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

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.

Study Overview

• Status: Completed
• Conditions: Ventilator Associated Pneumonia
• Intervention / Treatment: Drug: Gram stain-guided antibiotic choice; Drug: Guidelines-based antibiotics choice

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Nagasaki, Japan
    • Nagasaki University Hospital
  • Osaka, Japan
    • Osaka General Medical Center
  • Saga, Japan
    • Saga University Hospital
  • Wakayama, Japan
    • Wakayama Medical University Hospital
  • Aichi
    • Nagoya, Aichi, Japan
      • Chukyo Hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan
      • Sapporo City General Hospital
  • Hyogo
    • Toyooka, Hyogo, Japan, 668-8501
      • Tajima Emergency and Critical Care Medical Center
  • Ibaraki
    • Hitachi, Ibaraki, Japan
      • Hitachi General Hospital
  • Kanagawa
    • Ebina, Kanagawa, Japan
      • Ebina General Hospital
  • Okinawa
    • Nishihara, Okinawa, Japan
      • University of the Ryukyus Hospital
  • Osaka
    • Hirakata, Osaka, Japan
      • Kansai Medical University Hospital
    • Moriguchi, Osaka, Japan
      • Kansai Medical University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Gram stain-guided therapy group; 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; The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics.
ACTIVE_COMPARATOR: Guidelines-based therapy group; 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; Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Osaka General Medical Center
• Collaborators: Wakayama Medical University; Nagasaki University; University of the Ryukyus; Kansai Medical University; Saga University; Chukyo Hospital; Ebina General Hospital; Hitachi General Hospital; Kansai Medical University Medical Center; Tajima Emergency and Critical Care Medical Center; Sapporo City General Hospital
• Investigators: Principal Investigator: Jumpei Yoshimura, MD, Osaka General Medical Center; Study Director: Kazuma Yamakawa, MD, PhD, Osaka General Medical Center; Study Director: Takeshi Morimoto, MD, PhD, MPH, Hyogo College of Medicine

Publications and helpful links

General Publications

• Yoshimura J, Yamakawa K, Ohta Y, Nakamura K, Hashimoto H, Kawada M, Takahashi H, Yamagiwa T, Kodate A, Miyamoto K, Fujimi S, Morimoto T. Effect of Gram Stain-Guided Initial Antibiotic Therapy on Clinical Response in Patients With Ventilator-Associated Pneumonia: The GRACE-VAP Randomized Clinical Trial. JAMA Netw Open. 2022 Apr 1;5(4):e226136. doi: 10.1001/jamanetworkopen.2022.6136. Erratum In: JAMA Netw Open. 2022 Oct 3;5(10):e2240335.
• Yoshimura J, Yamakawa K, Kinoshita T, Ohta Y, Morimoto T. GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial: rationale and study protocol for a randomised controlled trial. Trials. 2018 Nov 8;19(1):614. doi: 10.1186/s13063-018-2971-2.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2018
• Primary Completion (ACTUAL): June 28, 2020
• Study Completion (ACTUAL): June 28, 2020

Study Registration Dates

• First Submitted: March 29, 2018
• First Submitted That Met QC Criteria: April 20, 2018
• First Posted (ACTUAL): April 23, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 19, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Sepsis; Mechanical ventilation; Intensive care; Antimicrobial therapy; Nosocomial infection; Empirical therapy; Gram staining
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: 29-C0707; UMIN000031933 (REGISTRY: University hospital Medical Information Network)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes