Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.

Background: Tranexamic acid (TXA) is an antifibrinolytic used for prophylaxis and treatment of acute bleeding. Although fixed dosing is often used in practice, weight-based dosing is sometimes used in the operating room (OR). The efficacy and safety of fixed-dose TXA is not well established in patients with above average weight or body mass index. Objective: To characterize the efficacy and safety of intravenous TXA in obese patients with major bleeding. Methods: This was a retrospective review of 165 patients receiving fixed-dose TXA for acute bleeding outside the OR. Blood product administration (BPA) before and after TXA was collected, along with demographic and bleed-related information. Thrombotic events were the major safety end point. A prespecified subgroup analysis was conducted in patients weighing at least 100 kg compared with a lower weight. Logistic regression was performed to determine whether an association exists between body weight and blood product requirement after TXA administration. Results: In the 24 hours after TXA, patients received an average of 4.17 units of blood product. Patients weighing at least 100 kg averaged 4.04 total units, compared with 4.19 units in the lower weight group ( P = 0.603). Administration of individual blood products did not differ between groups, and thrombotic events were similar. Regression analysis did not associate weight with total BPA. Conclusion and Relevance: In patients receiving fixed-dose TXA, weight does not appear to alter blood product requirements or rates of adverse thrombotic events. These data support continued use of fixed-dose TXA for treatment of acute major bleeding in obese patients.

Background Delirium develops frequently in intensive care unit (ICU) patients. Societal guidelines have suggested that benzodiazepines may cause delirium. This study investigates if a change in sedation administration use over time is associated with changes in delirium incidence. Methods This was a retrospective cohort study conducted over a 4 year time period in a medical ICU. All data was abstracted from a local data warehouse. The primary outcome of the study was the association between annual cumulative benzodiazepine use and incidence of delirium during the study period. Data was analyzed using descriptive characteristics and Spearman’s correlation coefficient. Additionally, multivariate logistic regression was performed to identify independent risk factors for delirium development. Results From 2015 to 2018, annual total benzodiazepine administration decreased from 62,215 mg to 18,105 mg lorazepam equivalents (p = <.01). The cumulative dose of dexmedetomidine increased, with 657,262 mcg administered in 2015 and 1,476,951 mcg in 2018 (p < .01). No differences in annual delirium incidence were found. Risk factors that were significantly correlated with delirium following multivariate logistic regression included acute respiratory distress syndrome, renal failure, hepatic failure, septic shock, severe alcohol withdrawal, vasopressor use, corticosteroid use, benzodiazepine use, antipsychotic use, opiate use, and propofol use. Conclusions A profound change in sedation medication paradigm did not influence delirium rates in a medical ICU.

Over the past decades, awareness and attention given to food allergies has extended further into the realm of pharmacotherapy. Despite the presence of similar ingredients, different intravenous lipid emulsion (ILE)-based medication products have a wide variety of warnings and contraindications for patients with food allergies. Only limited literature is available to guide clinicians in making appropriate medication therapy adjustments to reduce the risk of hypersensitivity reactions in atopic patient populations. Therefore, the authors sought to develop a comprehensive review of potential risk factors or approaches for management of patients with atopic history and need for ILE therapy. Through thorough review of available literature published worldwide, a description of potential contraindications, risk factors, and evaluation methods is presented. Although the current state of knowledge remains relatively poor, this review aims to provide clinicians a better understanding of which risk factors related to the development of hypersensitivity reactions are relevant to lipid emulsion products and how to best manage patients who may be at risk for severe reaction based on their history. Evaluating personal atopic history is essential to the development of an appropriate risk classification system and approaching an individual's therapeutic options. By applying this assessment to local populations, providers should be able to develop an institutional guideline for screening and minimizing risk of substantial hypersensitivity reactions. Finally, a brief review of methods for managing type 1 hypersensitivity reactions is provided in the event that a breakthrough reaction does occur.