INHALE WP3 Study - The Impact of Rapid PCR on ICU Antibiotic Stewardship and Clinical Outcomes

Background Introduction

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are common infections in intensive care unit (ICU) patients, with an incidence rate between 5% to 40%, and are associated with high morbidity and increased healthcare costs. The mortality rate for HAP and VAP is estimated to be between 10% to 50%, with the most severe impact on immunocompromised patients. Early effective antibiotic treatment can improve patient outcomes, but conventional microbiological testing usually takes 48 to 72 hours to provide results. Therefore, patients are typically given empirical broad-spectrum antibiotics, which are adjusted once laboratory data becomes available. However, the use of broad-spectrum antibiotics may lead to the development of antibiotic resistance, further exacerbating public health issues.

In recent years, rapid molecular diagnostic techniques based on polymerase chain reaction (PCR) have shown significant advantages in detecting pathogens and antibiotic resistance genes, surpassing traditional culture methods in speed and sensitivity. Nevertheless, the clinical application effects of these technologies still lack evidence from large-scale, multicenter randomized controlled trials (RCTs). To address this, the INHALE WP3 study was initiated to evaluate the impact of rapid, ICU-based PCR testing on antibiotic stewardship and clinical outcomes in patients with HAP and VAP.

Paper Source

This paper was co-authored by Virve I. Enne, Susan Stirling, Julie A. Barber, and other scholars from multiple hospitals and research institutions in the UK, including University College London, University of East Anglia, Royal Free Hospital, etc. The paper was published in the journal Intensive Care Medicine in 2024, with the DOI: 10.1007/s00134-024-07772-2.

Study Design and Process

INHALE WP3 is a multicenter, open-label, pragmatic randomized controlled trial designed to assess the effectiveness of rapid PCR testing within ICUs. The study included 554 adult and pediatric patients suspected or confirmed to have HAP/VAP, recruited from 14 ICUs (11 adult ICUs and 3 pediatric ICUs) across the UK. The primary objective of the study was to evaluate whether rapid PCR testing could improve antibiotic stewardship within 24 hours and achieve non-inferiority in clinical cure rates at 14 days compared to standard care.

The study was divided into two main steps:

1. Randomization and Intervention
   Patients were randomly assigned to either the intervention group or the control group. The intervention group received rapid PCR testing, with results combined with an antibiotic prescribing algorithm to guide treatment recommendations; the control group received standard care, i.e., antibiotic treatment based on traditional microbiological culture results. The PCR test used the Filmarray Torch pneumonia panel (Biomérieux), with a run time of approximately 70 minutes. Results from the intervention group were immediately provided to the ICU team and adjustments were made according to a localized antibiotic prescribing algorithm. Samples from the control group were frozen and later subjected to the same PCR testing, but these results were not used for clinical decision-making.

2. Primary and Secondary Outcome Assessments
   The primary outcomes of the study included:

   • Superiority in antibiotic stewardship: the proportion of patients receiving antibacterially appropriate and proportionate antibiotic therapy within 24 hours.
     
   • Non-inferiority in clinical cure: the clinical cure rate of pneumonia within 14 days post-randomization, defined as the absence of death, septic shock, recurrence of pneumonia, or other evidence of unresolved infection.
     Secondary outcomes included mortality, ICU length of stay, changes in organ dysfunction scores, etc.

Study Results

The main results of the study are as follows:

1. Superiority in Antibiotic Stewardship
   Within 24 hours, 76.5% (²⁰⁵⁄₂₆₈) of patients in the intervention group received antibacterially appropriate and proportionate antibiotic therapy, compared to 55.9% (¹⁴⁷⁄₂₆₃) in the control group. The absolute improvement in antibiotic stewardship in the intervention group was 21% (95% CI: 13%–28%), indicating that rapid PCR significantly enhanced the precision of antibiotic use.

2. Non-inferiority in Clinical Cure
   At 14 days, the clinical cure rate was 56.7% (¹⁵²⁄₂₆₈) in the intervention group and 64.5% (¹⁷¹⁄₂₆₅) in the control group. The difference between the intervention and control groups was -6% (95% CI: -15%–2%), failing to meet the predefined non-inferiority margin (-13%). This indicates that although rapid PCR improved antibiotic stewardship, it did not demonstrate non-inferiority in terms of clinical cure rates compared to standard care.

3. Secondary Outcomes
   In terms of secondary outcomes, there were small differences between the intervention and control groups in mortality, ICU length of stay, and changes in organ dysfunction scores, with no statistical significance. However, the incidence of antibiotic-associated diarrhea was higher in the intervention group (9.9% vs. 5.5%), potentially related to antibiotic adjustments guided by rapid PCR.

Conclusions and Implications

The INHALE WP3 study demonstrated that the application of rapid PCR testing in ICUs significantly improved antibiotic stewardship, reduced the use of broad-spectrum antibiotics, and enhanced treatment precision. However, the study failed to demonstrate non-inferiority in clinical cure rates, suggesting that despite improvements in antibiotic stewardship, patient clinical outcomes did not significantly improve. This result may be related to various factors, including the complex etiology of pneumonia, insufficient adherence to treatment algorithms, and the impact of the COVID-19 pandemic on study results.

Study Highlights

1. Innovativeness
   INHALE WP3 is the first large-scale, multicenter randomized controlled trial to evaluate the effectiveness of rapid PCR testing in ICUs. The study design is highly pragmatic, closely aligned with clinical practice, providing important references for future similar studies.

2. Significant Improvement in Antibiotic Stewardship
   The study confirmed that rapid PCR testing can significantly enhance the precision of antibiotic use, reduce the use of broad-spectrum antibiotics, thereby helping to mitigate the development of antibiotic resistance.

3. Unmet Expectations in Clinical Cure Rates
   Despite improvements in antibiotic stewardship, clinical cure rates did not meet expectations, indicating the need for further research to optimize the clinical application of rapid PCR and incorporate behavioral interventions to improve treatment outcomes.

Other Valuable Information

The study also found that COVID-19 patients accounted for 33.6% of the entire study population, and these patients had lower clinical cure rates, potentially impacting overall results. Additionally, the study emphasized that in low antibiotic resistance environments, the value of rapid PCR testing for antibiotic resistance genes is limited, but it may hold greater application potential in high-resistance settings.

The INHALE WP3 study provides crucial evidence for the application of rapid PCR in ICUs. Despite unmet expectations in clinical cure rates, its significant improvement in antibiotic stewardship remains of substantial public health importance. Future research should further explore how to optimize the clinical application of rapid PCR and integrate behavioral interventions to achieve better treatment outcomes.