Background: Antimicrobial resistance is increasing in sub-Saharan Africa, yet detailed data on prescribing practices remain limited. We characterise antimicrobial compounds prescribed as initial therapy at admission, assess their concordance with treatment guidelines, and examine antimicrobial compounds prescribed during hospitalisation. Methods: We conducted a one-year prospective observational study of febrile inpatients (≥5 months) at Masanga Teaching Hospital, Sierra Leone (September 2023–September 2024). Clinical data, diagnoses, and antimicrobial prescriptions were recorded. Antimicrobial compounds initiated at admission were stratified by indication and WHO AWaRe classification and assessed for concordance with hospital protocol and WHO guidance using predefined decision rules. Secondary analyses summarised antimicrobial compounds prescribed during hospitalisation, including treatment changes such as oral step-down and culture-directed therapy. Findings: Among 689 febrile inpatients, 70·7% (487/689) received one or more antimicrobial compounds at admission. In total, 882 antimicrobial compounds were prescribed, of which 65·0% (573/882) were WHO Access and 35·0% (309/882) Watch category antimicrobials. Ceftriaxone was the most frequently prescribed compound at admission (30·4%, 268/882). Lower respiratory tract infection, sepsis, and skin and soft tissue infections accounted for the largest share of compounds prescribed overall and within the Watch category. In total, 73·7% (650/882) of prescribed compounds were concordant with the hospital protocol compared with 55·7% (491/882) under WHO guidance. Discordance under both protocols was largely driven by compounds prescribed for sepsis, pneumonia, and uncomplicated malaria. During hospitalisation, 4·9% (58/1183) of antimicrobial compounds prescribed reflected oral step-down therapy and 6·2% (73/1183) were culture-directed. Interpretation: Most antimicrobial compounds were from the WHO Access category and were largely concordant with hospital guidance and, to a lesser extent, with WHO guidance. The observed prescribing patterns suggest that strengthening diagnostic capacity, refining treatment guidelines, improving health worker familiarity with guidance, and ensuring adequate antimicrobial availability could improve adherence, reduce WHO Watch category use, and strengthen antimicrobial stewardship in resource-limited settings. Funding statement.

Infection prevention and control (IPC) and antibiotic stewardship (ABS) represent promising approaches for reducing the prevalence of healthcare-associated infections (HAI) and antimicrobial resistance (AMR) in different healthcare settings. However, the combined use of IPC and ABS measures and ways to optimize their integrated implementation have been insufficiently considered and assessed. The REVERSE trial, funded by the European Union’s Horizon 2020 program, involves 24 acute care hospitals from four European countries, all with high rates of AMR and HAI. REVERSE aims to investigate whether the sequential implementation of an IPC and an ABS practice bundle is feasible and sustainable and whether externally guided tailoring as an enhanced implementation strategy leads to superior clinical and implementation outcomes compared to a basic implementation condition. REVERSE will be designed as a stepped wedge cluster randomized, hybrid type 2 trial, including an embedded implementation trial. Four cohorts of six acute care hospitals will sequentially enter the trial over 38 months and work to implement first IPC, and, after 1 year, add the ABS practice bundle. Simultaneously, hospitals will be provided basic implementation training and instructed to tailor their implementation, with half of the hospitals being self-guided in their tailoring, whereas hospitals in the enhanced implementation condition will receive time-limited external facilitation in practicing tailoring. Qualitative data will be collected longitudinally to investigate contextual conditions for implementing IPC and ABS locally and how they contribute to tailoring results. IPC and ABS feasibility, fidelity, and sustainability will be assessed together with tailoring fidelity using repeated measures. Retrospective, in-depth, explanatory case studies will be conducted to interpret hospital outcomes. REVERSE is an extensive and complex effectiveness-implementation trial aimed at investigating tailoring effectiveness. It will contribute to the still scarce evidence base for this adaptive approach to integrating research-supported interventions into routine healthcare settings. By identifying pathways toward strengthening the integration of IPC and ABS practices at European acute care hospitals, REVERSE also has the potential to inform much-needed concerted efforts to combat the growing challenge of antimicrobial resistance in the region. In November 2021, the REVERSE study was registered with the “International Standard Randomised Controlled Trial Number” (ISRCTN) register under nr.12956554.

