GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial

Study Overview
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Brief Summary
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Background: Optimising the use of antibiotic agents is a pressing challenge to overcoming the rapid emergence and spread of multidrug-resistant pathogens in intensive care units (ICUs). Although Gram staining may possibly provide immediate information for predicting pathogenic bacteria, Gram stain-guided initial antibiotic treatment is not well established in the ICU setting. The investigators planned the GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial to investigate whether Gram staining can safely restrict the use of broad-spectrum antibiotics in patients with ventilator-associated pneumonia (VAP), which is one of the most common hospital-acquired infections in ICUs. Methods/Design: The GRACE-VAP trial is a multicenter, randomised, open-label parallel-group trial to assess the non-inferiority of Gram stain-guided initial antibiotic treatment to guidelines-based initial antibiotic treatment for the primary endpoint of clinical cure rate in patients with VAP. Secondary endpoints include the coverage rates of initial antibiotic therapies, the selected rates of anti-pseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies, 28-day all-cause mortality, ICU-free days, ventilator-free days, and adverse events. Participants are randomly assigned to receive Gram stain-guided treatment or guidelines-based treatment at a ratio of 1:1. In the Gram stain group, results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. In the guidelines group, the combination of an anti-pseudomonal agent and anti-MRSA agent are administered. A total sample size of 200 was estimated to provide a power of 80% with a 1-sided alpha level of 2.5% and a non-inferiority margin of 20%, considering 10% non-evaluable participants. Discussion: The GRACE-VAP trial is expected reveal whether Gram staining can reduce the use of broad-spectrum antibiotics without impairing patient outcomes and thereby provide evidence for an antibiotics selection strategy in patients with VAP.

Official Title
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GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial

Conditions
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Ventilator Associated Pneumonia

Intervention / Treatment
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* Drug: Gram stain-guided antibiotic choice
* Drug: Guidelines-based antibiotics choice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing mechanical ventilation in the ICU Patients undergoing mechanical ventilation for at least 48 hours Patients diagnosed as having VAP, which is defined by a modified clinical pulmonary infection score of 5 or more Exclusion Criteria: Patients having an allergy to study medications Pregnant patients Patients discharged from ICU Patients diagnosed as having heart failure or atelectasis Patients administered antibiotics for more than 24 hours when they meet the inclusion criteria Patients declined to provide full life support Patients judged as inappropriate at the discretion of the study physician.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gram stain-guided therapy group<br>The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. The results of the Gram stains are categorised as Gram-positive cocci (GPC) chains, GPC clusters, Gram-positive bacilli (GPB), Gram-negative rods (GNR), or a combination of these. A non-pseudomonal beta-lactam antibiotic is selected when the Gram stain of the endotracheal aspirate shows only GPC chains and/or GPB. An anti-MRSA agent is selected when the Gram stain results show GPC clusters without GNR. An anti-pseudomonal agent is selected when the Gram stain results show GNR without GPC clusters. The combination of an anti-pseudomonal agent and an anti-MRSA agent is selected when the Gram stain results show both GPC clusters and GNR. | Drug: Gram stain-guided antibiotic choice<br>* The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics.<br>|
| Active Comparator: Guidelines-based therapy group<br>Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to the Infectious Disease Society of America and the American Thoracic Society (IDSA/ATS) guidelines because 47.7% of S. aureus isolates are MRSA in Japanese ICUs | Drug: Guidelines-based antibiotics choice<br>* Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical cure of VAP | Cure is defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings at the end of therapy (EOT), and resolution of signs and symptoms of pneumonia at the follow-up/test of cure visit (FU/TOC) conducted 7 days after EOT. Failure is defined as administration of study medication for 15 days or more, progression of radiological signs of pneumonia at EOT, or relapsed pneumonia at FU/TOC. | up to 22 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Select of anti-pseudomonal agents as initial antibiotic therapies |  | on day 1 | 
| Select of anti-MRSA agents as initial antibiotic therapies |  | on day 1 | 
| Coverage of initial antibiotic therapies | Therapies will be considered appropriate when all pathogens isolated with at least 1+ semi-quantitative growth from endotracheal aspirates are covered by the selected antibiotic agents. | on day 1 | 
| 28-day mortality |  | up to 28 days | 
| ICU-free days |  | up to 28 days | 
| Ventilator-free days |  | up to 28 days | 
| Duration of antibiotic therapies |  | up to 28 days | 
| Need of escalation or de-escalation of antibiotic therapies | The investigators evaluate whether antibiotic agents are changed during the treatments of VAP. | up to 28 days | 
| Adverse events related to antibiotics | renal impairment, thrombocytopenia, diarrhoea, Clostridium difficile infection, skin rash, and seizure | up to 7 days after the end of therapy | 
| Inflammation marker | Laboratory marker of inflammation (CRP, PCT) on 2, 4, 6, 8, and 14 days | up to 14 days | 
| Organ failure control | The investigators evaluate Sequential Organ Failure Assessment (SOFA) score on 2, 4, 6, 8, and 14 days. The SOFA score is made of 6 variables, each representing an organ system ( respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). The total SOFA score is calculated by the sum of each 6 variables (range, 0-24). | up to 14 days | 
| Renal function | The investigators evaluate whether participants are performed a renal replacement therapy. | up to 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gram staining, Antimicrobial therapy, Empirical therapy, Nosocomial infection, Mechanical ventilation, Intensive care, Sepsis