ATM-AVI for Bacterial Infections

Recruiting at 43 trial locations

Overseen By Pfizer CT.gov Call Center

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Pfizer

Must be taking: Intravenous antibiotics

Must not be taking: Prohibited concomitant medications

Disqualifiers: Pregnancy, Suicidal ideation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 14 days

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of Aztreonam (ATM, also known as Azactam) and Avibactam (AVI, also known as Emblaveo when combined with aztreonam) in children with serious bacterial infections. The researchers aim to assess how the body processes these drugs and evaluate their safety for hospitalized children needing intravenous antibiotics for severe infections, such as those in the abdomen, urinary tract, blood, or lungs. Participants will receive either the experimental ATM-AVI treatment or the best available therapy selected by the doctor. Suitable candidates are children suspected or known to have gram-negative infections and already receiving IV antibiotics in the hospital. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, contributing to significant medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that current use of any prohibited medications is not allowed. It's best to discuss your current medications with the study doctor to see if they are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of Aztreonam (ATM) and Avibactam (AVI) is generally safe for patients. Studies have found that this treatment does not cause serious medication-related side effects. The safety profile of ATM-AVI is similar to that of Aztreonam alone, which is already known to be safe for treating infections.

Participants in earlier studies did not encounter any new or unexpected safety issues, suggesting that ATM-AVI is a reliable option for treating serious infections. However, as with any treatment, monitoring for possible side effects and discussing them with a doctor is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard treatments for bacterial infections, which often rely on a range of broad-spectrum antibiotics, ATM-AVI combines two specific components: avibactam and aztreonam. This combination is unique because it targets bacteria that produce certain enzymes, making them resistant to many common antibiotics. Researchers are excited about ATM-AVI because it has the potential to effectively treat infections that are resistant to other drugs, offering hope for patients with limited treatment options. Additionally, the dosing flexibility based on weight and kidney function, along with the possibility of switching to oral therapy, makes it a versatile option for both patients and healthcare providers.

What evidence suggests that this trial's treatments could be effective for bacterial infections?

In this trial, participants will receive either the combination of Aztreonam (ATM) and Avibactam (AVI) or the best available therapy (BAT). Research has shown that the ATM-AVI combination effectively treats serious infections, particularly those resistant to other antibiotics. One study found that 42% of patients treated with ATM-AVI improved, while none improved with BAT. ATM-AVI is generally well-tolerated, allowing most people to take it without serious side effects. This combination is particularly effective against tough gram-negative bacteria, which can cause infections in various parts of the body. Overall, ATM-AVI offers a promising option for treating complicated infections, especially when other treatments fail. ^{2 3 4 6 7}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

This trial is for hospitalized children aged 9 months to less than 18 years with suspected or confirmed serious gram-negative infections, requiring IV antibiotics. It's not for those unlikely to respond to the study drugs within 14 days, pregnant/breastfeeding individuals without effective contraception, or those with certain medical conditions.

Inclusion Criteria

I have an infection suspected to be caused by gram-negative bacteria.

I am a woman and my pregnancy test was negative.

I need to be hospitalized for IV antibiotic treatment.

Exclusion Criteria

My kidney function is very low.

I am not currently taking any prohibited medications and have not participated in another drug study within the last 30 days or 5 half-lives.

Medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or make the participant inappropriate for the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 days

Treatment

Participants receive intravenous ATM-AVI or BAT for up to 14 days, with potential switch to oral therapy after 3 days

14 days

Daily in-hospital visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a phone contact 28 to 35 days after the last study treatment

33 to 50 days

1 in-person visit after discharge, phone contact

Test of Cure (TOC)

Clinical assessment of cure within 7 to 14 days after the last antibiotic treatment

7 to 14 days

What Are the Treatments Tested in This Trial?

Interventions

• Avibactam
• Aztreonam

Trial Overview The trial compares Aztreonam and Avibactam (ATM-AVI) combination against the best available therapy (BAT) in treating complicated infections like abdominal, urinary tract, bloodstream, and lung infections. ATM-AVI dosage depends on weight and kidney function; treatment lasts up to 14 days with possible switch to oral therapy.

How Is the Trial Designed?