BACKGROUND:The global spread of multidrug-resistant gram-negative bacteria has led to the introduction of several novel antibiotics. However, emerging resistance threatens their long-term utility, emphasizing the importance of antimicrobial stewardship programmes (ASPs). OBJECTIVES:This narrative review synthesizes current evidence on ASP interventions optimizing the use of recently approved antibiotics against multidrug-resistant gram-negative pathogens and identifies priorities for sustainable implementation. SOURCES:A literature search (PubMed, Scopus, 2010-2025) identified interventional and quasiexperimental studies addressing stewardship strategies for novel agents such as ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, imipenem/relebactam, cefiderocol, sulbactam/durlobactam, eravacycline, and aztreonam/avibactam. CONTENT:Seven studies were included, encompassing educational bundles, pharmacokinetic/pharmacodynamic optimization, decision-support tools, formulary restrictions, and multidisciplinary models. Most relied on enablement strategies-education, feedback, and therapeutic monitoring-often integrated with diagnostics or digital support. These interventions improved therapy appropriateness and microbiological outcomes, though evidence remains limited by small, single-centre, and heterogeneous studies. IMPLICATIONS:Effective stewardship of new gram-negative antibiotics requires combining enablement, personalized pharmacology, and selective restriction within multidisciplinary ASPs. Strengthening real-world evidence, digital infrastructure, and standardized outcome measures is essential to guide equitable and sustainable implementation.

Importance:Antimicrobial stewardship (AMS) programs optimize antibiotic use and mitigate antimicrobial resistance. The literature on the efficacy of AMS programs in pancreatic surgery is limited. Objective:To investigate the association of a multifaceted AMS intervention targeting surgical antibiotic prophylaxis (SAP) with the rate of surgical site infections (SSIs) following pancreatic surgery. Design, Setting, and Participants:This cross-sectional study was a multicenter, before-and-after analysis conducted at 3 Italian centers. The intervention cohort included adult patients aged 18 years or older who underwent pancreatectomy between January 1, 2020, and December 31, 2022, while the historical cohort included patients from January 1, 2015, to December 31, 2019. Exposure:A multiprofessional, multidimensional ASM program that included a bundle of interventions and pivoted on preoperative rectal screening for multidrug-resistant bacteria and targeted SAP. Main Outcomes and Measures:The primary outcomes were SSI incidence and SAP appropriateness, assessed through the coverage rate of rectal and biliary isolates. Data were analyzed using propensity score weighting. Secondary outcomes evaluated were other postoperative outcomes (eg, pancreatic fistula rate, length of stay), antibiotic use, and costs. Results:A total of 3387 patients (median [IQR] age, 66 [66-73] years; 1788 male [52.8%]) were included, with 1219 in the intervention cohort and 2168 in the historical cohort. After implementing the AMS program, a statistically significant reduction was found in rates of overall (30.1% vs 20.6%), superficial (5.8% vs 2.5%), deep (0.9% vs 0.3%), and organ-space (26.3% vs 19.3%) SSIs. After propensity score weighting, the odds ratios for the estimated mean treatment effect were 0.92 (95% CI, 0.89-0.96) for overall, 0.85 (95% CI, 0.78-0.93) for superficial, and 0.95 (95% CI, 0.92-0.99) for organ-space SSIs. Surgical antibiotic prophylaxis coverage increased significantly for rectal screening (87.2% vs 100%) and biliary bacterial colonization (59.7% vs 68.7%). Complications, infections, length of stay, and antibiotic consumption also decreased, with an overall cost savings of 247 460 euros. Conclusions and Relevance:These findings suggest that a multifaceted, pancreatic surgery-specific AMS program is associated with decreased rates of SSIs, increased coverage of isolated bacteria, improved clinical outcomes, more judicious antibiotic use, and lower costs.

