Structural/mechanistic insights into the efficacy of non-classical β-lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Clavulanic acid and avibactam are clinically deployed serine β-lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo β-lactamases. Here we show that avibactam and a bicyclic boronate inhibit L2 (serine β-lactamase) but not L1 (metallo β-lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X-ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine. Both inhibitors reverse ceftazidime resistance in S. maltophilia because, unlike clavulanic acid, they do not induce L1 production. Ceftazidime/inhibitor resistant mutants hyper-produce L1, but retain aztreonam/inhibitor susceptibility because aztreonam is not an L1 substrate. Importantly, avibactam, but not the bicyclic boronate is deactivated by L1 at a low rate; the utility of avibactam might be compromised by mutations that increase this deactivation rate. These data rationalize the observed clinical efficacy of ceftazidime/avibactam plus aztreonam as combination therapy for S. maltophilia infections and confirm that aztreonam-like β-lactams plus non-classical β-lactamase inhibitors, particularly avibactam-like and bicyclic boronate compounds, have potential for treating infections caused by this most intractable of drug resistant pathogens

Sports Medicine Curricular Recommendations for Undergraduate Medical Education.

Sports medicine is a unique field encompassing many specialties and aspects of medicine. While musculoskeletal medicine is a significant aspect of sports medicine, the breadth of sports medicine extends beyond the musculoskeletal system and includes the spectrum of care for the patient who is or desires to be physically active. This article provides recommendations for sports medicine education in undergraduate medical education. The framework highlighting these recommendations uses domains of competence. Entrustable professional activities, measures that are endorsed by the Association of American Medical Colleges, were matched to domains of competence to provide objective markers of achievement. In addition to recommended sports medicine educational content, there should be consideration of both methods of assessment and implementation catered to each individual institution\u27s needs and resources. These recommendations may serve as a guide for medical educators and institutions pursing optimization of sports medicine education