COTRIVAP: Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05696093

Collaborator

(none)

628

Enrollment

Arms

38.2

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Efficacy of cotrimoxazole as a de-escalation treatment for adult patients Ventilator-Associated Pneumonia in intensive care unit Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP

Condition or Disease	Intervention/Treatment	Phase
Ventilator Associated Pneumonia	Drug: cotrimoxazole Drug: standard antibiotic therapy	Phase 4

Detailed Description

Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP. Selection of patients will be done by physicians in ICU. All clinically suspected VAP will be confirmed with a lung sample (bronchoalveolar lavage or protected distal specimen). Patients with a microbiologically confirmed VAP due to an Enterobacteriaceae susceptible to cotrimoxazole and at least one antibiotic of the empiric antibiotic therapy (based on international recommendations) will be included. After written informed consent, they will be randomized (1:1), using a computer-generated randomization scheme of various-sized blocks, stratified by presence of septic shock at VAP diagnosis and by presence of COVID-19 pneumonia on ICU admission, through a centralized 24 hours internet service (CleanWEB™) to cotrimoxazole, or best standard of care (either a beta-lactam or a fluoroquinolone), after randomization for a total duration of 7 days (including empiric initial appropriate treatment). Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patients. Because antibiotic therapy will be variable in the control group, single or double blind is not appropriate. Daily follow-up until death or ICU discharge or day 28 will be performed (vital status, antibiotic therapy, new infection, Clostridium-difficile infection). Clinical (arterial blood gas, temperature, haematology, tracheal secretions) and radiological cure (chest X-ray) will be assessed at Day 7. Systematic MDR bacteria screening will be performed weekly and at ICU discharge. Vital status will be assessed at day 90. Alive patients leaving ICU before 90 days will be contacted by phone (if discharge at home) or by interview at hospital (if transferred in a different ward). Assessment of the clinical and radiological cure by an independent committee (1 specialist in infectious disease and 1 intensivist), blinded of the randomization arm (PROBE methodology).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

628 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP.Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit. Multicentric Non-inferiority Randomised Controlled Trial

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Apr 29, 2026

Anticipated Study Completion Date :

Jun 6, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: cotrimoxazole Use of cotrimoxazole for enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.	Drug: cotrimoxazole Use of cotrimoxazole therapy for enterobacterial VAP
Active Comparator: standard antibiotic therapy Use of standard antibiotic therapy enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.	Drug: standard antibiotic therapy Use of standard antibiotic therapy for enterobacterial VAP

Arm

Intervention/Treatment

Experimental: cotrimoxazole

Use of cotrimoxazole for enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.

Drug: cotrimoxazole

Use of cotrimoxazole therapy for enterobacterial VAP

Active Comparator: standard antibiotic therapy

Use of standard antibiotic therapy enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.

Drug: standard antibiotic therapy

Use of standard antibiotic therapy for enterobacterial VAP

Outcome Measures

Primary Outcome Measures

To demonstrate that cotrimoxazole is non-inferior to best standard of care for the treatment of VAP in ICU in term of survival at day 28 [28 days after inclusion]
Vital status at day 28

Secondary Outcome Measures

To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in term of mortality at day 90 [90 days after inclusion]
Vital status at day 90
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in IC in terms of mechanical ventilation (MV)-free-days at day 28 [28 days after inclusion]
number of MV-free-days through day 28
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of rate of cure between days 7 and 10 [days 7 and 10 after inclusion]
Clinical, biological and radiological cure evaluated 7 to 10 days after VAP diagnosis, defined as the combination of resolution of signs and symptoms present at enrolment, biological improvement, and improvement or lack of progression of radiological signs, as adjudicated by an independent committee (PROBE methodology)
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of VAP recurrence [28 days after inclusion]
new episode of VAP with the same Enterobacteriaceae
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of ICU length of stay [28 days after inclusion]
ICU length of stay
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of hospital length of stay [28 days after inclusion]
hospital length of stay
To assess the safety of cotrimoxazole compared to best standard of care at day 28 in terms of allergy to antibiotics [28 days after inclusion]
safety (rate of allergy due to antimicrobial drug)
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of mortality at day 28 [28 days after inclusion]
Vital status at day 28
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of overall antibiotic consumption [day 28 after inclusion]
antibiotic-free days at day 28
To assess the ecological impact of the treatment in terms of acquisition of MDR bacteria in ICU [28 days after inclsuion]
evolution of rate of MDR bacterial colonization on systematic screening at enrolment until ICU discharge
To assess the ecological impact of the treatment in terms of rate of Clostridioides difficile infection [28 days after inclusion]
diagnostic of Clostridioides difficile infection between inclusion and day 28

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patients hospitalized in an ICU
Under mechanical ventilation for at least five days
Microbiologically confirmed VAP on a distal lung sample (bronchoalveolar lavage or protected distal specimen)
Enterobacteriaceae susceptible to cotrimoxazole, and for polymicrobial VAP, all bacteria susceptible to cotrimoxazole

Exclusion Criteria:

Haemodynamic instability (increasing dose of a catecholamine in the last 24 hours)
Contra-indication to cotrimoxazole:
allergy,
advanced liver insufficiency,
renal dysfunction with clearance <15 mL/min/1.73 m² without hemodialysis
G6PD deficiency
Pregnant women at the time of inclusion and breastfeeding women
Infection requiring prolonged antibiotic-therapy (pleural empyema, lung abscess, necrotizing pneumonia, etc…)
Cystic fibrosis
Immunosuppression (neutropenia, HIV with CD4 lymphocytes below 200/mm3, immunosuppressive therapy or corticosteroid therapy >0.5 mg/kg/j before ICU admission)
Cardiac arrest without awakening
Moribund state (patient likely to die within 24h)
Limitation of life support (comfort care applied only) at the time of screening
Enrolment to another interventional study on VAP care/management
Subject deprived of freedom, subject under a legal protective measure
No affiliation to any health insurance system
Refusal to participate to the study (patient or legal representative or family member or close relative if present) Patients previously included in the study