Healthcare-associated infections (HAIs) and multidrug-resistant (MDR) pathogens present significant challenges to global health, exacerbated by emerging threats such as SARS-CoV-2 and the growing immunocompromised population. While isolation precautions are critical for infection prevention and control (IPC), their indiscriminate application can strain resources and impact patient well-being. This review proposes a patient-centered framework for optimizing isolation strategies by integrating pathogen-related factors, individual patient risks, and healthcare facility resources to optimize isolation precautions. By incorporating targeted risk assessments, advanced analytics (e.g., omics and machine learning), and infection preventionist leadership, this approach aligns isolation measures with clinical and operational realities. It aims to enhance IPC efficacy while balancing patient needs and resource efficiency. We highlight strategies to ensure isolation precautions remain evidence-based, adaptable, and sustainable within healthcare settings. A patient-focused approach to isolation improves both infection prevention and overall quality of patient care.

BACKGROUND:The 2017 WHO Bacterial Priority Pathogens List (BPPL) has been instrumental in guiding global policy, research and development, and investments to address the most urgent threats from antibiotic-resistant pathogens, and it is a key public health tool for the prevention and control of antimicrobial resistance (AMR). Since its release, at least 13 new antibiotics targeting bacterial priority pathogens have been approved. The 2024 WHO BPPL aims to refine and build on the previous list by incorporating new data and evidence, addressing previous limitations, and improving pathogen prioritisation to better guide global efforts in combating AMR. METHODS:The 2024 WHO BPPL followed a similar approach to the first prioritisation exercise, using a multicriteria decision analysis framework. 24 antibiotic-resistant bacterial pathogens were scored based on eight criteria, including mortality, non-fatal burden, incidence, 10-year resistance trends, preventability, transmissibility, treatability, and antibacterial pipeline status. Pathogens were assessed on each of the criteria on the basis of available evidence and expert judgement. A preferences survey using a pairwise comparison was administered to 100 international experts (among whom 79 responded and 78 completed the survey) to determine the relative weights of the criteria. Applying these weights, the final ranking of pathogens was determined by calculating a total score in the range of 0-100% for each pathogen. Subgroup and sensitivity analyses were conducted to assess the impact of experts' consistency, background, and geographical origin on the stability of the rankings. An independent advisory group reviewed the final list, and pathogens were subsequently streamlined and grouped into three priority tiers based on a quartile scoring system: critical (highest quartile), high (middle quartiles), and medium (lowest quartile). FINDINGS:The pathogens' total scores ranged from 84% for the top-ranked bacterium (carbapenem-resistant Klebsiella pneumoniae) to 28% for the bottom-ranked bacterium (penicillin-resistant group B streptococci). Antibiotic-resistant Gram-negative bacteria (including K pneumoniae, Acinetobacter spp, and Escherichia coli), as well as rifampicin-resistant Mycobacterium tuberculosis, were ranked in the highest quartile. Among the bacteria commonly responsible for community-acquired infections, the highest rankings were for fluoroquinolone-resistant Salmonella enterica serotype Typhi (72%), Shigella spp (70%), and Neisseria gonorrhoeae (64%). Other important pathogens on the list include Pseudomonas aeruginosa and Staphylococcus aureus. The results of the preferences survey showed a strong inter-rater agreement, with Spearman's rank correlation coefficient and Kendall's coefficient of concordance both at 0·9. The final ranking showed high stability, with clustering of the pathogens based on experts' backgrounds and origins not resulting in any substantial changes to the ranking. INTERPRETATION:The 2024 WHO BPPL is a key tool for prioritising research and development investments and informing global public health policies to combat AMR. Gram-negative bacteria and rifampicin-resistant M tuberculosis remain critical priority pathogens, underscoring their persistent threat and the limitations of the current antibacterial pipeline. Focused efforts and sustained investments in novel antibacterials are needed to address AMR priority pathogens, which include high-burden antibiotic-resistant bacteria such as Salmonella and Shigella spp, N gonorrhoeae, and S aureus. Beyond research and development, efforts to address these pathogens should also include expanding equitable access to existing drugs, enhancing vaccine coverage, and strengthening infection prevention and control measures. FUNDING:This work is based on the development of the 2024 WHO BPPL, which was conducted by the WHO AMR Division through grants from the Government of Austria, the Government of Germany, the Government of Saudi Arabia, and the European Commission's Health Emergency Preparedness and Response Authority. TRANSLATIONS:For the Arabic, French, Italian, Japanese and Spanish translations of the abstract see Supplementary Materials section.

