CERTAIN: Ceftolozane/Tazobactam Continuous Infusion for Infective Exacerbations of Cystic Fibrosis and Bronchiectasis

Sponsor

Sunshine Coast Hospital and Health Service (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06035055

Collaborator

The Prince Charles Hospital (Other), Mater (Other)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The goal of this clinical trial is to assess the feasibility of ceftolozane/tazobactam (C/T) administered on an outpatient parenteral antibiotic therapy programme to patients with a current infective exacerbation of bronchiectasis or cystic fibrosis related to pseudomonas aeruginosa or burkholderia cepacia spp. organisms. The main question[s] it aims to answer are:

Is C/T effective, safe, well-tolerated and able to induce clinical and microbiologic response?
What are mechanisms of antimicrobial resistance are induced by administration of C/T?

Condition or Disease	Intervention/Treatment	Phase
Bronchiectasis Cystic Fibrosis Pseudomonas Aeruginosa Burkholderia Cepacia Infection	Drug: Ceftolozane/tazobactam	Phase 4

Detailed Description

For patients with cystic fibrosis (CF) and non-CF bronchiectasis, chronic airway infection with Gram-negative organisms such as Pseudomonas aeruginosa and Burkholderia cepacia complex species (BCC) is highly challenging to treat and associated with significant morbidity and mortality. These organisms are naturally resistant towards many antibiotic classes, limiting the available arsenal of effective antibiotics for their treatment and eradication. Therefore, there is a pressing need for new antimicrobial therapy options for infective exacerbations associated with these organisms.

There are clear logistical and financial benefits for acute infective exacerbations of CF and non-CF bronchiectasis to be managed on OPAT programs. Many acute infective exacerbations can be safely managed in this way, and a substantial body of evidence supports non-inferiority of OPAT compared with inpatient care. From a logistical perspective, feasibility of OPAT programs is greatly improved by antibiotics being infused over a 24-hour period rather than via bolus several times per day. Unfortunately, many mainstay anti-pseudomonal and anti-Burkholderia antibiotics (including meropenem, imipenem and ceftazidime) are not stable for 24 hours at room/body temperature therefore are unsuitable for use on OPAT.

This study aims to assess viability of ceftolozane/tazobactam (C/T) administered via OPAT in adult patients with exacerbations of CF or non-CF bronchiectasis. Secondary aims are to describe clinical outcomes of patients receiving C/T, tolerability of C/T, relative sputum bacterial load throughout treatment and assess development of resistance to C/T and other antibiotics. We aim to recruit 30 patients, colonized with either pseudomonas aeruginosa or burkholderia cepacia complex, with a current infectious exacerbation requiring intravenous antibiotic treatment. We propose to administer C/T via infusion for 10-14 days with review at day 0-3, 5-7 and 10-14. Blood testing, sputum testing, lung function testing, administration of CF- and bronchiectasis-specific questionnaires and adverse event reporting will be carried out at these times. Serum levels of C/T will be monitored using a validated assay. Clinical review at day 28-42 will be carried out to assess for recrudescence of symptoms and further need for antibiotics and a follow-up phone call will be made at 3 months to assess whether any further antibiotics were needed for new/recrudescent symptoms of infection.

We expect to find that C/T is safe, well-tolerated and effective in treating infective exacerbations of bronchiectasis in OPAT settings. We expect to find that bacterial density in sputum samples reduces over the course of treatment, and that development of antimicrobial resistance is minimal.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

30 patients will be recruited and will receive the study intervention.30 patients will be recruited and will receive the study intervention.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

The Feasibility of Ceftolozane/Tazobactam Continuous Infusion for Exacerbations of Cystic Fibrosis and Bronchiectasis Treated in an Outpatient Parenteral Antibiotic Therapy (OPAT) Setting

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ceftolozane/tazobactam 9g infusion 9g ceftolozane/tazobactam in 240 millilitres 0.9% sodium chloride IV infusion given over 24 hours for 10-14 days	Drug: Ceftolozane/tazobactam 9g ceftolozane/tazobactam in 240 millilitres 0.9% sodium chloride IV infusion given over 24 hours for 10-14 days

Arm

Intervention/Treatment

Experimental: Ceftolozane/tazobactam 9g infusion

9g ceftolozane/tazobactam in 240 millilitres 0.9% sodium chloride IV infusion given over 24 hours for 10-14 days

Drug: Ceftolozane/tazobactam

9g ceftolozane/tazobactam in 240 millilitres 0.9% sodium chloride IV infusion given over 24 hours for 10-14 days

Outcome Measures

Primary Outcome Measures

The feasibility of the use of ceftolozane/tazobactam given via continuous infusion in an OPAT setting for the treatment of acute exacerbations of CF and bronchiectasis. [Day 0 to day 90 post commencement of intervention.]
The feasibility of the use of ceftolozane/tazobactam given via continuous infusion in an OPAT setting for the treatment of acute exacerbations of CF and bronchiectasis will be assessed. Feasibility will be determined as a composite of clinical response (as assessed by disease-specific questionnaires, serum inflammatory marker monitoring and spirometry in the case of patients with cystic fibrosis), adverse events and report of relapse of respiratory infection at 3 months.

Secondary Outcome Measures

Safety and tolerability [Day 0 to day 90 post commencement of intervention.]
Safety and tolerability of continuous infusion ceftolozane/tazobactam. Ceftolozane/tazobactam has a very similar adverse event (AE) profile to other broad spectrum intravenous antibiotics, e.g. piperacillin/tazobactam and meropenem. Possible symptomatic AE's include: nausea, diarrhoea, headache, vomiting, constipation, insomnia, rash and fever. These will be assessed direct questioning of participants at the time of research visits, by clinical examination and and by participants self-reporting symptoms of concern to the research team any time during or after their course of ceftolozane/tazobactam. Possible laboratory abnormalities include: liver function test derangement and acute kidney injury. These will be monitored by regular blood tests during and after the course of ceftolozane/tazobactam.
Relative bacterial load [Day 0-1, Day 5-7, Day 10-14, Day 28-42]
To describe relative bacterial load over the course of ceftolozane/tazobactam treatment as assessed by quantitative PCR (qPCR) on sputa.
In vitro antimicrobial susceptibility/resistance [Day 0-1, Day 5-7, Day 10-14, Day 28-42]
To describe in vitro antimicrobial susceptibility of airway pathogens to ceftolozane/tazobactam and other anti-pseudomonal/anti-Burkholderia antibiotics over the course of ceftolozane/tazobactam treatment. This will be determined by a composite outcome of antimicrobial susceptibility testing, whole-genome sequencing (WGS), culturomic sequencing, and bioinformatic analysis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of CF or non-CF bronchiectasis
Colonised with P. aeruginosa or BCC species
Current infectious exacerbation requiring treatment with intravenous antibiotics
Productive of sputum

Exclusion Criteria:

Unable to consent
Active pregnancy (as confirmed by urine beta-HCG)
Not appropriate for OPAT (as determined by treating clinician)
Estimated Creatinine Clearance < 50 millilitres/min
History of hypersensitivity reaction to piperacillin/tazobactam or members of the cephalosporin class of antibiotics
Unable to expectorate

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Sunshine Coast Hospital and Health Service
The Prince Charles Hospital
Mater

Investigators

Principal Investigator: Julia J Bashford, BSc, MBBS, Sunshine Coast University Hospital
Principal Investigator: Andrew Burke, MBBS, The Prince Charles Hospital