Group I: ATM-AVI Experimental Treatment 1 Intervention

ATM-AVI administered iv every 6 or 8 hours and dosed according to participant's weight and kidney function for up to 14 days depending on response. At the investigator's discretion, the participant may be switched to oral therapy after 3 days of iv ATM-AVI therapy

Group II: Best available therapy (BAT) Active Control 1 Intervention

BAT will be selected by the investigator and administered iv. At the investigator's discretion, the participant may be switched to oral therapy after 3 days of iv BAT

Avibactam is already approved in United States, European Union for the following indications:

Approved in United States as Avycaz for:

• Complicated Urinary Tract Infections (cUTI) including Pyelonephritis
• Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

Approved in European Union as Emblaveo for:

• Complicated intra-abdominal infections (cIAI)
• Hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP)
• Complicated urinary tract infections (cUTI), including pyelonephritis

Who Is Running the Clinical Trial?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

A new pre-diffusion assay using ceftazidime/avibactam disks can effectively predict the in vitro efficacy of the aztreonam/avibactam (ATM-AVI) combination against NDM-producing Klebsiella, based on a study of 113 bacterial isolates.

The study found that while 38.4% of isolates were susceptible to aztreonam alone, all isolates had low minimum inhibitory concentrations (MICs) for ATM-AVI, indicating strong potential for this combination therapy in treating infections caused by these resistant bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A simple disk pre-diffusion test to predict in vitro aztreonam/avibactam activity against NDM-producing Klebsiella pneumoniae complex. Lima, KO., de Lima, AV., Rocha, DADC., et al.[2022]

Aztreonam/avibactam (ATM-AVI) demonstrated high efficacy against Klebsiella pneumoniae isolates, with over 99.9% of isolates inhibited at a minimum inhibitory concentration (MIC) of ≤4 mg/L, indicating strong potential as a treatment option.

The study found that ATM-AVI is particularly effective against meropenem-resistant strains, with all tested meropenem-resistant metallo-β-lactamase positive isolates inhibited at an MIC of ≤0.5 mg/L, showcasing its importance in combating antibiotic-resistant infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of aztreonam/avibactam against a global collection of Klebsiella pneumoniae collected from defined culture sources in 2016 and 2017. Esposito, S., Stone, GG., Papaparaskevas, J.[2021]

The study found that adding ceftazidime to the aztreonam/avibactam combination did not change the minimum inhibitory concentrations (MICs) of aztreonam/avibactam for 37 antibiotic-resistant Enterobacterales isolates, indicating no synergistic or antagonistic effect.

These results suggest that aztreonam/avibactam can be reliably tested in clinical settings without the influence of ceftazidime, supporting its use against highly resistant MBL-producing Enterobacterales.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing the in vitro impact of ceftazidime on aztreonam/avibactam susceptibility testing for highly resistant MBL-producing Enterobacterales. Bhatnagar, A., Ransom, EM., Machado, MJ., et al.[2021]

Aztreonam-avibactam shows strong in vitro effectiveness against metallo-beta-lactamase (MBL)-producing Enterobacterales, with MIC50 and MIC90 values indicating low concentrations needed for inhibition.

The drug combination is currently pending phase 3 clinical trials, suggesting it could be a promising treatment option for severe infections caused by resistant bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aztreonam-Avibactam Susceptibility Testing Program for Metallo-Beta-Lactamase-Producing Enterobacterales in the Antibiotic Resistance Laboratory Network, March 2019 to December 2020. Bhatnagar, A., Boyd, S., Sabour, S., et al.[2022]

In a study of 102 patients with bloodstream infections caused by metallo-β-lactamase-producing Enterobacterales, the combination of ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) significantly reduced the 30-day mortality rate to 19.2%, compared to 44% in those treated with other active antibiotics.

The CAZ-AVI + ATM treatment also led to lower clinical failure rates at day 14 and shorter hospital stays, indicating its potential as a more effective therapy for these serious infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Ceftazidime-avibactam Plus Aztreonam in Patients With Bloodstream Infections Caused by Metallo-β-lactamase-Producing Enterobacterales. Falcone, M., Daikos, GL., Tiseo, G., et al.[2021]

In a study of 43 clinical isolates of NDM-producing Enterobacterales, the combination of ceftazidime/avibactam (CAZ/AVI) and aztreonam (ATM) showed significant synergy, restoring ATM effectiveness in 89% of ATM-resistant isolates.

The Etest/disc method proved to be a reliable and quick laboratory technique for assessing this synergy, correlating well with traditional broth dilution methods in 81% of cases, making it a practical tool for microbiology labs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A practical laboratory method to determine ceftazidime-avibactam-aztreonam synergy in patients with New Delhi metallo-beta-lactamase (NDM)-producing Enterobacterales infection. Rawson, TM., Brzeska-Trafny, I., Maxfield, R., et al.[2023]

Ceftazidime-avibactam is effective against a wide range of drug-resistant Gram-negative bacteria, including those producing extended-spectrum β-lactamases, making it a valuable treatment for complicated infections like urinary tract infections and hospital-acquired pneumonia.

