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.
Abstract Invasive fungal diseases (IFDs) present significant challenges in clinical practice due to high morbidity and mortality rates, compounded by antifungal resistance, diagnostic limitations and pharmacokinetic (PK) and pharmacodynamic (PD) complexities. The main antifungal classes, triazoles, polyenes, echinocandins and pyrimidine analogues, are essential for managing IFDs but are increasingly undermined by resistance due to genetic mutations, efflux pump over-expression and biofilm formation. Some fungal pathogens, such as Candidozyma auris, can resist multiple antifungal classes by deploying a combination of mechanisms. PK/PD indices, including Cmax/minimum inhibitory concentration (MIC), AUC/MIC and percentage of time (%T) > MIC, are essential for optimizing antifungal therapy and improving the likelihood of adequate efficacy, while potentially limiting resistance selection through improved exposure. However, achieving these targets is often hindered by factors such as physiological variability, drug–drug interactions and inadequate tissue penetration, particularly in difficult-to-treat infections like fungal meningitis. Newer antifungal agents, including rezafungin, with its once-weekly dosing, and ibrexafungerp, the first-in-class oral triterpenoid, offer potentially useful additions to current therapy, although clinical experience and resistance-related outcome data remain limited for newer agents. These drugs feature enhanced PK/PD profiles and activity against resistant strains. Furthermore, therapeutic drug monitoring and advanced modelling techniques, such as Monte Carlo simulations, are vital for tailoring treatment regimens to individual patients. This review highlights the importance of integrating PK/PD principles, novel antifungal therapies and stewardship strategies to optimize antifungal exposure and support patient management in IFDs. These approaches may help reduce treatment failure and resistance selection, although direct clinical evidence for prevention of acquired resistance remains limited.
Abstract Background Antimicrobial stewardship (AMS) is essential to addressing antimicrobial resistance, but its implementation remains variable, particularly in settings with resource limitations. Hospitals serving deprived or underserved populations often work with limited diagnostic capacity, workforce pressures and variable digital infrastructure, which shape stewardship delivery. The Antimicrobial Stewardship Disparities Programme (ASDP) was established to strengthen stewardship capability in such settings and to support progress towards accreditation under the Global AMS Accreditation Scheme (GAMSAS). Methods A mixed-methods evaluation was undertaken across six centres in Botswana, Kenya, Lebanon, Mexico, Pakistan and the USA. Centres completed baseline and end of programme self-assessments against 17 AMS, infection prevention and control (IPC) and laboratory standards mapped to 4 pillars (structures, guidance, education and surveillance). Programme documentation was analysed to identify themes, contextual influences and barriers. All work was delivered within existing resources. Results Centres achieved improvements across AMS, IPC and laboratory standards, with consistent progress in surveillance. Governance was strengthened through clearer AMS committee structures, and guidance improved through prescribing tools embedded in practice. Education and laboratory standards showed limited change, reflecting workforce pressures, lack of protected time and constrained diagnostic capacity. Three centres achieved GAMSAS accreditation. Qualitative findings highlighted strategies to advance stewardship within structural constraints, including surveillance systems, training and locally adapted guidance. Conclusions Local aims, supported by a standards framework and mentorship, enabled centres to strengthen stewardship capability within existing resources. Workforce capacity, diagnostic access and digital infrastructure remain key determinants. Structured assessment and shared learning support scalable AMS in underserved settings.