Antimicrobial-resistant (AMR) related deaths were predicted to have the greatest impact in Türkiye, Greece, Italy, and Portugal by 2050. Outpatient misuse and overuse of antibiotics are major contributors. We aimed to identify the underlying causes of inappropriate antibiotic use in outpatient settings and to develop context-specific, expert-driven solutions. A two-round e-Delphi process was used among experts, including primary care physicians, infectious disease specialists, ENT doctors, emergency medicine physicians, public health professionals, pharmacists, and policymakers working in outpatient settings. A 7-point Likert scale assessed 47 potential causes and 25 proposed solutions. Consensus was defined using interquartile range, median, and percent agreement. Expert agreement was assessed using Kendall's W. 109 experts from 52 cities in Greece, Italy, Portugal, and Türkiye participated, with a response rate of 88

Scope This ESCMID guideline provides evidence-based recommendations to support a selection of appropriate antibiotic use practices for patients seen in the emergency department (ED) and guidance for their implementation.The topics addressed in this guideline are: 1) Do biomarkers or rapid pathogen tests improve antibiotic prescribing and/or clinical outcomes? 2) Does taking blood cultures in common infectious syndromes improve antibiotic prescribing and/or clinical outcomes? 3) Does watchful waiting without antibacterial therapy or with delayed antibiotic prescribing reduce antibiotic prescribing without worsening clinical outcomes in patients with specific infectious syndromes? 4) Do structured culture follow-up programs in patients discharged from the ED with cultures pending improve antibiotic prescribing? Methods An expert panel was convened by ESCMID and the guideline chair. The panel selected in consensus the four most relevant AMS topics according to pre-defined relevance criteria. For each main question for the four topics, a systematic review was performed, including randomized controlled trials and observational studies. Both clinical outcomes as well as stewardship process outcomes related to antibiotic use were deemed relevant. The literature searches were conducted between May 2021 and March 2022. In April 2022, the panel members were formally asked to suggest additional studies that were not identified in the initial searches. Data were summarized in a meta-analysis if possible or otherwise summarized narratively. The certainty of the evidence was classified according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. The guideline panel reviewed the evidence per topic critically appraising the evidence and formulated recommendations through a consensus-based process. The strength of the recommendations was classified as strong or weak. To substantiate the implementation process, implementation trials or observational studies describing facilitators/barriers for implementation were identified from the same searches and were summarized narratively. Recommendations The recommendations on the use of biomarkers and rapid pathogen diagnostic tests focus on the initiation of antibiotics in patients admitted through the ED. Their effect on the discontinuation or de-escalation of antibiotics during hospital stay was not reported, neither was their effect on hospital infection prevention and control practices. The recommendations on watchful waiting (i.e., withholding antibiotics with some form of follow-up) focus on specific infectious syndromes for which the primary care literature was also included. The recommendations on blood cultures focus on the indication in three common infectious syndromes in the ED explicitly excluding patients with sepsis or septic shock.Most recommendations are based on very-low- and low-certainty of evidence, leading to weak recommendations or, when no evidence was available, to best practice statements. Implementation of these recommendations needs to be adapted to the specific settings and circumstances of the ED. The scarcity of high-quality studies in the area of antimicrobial stewardship in the ED highlights the need for future research in this field.

Background: Antibiotic stewardship (AS) interventions in paediatrics are still not stand-ardized regarding methodology, metrics, and outcomes. We report the results of an AS intervention in the paediatric area based on education and guideline provision via an electronic App. Materials and methods: The AS intervention was conducted in 2021 through observation, education, audit and feedback and provision of an electronic App (Firstline.org) to support antibiotic prescription based on local susceptibility data. The primary outcome was the antibiotic consumption in the 12 months following the intervention (year 2022) compared with a historical 12-month control (year 2019) via an interrupted time series analysis. Secondary outcomes were appropriateness of therapy, length of stay, 30-day readmission, transfers to the paediatric intensive care unit, in-hospital mortality, and prevalence of antimicrobial resistance (AMR). Results: During the post-intervention phase, 29 cross-sectional audits and feedback were conducted including 467 patients. Prescriptions were appropriate according to the guidelines in 85.7% of cases, with a stable trend over time. A significant decrease in antibiotic consumption was measured in terms of defined daily doses per 1000 patient days (-222.13; P<0.001) and days of therapy per 1000 patient days (-452.49; P<0.001) in the post-intervention period with a clear inversion of the Access to Watch ratio (from 0.7 to 1.7). Length of stay, in-hospital mortality, intensive care unit transfers, and incidence of AMR infections remained stable, while 30-day readmission decreased from 4.9 per 100 admissions to 2.8 per 100 admissions (P<0.001). Conclusions: The intervention was associated with a significant reduction in antimicrobial consumption and an increase in the appropriateness of prescriptions. Electronic tools can be of value in promoting adherence to guidelines and ensuring the sustainability of results. (c) 2023 The Author(s). Published by Elsevier Ltd

