Rapid molecular diagnostics for pathogen identification in hospital-acquired and ventilator-associated pneumonia in critical care: INHALE research programme including RCT

Background: Intensive care unit patients are vulnerable to hospital-acquired and ventilator-associated pneumonias. Immediate antibiotic therapy is warranted. Because: (1) many different bacterial species can be responsible and (2) it takes at least 2 days for conventional microbiological investigation, empirical broad-spectrum agents are given. This creates two hazards. First, these may promote overgrowth of undesirable bacteria in the patient's gut. Second, the pneumonia may involve bacteria resistant to the antibiotic, precipitating failure. An alternative strategy - explored by the INHALE programme - is to use molecular tests to rapidly characterise the pathogen(s), facilitating early tailoring of antimicrobial therapy. Selecting a molecular test to trial in hospital-acquired and ventilator-associated pneumonias: INHALE's work package 1 used routinely collected respiratory samples (n = 652) from intensive care units at 15 hospitals, comparing the organisms found by two multiplex polymerase chain reaction systems (FilmArray and Unyvero) with those from routine culture. The molecular tests found bacteria in more specimens (74.2–60.4% vs. 44.2%) and found them more quickly (70 minutes to 6 hours vs. > 2 days). Diagnostic accuracy performance was similar, but the FilmArray Pneumonia Panel was swifter, more convenient and better supported. Accordingly, it was carried forward to the work package 3 randomised controlled trial. Defining the epidemiology and management of hospital-acquired and ventilator-associated pneumonias: Work package 2 reviewed patient-level data for hospital-acquired/ventilator-associated pneumonias at four intensive care units in England; 142 patients were considered, of whom only 46.5% received appropriate empirical therapy. The cure rate of pneumonia was 62.7%. Enterobacterales, Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae predominate, corresponding with international literature. Compliance with local guidelines varied considerably among sites, as did the guidelines' recommendations. Clinical trial of the effects of rapid microbiology on antibiotic stewardship and clinical cure: Intensive care unit hospital-acquired/ventilator-associated pneumonias patients about to receive new or changed antibiotics were randomised to: (1) a FilmArray Pneumonia Panel test, supported by an algorithm translating its outputs into treatment advice, or (2) 'standard-of-care', with empirical antibiotics based on the hospital's guidelines. Fourteen intensive care units participated, recruiting 545 adults and children over 2 years, with a 4-month-interruption owing to coronavirus disease discovered in 2019. Molecular tests were performed in intensive care unit, obviating transport delays. Two coprimary outcomes were considered. First, the proportion of patients on 'active and proportionate' antibiotics 24 hours after randomisation. This was substantially higher in the intervention arm (76.5% vs. 55.9%). Second, the proportion of patients with clinical cure of pneumonia 14 days post randomisation. This was marginally inferior in the intervention arm (56.4% vs. 64.7%), with the 95% confidence interval for the difference failing to exclude a preset 13% non-inferiority margin. Among secondary outcomes, there were slightly more deaths in the intervention arm, and slower improvement of clinical [sequential organ failure assessment and paediatric logistic organ dysfunction (PELOD)] scores, without statistical significance. Various interpretations are possible. Worse clinical outcomes may represent chance, given the borderline statistics. Alternatively, hospital pneumonia may, in its early stages, involve mixed bacteria, leading to a benefit from broad-spectrum therapy, which was more often given in the control arm. Behavioural studies: INHALE work package 4 used mixed-method designs to examine prescribers' perceptions of the Pneumonia Panel and its use. Although most recognised the value of rapid results and the importance of antibiotic stewardship, Pneumonia Panel results had a limited impact on prescribing behaviour. Many clinicians were reluctant to avoid or stop initial broad-spectrum in response to test results. The decision to prescribe and maintain broad-spectrum antibiotics often represented an attempt to 'err on the side of caution' to protect the patient (and clinician), where the proximal need to protect was more imperative than the more distal threat of antibiotic resistance. Costs and cost-effectiveness of rapid molecular microbiology for hospital-acquired and ventilator-associated pneumonias: The additional cost of the Pneumonia Panel (£198) represents a very small component of total intensive care unit costs and are typically below 2% of total costs per intensive care unit patient (base case). We found a reduction in total costs with patients in the intervention arm averaging £33148 and patients in the control arm averaging £40951. However, it remains unclear how this arises. There was evidence of the Pneumonia Panel being cost-effective in terms of stewardship, but not for clinical cure; consequently, we cannot conclude an economic advantage for the Pneumonia Panel. However, this does not take account of the potential benefit of improved stewardship in terms of reduced antimicrobial resistance. Limitations: The multiplex systems compared in work package 1 are subject to repeated updating, meaning that the better system might change with time. Both work package 1 and work package 3 were limited by the low prevalence of antibiotic resistance in England, precluding rigorous evaluation of resistance gene detection. Last, and critically, the coronavirus disease pandemic substantially changed the types of patients recruited. Conclusions and future work: Overall, INHALE demonstrates the potential of molecular testing to swiftly detect pathogens in the respiratory secretions of intensive care unit pneumonia patients and shows that these data can influence prescribing. What remains elusive, needing further work, is translating the results into optimal therapy and improved clinical outcomes.