INHALE: Potential of Molecular Diagnostics for Hospital-Acquired and Ventilator-Associated Pneumonia in UK Critical Care

Aims and Objectives To define, across 4 different intensive care units (ICUs), the accuracy of 3 molecular diagnostic systems claiming to rapidly identify pathogens and their resistance genes in respiratory specimens from patients with hospital-acquired and ventilator-associated pneumonia (HAP/VAP) Based on (1) above, to select the best-performing test and to conduct a RCT, comparing clinical outcomes and antibiotic utilisation in patients whose treatment is guided by the test vs. those managed conventionally with empirical treatment refined by microbiological culture. To measure clinicians willingness to adopt molecular diagnostics and treat patients based on their results; To determine whether the outcomes justify the cost. Background and rationale HAP and VAP are frequent and life threatening in ICUs. Antibiotics are administered empirically and refined based upon microbiology results 48–72h later. This is unsatisfactory because: (1) laboratories fail to isolate pathogens from ca. 50% patients; (2) some patients have pathogens resistant to empirical therapy, increasing mortality; (3) many more patients are over-treated because they might have a resistant pathogen. CMO s Report highlights the potential for molecular diagnostics to identify pathogens and resistances in hours – allowing earlier refinement of antibiotic therapy, potentially benefitting both patients and antibiotic stewardship. Research plan Three PCR-based pathogen- and resistance- detection systems (Curetis Unyvero, Biofire Filmarray and Mobidiag GeneSpress) are available for HAP/VAP. We will first (WP1) compare their performance across four widely different ICUs (London tertiary, high resistance; Norwich tertiary, low resistance; London Children s; London private, with frequent imported resistance). We will include routine samples from ICU patients with HAP/VAP and about to receive antimicrobials, comparing System results with Gold Standard conventional microbiology. The study requires at least 868 samples to estimate sensitivity / specificity at ± 2%; we will test 1000 samples over 18 months, a feasible target. In parallel (WP2), we will survey HAP/VAP patient characteristics, bacterial epidemiology, and resistance rates at the four ICUs; also prescribing patterns and clinical outcomes. Based on these results, and on cost and convenience factors, we will select the best-performing system to include in a RCT run across the four ICUs (WP3). HAP/VAP patients will be randomised 1:1 to treatment guided by the system (one dose of empirical antibiotics followed by drug based on the pathogen and resistance genes identified) or to standard care (empirical antibiotics for 48-72h followed by culture-directed therapy). The primary outcome will be "Non-inferiority in clinical cure (at 21 days) with improvement in antimicrobial stewardship". This composite outcome is driven by the UK Government s 5-Year Antimicrobial Resistance Strategy target whilst ensuring our approach does not harm patients. Stewardship success will be defined as patients on effective, and (for far as possible) narrow-spectrum antimicrobials within 24 h of diagnosis. Secondary outcomes will include ICU length of stay and ventilator-free days; mortality; evolution of relevant clinical scores; % patients on appropriate/inappropriate/broad-spectrum/narrow-spectrum antibiotics at 24 and 72h, antibiotic-related adverse events and incidence of secondary infections. Statistical analyses will follow a predefined plan. Throughout, the Norwich Clinical Trials Unit will provide support. A qualitative behavioural study (WP4) at the four ICUs will identify clinicians beliefs about molecular diagnostics, empirical prescribing and logistic factors influencing adoption. Before the RCT, Process Mapping and Root-Cause Analysis will inform materials to support adoption within the RCT. During the RCT it will assess fidelity and create new knowledge to optimise ado