Immediate Versus Substantiated Antibiotic Therapy in Suspected Non-Severe Ventilator-Associated Pneumonia

Nantes University Hospital686 enrolled

Overview

Ventilator-associated pneumonia is the leading nosocomial infection in the intensive care units, and is associated with prolonged mechanical ventilation and overuse of antibiotics. Initiating antibiotic therapy immediately after bacteriological sampling (immediate strategy) may expose uninfected patients to unnecessary treatment, while waiting for bacteriological confirmation (conservative strategy) may delay ventilator-associated pneumonia in infected patients. The decision to start antibiotic therapy for ventilator-associated pneumonia takes three points into account: diagnostic probability, the risks to the patient if Antibiotic Therapy is delayed, and the risk of selection of resistant bacteria. Diagnostic probability is limited, given the subjective and non-specific nature of the diagnostic criteria, and only 30-50% of suspected cases are confirmed bacteriologically (whereas samples are only taken when the pre-test probability is sufficient). The risks associated with delayed antibiotic therapy are unknown, as few observational studies have directly assessed the impact of the timing of Antibiotic Therapy initiation on outcome (frequent confusion between delayed and inappropriate Antibiotic Therapy). Iregui et al. found that delaying Antibiotic Therapy by more than 24 hours was associated with higher mortality. However, more recent before-and-after studies have shown that the conservative strategy was associated with lower mortality, more frequently appropriate initial Antibiotic Therapy and shorter duration of Antibiotic Therapy. Similarly, in a recent before-and-after study by our team, initiating antibiotic therapy only upon microbiological confirmation of ventilator-associated pneumonia without septic shock or severe acute respiratory distress syndrome was not associated with an increase in ventilation time, length of stay or excess mortality at D28; but was associated with antibiotic therapy that was more often appropriate (DELAVAP, MARTIN et al, Annals of Intensive Care, 2024). Finally, the recent multicenter TARPP pilot study in surgical intensive care suggests that antibiotic therapy initiated on the basis of microbiological data in patients with suspected ventilator-associated pneumonia not requiring vasopressor support is not associated with a poorer outcome than immediate antibiotic therapy without documentation (the only randomized study on this subject). Antibiotic Therapy for suspected ventilator-associated pneumonia that is not subsequently confirmed is an unnecessary use of antibiotics and carries a risk of selection of resistant bacteria, with adverse effects on public health. It has been reported that a conservative Antibiotic Therapy prescription strategy for intensive care units -acquired infections reduces Antibiotic Therapy use and the incidence of acquired β-lactamase-producing Enterobacteriaceae infections. Overall, in patients with suspected ventilator-associated pneumonia but no signs of clinical severity, given the uncertainty about attributable mortality and concerns about bacterial resistance, the evaluation of the conservative Antibiotic Therapy strategy is reasonable. Some French intensive care units already delay Antibiotic Therapy until confirmation of ventilator-associated pneumonia, except in patients with severe hypoxemia or the need for vasopressor support.

Interventions

control groupPROCEDURE

immediate empiric Antibiotic Therapy (started within 1 hour after randomization) with antibiotic(s) chosen by the bedside physician based on time of ventilator-associated pneumoniaoccurrence, risk of antimicrobial resistance, local ecology, and local protocol. If the respiratory samples are negative, Antibiotic Therapy will be stopped. If ventilator-associated pneumonia is confirmed by positive samples, Antibiotic Therapy active against the recovered bacterial specie(s) will be given for a total of 7 days.

