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This Phase 1 trial described the intrapulmonary pharmacokinetics and safety profile of IV fosfomycin in healthy participants . Fosfomycin, a broad-spectrum antibiotic mainly used to treat urinary tract infections, is being considered for treatment of more complex conditions, including lung infections, due to the emergence of multidrug-resistant (MDR) organisms. Despite its potential, the pharmacokinetics and safety profile of intravenous (IV) fosfomycin, particularly its penetration into the lower respiratory tract, are unknown. To address this gap, we conducted a Phase 1, open-label trial to assess the safety and pulmonary pharmacokinetics of IV fosfomycin in healthy participants. Thirty-seven healthy volunteers aged 18-45 years received three doses of 6 g IV fosfomycin every 8 hours. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at randomly assigned time points after the third dose. BAL fluid, BAL cell pellets, and blood plasma samples for fosfomycin were analyzed using validated assays of liquid chromatography with tandem mass spectrometry (LC-MS/MS). Adverse events (AEs) were assessed. Fosfomycin exhibited penetration into alveolar macrophages (AM) at a rate of 16.8% and into the extracellular lining fluid (ELF) at 30.8%. Mean AM fosfomycin concentration ranged from 14.8 to 32 μg/mL, while the mean ELF concentration ranged from 15.7 to 82.5 μg/mL. All participants experienced at least one treatment-emergent adverse event (TEAE), mostly mild/grade 1, with no serious adverse events (SAEs) reported. Intravenous fosfomycin effectively penetrates both the extracellular (ELF) and intracellular (AM) compartments of the lower respiratory tract in healthy participants. The overall tolerability of IV fosfomycin was favorable, suggesting its potential as an effective antibacterial treatment for lower respiratory tract infections., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT03910673.

Importance: Preterm infants are recommended to receive most vaccinations at the same postnatal age as term infants. Studies have inconsistently observed an increased risk for postvaccination apnea in preterm infants., Objective: To compare the proportions of hospitalized preterm infants with apnea and other adverse events in the 48 hours after 2-month vaccinations vs after no vaccinations., Design, Setting, and Participants: This randomized, open-label clinical trial took place at 3 US neonatal intensive care units between August 2018 and October 2021. Infants between 6 and 12 weeks' postnatal age who were born at less than 33 weeks' gestational age and were eligible to receive 2-month vaccines were included., Intervention: Infants were randomized 1:1 to vaccinated (received vaccines within 12 hours of randomization) or unvaccinated (no vaccines received during the study period) groups. Cardiorespiratory data were collected during the 48 hours after vaccination or randomization (unvaccinated group)., Main Outcomes and Measures: The primary outcome was apnea, defined as a respiration pause greater than 20 seconds or a respiration pause greater than 15 seconds with associated bradycardia less than 80 beats per minute. Other outcomes included the number and duration of apnea episodes, serious adverse events, respiratory support escalation, and receipt of positive pressure ventilation., Results: Of 223 randomized infants (117 female; median [range] gestational age, 27.6 [23.0-32.9] weeks), 107 (48%) were vaccinated, and 116 (52%) were unvaccinated. For 2 infants in the vaccinated group, the primary outcome was unable to be assessed. The proportion of infants with 1 or more apnea event was 25 of 105 (24%) in the vaccinated group vs 12 of 116 (10%) in the unvaccinated group (adjusted odds ratio, 2.70; 95% CI, 1.27 to 5.73; P = .01). The mean number of apneic episodes did not significantly differ (model point estimate of difference, 0.54; 95% CI, -0.12 to 1.21) between the vaccinated (2.72) and unvaccinated (2.00) groups. The mean duration of apneic episodes did not significantly differ (model point estimate of difference, 4.6; 95% CI, -5.4 to 14.7) between the vaccinated (27.7) and unvaccinated (32.3) groups. No serious adverse events occurred during the 48-hour monitoring period. Other outcomes were not significantly different between groups., Conclusions and Relevance: In hospitalized preterm infants, the odds of apnea within 48 hours were higher after 2-month vaccinations vs after no vaccinations. The similar number and duration of apneic events and lack of serious adverse events suggest that current vaccination recommendations for hospitalized preterm infants are appropriate. Neonatal clinicians should continue providing evidence-based anticipatory guidance about postvaccination apnea risk., Trial Registration: ClinicalTrials.gov Identifier: NCT03530124.

Introduction: Pandemic influenza vaccine development focuses on the hemagglutinin (HA) antigen for potency and immunogenicity. Antibody responses targeting the neuraminidase (NA) antigen, or the HA stalk domain have been implicated in protection against influenza. Responses to the NA and HA-stalk domain following pandemic inactivated influenza are not well characterized in humans., Material and Methods: In a series of clinical trials, we determine the vaccines' NA content and demonstrate that NA inhibition (NAI) antibody responses increase in a dose-dependent manner following a 2-dose priming series with AS03-adjuvanted influenza A(H7N9) inactivated vaccine (A(H7N9) IIV). NAI antibody responses also increase with interval extension of the 2-dose priming series or following a 5-year delayed boost with a heterologous adjuvanted A(H7N9) IIV. Neither concomitant seasonal influenza vaccination given simultaneously or sequentially, nor use of heterologous A(H7N9) IIVs in the 2-dose priming series had an appreciable effect on NAI antibody responses. Anti-HA stalk antibody responses were minimal and not durable., Conclusions: We provide evidence for strategies to improve anti-neuraminidase responses which can be further standardized for pandemic preparedness., Clinical Trial Registry Numbers: NCT03312231, NCT03318315, NCT03589807, NCT03738241., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)