Dataset Information

Exploration of a Potential DOOR Endpoint for Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

ABSTRACT:

Background

Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).

Methods

Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator.

Results

DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Although infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar.

Conclusions

Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design.

SUBMITTER: Kinamon T

PROVIDER: S-EPMC11259224 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

Exploration of a Potential DOOR Endpoint for Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

Kinamon Tori T Waack Ursula U Needles Mark M Rubin Daniel D Collyar Deborah D Doernberg Sarah B SB Evans Scott R SR Hamasaki Toshimitsu T Holland Thomas L TL Howard-Anderson Jessica J Chambers Henry H Fowler Vance G VG Nambiar Sumati S Kim Peter P Boucher Helen W HW Gopinath Ramya R

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20240701 1

<h4>Background</h4>Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).<h4>Methods</h4>Through comprehensive examination ...[more]

PMID: 38527855

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Project description:BackgroundResistant bacterial infections, particularly those caused by gram-negative pathogens, are associated with high mortality and economic burdens. Ceftolozane/tazobactam demonstrated efficacy comparable to meropenem in patients with ventilated hospital-acquired bacterial pneumonia in the ASPECT-NP study. One cost-effectiveness analysis in the United States revealed that ceftolozane/tazobactam was cost effective, but no Japanese studies have been conducted. Therefore, the objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam compared to meropenem for patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia from a health care payer perspective.MethodsA hybrid decision-tree Markov decision-analytic model with a 5-year time horizon were developed to estimate costs and quality-adjusted life-years and to calculate the incremental cost-effectiveness ratio associated with ceftolozane/tazobactam and meropenem in the treatment of patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. Clinical outcomes were based on the ASPECT-NP study, costs were based on the national fee schedule of 2022, and utilities were based on published data. One-way sensitivity analysis and probabilistic sensitivity analysis were also conducted to assess the robustness of our modeled estimates.ResultsAccording to our base-case analysis, compared with meropenem, ceftolozane/tazobactam increased the total costs by 424,731.22 yen (£2,626.96) and increased the quality-adjusted life-years by 0.17, resulting in an incremental cost-effectiveness ratio of 2,548,738 yen (£15,763.94) per quality-adjusted life-year gained for ceftolozane/tazobactam compared with meropenem. One-way sensitivity analysis showed that although the incremental cost-effectiveness ratio remained below 5,000,000 yen (£30,925) for most of the parameters, the incremental net monetary benefit may have been less than 0 depending on the treatment efficacy outcome, especially the cure rate and mortality rate for MEPM and mortality rate for CTZ/TAZ. 53.4% of the PSA simulations demonstrated that CTZ/TAZ was more cost-effective than MEPM was.ConclusionAlthough incremental cost-effectiveness ratio was below ￥5,000,000 in base-case analysis, whether ceftolozane/tazobactam is a cost-effective alternative to meropenem for ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia in Japan remains uncertain. Future research should examine the unobserved heterogeneity across patient subgroups and decision-making settings, to characterise decision uncertainty and its consequences so as to assess whether additional research is required.

Project description:Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 μg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

Project description:ObjectivesVentilator-acquired pneumonia (VAP) is the leading cause of serious associated infections in Intensive Care Units (ICU) and is associated with significant morbidity. The use of hyperbaric oxygen therapy (HBOT) in patients on mechanical ventilation may increase exposure to certain risk factors such as hyperoxemia and the need for multiple transfers. The aim of our study was to assess the relationship between HBOT and VAP.MethodThis retrospective observational study was performed from March 2017 to March 2018 in a 10-bed ICU using HBOT. All patients receiving mechanical ventilation (MV) for more than 48 hours were eligible. VAP was defined using clinical and radiological criteria. Data collection was carried out via digital medical records. Risk factors for VAP were determined by univariate and multivariate analysis.ResultsForty-two (23%) of the 182 patients enrolled developed at least one episode of VAP. One hundred and twenty-four (68%) patients received HBOT. The incidence rate of VAP was 34 per 1000 ventilator days. The occurrence of VAP was significantly associated with immunosuppression (p<0.029), MV duration (5 [3-7] vs 8 [5-11.5] days, p<0.0001), length of stay (8 [5-13] vs 19.5 [13-32] days, p<0.0001), reintubation (p<0.0001), intra-hospital transport (p = 0.001), use of paralytic agents (p = 0.013), tracheotomy (p = 0.003) and prone position (p = 0.003). The use of HBOT was not associated with the occurrence of VAP. Multivariate analysis identified reintubation (OR: 8.3 [2.6-26.6]; p<0.0001), intra-hospital transport (OR: 3.5 [1.3-9.2]; p = 0.011) and the use of paralytic agents (OR: 3.3 [1.3-8.4]; p = 0.014) as independent risk factors for VAP.ConclusionKnown risk factors for VAP are to be found within our ICU population. HBOT, however, is not an extra risk factor for VAP within this group. Further experimental and clinical investigations are needed to understand the impact of HBOT on the occurrence of VAP and on physiological microbiome.

Dataset Information

Exploration of a Potential DOOR Endpoint for Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

Background

Methods

Results

Conclusions

Publications

Exploration of a Potential DOOR Endpoint for Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

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