Similar outcomes in patients with ventilator-associated pneumonia (VAP) suggest that antibiotics selected by Gram staining were noninferior to those based on guidelines and also significantly decreased the use of broad-spectrum antibiotics in this patient population.
The findings were published Friday, April 8, in JAMA Network Open. The multicenter, open-label, noninferiority, randomized trial, Gram Stain-Guided Antibiotics Choice for VAP (GRACE-VAP), was conducted for 2 years in intensive care units (ICUs) of a dozen tertiary referral hospitals in Japan, from April 1, 2018, through May 31, 2020.
The authors note in their paper that the 2016 clinical practice guidelines for VAP published by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society recommend antibiotic agents active against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa as an empirical treatment. Adherence to these guidelines may lead to overuse of broad-spectrum antibiotic agents and could be associated with the accelerated emergence of antimicrobial-resistant organisms, the authors postulate.
The study sought to answer the question: Can Gram staining be used as an alternative to established guidelines to direct antibiotic use — thereby curbing the use of broad-spectrum antibiotics — without compromising patient safety and clinical outcomes?
A total of 206 patients, with a mean age of 69, took part in the study. The same number of patients were assigned to each arm. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included.
Investigators reported that 79 patients (76.7%) responded to antibiotics in the Gram stain-guided group and 74 (71.8%) responded in the guideline-based group (risk difference, 0.05; 95% confidence interval [CI], -0.07 to 0.17; P < .001, for noninferiority).
There was a decrease in antipseudomonal agent use comparing the Gram stain-guided group with the guideline-based group (30.1%; 95% CI, 21.5% to 39.9%; P < .001). There also was a decrease in anti-MRSA agents in the Gram stain-guided group compared with the guideline-based group (38.8%; 95% CI, 29.4% to 48.9%; P < .001).
The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group vs 17.5% (n = 18) in the guideline-based group. Escalation of antibiotics according to culture results was performed in seven patients (6.8%) in the Gram stain-guided group and in one patient (1.0%) in the guideline-based group. No significant differences in study arms were observed on other measures, such as ICU-free days, ventilator-free days, and adverse events.
The authors concluded that their findings support the use of Gram staining as a strategy to manage infectious diseases and contain the development of multidrug resistant organisms (MDROs) in the setting of critical care.
“In the GRACE-VAP trial, we used the time-honored Gram stain technique as part of the daily management of infectious diseases. We believe that the trial results are acceptable and have the potential to change the strategy of antibiotic choice worldwide,” the authors wrote.
Benjamin D. Galvan MLS(ASCP), CIC, an infection preventionist with a professional background in clinical microbiology, noted that Gram staining is more accessible and significantly less costly than the rapid polymerase chain reaction testing certain institutions use to rapidly identify MDROs to help tailor therapy.
But one of the pitfalls with relying on Gram stain collection to guide antibiotic use is that it is operator-dependent and subject to extrinsic factors, like prior antibiotic use, he pointed out.
“If it is not collected, set up, and read properly, the Gram stain is not going to necessarily be reliable” said Galvan, also a member of the national communications committee for the Association for Professionals in Infection Control and Epidemiology. He added that the sample in the study was not representative of institutions dealing with elevated rates of multidrug resistance.
“Even from their own results, they were looking at hospitals that have a low rate of multidrug resistance,” Galvan said. “It was not clear if MRSA or just Staphylococcus aureus was identified in significant quantities upon review, and they recognized a lower-than-expected number of isolates of Pseudomonas aeruginosa.”
Establishing antibiotic treatment from the results of Gram-stain collection may not be sufficiently comprehensive, Galvan said.
“Generally speaking, basing it (antibiotic therapy) solely off of a Gram stain is not looking at the whole picture,” said Galvan, noting that the 2016 IDSA guidelines call for an evaluation of the clinical status, including risk, of the individual patient, as well as locally available antibiotic resistance data.
Moreover, the evidence-based IDSA guidelines are in place to help address the issue of antimicrobial resistance trends, already recommending tailoring empiric antibiotic therapy based upon the levels of resistance in the local population, according to Galvan.
While the study suggests that this Gram-stain-driven tailoring of empiric antibiotic therapy may be noninferior to current guidelines in healthcare settings with low MDRO rates, its utility may not be suitable in hospitals that are already dealing with high rates of MDROs, such as Pseudomonas aeruginosa and Acinetobacter baumannii, or severe clinical cases of VAP, Galvan explained.
JAMA Network Open. Published online April 8, 2022. Full text
Corresponding author Yamakawa reported receiving grants from Asahi Kasei Pharma and grants from Nihon Pharmaceutical outside the submitted work. Benjamin Galvan disclosed no relevant financial relationships.