E. Weiss

Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE’s STAT-Net

PurposeIn this era of rising antimicrobial resistance, slowly refilling antibiotic development pipelines, and an aging population, we need to ensure that randomized clinical trials (RCTs) determine the added benefit of new antibiotic agents effectively and in a valid way, especially for severely ill patients. Unfortunately, universally accepted endpoints for the evaluation of new drugs in severe infections are lacking.MethodsWe review and discuss the current practices and challenges regarding endpoints in RCTs in this field and propose novel approaches.ResultsUsual endpoints actually recommended for drug development suffer from important flaws. Mortality requires large sample size and only partly related to the infectious process. Clinical cure rate is highly subjective in critically ill patients where symptoms may be related to other intercurrent events. Currently, composite endpoints, hierarchical nested designs, and competing risks analysis seem to be the most promising new tools for designing and analyzing clinical trials in this area, although they require further validation.ConclusionRegulatory authorities, pharmaceutical companies, and clinicians need to agree on the most appropriate clinical endpoints for severe infections to ensure efficient approval of new, effective antibiotic agents.

Pre-therapy liver transcriptome landscape in Indian and French patients with severe alcoholic hepatitis and steroid responsiveness

Patients with severe alcoholic hepatitis (SAH) not responding to glucocorticoid therapy have higher mortality, though they do not differ in their baseline clinical characteristics and prognostic scores from those who respond to therapy. We hypothesized that the baseline hepatic gene expression differs between responders (R) and non-responders (NR). Baseline liver transcriptome was compared between R and NR in Indian (16 each) and French (5 NR, 3 R) patients with SAH. There were differentially expressed genes (DEGs) between NR and R, in Indian (1106 over-expressed, 96 under-expressed genes) and French patients (65 over-expressed, 142 under-expressed genes). Indian NR had features of hepatocyte senescence and French NR exhibited under-expression of genes involved in cell division, indicating a central defect in the capacity of hepatocytes for self-renewal in both populations. Markers of hepatic progenitor cell proliferation were either very few (Indian patients) or absent (French patients). No DEGs were enriched in inflammatory pathways and there were no differences in nuclear receptor subfamily 3 group C member 1 (NR3C1) transcript expression and splicing between NR and R. Our results reveal that baseline hepatic transcriptome is reflective of subsequent glucocorticoid non-response and indicate impaired regenerative potential of the liver as an underlying phenomenon in NR.

Time trends in the reporting of conflicts of interest, funding and affiliation with industry in intensive care research: a systematic review

PurposeConflict of interest (COI) may compromise, or have the appearance of compromising, a researcher’s judgment or integrity in conducting or reporting research. We sought to assess time trends of COI and funding statement reporting in the critical care literature.MethodsPubMed was searched by using Medical Subject Headings and the appropriate corresponding keywords: “INTENSIVE CARE UNIT” or “ICU” as a major topic. Fourxa0years in a 15-year time period (2001–2016) were arbitrarily chosen and one study month was randomly selected for each study period. Studies published during the selected months were included in the analysis.ResultsThree hundred and seventy-four studies were evaluated, including five reviews (1.3%) and ten randomized clinical trials (RCTs) (2.7%). COI statements were available in 65% of the studies and 8% had declared COI. COI statement rate, declared COI and funding statements increased over time, while the number of authors affiliated with industry and the discordance between the lack of COI statement and affiliation with industry decreased. Declared COI were more frequent in 2011–2016 as compared to 2001–2010 (OR 4.06; 95% CI 1.15–25.79) and in the higher quartile of a journal’s impact factor (OR of 16.73; 95% CI 3.28–306.20). Surprisingly, focus of the study, country of the first author and/or endorsement of the study by a trial group were not associated with COI statements.ConclusionOur study suggests COI reporting to have been unintuitive to most investigators and unreliable before ICMJE statements, and that strong incentives are needed to implement adequate reporting of COI.

Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE’s STAT-Net

Abstract Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.

609 LPS INDUCES AN UNEXPECTED ENDOPLASMIC RETICULUM UNFOLDED PROTEIN RESPONSE (UPRER) IN IMMUNE CELLS FROM PATIENTS WITH CIRRHOSIS

Methods: MRNAs obtained from PBMCs were stimulated by LPS or left un-stimulated for 4h. We first used the Affymetrix Human Exon Array to analyze regulation of 14,851 and 15,334 expressed genes out of the 32,778 on the array in four patients and four ‘healthy’ subjects respectively. Results were validated using RTqPCR to measure expression of 63 genes of interest in a prospective cohort of 57 patients and 9 ‘healthy’ subjects. Results: Gene profiling revealed a core of 741 genes that were similarly regulated by LPS in cirrhotic and ‘healthy’ PBMCs. Among them, 300 LPS-induced genes were enriched in GO categories ‘regulation of mononuclear cell proliferation’ and ‘cytokine activity’. 441 shared LPS-downregulated genes were involved in recognition of PAMPs, chemotaxis, cell migration and lysosome suggesting that LPS-induced immune paralysis is a universal response. Comparison of functions associated with the 1,356 genes that were specifically regulated by LPS in cirrhotic cells to functions of the 1,049 genes specifically regulated in ‘healthy’ cells allowed to define a cirrhosis specific phenotype. Unlike healthy cells, LPS-stimulated cirrhotic cells did not exhibit the interferon (type I and II)-mediated program (e.g. IRF1, IRF2, IRF7, IFNG, IFI6, STAT1, STAT2, IFITM2), which is critical for immune host defense and resolution of inflammation. Consistent with these results, CXCL10 and CXCL11, two interferoninduced chemokines were induced by LPS in ‘healthy’ but not in cirrhotic PBMCs. Moreover, LPS-stimulated cirrhotic cells had downregulation of endocytic trafficking genes, which may results in decreased TLR4 endocytosis and inhibition of TRIF-mediated interferon pathway. Conclusions: Both LPS-stimulated cirrhotic and ‘healthy’ PBMCs exhibit features of immune paralysis. Moreover, LPS stimulated cirrhotic PBMCs have a specific defect of induction of interferon target genes involved in host defense and resolution of inflammation. These findings may explain the severity of bacterial infections in cirrhosis.