BackgroundGlobal estimates of sepsis mortality are based on multiple causes of death (MCOD, any mention of the condition on death certificates); however, MCOD data are sparse and mainly referring to the pre-pandemic period.ObjectivesTo investigate recent trends in sepsis-related mortality, associated sites of infection, and comorbidities in Veneto (Northeastern Italy).MethodsMortality records from 2008 to 2022 were extracted, and sepsis-related mortality was assessed based both on the underlying cause of death (UCOD) and on MCOD. The average annual percent change in age-standardised rates was estimated by join point regression through the whole study period. MCOD records were investigated to retrieve infection sites and comorbidities.ResultsSepsis was mentioned in 63,479 death certificates, growing from 4.9% out of all deaths in 2008 to 12.9% in 2022. Age-standardised mortality rates increased yearly by 8.2% (95%CI 2.1-14.7%) based on the UCOD and by 5.9% (95%CI 5.3-6.5%) based on MCOD. Sharp peaks in monthly mortality were observed in correspondence with flu epidemics, COVID-19 pandemic waves, and periods of extreme heat. The percentage of sepsis-related deaths associated to urinary tract infections, and with mention of neurodegenerative disorders and chronic kidney disease increased over time.ConclusionRaised awareness of physicians, ageing of the population, spread of antimicrobial resistance further fuelled by the COVID-19 pandemic are among reasons of increasing sepsis-related mortality in Italy. Continuous monitoring of sepsis by means of MCOD data and other surveillance tools is warranted.

Background:Antibiotics are the most prescribed drugs for children worldwide, but overuse and misuse have led to an increase in antibiotic resistance. Antimicrobial stewardship programmes (ASPs) have proven feasible in reducing inappropriate antimicrobial use. The study aimed at evaluating the impact and sustainability of an ASP with multiple interventions over 8 years. Methods:This quasi-experimental study was conducted between 2014 and 2022 in the paediatric acute care unit of Padua University Hospital. Demographic and clinical data were retrieved from the electronic clinical records. Daily prescriptions were collected and analysed based on the AWaRe classification and using days of therapy (DOT) out of 1000 patient days (DOT/1000PDs). The primary outcome was to assess the change in overall antibiotic consumption and of access and watch antibiotics, stratifying patients with and without comorbidities. Trends in antibiotic consumption (DOTs/1000PD) were assessed using joinpoint regression analysis. Findings:A total of 3118 children were included. Total antibiotic consumption remained stable and low in patients without comorbidities, ∼300 DOT/1000PDs, whereas a statistically significant constant reduction was observed in children with comorbidities, from almost 500 DOT/1000PPDs to <400 DOT/1000PDs. Access consumption increased in both groups of patients, whereas watch consumption constantly decreased, although statistically significant only in children with comorbidities. Interpretation:Implementing a multistep ASP has proven feasible and sustainable in improving antibiotic prescriptions for previously healthy and fragile children. All the implemented interventions were low cost, and with efficient use of resources, ensuring an ASP that was effective, practical, and easily replicable and implementable in various healthcare settings.