In clinical trials, ceftazidime-avibactam demonstrated high response rates and was generally well tolerated, showing a safety profile similar to that of ceftazidime alone, which supports its use as a new treatment option for serious infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceftazidime-Avibactam: A Review in the Treatment of Serious Gram-Negative Bacterial Infections. Shirley, M.[2019]

In a study of 61 patients with multidrug or extremely resistant Pseudomonas aeruginosa infections, ceftazidime-avibactam (CAZ-AVI) achieved a clinical cure rate of 54.1% by day 14, indicating its efficacy as a treatment option.

CAZ-AVI was well-tolerated, with only 4.9% of patients experiencing treatment-related adverse events, and no emergence of drug resistance was detected, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of ceftazidime-avibactam for the treatment of infections due to Pseudomonas aeruginosa. Corbella, L., Boán, J., San-Juan, R., et al.[2022]

Ceftazidime-avibactam (CAZ-AVI) showed initial effectiveness against a carbapenem-resistant Klebsiella pneumoniae infection, but resistance developed during treatment due to mutations in the blaKPC gene, indicating a need for careful monitoring of resistance evolution.

Pharmacokinetic/pharmacodynamic (PK/PD) analysis revealed that suboptimal drug exposure during the early days of treatment contributed to the emergence of resistant bacterial subpopulations, emphasizing the importance of achieving optimal drug levels to prevent resistance in critically ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient. Gaibani, P., Gatti, M., Rinaldi, M., et al.[2022]

Ceftazidime-avibactam combined with aztreonam showed high synergy against resistant bacteria, particularly in Klebsiella pneumoniae (86% synergy) and Pseudomonas aeruginosa (70%), based on tests conducted on 153 bacterial isolates.

Rapid synergy testing in the lab allowed for better treatment decisions, highlighting the importance of this method in managing infections caused by metallobetalactamase-producing bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic synergy testing of ceftazidime-avibactam with aztreonam in a university hospital having high number of metallobetalactamase producing bacteria. Sahu, C., Pal, S., Patel, SS., et al.[2021]

Ceftazidime-avibactam (Avycaz) is effective in treating complicated infections, particularly those caused by multidrug-resistant bacteria.

The combination of ceftazidime and avibactam enhances the efficacy of treatment by inhibiting bacterial resistance mechanisms, making it a valuable option for difficult-to-treat infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceftazidime-Avibactam (Avycaz): For the Treatment of Complicated Intra-Abdominal and Urinary Tract Infections. Mosley, JF., Smith, LL., Parke, CK., et al.[2020]

Ceftazidime/avibactam is an effective new antibiotic combination that restores the antibacterial activity of ceftazidime against drug-resistant bacteria, particularly those producing carbapenemase, such as KPC-producing Klebsiella pneumoniae.

The medication has shown promise in treating various infections, including lung, abdominal, bloodstream, and urinary tract infections, while also addressing clinical safety and indications for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Several key points that need to be concerned in the clinical application of ceftazidime/avibactam]. Tang, B., Cui, N.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12301880/

Aztreonam–avibactam for the treatment of serious infections ... Clinical cure rates at TOC were 5/12 (42%) for aztreonam–avibactam and 0/3 (0%) for BAT. Per-patient microbiological responses were generally ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40986278/

Cost-Effectiveness Analysis of Aztreonam-Avibactam (ATM ... Results: The ATM-AVI treatment sequence (ATM-AVI ± metronidazole followed by cefiderocol after treatment failure) had improved clinical outcomes ...

3. pfizer.com pfizer.com/news/press-release/press-release-detail/phase-3-studies-pfizers-novel-antibiotic-combination-offer

Phase 3 Studies of Pfizer's Novel Antibiotic Combination ... Data support that ATM-AVI is effective and well-tolerated, with no new safety findings and a similar safety profile to aztreonam alone. “We ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1198743X24005329

Aztreonam and avibactam combination therapy for metallo- ... This review provides insights into the potential clinical management implications of ATM-AVI for treating carbapenem-resistant gram-negative infections.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06462235

NCT06462235 | A Study to Learn About the ... The purpose of this study is to learn about the safety and effects of ATM-AVI for the possible treatment of infections caused by a type of bacteria called ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10676936/

2893 A. Efficacy and Safety of Aztreonam-Avibactam for the ... ATM-AVI was generally well tolerated. These data support potential use of ATM-AVI for the treatment of serious infections caused by susceptible ...

7. academic.oup.com academic.oup.com/jacamr/article/7/4/dlaf131/8214755

Aztreonam–avibactam for the treatment of serious infections ... Aztreonam–avibactam was generally well-tolerated, with no treatment-related serious adverse events. Conclusions. These Phase 3 data provide ...