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

Institut Paoli-Calmettes398 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Hospital mortality

death from any cause during hospital stay

Time frame: From day of inclusion until day of ICU discharge, up to 3 months

Secondary Outcomes

Death

death from any cause into the ICU, day 28 and day 90

Time frame: From day of inclusion until ICU discharge, day 28 and day 90

ICU length of stay

Time frame: From day of inclusion until ICU discharge (until day 90)

Hospital length of stay

Time frame: From day of inclusion until ICU discharge (until day 90)

Severe organ dysfunctions

A Sepsis-related Organ Failure Assessment (SOFA) score\>2 for each organ (respiratory, hematologic, cardiac, neurologic, hepatic, renal)

Time frame: From day of inclusion until ICU discharge (until day 90)

Respiratory dysfunction-free days at day 28

days without respiratory dysfunction (respiratory SOFA score\<3)

Time frame: from inclusion to day 28

Renal dysfunction-free days at day 28

days without renal dysfunction (renal SOFA score\<3)

Time frame: from inclusion to day 28

Neurologic dysfunction-free days at day 28

days without neurologic dysfunction (neurologic SOFA score\<3)

Time frame: from inclusion to day 28

Cardiac dysfunction-free days at day 28

days without cardiac dysfunction (cardiac SOFA score\<3)

Time frame: from inclusion to day 28

Hepatic dysfunction-free days at day 28

days without hepatic dysfunction (hepatic SOFA score\<3)

Time frame: From inclusion to day 28

Hematologic dysfunction-free days at day 28

days without hematologic dysfunction (hematologic SOFA score\<3)

Time frame: From inclusion to day 28

Ventilator-free days at day 28

days without invasive mechanical ventilation

Time frame: From inclusion to day 28

Vasopressors-free days at day 28

days without vasopressors treatment

Time frame: From inclusion to day 28

Dialysis-free days at day 28

days without dialysis treatment

Time frame: From inclusion to day 28

Duration of antibiotic treatment during ICU stay

Duration between the first antibiotic initiation and the last antibiotic stop

Time frame: From day of admission to ICU until day 90

Number of antibiotics de-escalated

Number of antibiotics de-escalated in each arm

Time frame: From inclusion to ICU discharge until day 90

Number of antifungal de-escalated

Number of antifungal de-escalated in each arm

Time frame: From inclusion to ICU discharge until day 90

Number of antiviral de-escalated

Number of antiviral de-escalated in each arm

Time frame: From inclusion to ICU discharge until day 90

Antibiotic-free days at day 28

days without antibiotic treatment

Time frame: From inclusion to day 28

Antibiotic-free days during ICU stay

days without antibiotic treatment

Time frame: From admission to ICU to ICU discharge until day 90

Antibiotic-free days during hospital stay

Days without antibiotic treatment

Time frame: From admission to ICU to hospital discharge until day 90

Antibiotic-free days at day 90

Days without antibiotic treatment

Time frame: From admission to ICU to day 90

Antifungal-free days at day 28

Days without antifungal treatment

Time frame: From admission to ICU to day 28

Antiviral-free days at day 28

Days without antiviral treatment

Time frame: From admission to ICU to day 28

Antifungal-free days during ICU stay

Days without antifungal treatment

Time frame: From admission to ICU to ICU discharge until day 90

Antiviral-free days during ICU stay

Days without antiviral treatment

Time frame: From admission to ICU to ICU discharge until day 90

Antiviral-free days during hospital stay

Days without antiviral treatment

Time frame: From admission to ICU to hospital discharge until day 90

Antifungal-free days during hospital stay

Days without antifungal treatment

Time frame: From admission to ICU to hospital discharge until day 90

Antifungal-free days at day 90

Days without antifungal treatment

Time frame: From admission to ICU to day 90

Antiviral-free days at day 90

Days without antiviral treatment

Time frame: From admission to ICU to day 90

Number of days of exposure to each antibiotic per 1000 inpatient days

For the entire cohort:(number of antibiotic days / number of ICU days)\*1000

Time frame: From admission to ICU to ICU discharge until day 90

Number of days of exposure to each antifungal per 1000 inpatient days

For the entire cohort:(number of antifungal days / number of ICU days)\*1000

Time frame: From admission to ICU to ICU discharge until day 90

Number of days of exposure to each antiviral per 1000 inpatient days

For the entire cohort:(number of antiviral days / number of ICU days)\*1000

Time frame: From admission to ICU to ICU discharge until day 90

Adverse events

Adverse events assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0

Time frame: From inclusion to ICU discharge until day 90

Compliance to de-escalation strategy

number of patients de-escalated/number of patients included in the experimental arm

Time frame: From inclusion to ICU discharge until day 90

Compliance to the continuation strategy

number of patients not de-escalated/number of patients included in the continuation group

Time frame: From inclusion to ICU discharge until day 90

Percentage of emerging multidrug-resistant bacteria

Percentage of emerging multidrug-resistant bacteria isolated from specimen taken for routine microbiological assessments

Time frame: From inclusion until day 28

Cost of antibiotic treatment

Time frame: From inclusion to ICU discharge until day 90

Patients presenting with bacterial pneumoniae,

Time frame: From inclusion to ICU discharge until day 90

Patients presenting with Intra-abdominal infection.

Time frame: From inclusion to ICU discharge until day 90

Patients presenting with bacteraemia

Time frame: From inclusion to ICU discharge until day 90

Number of patients in the de-escalation group without de-escalation

Time frame: From inclusion to ICU discharge until day 90

Rate of new infectious episode requiring a new antibiotic treatment

Time frame: From inclusion to ICU discharge until day 90

Rate of patients requiring an escalation after de-escalation

Time frame: From inclusion to ICU discharge until day 90

Rate of recovery from infection

Time frame: From inclusion to ICU discharge until day 90

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes