A Phase 4 interventional study of Gram stain-guided antibiotic choice and Guidelines-based antibiotics choice in Ventilator Associated Pneumonia, sponsored by Osaka General Medical Center. Completed at 12 sites in Japan. Open to participants aged 15 Years and older. Per ClinicalTrials.gov, last updated 2022-09-21.
Sponsored by Osaka General Medical Center · Phase 4, Interventional, and Treatment
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.
2,044 studies on the registry are indexed under Pneumonia; 283 are open to participants now.
This study's enrollment of 206 is above the median of 106 across 1,247 interventional studies indexed under Pneumonia.
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Exclusion Criteria:
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
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
The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics.
Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines
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.
Time frame: up to 22 days
Select of anti-pseudomonal agents as initial antibiotic therapies
Time frame: on day 1
Select of anti-MRSA agents as initial antibiotic therapies
Time frame: 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.
Time frame: on day 1
28-day mortality
Time frame: up to 28 days
ICU-free days
Time frame: up to 28 days
Ventilator-free days
Time frame: up to 28 days
Duration of antibiotic therapies
Time frame: 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.
Time frame: up to 28 days
Adverse events related to antibiotics
renal impairment, thrombocytopenia, diarrhoea, Clostridium difficile infection, skin rash, and seizure
Time frame: 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
Time frame: 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).
Time frame: up to 14 days
Renal function
The investigators evaluate whether participants are performed a renal replacement therapy.
Time frame: up to 14 days
Plan to share: Undecided
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Osaka General Medical Center