Conservative strategyPROCEDURE

No Antibiotic Therapy until receipt of the respiratory sample culture and/or polymerase chain reaction results. If these results are negative, no Antibiotic Therapy is given. If they are positive (confirmed ventilator-associated pneumonia), Antibiotic Therapy is started as appropriate for the bacterial specie(s) detected by culture and/or polymerase chain reaction, without considering gram-stain results and without waiting for antimicrobial susceptibility testing results, and continued for a total of 7 days of Antibiotic Therapy active against the identified bacterial specie(s).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Invasive mechanical ventilation for longer than 48 hours * Respiratory sample collection taken less than two hours ago (at physician discretion, according to local protocol) for a first episode of suspected ventilator-associated pneumonia (meeting the following prespecified criteria) : * new or changing chest X-ray infiltrates * plus at least two of the following: * body temperature ≥38.5°C or ≤35.5°C, * blood leukocyte count \>12 000/µL or \<4000/µL, * purulent tracheobronchial aspirate. * Age ≥18 years * Informed consent from the patient or next of kin to participation in the trial, or emergency procedure if no next of kin is available * Patients affiliated to a social security system Non-inclusion Criteria: * Criteria for severe ventilator-associated pneumonia defined as: * Vasopressor therapy for onset of septic shock around the time of ventilator-associated pneumonia suspicion * Onset or severe worsening of hypoxemia (PaO2/FiO2\<150 with 60% FiO2 and 10 mm H2O peak expiratory pressure, or patient on veno-venous extracorporeal membrane oxygenation) * Immunosuppression defined as : * leukocytes \<1G/L or neutrophils \<0,5 G/L * within the last 3 months * hematopoietic stem-cell transplant or organ transplant with chronic immunosuppressant therapy * HIV infection with CD4\<50/mm3 * chronic corticosteroid use (\>0.5 mg/kg day for at least one month within the last three months). * Patient already on Antibiotic Therapy of predicted duration ≥4 weeks (endocarditis, spondylodiscitis, abscess...) * Previous ventilator-associated pneumonia suspicion with sampling and/or Antibiotic Therapy for suspected ventilator-associated pneumonia * Previous inclusion in the trial * Patient included in an interventional study on ventilator-associated pneumonia management with the same primary endpoint. * Pregnancy, recent delivery, or breastfeeding * Correctional facility inmate, adult under guardianship * Patient under legal protection * Life expectancy less than 48 hours and/or decision to withhold and/or withdraw life-sustaining therapies * Organ donor reanimation

Outcomes

Primary Outcomes

Proportion of patients who die whithin 28 days or are still on invasive mechanical ventilation on day 28

To assess, in intensive care units patients with suspected nonsevere ventilator-associated pneumonia (no septic shock or severe acute respiratory distress syndrome), whether delaying antibiotic therapy until ventilator-associated pneumonia is confirmed by a positive respiratory-sample culture and/or polymerase chain reaction test (conservative strategy) neither increases day-28 mortality nor prolongs invasive mechanical ventilation , compared to antibiotic therapy initiation immediately after sampling (immediate strategy).

Time frame: From day 0 to day 28

Secondary Outcomes

Sequential Organ Failure Assessment (SOFA) score

Daily Sequential Organ Failure Assessment (SOFA)

Time frame: From day 0 to day 7

Modified clinical pulmonary infection score (mCPIS)

Daily mcPIS

Time frame: From day 0 to day 7

Clinical cure

Clinical cure is defined as the combination of resolution of signs and symptoms present at enrollment, and improvement or lack of progression of radiological signs

Time frame: day 7

Invasive mechanical ventilation duration

Days of invasive mechanical ventilation

Time frame: From day 0 to day 28

Ventilator free days

Time frame: From day 0 to day 28

Use of vasopressors

Days on vasopressors

Time frame: From day 0 to day 28

Use of renal replacement therapy

Days on renal replacement therapy

Time frame: From day 0 to day 28

Mortality rates

ICU discharge mortality rates

Time frame: ICU discharge, an average of 10 days

Mortality rates

Mortality rates at day 28

Time frame: day 28

Mortality rates

Mortality rates at day 90

Time frame: day 90

Mortality rates

Mortality rates at hospital discharge

Time frame: Hospital discharge, an average of 20 days

ICU stay lenghts

ICU stay lenghts (days)

Time frame: From day 0 until the day of discharge from ICU, an average of 10 days

Hospital stay lenghts

Hospital stay lenghts (days)

Time frame: From day 0 until the day of discharge from Hospital, an average of 20 days

Incidence of ventilator associated pneumonia related abscess

Time frame: From day 0 until the day of discharge from ICU, an average of 10 days

Incidence of ventilator associated pneumonia related bacteria

Time frame: From day 0 until the day of discharge from ICU, an average of 10 days

Incidence and timing of subsequent ventilator associated pneumonia during the hospital stay

Incidence and timing of subsequent ventilator associated pneumonia during the hospital stay: relapse, recurrence, superinfection, ventilator associated pneumonia occurrence after a suspected but refuted ventilator associated pneumonia episode; recurrence is defined as improvements in manifestations (fever, secretions, vasopressor needs, inflammatory biomarkers, and chest radiograph infiltrates) after 7 days' treatment with at least ne antibiotic active on all documented bacteria, followed by the return or worsening of these manifestations with a new respiratory sample (culture, with or without PCR) positive for at least one bacterial species in significant concentrations; the same scenario with a respiratory sample positive for at least one of the initial causative bacteria defined relapse; no improvement in manifestations after 7 days' active treatment with a respiratory sample positive for at least one of the initial causative bacteria defined superinfection.

