Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials

Abstract

Background Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. Methods Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. Results The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation–free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7–10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation–free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). Conclusions We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

Progression of the Radiologic Severity Index is associated with increased mortality and healthcare resource utilisation in acute leukaemia patients with pneumonia

“…An expert panel determined by majority that clinical cure of pneumonia could be defined by stability or improvement in the chest radiograph 7–10 days after the initiation of therapy 8. However, this endpoint would depend heavily on the time of initial imaging.…”

“…However, in the scenario where radiological severity is modest at baseline, progression of radiological severity at a prespecified timepoint as a measure of clinical failure may be a more suitable endpoint, as the FDA has previously suggested 28. The precise timing of when to measure clinical cure or treatment failure is controversial 8 29 30. Various groups have advocated that clinical success or failure be measured at 3, 5, 7 or 10 days after treatment initiation, and this discrepancy likely reflects, in part, on differences in rates of pneumonia progression in different populations.…”

“…A recent international expert panel cited clinical cure, defined as (1) resolution of signs and symptoms of pneumonia and (2) resolution or stability of radiological signs of pneumonia, as the most relevant endpoint in pneumonia trials 8. Radiological progression of pneumonia would therefore constitute a failure to achieve clinical cure,9 10 but tools to precisely quantify radiological severity have only recently been developed 11–13.…”

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

“…Clinical cure at the end of treatment, length of ICU and hospital stay (LOS), 7-and 30-day all-cause mortality, in-hospital mortality, and microbiological data (isolated organism, MIC value, and microbiological eradication) were recorded. Clinical cure was defined as the resolution of signs and symptoms present at enrolment and the resolution or lack of progression of radiological signs of pneumonia during follow-up (7 to 10 days after treatment initiation) [21]. Microbiological eradication was defined as the eradication of the microorganisms cultured from respiratory samples at baseline and at the end of treatment [22].…”

What is new in non-ventilated ICU-acquired pneumonia?

“…Many infectious and non-infectious diseases may cause fever and impaired oxygenation complicating the diagnosis of NV-ICUAP [6]. A recent study using the Delphi method suggested that the main clinical/biological features to diagnose NV-ICUAP (73% final agreement) were: worsening gas exchange, fever or hypothermia, purulent tracheal secretions, dyspnoea, leucocytosis or leucopenia, and hypotension and/or vasopressor requirements [7]. The clinical pulmonary infection score (CPIS) > 6 showed a sensitivity of 42% (95% CI 29-26%) and a specificity of 87% (95% CI 74-95%) for the diagnosis of HAP [8], eventually not retained by a group of expert panellists.…”