Antibiotic De-escalation in Onco-hematology Patients for Sepsis or Septic Shock (DéPOH)

• ClinicalTrials.gov Identifier: NCT03683329
• Recruitment Status: Recruiting
• First Posted: September 25, 2018
• Last Update Posted: May 6, 2021
• Sponsor: Institut Paoli-Calmettes
• Information provided by (Responsible Party): Institut Paoli-Calmettes

Study Description

Brief Summary:

De-escalation aims at reducing the use of broad-spectrum antibiotics and therefore the emergence of multidrug-resistant (MDR) pathogens.

Observational studies suggested that this strategy seems to be safe. However, there is no adequate, direct evidence showing de-escalation of antimicrobial agents to be effective and safe for onco-hematology patients with sepsis or septic shock. Thus, randomized clinical trials are needed for testing the safety and efficiency of de-escalation of antimicrobial therapy.

The investigator's hypothesis is that de-escalation of empirical antimicrobial therapy in onco-hematology patients with sepsis or septic shock is noninferior to the continuation of empirical antimicrobial therapy.

The first aim of the study is to demonstrate that de-escalation is noninferior to the continuation of broad-spectrum antibiotics in terms of hospital mortality.

The secondary aims are to compare the two strategies in terms of mortality, duration of antimicrobial therapy, durations of mechanical ventilation, vasopressor use, numbers of superinfections, organ failure.

Antimicrobial de-escalation (ADE) of antimicrobial therapy is a strategy proposed to allow for the rational use of broad-spectrum antimicrobial therapy as the empiric treatment for infections and minimize the overall exposure to these broad-spectrum agents. The need for prompt, effective antimicrobial therapy for patients with known or suspected infections is widely accepted. This principle leads to the use of very broad-spectrum antimicrobial therapy to increase the odds that all suspected potential pathogens are adequately treated. However, the potential drawback is selection of multidrug-resistant (MDR) organisms.

ADE is widely recommended in the management of antimicrobial therapy in intensive care unit (ICU) patients. The Surviving Sepsis Campaign guidelines describe and recommend the process for selecting antimicrobial therapy as commencement of antimicrobials within the first hour, antimicrobial therapy broad enough to cover all likely pathogens, and daily reassessment for potential ADE.

To date, no randomized study assessing this strategy is available for this specific population of cancer critically ill patients. In a recent systematic review based on 13 observational studies and one randomized controlled trial, the authors conclude that the equipoise remains and a large randomized trial is required to assess the effect of the antibiotics de-escalation strategy on the bacterial ecosystem, on MDR carriage, and on patient outcomes.

Condition or disease	Intervention/treatment	Phase
Critical Care; Cancer	Other: Antibiotic de-escalation; Other: Standard treatment	Phase 3

Detailed Description:

An interim analysis planned after inclusion of 233 patients.

* Subgroup analyses will be performed on patient subsets:

• Patients with allogeneic HCST,
• Neutropenic patients (Neutrophils < 0.5 Giga/L),
• Hematological disease,
• Oncological disease,
• Polymicrobial sepsis,
• Multi-drug resistant organisms,
• Patients presenting with bacterial pneumoniae,
• Patients presenting with Intra-abdominal infection,
• Patients presenting with bacteraemia,
• Patients presenting with gram negative bacteria infection,
• Patients presenting with gram positive cocci infection,
• Patients presenting with septic shock,
• Patients presenting with sepsis.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 466 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Antibiotic De-escalation in Onco-hematology Patients for Sepsis or Septic Shock
• Actual Study Start Date: November 26, 2018
• Estimated Primary Completion Date: February 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Antibiotic de-escalation; According to the results of the antibiogram of the suspected causative bacteria, the ''pivotal'' antibiotic (antipseudomonal betalactam) used for empirical treatment is switched to an antibiotic with a spectrum as narrow as possible according to the targeted pathogens,; Stop the companion antibiotic (aminoglycoside, fluoroquinolone, macrolide) between day 2 and day 3 of antibiotic treatment as much as possible,; Stop the empirical antibiotic directed against methicillin-resistant staphylococcus aureus (MRSA) or an enterococcus in the absence of these bacteria in the culture.	Other: Antibiotic de-escalation; All the therapeutic protocols made the object of a consensus between the different partners of the study. Antibiotic treatment will be delivered according to current practice, in agreement with the national and international recommendation.
Active Comparator: Standard treatment without de-escalation; The companion antibiotic is stopped between day 3 and day 5 of antibiotic treatment as much as possible and according to the local prescription,; Empirical antibiotics directed against MRSA or enterococcus were used according to local prescription and/or international guidelines,; The pivotal antibiotic of the empirical treatment is continued for the entire duration of the treatment, independently of microbiological results. For prolonged treatment, the physician has the choice of de-escalating after 8-15 days of treatment.	Other: Standard treatment; Antibiotic treatment will be delivered according to current practice, in agreement with the national and international recommendation.