BACKGROUND:Significant variations in the variables collected in clinical studies focusing on bacteremia lead to inconsistency in the evaluation of risk factors for mortality. OBJECTIVE:We aimed to define a minimum set of risk factors that should be assessed and reported in all studies assessing survival in bacteremia. STUDY ELIGIBILITY:We conducted a systematic review including observational prospective and retrospective cohort studies that assessed all-cause mortality among patients with bacteremia. We included only studies computing an adjusted analysis for mortality, with >500 participants. EXPOSURES:Independently significant risk factors for all-cause, preferably 30-day, mortality. DATA SOURCES:PubMed was used to identify eligible studies published between 2000-2020. A Delphi survey among experts was used to evaluate and prioritize the factors identified by the systematic review. RISK OF BIAS:SIGN checklist complemented by risk of bias assessment of the adjusted analysis. DATA SYNTHESIS:Definite universal risk factors were defined as those assessed in >50% of all included studies and significant in >50% of those. Potential universal risk factors were defined as those significant in >50% of studies evaluating the factor and A subgroup analysis was performed for studies of Staphylococcus aureus (SA) bacteremia. RESULTS:We included in the systematic review 62 studies, comprising more than 300,000 patients, from which a list of 17 risk factors was derived, whose association with all-cause mortality was statistically significant in most studies. The factors address baseline patient variables, the setting of infection acquisition, factors associated with the specific infection, the inflammatory response at onset of sepsis and management parameters where relevant. There were 14 risk factors for SA bacteremia. CONCLUSION:We identified a minimum set of universal factors to be collected, reported, and assessed, in all future studies evaluating factors associated with mortality in bacteremia to improve study quality and harmonization.

Objective: To describe the implementation of a multi-step antimicrobial stewardship program in a haemato-oncology and stem cell transplantation program unit. Methods: Pre-post quasi-experimental study with two interrupted time-series analyses, conducted between 01/01/2019 and 31/12/2022 in the Paediatric Haemato-Oncology Unit of the Padua Paediatric Hospital. The interventions were: (1) 02/2020: dissemination of febrile neutropenia clinical pathways, (2) April 2021: provision of the clinical pathways via a customized App (Firstline.org) and implementation of a twice-a-week prospective audit and feedback. The main outcome was antibiotic consumption measured by days of administered therapy (DOTs)/1000 patients’ days for all antibiotics and most used molecules. Results: The first intervention (clinical pathways) resulted in a decrease in the overall antibiotic use by the haemato-oncology unit, with an abrupt reduction of 3-gen cephalosporins in favor of piperacillin-tazobactam, as indicated by the clinical pathways. Meropenem and glycopeptide use did not vary. The second intervention (antimicrobial stewardship) further decreased total antibiotic consumption, and a significant decline in meropenem, amikacin, and glycopeptides was achieved. Conclusions: Multi-step stewardship based on guidelines dissemination, multidisciplinary team intervention and collaboration (“handshake” stewardship) was highly effective in optimizing guidelines adherence and reducing overprescriptions in a fragile patient cohort.

Background Following intense efforts to revive the dry antibiotic research and development pipeline, a few highly awaited antibiotics with activity against multidrug-resistant (MDR) bacteria were recently approved. Objectives We aim to highlight gaps in the evidence generated for new antibiotics by the time of their approval and to review the consequent limitations of treatment guidelines for priority MDR bacteria. We also report on the availability of the new antibiotics, reimbursement strategies allowing the use of these antibiotics in hospitals, and antibiotic stewardship efforts. Sources We searched PubMed for phase 3 randomized controlled trials, guidelines, and publications on access, usage, regulatory aspects and antimicrobial stewardship of antibiotics approved for use against MDR bacteria between 2013 and 2023. Other sources included governmental and professional documents regarding policies for reimbursement and use of the new antibiotics. Content Several gaps in the evidence available regarding the new antibiotics are described related to the trials' target populations, comparators, management algorithm within the trial, non-inferiority hypotheses, and assessment of resistance development within the studies. We highlight the risk of current guidelines to increase the usage of new antibiotics and consequently accelerate resistance development. Updated mapping of antibiotic availability reveals critical inequality in access to the new antibiotics. Finally, strategies used nationally in Europe to provide access to the new antibiotics are not sufficiently balanced by antibiotic stewardship efforts to calibrate the judicious use of the new antibiotics. Implications Antibiotic resistance is an immediate threat. The present review highlights areas where more systematic and uniform strategies across countries and geographical regions are warranted to improve evidence, availability, and use of new broad-spectrum antibiotics.

