RESUMO
BACKGROUND: Benzodiazepines are the gold standard for treatment of alcohol withdrawal, yet the selection of a preferred benzodiazepine is limited due to a lack of comparative studies. OBJECTIVES: The primary objective of this study was to compare the efficacy and safety of injectable lorazepam (LZP) and diazepam (DZP) in the treatment of severe alcohol withdrawal syndrome (AWS). METHODS: Retrospective cohort study of adult patients admitted to an intensive care unit with a primary diagnosis of AWS. Subjects who received at least 12 LZP equivalent units (LEU) of injectable DZP or LZP within 24 hours of initiation of the severe AWS protocol were included. The primary outcome was time with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores at goal over the first 24 hours of treatment. RESULTS: A total of 191 patients were included (DZP n = 89, LZP n = 102). Time with CIWA-Ar scores at goal during the first 24 hours was similar between groups (DZP 12 hours [interquartile range, IQR, = 9-15] vs LZP 14 hours [IQR = 10-17]), P = 0.06). At 24 hours, LEU requirement was similar (DZP 40 [IQR = 22-78] vs LZP 32 [IQR = 18-56], P = 0.05). Drug cost at 24 hours was higher in the DZP group ($204.6 [IQR = 112.53-398.97] vs $8 [IQR = 4.5-14], P < 0.01). CONCLUSION AND RELEVANCE: DZP or LZP are equally efficacious for the treatment of severe AWS. LZP may be preferred due to cost but both medications can be used interchangeably based on availability.
RESUMO
To identify novel inhibitors of the carbapenemase New Delhi metallo-ß-lactamase (NDM) as possible therapeutic compounds, we conducted a high-throughput screen of a 43,358-compound library. One of these compounds, a 2-quinazolinone linked through a diacylhydrazine to a phenyl ring (QDP-1) (IC50 = 7.9 ± 0.5 µM), was characterized as a slow-binding reversible inhibitor (Kiapp = 4 ± 2 µM) with a noncompetitive mode of inhibition in which substrate and inhibitor enhance each other's binding affinity. These studies, along with differential scanning fluorimetry, zinc quantitation, and selectivity studies, support an allosteric mechanism of inhibition. Cotreatment with QDP-1 effectively lowers minimum inhibitory concentrations of carbapenems for a panel of resistant Escherichia coli and Klebsiella pneumoniae clinical isolates expressing NDM-1 but not for those expressing only serine carbapenemases. QDP-1 represents a novel allosteric approach for NDM drug development for potential use alone or with other NDM inhibitors to counter carbapenem resistance in enterobacterales.
