Title: INHALE: Potential of Molecular Diagnostics for Hospital-Acquired and Ventilator-Associated Pneumonia in UK Critical Care
Funder: Department of Health and Social Care

Abstract: 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&ndash;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 &ndash; 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 &plusmn; 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 &ldquo;Non-inferiority in clinical cure (at 21 days) with improvement in antimicrobial stewardship&rdquo;. 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 adoption after the trial, supplemented by a case-scenario study of UK ICU leads. A cost-effectiveness study (WP5) will be run from an NHS perspective, examining the incremental test cost per additional patient receiving appropriate and proportionate antibiotics at 24 h, and whether this is offset by savings in treatment costs and duration of ICU stay. Further, we will construct a decision tree economic model to investigate the impact of the diagnostic test, allowing testing of study data and assumptions. Projected outputs & dissemination plans Key outputs will include, (a) scientific papers (one major paper per WP) (b) a treatment algorithm, as step-up/step-down antibiotic guidance predicated on the pathogens and resistance genes found, and (c) presentations at specialist national and international conferences. Public and professionals will be engaged via a website, brochure and press releases. Specialist dissemination workshops in INHALE s final months will disseminate findings to key stakeholders. NHS managers involved will explore possible benefits and feasibility of nationwide adoption. Key decision-making bodies will be engaged through PHE, ARHAI and NHSE structures. Benefits to patients and the NHS The work is vital because the current, often unnecessary, use of broad-spectrum empirical antibiotics is becoming unsustainable, with resistance accumulating faster than new agents are developed. Early step-down to narrow-spectrum antibiotics, guided by rapid recognition of pathogens and their resistances, provides the most realistic mitigation from this relentless erosion. It is nevertheless essential to test elements of risk in the strategy: namely: Will it work?; Is it logistically feasible?; Will physicians accept it?; Is it cost effective?

Lay abstract: Severely-ill hospital patients often develop pneumonia. To treat this effectively, with the right antibiotic, doctors must know the type of bacteria responsible. Secretions from the lungs and respiratory tract are sent to the laboratory to identify the bacteria and to see which antibiotics kill them. Testing takes 2 days or more, and a so-called &ldquo;broad-spectrum antibiotic&rdquo;, capable of killing many different types of bacteria, is given until the results become available. This isn t ideal. Some patients with pneumonia symptoms don t have bacterial infection. Some have highly resistant bacteria, not killed even by broad-spectrum antibiotics; this doubles the risk of death in severe pneumonia. Broad-spectrum antibiotics promote undesirable side effects too, for example C diff diarrhoea, and can increase resistance, making future infections harder to treat. Many pneumonia patients have very susceptible bacteria and are over-treated until the lab result becomes available. New molecular diagnostic tests, which work by identifying bacteria directly from their genetic material present in a clinical sample, claim to identify bacteria and their resistances within 1-4 hours. This would allow treatments to be optimised earlier, benefitting individual patients and allowing the most potent antibiotics to be reserved for those who really need them. However, we don t know how well these tests compare with current methods, whether they find all the important types of resistant bacteria, whether they represent value for money, or whether doctors will accept the results and use the tests. INHALE addresses these important questions. Firstly, we will test samples from patients with suspected pneumonia in the intensive care units of four hospitals, carefully chosen to represent a cross-section of healthcare in the UK. We will test three new molecular diagnostic systems; see how accurate they are and see how easy they are to use. At this stage these systems won t be used to guide treatment, only to select the best one for the next stage of the study. This system will then be compared to conventional treatment in a clinical trial, with half the patients receiving treatment guided by the molecular diagnostic whilst the other half receive treatment guided by current practice. Clinical outcomes and the quality of antibiotic choice will be compared across the two groups, asking whether the molecular test allows equal or better outcomes with less use of the broad-spectrum antibiotics. We ll review whether savings from treatment and better use of antibiotics offset the extra cost of the test. Finally, we will investigate how critical-care doctors, whose buy-in is essential, receive this new technology. Will they act upon the results, both when these say the patient has very resistant bacteria, demanding an unconventional antibiotic, and when they say that the patient has susceptible bacteria, permitting use of a simpler, older drug?

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION