Cancer, Critical Care
Conditions
Keywords
critical care, cancer, antimicrobial treatment, de-escalation, septic shock, sepsis
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.
Detailed description
An interim analysis planned after inclusion of 233 patients. \* Subgroup analyses will be performed on patient subsets: * Patients with allogeneic hematopoietic stem cell transplant, * 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.
Interventions
OTHERAntibiotic 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.
OTHERStandard treatment
Antibiotic treatment will be delivered according to current practice, in agreement with the national and international recommendation.
Sponsors
Institut Paoli-Calmettes
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hospital mortality | From day of inclusion until day of ICU discharge, up to 3 months | death from any cause during hospital stay |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antifungal-free days at day 90 | From admission to ICU to day 90 | Days without antifungal treatment |
| Antiviral-free days at day 90 | From admission to ICU to day 90 | Days without antiviral treatment |
| Antiviral-free days during ICU stay | From admission to ICU to ICU discharge until day 90 | Days without antiviral treatment |
| Antiviral-free days during hospital stay | From admission to ICU to hospital discharge until day 90 | Days without antiviral treatment |
| Death | From day of inclusion until ICU discharge, day 28 and day 90 | death from any cause into the ICU, day 28 and day 90 |
| ICU length of stay | From day of inclusion until ICU discharge (until day 90) | — |
| Hospital length of stay | From day of inclusion until ICU discharge (until day 90) | — |
| Severe organ dysfunctions | 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) |
| Respiratory dysfunction-free days at day 28 | from inclusion to day 28 | days without respiratory dysfunction (respiratory SOFA score\<3) |
| Renal dysfunction-free days at day 28 | from inclusion to day 28 | days without renal dysfunction (renal SOFA score\<3) |
| Neurologic dysfunction-free days at day 28 | from inclusion to day 28 | days without neurologic dysfunction (neurologic SOFA score\<3) |
| Cardiac dysfunction-free days at day 28 | from inclusion to day 28 | days without cardiac dysfunction (cardiac SOFA score\<3) |
| Hepatic dysfunction-free days at day 28 | From inclusion to day 28 | days without hepatic dysfunction (hepatic SOFA score\<3) |
| Hematologic dysfunction-free days at day 28 | From inclusion to day 28 | days without hematologic dysfunction (hematologic SOFA score\<3) |
| Ventilator-free days at day 28 | From inclusion to day 28 | days without invasive mechanical ventilation |
| Vasopressors-free days at day 28 | From inclusion to day 28 | days without vasopressors treatment |
| Dialysis-free days at day 28 | From inclusion to day 28 | days without dialysis treatment |
| Duration of antibiotic treatment during ICU stay | From day of admission to ICU until day 90 | Duration between the first antibiotic initiation and the last antibiotic stop |
| Number of antibiotics de-escalated | From inclusion to ICU discharge until day 90 | Number of antibiotics de-escalated in each arm |
| Number of antifungal de-escalated | From inclusion to ICU discharge until day 90 | Number of antifungal de-escalated in each arm |
| Number of antiviral de-escalated | From inclusion to ICU discharge until day 90 | Number of antiviral de-escalated in each arm |
| Antibiotic-free days at day 28 | From inclusion to day 28 | days without antibiotic treatment |
| Antibiotic-free days during ICU stay | From admission to ICU to ICU discharge until day 90 | days without antibiotic treatment |
| Antibiotic-free days during hospital stay | From admission to ICU to hospital discharge until day 90 | Days without antibiotic treatment |
| Antibiotic-free days at day 90 | From admission to ICU to day 90 | Days without antibiotic treatment |
| Antifungal-free days at day 28 | From admission to ICU to day 28 | Days without antifungal treatment |
| Antiviral-free days at day 28 | From admission to ICU to day 28 | Days without antiviral treatment |
| Antifungal-free days during ICU stay | From admission to ICU to ICU discharge until day 90 | Days without antifungal treatment |
| Number of days of exposure to each antibiotic per 1000 inpatient days | From admission to ICU to ICU discharge until day 90 | For the entire cohort:(number of antibiotic days / number of ICU days)\*1000 |
| Number of days of exposure to each antifungal per 1000 inpatient days | From admission to ICU to ICU discharge until day 90 | For the entire cohort:(number of antifungal days / number of ICU days)\*1000 |
| Number of days of exposure to each antiviral per 1000 inpatient days | From admission to ICU to ICU discharge until day 90 | For the entire cohort:(number of antiviral days / number of ICU days)\*1000 |
| Adverse events | From inclusion to ICU discharge until day 90 | Adverse events assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 |
| Compliance to de-escalation strategy | From inclusion to ICU discharge until day 90 | number of patients de-escalated/number of patients included in the experimental arm |
| Compliance to the continuation strategy | From inclusion to ICU discharge until day 90 | number of patients not de-escalated/number of patients included in the continuation group |
| Percentage of emerging multidrug-resistant bacteria | From inclusion until day 28 | Percentage of emerging multidrug-resistant bacteria isolated from specimen taken for routine microbiological assessments |
| Cost of antibiotic treatment | From inclusion to ICU discharge until day 90 | — |
| Patients presenting with bacterial pneumoniae, | From inclusion to ICU discharge until day 90 | — |
| Patients presenting with Intra-abdominal infection. | From inclusion to ICU discharge until day 90 | — |
| Patients presenting with bacteraemia | From inclusion to ICU discharge until day 90 | — |
| Number of patients in the de-escalation group without de-escalation | From inclusion to ICU discharge until day 90 | — |
| Rate of new infectious episode requiring a new antibiotic treatment | From inclusion to ICU discharge until day 90 | — |
| Rate of patients requiring an escalation after de-escalation | From inclusion to ICU discharge until day 90 | — |
| Antifungal-free days during hospital stay | From admission to ICU to hospital discharge until day 90 | Days without antifungal treatment |
| Rate of recovery from infection | From inclusion to ICU discharge until day 90 | — |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORMOKART Djamel, MD
Institut Paoli-Calmettes
Outcome results
None listed