Evaluation of Pharmacokinetics, Safety, and Tolerability of Aztreonam-Avibactam ± Metronidazole in Neonates and Infants with Gram-Negative Infections

The primary objective of this study is to evaluate the **pharmacokinetics** (PK) of Aztreonam and Avibactam (ATM-AVI) in the treatment of gram-negative bacterial infections, including complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP), bloodstream infection (BSI), or sepsis in hospitalized neonates and infants from birth to less than 9 months of age. Additionally, the study aims to assess the safety and tolerability of ATM-AVI in this patient population. Understanding the PK profile is crucial for optimizing dosing regimens, ensuring therapeutic efficacy, and minimizing potential adverse effects in this vulnerable group.

Secondary objectives include describing the efficacy of ATM-AVI for the treatment of serious gram-negative bacterial infections, such as cUTI, cIAI, HAP/VAP, BSI, or sepsis in hospitalized neonates and infants from birth to less than 9 months. This evaluation is important for determining the clinical effectiveness of ATM-AVI in managing these infections, which are associated with significant morbidity and mortality in neonates and infants.

The clinical trial involves a total of **26 participants** who are hospitalized neonates and infants from birth to less than 9 months of age, including those born preterm. The study population comprises both **male and female subjects**, and it is noted that the participants are considered a vulnerable population. The trial focuses on evaluating the pharmacokinetics, safety, and tolerability of ATM-AVI for the treatment of gram-negative bacterial infections, such as complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia, ventilator-associated pneumonia, bloodstream infection, or sepsis. Participants were selected based on their hospitalization status and the requirement for intravenous antibiotic treatment for suspected or confirmed bacterial infections. The trial does not specify any particular lifestyle considerations such as diet or physical activity, given the young age and health status of the participants.

The clinical trial is designed as a **Phase 2A**, open-label, non-randomized, multicenter study to evaluate the pharmacokinetics, safety, and tolerability of Aztreonam and Avibactam, with or without **Metronidazole**, in neonates and infants from birth to less than 9 months of age. The trial targets patients with suspected or confirmed infections due to gram-negative pathogens requiring intravenous antibiotic treatment. The study will involve two parts, with participants receiving either single or multiple doses of the investigational drugs. The trial is expected to commence recruitment on July 1, 2025, and conclude by August 3, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, hospitalization status, and the need for intravenous antibiotics. The primary inclusion criteria include hospitalization and age from birth to less than 9 months, with a requirement for intravenous antibiotics for suspected or confirmed bacterial infections. The trial will exclude participants based on specific exclusion criteria, which are not detailed in the provided data. Following the screening, participants will attend follow-up visits to monitor pharmacokinetic parameters, including clearance, maximum plasma concentration, area under the plasma concentration-time curve, and half-life. Safety assessments will include monitoring adverse events, serious adverse events, and liver and renal function tests at baseline, during treatment, and after treatment completion.

The expected duration of participant involvement is up to 14 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include adverse events leading to discontinuation or resulting in death. The end-of-study visit will evaluate clinical outcomes at the end of intravenous treatment, end of treatment, and test of cure, specifically for Part B of the study. The trial aims to provide comprehensive data on the pharmacokinetics, safety, and efficacy of the investigational drugs in the specified pediatric population, contributing to the understanding of their use in treating complicated infections in neonates and infants.

The clinical trial involves the administration of **Metronidazole 500 mg / 100 ml Intravenous Infusion**, a **solution for infusion** provided by Baxter Healthcare Ltd. This medication is administered via **intravenous infusion**. The maximum daily dose is 40 mg/kg, with a total maximum dose of 560 mg/kg over a treatment period of up to 14 days. The active substance, **metronidazole**, is of chemical origin and is used to treat infections caused by anaerobic bacteria and certain parasites.

Another experimental treatment in the trial is **Aztreonam and Avibactam (1.5g/0.5g) Powder for Concentrate for Solution for Infusion**, manufactured by Pfizer Inc. This medication is also administered as a **solution for infusion** via **intravenous infusion**. The maximum daily dose is 173.3 mg/kg, with a total maximum dose of 2253.3 mg/kg over a 14-day treatment period. The active substances, **aztreonam** and **avibactam sodium**, are chemically derived and are used to treat serious infections caused by gram-negative bacteria.

The trial also includes the use of **Metronidazole**, provided by Inforlife S.A., in the form of a **solution for injection**. This medication is administered intravenously, with a maximum daily dose of 40 mg/kg and a total maximum dose of 560 mg/kg over a 14-day period. The active substance, **metronidazole**, is chemically synthesized and is effective against anaerobic bacterial infections.

Additionally, **Metronidazole 500mg/100ml Solution for Infusion** from B.Braun Melsungen AG is used in the trial. This **solution for infusion** is administered intravenously, with the same dosing regimen as the other metronidazole formulations: a maximum daily dose of 40 mg/kg and a total maximum dose of 560 mg/kg over a 14-day treatment period. The active substance, **metronidazole**, is of chemical origin and is utilized for its antimicrobial properties against anaerobic bacteria.

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoints include pharmacokinetic (PK) parameters such as clearance (CL), maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), and half-life (t1/2). Additionally, plasma concentrations of **Aztreonam (ATM)** and **Avibactam (AVI)** will be measured on Day 1 and at steady state (Day 2 or later). Safety assessments will include monitoring adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, and adverse events resulting in death. Liver and renal function tests will be conducted at baseline, during treatment, and after the end of treatment.

Secondary endpoints will focus on clinical outcomes at the End of Intravenous Treatment (EOIV), End of Treatment (EOT), and Test of Cure (TOC) for Part B of the trial. Microbiological responses will be evaluated per-pathogen at EOIV/EOT and TOC, as well as per-participant at TOC. The emergence of new infections will also be monitored. These assessments will provide comprehensive data on the efficacy of the treatment regimen in neonates and infants with suspected or confirmed infections due to gram-negative pathogens.