Time frame: From day 0 until the day of discharge from Hospital, an average of 20 days

Incidence of noscomial infections between randomisation and hospital discharge

Nosocomial infections including ventilator asssociated pneumonia, nosocomial pneumonia, bacteremia, catheter-related bloodstream infection, urinary-tract infection, soft-tissue infection, C. difficile infection, and other infections

Time frame: From day 0 until the day of discharge from Hospital, an average of 20 days

Incidence of in-hospital nosocomial infections by multiresistant bacteria (MRB)

Defined as any of the following: methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant Enterococcus (VRE), extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-e), carbapenemase-producing Enterobacterales (CPE), and imipenem-resistant Acinetobacter baumannii (IRAB).

Time frame: From day 0 until the day of discharge from Hospital, an average of 20 days

Incidences of allergies and of diarrhea

Time frame: From day 0 until the day of discharge from Hospital, an average of 20 days

Antibiotic-free days

Time frame: day 10

Number of antibotic therapy days by day 28

computed as days of therapy (DOT), defined as the number of days on AT, with each day multiplied by the number of individual antimicrobial agents given on that day, irrespective of the number of doses given.

Time frame: day 28

Broad-spectrum days of therapy (DOT) by day 28

(ceftazidime, piperacillin/tazobactam, cefepime, fluoroquinolones, carbapenems, or new AT for multidrug-resistant Gram-negative bacilli) (number of days on broad-spectrum AT multiplied by the number of individual antimicrobial agents given on each of those days, irrespective of the number of doses given)

Time frame: day 28

Carbapenom days of therapy (DOT) by day 28

Carbapenem DOT by day 28 (number of calendar days during which the patient received at least one carbapenem dose multiplied by the number of individual antimicrobial agents given on each of those days, until day 28, irrespective of the number of doses given).

Time frame: day 28

Ventilator associated pneumonia antibiotic therapy

Descriptive data : dual therapy, median time from respiratory sampling to AT, duration, de-escalation (defined as empirical AT stopped or number of empirical antimicrobials decreased or spectrum of empirical AT narrowed, based on AST results)

Time frame: From day 0 to day 28

Descriptive antibiotic therapy data

Ventilator associated pneumonia antibiotic therapy: antimicrobial(s), dual therapy, median time from respiratory sampling to antibiotic therapy, duration, de-escalation (defined as empirical AT stopped or number of empirical antimicrobials decreased or spectrum of empirical antibiotic therapy narrowed, based on AST results) , antibiotic therapy for reasons other than suspected VAP: antimicrobial, duration, reason

Time frame: From day 0 to day 28

Descriptive bacteriological data

gram stain, organisms recovered (cultured and/or identified by PCR), and antimicrobial resistance profiles

Time frame: From day 0 to day 28

Descriptive clinical, laboratory and radiological data 48 hours before ventilator associated pneumonia suspicion

Time frame: 48 hours before ventilator asociated pneumonia suspicion

Proportion of patients with confirmed ventilator associated pneumonia

Time frame: From day 0 to day 28

Number of patients given active/inactive/unnecessary antibiotic therapy on day 0 and on the day of antibiotic therapy initiation

Number of patients given active/inactive/unnecessary antibiotic therapy on day 0 and on the day of antibiotic therapy initiation (with active defined as at least one antimicrobial agent active against each bacterial species isolated from respiratory samples in concentrations greater than prespecified thresholds, based on AST; inactive defined as not meeting criteria for active AT; and unnecessary defined as antibiotic therapy given before sample results with these being negative)

Time frame: Day 0 and on the day of antibiotic therapy initiation, an average of 1 day

Number of patients with suitable antibotic therapy (defined as active antibiotic therapy or spared antibiotic therapy as defined below) on day 0 and on the day of antibiotic therapy initiation in the conservative strategy arm

* Number of patients given substantiated antibotic therapy defined as started upon receipt of positive respiratory-sample culture and/or PCR test results * Number of patients given rescue antibotic therapy defined as started, in a conservative group patient, after sampling but before culture and/or PCR results, due to the development of ventilator associated pneumonia severity criteria (shock or severe ARDS) * Number of patients spared antibotic therapy for the suspected ventilator associated pneumonia episode, that is, not given antibotic therapy after sampling and having negative respiratory-sample results

Time frame: Day 0 and on the day of antibiotic therapy initiation, until discharge from intensive care unit or up to 28 days

Incremental cost-utility ratio (ICUR)

The incremental cost-utility ratio (ICUR, cost per quality-adjusted life year \[QALY\] gained) of the two strategies will be computed from a collective perspective and with a 90-day time horizon then compared between the two groups.

Time frame: day 90

Immediate Versus Substantiated Antibiotic Therapy in Suspected Non-Severe Ventilator-Associated Pneumonia

Overview

Conditions

Interventions

Eligibility

Locations (41)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts