Abstract Background The continued emergence of multidrug-resistant Mycobacterium tuberculosis (M. tb) has substantially limited treatment options and highlights the need for new antimycobacterial agents. Although terpenoids comprise one of the largest classes of natural products with diverse biological activities, their antimycobacterial potential has not been systematically investigated. Methods A library comprising 354 natural terpenoid compounds were screened against M. tb. Lead compounds were subsequently characterized by determining minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), time–kill kinetics, activity against clinical drug-sensitive and drug-resistant isolates, cytotoxicity in THP-1–derived macrophages and intracellular antimycobacterial activity using colony-forming unit assays. Results Primary screening identified 10 compounds with strong antimycobacterial activity, among which valepotriate showed as a novel antimycobacterial agent. Valepotriate inhibited extracellular M. tb growth with an MIC of 10 μM and an MBC of 20 μM. Time–kill assays demonstrated rapid concentration-dependent bactericidal activity, reducing bacterial counts by >2 log10 cfu within 24 h at 4× MIC and completely eradicating viable bacteria within 24 h at 8× and 16× MIC. Valepotriate retained activity against 14 clinical drug-sensitive and drug-resistant isolates with MIC values ranging from 5 to 20 μM. Valepotriate significantly reduced the intracellular bacterial burden at bactericidal concentrations that were well tolerated by THP-1–derived macrophages. Conclusions Systematic screening identified valepotriate as a rapidly bactericidal antimycobacterial lead compound with activity against both drug-susceptible and drug-resistant M. tb, highlighting its potential as a natural product-derived scaffold for developing new antimycobacterial agents and motivating further optimization of its antibacterial potency.
Abstract Background Antimicrobial resistance (AMR) is a global problem that requires coordinated action. Most antibiotics in England are used in community settings, giving all community health and care professionals potentially important roles in antimicrobial stewardship (AMS). Currently little evidence exists on how the adult social care workforce, including domiciliary carers providing care at home, contribute to AMS, despite the unique opportunities of their role. Objectives To explore domiciliary care workers’ knowledge of AMR and identify existing contributions and opportunities to improve AMS. Methods We used a purposive sampling approach to recruit a diverse sample of domiciliary carers working in England and administered a semi-structured interview exploring their views and practices relating to AMS. Thematic analysis was applied. Results We interviewed 30 domiciliary carers. Analysis of participants’ responses indicated that carers supported AMS in the following ways: infection prevention and control (IPC), and signposting clients to healthcare and antibiotic administration. However, carers generally did not recognize themselves as actively contributing to AMS. Conclusions We identified unrecognized areas of good AMS practice, along with opportunities to enhance domiciliary carers’ impact on AMS. Potential interventions include improving timeliness of adding antibiotics to care plans as well as inclusion of AMS behaviours in them, co-developing training with carers on AMR to reinforce their AMS practices, clear distinction of carers’ contributions as part of a whole-system approach to tackling AMR, and embedding AMS competencies into the Care Certificate for greater reach and consistency.
Abstract Background The occurrence of infections caused by Gram-negative bacteria with difficult-to-treat resistance (DTR) is rapidly increasing, generally requiring the use of recently approved, last-resort antimicrobial agents or old compounds that are more toxic and/or less effective. We evaluated the activity of aztreonam–avibactam and comparators against DTR Enterobacterales. Methods A total of 42 295 Enterobacterales isolates were consecutively collected (one per patient) from 85 US medical centres in 2020–24 and susceptibility tested by Clinical Laboratory Standards Institute broth microdilution. The collection included 450 carbapenem-resistant Enterobacterales (CRE) and 284 DTR isolates, which were screened for β-lactamases by whole genome sequencing. Results Aztreonam–avibactam was active against 98.2% of DTR (minimum inhibitory concentration for 50%/90% of the collection, 0.25/1 mg/L) and 97.1% of CRE isolates and retained potent activity (≥90.0% susceptibility) against DTR isolates non-susceptible to ceftazidime–avibactam, meropenem–vaborbactam and/or cefiderocol. Cefiderocol was active against 92.8% of DTR isolates, whereas ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam and the aminoglycosides exhibited limited activity against these organisms. Aztreonam–avibactam and cefiderocol were active against 97.8% and 84.4% of DTR metallo-β-lactamase (MBL) producers, respectively. The most common carbapenemase genes identified among DTR isolates were blaKPC (57.7% of isolates) and blaNDM (29.9%). An MBL gene was observed in 31.7% of DTR and 25.1% of CRE isolates. Conclusions Aztreonam–avibactam retained potent activity against DTR Enterobacterales from US medical centres, and its activity was not adversely affected by clinically relevant carbapenemases or resistance to agents used to treat multidrug-resistant Enterobacterales. The activities of other β-lactam/β-lactamase inhibitor combinations and cefiderocol were compromised by the increased occurrence of MBL producers.
Abstract Objectives To describe and evaluate a needs-assessment informed model for embedding a non-allergist penicillin allergy de-labelling (PADL) service within an Acute Medical Unit (AMU), including stakeholder experience. Methods A four-phase quality improvement project in one UK AMU, reported per SQUIRE 2.0. Phase 1: needs-assessment survey of 124 staff (pharmacists, doctors, nurses, immunology staff). Phase 2: a multidisciplinary team translated Phase 1 barriers into a PEN-FAST-guided direct oral amoxicillin challenge (DOC) protocol delivered by acute medicine consultants and pharmacists; design decisions were retrospectively mapped to the capability, opportunity and motivation model for behavioural change and Behaviour Change Wheel. Phase 3: DOC in 60 adult inpatients penicillin allergy labels. Phase 4: post-implementation survey of 54 patients and staff. Results Before implementation, 90% of staff anticipated a service would be useful, but identified time, education, safety concerns and staffing as the main barriers. Fifty-nine of 60 patients (98.3%) were de-labelled, with one mild Type 4 reaction but no anaphylaxis. All 21 (35.6%) who needed antibiotics within six months received a penicillin without reported reaction. All 54 post-implementation respondents rated the service extremely useful and would recommend or refer into it; as Phase 1 and Phase 4 cohorts were non-matched, this comparison is indicative only. Patients described years of unwarranted anxiety about antibiotic use that resolved after de-labelling. Conclusions A needs-assessment-informed model translated staff-identified barriers into design decisions and was associated with high stakeholder endorsement, durable penicillin use and an under-recognized psychological benefit for patients. It offers a practical, replicable template for non-allergist PADL in acute medicine.
Abstract Background and objectives The Scottish Antimicrobial Prescribing Group (SAPG) formed a multidisciplinary outpatient parenteral antimicrobial therapy (OPAT) working group in September 2020 to develop a national consensus on OPAT treatments and to support service development. Methods The development of a national OPAT skin and soft tissue (SSTI) clinical pathway for adults was identified as a key initiative to support admission avoidance. The pathway was modelled on an established pathway in one health board and agreed by consensus with representation from 12 of the 14 territorial Scottish health boards. A survey to assess pathway uptake was conducted in February 2025, and a follow-up survey of boards that had not adopted the pathway was conducted in April 2026. Results IV ceftriaxone was agreed by the SAPG as initial OPAT SSTI therapy, with daptomycin or teicoplanin as alternatives, and with dalbavancin to support care of vulnerable adults or if daily IV therapy was not possible. The pathway was circulated to all health boards in June 2022. By April 2026 the pathway had been adopted by 11 (2 island and 9 mainland) health boards across 28 separate acute services including OPAT, hospital at home, emergency departments and ambulatory care units. The remaining three health boards reported OPAT activity but without formal adoption of the pathway. Conclusions A national OPAT SSTI pathway has been successfully developed and rolled out across approximately 91% of the adult population in Scotland, including remote and rural areas. Further work to evaluate use and wider rollout is ongoing.
