in addition to SOC AST. Subjects in both study arms will be reviewed by antibiotic stewardship clinicians who will recommend changes to antibiotic therapy, if indicated. The primary outcome is a composite three-category Desirability of Outcome Ranking (DOOR) defined using three ordered levels: alive without deleterious events, alive with at least one deleterious event, and death. Key secondary outcomes include mortality, length of stay, and time to antibiotic escalation or de-escalation within 3 days of randomization. Exploratory outcomes include a five-category DOOR, categorial agreement between VITEK REVEAL™ and SOC testing, clinician compliance with antibiotic stewardship recommendations, and desirability of treatment selection based on antibiotic spectrum, activity, and bloodstream isolate susceptibility profile (DOOR MAT). The primary analysis will be conducted on the modified intention-to-treat population. Discussion This trial will evaluate whether use of a rapid phenotypic AST method improves outcomes compared to use of conventional methods for patients with Gram-negative bloodstream infections in clinical settings with high antibiotic resistance rates. Trial registration ClinicalTrials.gov ID NCT06174649. Registered on Dec 18 2023. Protocol version Number 20-0021, version 5.0, 11-April-2024.