Outcome Measures

Primary Outcome Measures :

1. Hospital mortality [ Time Frame: From day of inclusion until day of ICU discharge, up to 3 months ]
   death from any cause during hospital stay

Secondary Outcome Measures :

1. Death [ Time Frame: From day of inclusion until ICU discharge, day 28 and day 90 ]
   death from any cause into the ICU, day 28 and day 90
2. ICU length of stay [ Time Frame: From day of inclusion until ICU discharge (until day 90) ]
3. Hospital length of stay [ Time Frame: From day of inclusion until ICU discharge (until day 90) ]
4. Severe organ dysfunctions [ Time Frame: From day of inclusion until ICU discharge (until day 90) ]
   A Sepsis-related Organ Failure Assessment (SOFA) score>2 for each organ (respiratory, hematologic, cardiac, neurologic, hepatic, renal)
5. Respiratory dysfunction-free days at day 28 [ Time Frame: from inclusion to day 28 ]
   days without respiratory dysfunction (respiratory SOFA score<3)
6. Renal dysfunction-free days at day 28 [ Time Frame: from inclusion to day 28 ]
   days without renal dysfunction (renal SOFA score<3)
7. Neurologic dysfunction-free days at day 28 [ Time Frame: from inclusion to day 28 ]
   days without neurologic dysfunction (neurologic SOFA score<3)
8. Cardiac dysfunction-free days at day 28 [ Time Frame: from inclusion to day 28 ]
   days without cardiac dysfunction (cardiac SOFA score<3)
9. Hepatic dysfunction-free days at day 28 [ Time Frame: From inclusion to day 28 ]
   days without hepatic dysfunction (hepatic SOFA score<3)
10. Hematologic dysfunction-free days at day 28 [ Time Frame: From inclusion to day 28 ]
    days without hematologic dysfunction (hematologic SOFA score<3)
11. Ventilator-free days at day 28 [ Time Frame: From inclusion to day 28 ]
    days without invasive mechanical ventilation
12. Vasopressors-free days at day 28 [ Time Frame: From inclusion to day 28 ]
    days without vasopressors treatment
13. Dialysis-free days at day 28 [ Time Frame: From inclusion to day 28 ]
    days without dialysis treatment
14. Duration of antibiotic treatment during ICU stay [ Time Frame: From day of admission to ICU until day 90 ]
    Duration between the first antibiotic initiation and the last antibiotic stop
15. Number of antibiotics de-escalated [ Time Frame: From inclusion to ICU discharge until day 90 ]
    Number of antibiotics de-escalated in each arm
16. Number of anfungal de-escalated [ Time Frame: From inclusion to ICU discharge until day 90 ]
    Number of anfungal de-escalated in each arm
17. Number of antiviral de-escalated [ Time Frame: From inclusion to ICU discharge until day 90 ]
    Number of antiviral de-escalated in each arm
18. Antibiotic-free days at day 28 [ Time Frame: From inclusion to day 28 ]
    days without antibiotic treatment
19. Antibiotic-free days during ICU stay [ Time Frame: From admission to ICU to ICU discharge until day 90 ]
    days without antibiotic treatment
20. Antibiotic-free days during hospital stay [ Time Frame: From admission to ICU to hospital discharge until day 90 ]
    Days without antibiotic treatment
21. Antibiotic-free days at day 90 [ Time Frame: From admission to ICU to day 90 ]
    Days without antibiotic treatment
22. Antifungal-free days at day 28 [ Time Frame: From admission to ICU to day 28 ]
    Days without antifungal treatment
23. Antiviral-free days at day 28 [ Time Frame: From admission to ICU to day 28 ]
    Days without antiviral treatment
24. Antifungal-free days during ICU stay [ Time Frame: From admission to ICU to ICU discharge until day 90 ]
    Days without antifungal treatment
25. Antiviral-free days during ICU stay [ Time Frame: From admission to ICU to ICU discharge until day 90 ]
    Days without antiviral treatment
26. Antiviral-free days during hospital stay [ Time Frame: From admission to ICU to hospital discharge until day 90 ]
    Days without antiviral treatment
27. Antifungal-free days during hospital stay [ Time Frame: From admission to ICU to hospital discharge until day 90 ]
    Days without antifungal treatment
28. Antifungal-free days at day 90 [ Time Frame: From admission to ICU to day 90 ]
    Days without antifungal treatment
29. Antiviral-free days at day 90 [ Time Frame: From admission to ICU to day 90 ]
    Days without antiviral treatment
30. Number of days of exposure to each antibiotic per 1000 inpatient days [ Time Frame: From admission to ICU to ICU discharge until day 90 ]
    For the entire cohort:(number of antibiotic days / number of ICU days)*1000
31. Number of days of exposure to each antifungal per 1000 inpatient days [ Time Frame: From admission to ICU to ICU discharge until day 90 ]
    For the entire cohort:(number of antifungal days / number of ICU days)*1000
32. Number of days of exposure to each antiviral per 1000 inpatient days [ Time Frame: From admission to ICU to ICU discharge until day 90 ]
    For the entire cohort:(number of antiviral days / number of ICU days)*1000
33. Adverse events [ Time Frame: From inclusion to ICU discharge until day 90 ]
    Adverse events assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0
34. Compliance to de-escalation strategy [ Time Frame: From inclusion to ICU discharge until day 90 ]
    number of patients de-escalated/number of patients included in the experimental arm
35. Compliance to the continuation strategy [ Time Frame: From inclusion to ICU discharge until day 90 ]
    number of patients not de-escalated/number of patients included in the continuation group
36. Percentage of emerging multidrug-resistant bacteria [ Time Frame: From inclusion until day 28 ]
    Percentage of emerging multidrug-resistant bacteria isolated from specimen taken for routine microbiological assessments
37. Cost of antibiotic treatment [ Time Frame: From inclusion to ICU discharge until day 90 ]
38. Patients presenting with bacterial pneumoniae, [ Time Frame: From inclusion to ICU discharge until day 90 ]
39. Patients presenting with Intra-abdominal infection. [ Time Frame: From inclusion to ICU discharge until day 90 ]
40. Patients presenting with bacteraemia [ Time Frame: From inclusion to ICU discharge until day 90 ]
41. Number of patients in the de-escalation group without de-escalation [ Time Frame: From inclusion to ICU discharge until day 90 ]
42. Rate of new infectious episode requiring a new antibiotic treatment [ Time Frame: From inclusion to ICU discharge until day 90 ]
43. Rate of patients requiring an escalation after de-escalation [ Time Frame: From inclusion to ICU discharge until day 90 ]
44. Rate of recovery from infection [ Time Frame: From inclusion to ICU discharge until day 90 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Written informed consent from the patient or proxy (if present) before inclusion or once possible when patient has been included in a context of emergency
2. Age ≥ 18 years,

