Antibacterial Agents, Beta-lactam Antibiotics, Drug Resistance, Multiple, Bacterial, Prognosis, Pseudomonas Aeruginosa, Pseudomonas Infections
Conditions
Brief summary
The primary objective of the ADDICT study is to assess and compare the clinical efficacy of available options for antimicrobial therapy (new beta-lactam/beta-lactamase inhibitor combination, cefiderocol or older agents such as aminoglycosides and colistin) in unselected patients with infection due to difficult-to-treat P. aeruginosa.
Detailed description
Infections due to Pseudomonas aeruginosa isolates with acquired resistances to all first-line antipseudomonal beta-lactams and fluoroquinolones (difficult-to-treat isolates - DTR), pose serious therapeutical challenges, especially in critically ill and/or immunocompromised patients. Certain new beta-lactam/beta-lactamase inhibitor combinations (BL/BLI (beta lactamine/ beta lactamase inhibitor) - i.e., ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, others) and cefiderocol have shown promising results for the treatment of infections due to DTR P. aeruginosa. However, multicenter data on their real-life utilization in this indication are still scarce. The ADDICT study is a prospective, multicenter cohort study including unselected patients with DTR P. aeruginosa infection requiring definite intravenous antimicrobial therapy. The primary objective of the study is to investigate the clinical efficacy of available options (new BL/BLI, cefiderocol or older agents such as aminoglycosides and colistin) in this population. Secondary objectives are to compare the clinical and microbiological efficacy of available options in infections due to DTR P. aeruginosa with in vitro susceptibility to more than one last-resort drug, to compare the incidence of non-ecological adverse events observed with these drugs, to assess the incidence of resistance emergence under therapy and to elucidate the molecular mechanisms of resistance emergence, to assess the benefits and risks of combination therapy in this indication, to compare the acquisition rates of multidrug-resistant bacteria other than DTR P. aeruginosa, and Clostridioides difficile infection, to compare Day-28 and in-hospital all-cause mortality rates. Patients will be recruited in 60 hospital centers contributing to four French networks of research in infectious diseases and critical care (CRICS-TRIGGERSEP, ReaRezo, OutcomeRéa, RENARCI - PROMISE metanetwork). Clinical variables will be collected through an electronic case-report form. DTR P. aeruginosa isolates will be sent to the National Reference Center of Antimicrobial Resistance in P. aeruginosa for centralized analyses (extended antimicrobial susceptibility testing, MLST, whole-genome sequencing of successive isolates if resistance emergence under therapy).
Interventions
None listed
Sponsors
Centre Hospitalier Régional d'Orléans
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All patients aged 18 or over and requiring intravenous definite antimicrobial therapy for a DTR P. aeruginosa infection
Exclusion criteria
* Cystic fibrosis * P. aeruginosa DTR colonization or P. aeruginosa DTR infection not requiring definitive intravenous antibiotic therapy * Protected person (under guardianship or curatorship) * Persons under court protection * Persons deprived of liberty * Opposition expressed for participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical cure rate | Test of cure visit | Clinical responses will be assessed by local investigators. Clinical cure will be defined as a composite endpoint of survival with no relapse occurring since the end of definite therapy and the complete resolution of all initial clinical signs of infection at the ToC visit (all-cause deaths at the ToC visit will be considered as clinical failures). |
| Clinical cure | Day 7±2 after the completion of definite therapy | Clinical responses will be assessed by local investigators. Clinical cure will be defined as a composite endpoint of survival with no relapse occurring since the end of definite therapy and the complete resolution of all initial clinical signs of infection at the ToC visit (all-cause deaths at the ToC visit will be considered as clinical failures). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Microbiological eradication | Day 7 | Negativation of cultures for DTR P. aeruginosa in participants with at least one collected follow-up bacteriological sample (when clinically indicated) before the ToC visit |
| Resistance emergence | Up to hospital discharge, an average of 1 month | Any culture growing a DTR P. aeruginosa isolate with resistance to at least one new antimicrobial agent (compared to the first isolate) between the second day of definite therapy and hospital discharge |
| Non-ecological adverse events | At test-of-cure visit, 7±2 days after the completion of definite therapy | Any toxicity or allergic reaction attributed to the antimicrobial agent by the local investigator |
| Acquisition of multidrug-resistant bacteria other than DTR P. aeruginosa | Up to hospital discharge, an average of 1 month | Culture of any clinical or surveillance sample growing a multidrug-resistant bacteria other than P. aeruginosa |
| Clostridioides difficile infection | Up to hospital discharge, an average of 1 month | Documented C. difficile infection |
| In-hospital death | Up to hospital discharge, an average of 1 month | All-cause death |
| Death at Day 28 | Day 28 | All-cause death |
Countries
France, Reunion
Contacts
CONTACTFRANCOIS BARBIER, Professor
PRINCIPAL_INVESTIGATORFrancois BARBIER, Professor
Centre Hospitalier Universitaire d'Orléans
Outcome results
None listed