Infection control programs and antimicrobial stewardship have been proven effective in reducing the burden of diseases due to multidrug-resistant organisms, but quantifying the effect of each intervention is an open issue. For this aim, we propose a model to characterize the effect of interventions at single ward level. We adapted the Ross-Macdonald model to describe hospital cross-transmission dynamics of carbapenem resistant Klebsiella pneumoniae (CRKP), considering healthcare workers as the vectors transmitting susceptible and resistant pathogens among admitted patients. The model parameters were estimated from a literature review, further adjusted to reproduce observed clinical outcomes, and validated using real life data from a 2-year study in a university hospital. The model has been further explored through extensive sensitivity analysis, in order to assess the relevance of single interventions as well as their synergistic effects. Our model has been shown to be an effective tool to describe and predict the impact of interventions in reducing the prevalence of CRKP colonisation and infection, and can be extended to other specific hospital and pathological scenarios to produce tailored estimates of the most effective strategies.

Background and purpose Bacterial infections represent a major cause of morbidity and mortality in cirrhotic patients. Our aim was to assess the incidence of bacterial infections, in particular due to multidrug-resistant organisms (MDROs) before and after the introduction of the antimicrobial stewardship program, "Stewardship Antimicrobial in VErona" (SAVE). In addition, we also analysed the liver complications and the crude mortality during the whole follow up. Methods We analysed 229 cirrhotic subjects without previous hospitalization for infections enrolled at the University Verona Hospital from 2017 to 2019 and followed up until December 2021 (mean follow-up 42.7 months). Results 101 infections were recorded and 31.7% were recurrent. The most frequent were sepsis (24.7%), pneumonia (19.8%), spontaneous bacterial peritonitis (17.8%). 14.9% of infections were sustained by MDROs. Liver complications occurred more frequently in infected patients, and in case of MDROs infections with a significantly higher MELD and Child-Pugh score. In Cox regression analysis, mortality was associated with age, diabetes and bacterial infections episodes (OR 3.30, CI 95%: (1.63-6.70). Despite an increase in total infections over the past three years, a decrease in the incidence rate in MDROs infections was documented concurrently with the introduction of SAVE (IRD 28.6; 95% CI: 4.6-52.5, p = 0.02). Conclusions Our study confirms the burden of bacterial infections in cirrhotic patients, especially MDROs, and the strong interconnection with liver complications. The introduction of SAVE decreased MDROs infections. Cirrhotic patients require a closer clinical surveillance to identify colonized patients and avoid the horizontal spread of MDROs in this setting.

Promoting the optimal use of antibiotics through evidence-based recommendations should be regarded as a crucial step in the global fight against antimicrobial resistance. Within this scope, several guidelines and guidance documents for antibiotic therapy have been published in recent years. All documents underline the limitations of existing evidence and remark on the need for tailoring recommendations at the national level, based on local epidemiology, availability of diagnostics and drugs, and antimicrobial stewardship principles. The GRADE-ADOLOPMENT methodology is an evidence-based methodology that allows the adoption, adaptation, and update of existing recommendations to specific settings without performing de novo systematic reviews and grading of the evidence. However, procedures to integrate this evidence with stewardship principles, countries' surveillance data, and capacity in terms of diagnostics and antibiotics' availability have never been defined. This Personal View provides the first example of a country's calibration of international evidence-based guidance documents on treating infections caused by multidrug-resistant bacteria. A panel of experts convened by the Italian Medicine Agency (AIFA) used the GRADE methodology for systematically extracting and evaluating 100 recommendations on the treatment of infections due to multidrug-resistant Gram-negative bacteria from 11 guidance documents and 24 systematic reviews. The ADOLOPMENT procedure was used to calibrate the existing recommendations to the national context, leading to the adoption of 64, the adaptation of 27, and the rejection of nine recommendations. We discuss the technical details of the GRADE-ADOLOPMENT application, the calibration process, and the human resources required to support such an effort. This Personal View also covers the challenges of integrating antibiotic stewardship principles in evidence-based recommendations for treating infections with very limited therapeutic and diagnostic options. The details presented here could support the easy transferability of the methodology to other countries and settings, particularly where the incidence of antibiotic-resistant infections is high.