3. Onco-hematology patient admitted to intensive care for sepsis or septic shock according to the following criteria:

   • Sepsis:

     • A suspected infection
     • And an acute increase of ≥ 2 SOFA points (a proxy for organ dysfunction)

   • Septic shock:

     • sepsis
     • and vasopressor therapy needed to elevate MAP ≥65 mm Hg and lactate >2 mmol/L despite adequate fluid resuscitation
4. Patient treated with an empirical antibiotic treatment,
5. Patient with at least one microbiological sample collected at least within the first 48 hours following the diagnosis of sepsis in ICU
6. Patient with an identified infectious site according to the definitions,
7. Patient with an identified bacteria microorganism after microbiological examination,
8. Patient affiliated to the national French statutory healthcare insurance system or beneficiary of this regimen.

Exclusion Criteria:

1. Patient colonized with a multi-drug resistant organisms preventing de-escalation antibiotic,
2. Pregnant or breast-feeding woman,
3. No affiliation to the national French statutory healthcare insurance system,
4. Patients deprived of liberty or placed under the authority of a tutor,
5. Inappropriate probabilistic antibiotic treatment,
6. Expected mortality within 48 hours,
7. Patient admitted to the ICU for end-of-life care (do-not-resuscitate patients) . Do-not-intubate (DNI) patients can be included.

Contacts and Locations

Contacts

Contact: GENRE Dominique, MD; + 33 4 91 22 37 78; drci.up@ipc.unicancer.fr

Contact: COURNIER Sandra; + 33 4 91 22 37 78; drci.up@ipc.unicancer.fr

Locations

France

GENRE; Recruiting

Marseille, France, 13273

Contact: GENRE Dominique, MD + 33 4 91 22 37 78 drci.up@ipc.unicancer.fr

Contact: COURNIER Sandra + 33 4 91 22 37 78 drci.up@ipc.unicancer.fr

Principal Investigator: Mokart Djamel, MD, PhD

Sponsors and Collaborators

Institut Paoli-Calmettes

Investigators

• Principal Investigator: MOKART Djamel, MD; Institut Paoli-Calmettes

More Information

Additional Information:

Institut Paoli-Calmettes 

• Responsible Party: Institut Paoli-Calmettes
• ClinicalTrials.gov Identifier: NCT03683329
• Other Study ID Numbers: DéPOH-IPC 2015-022
• First Posted: September 25, 2018
• Last Update Posted: May 6, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut Paoli-Calmettes:

critical care; cancer; antimicrobial treatment; de-escalation; septic shock; sepsis

Additional relevant MeSH terms:

Sepsis; Shock, Septic; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Shock; Anti-Bacterial Agents; Anti-Infective Agents