Effectiveness, Safety, and Patterns of Real-World Isavuconazole Use in Europe (2015-2019).

INTRODUCTION: Real-world data from multinational observational studies are required to better understand the role and performance of isavuconazole in real-world practice in Europe. METHODS: A retrospective medical record review was conducted at 16 sites in Europe (France, Germany, Italy, Spain, and the United Kingdom). Eligible records were from patients aged ≥ 18 years at the time of isavuconazole initiation and received at least one dose of isavuconazole for suspected or confirmed invasive aspergillosis (IA) or invasive mucormycosis (IM) during the eligibility period (October 15, 2015 to June 30, 2019). Data were descriptively analysed. Success rates, overall survival, and times to these events were descriptively analysed. RESULTS: Data were abstracted from 218 patients (201, IA; 17, IM) who received isavuconazole as monotherapy (initiated as infusion, 52%; oral, 46%). Isavuconazole was initiated as primary therapy in 92 patients (42.2%) and salvage therapy in 121 patients (55.5%) (unknown for five patients). Mean (standard deviation) age was 56.8 (15.6) years, 66% were men and 62% had at least three comorbidities, most frequently haematologic malignancy (62%). Estimated clinical response rate at week 24 was 54.5% (95% confidence interval [CI], 38.2-66.5%) for primary treatment and 73.5% (95% CI, 62.7-81.1%) for salvage therapy. Overall, 45 patients (21%) experienced at least one adverse event (AE). Serious AEs were experienced by 37 patients (17%), with seven related to isavuconazole; five patients (2.3%) discontinued isavuconazole monotherapy due to the serious AE. A total of 137 patients (63%) died, with 17 deaths (12.4%) related to their invasive fungal infection, 11 of whom initiated isavuconazole as salvage therapy. CONCLUSIONS: This study adds to the growing body of evidence that whether used as first-line therapy or after the failure of other antifungal therapies, isavuconazole appears to have a promising clinical response and a good safety profile as an antifungal agent in patients with varied underlying conditions.

Orbital Myositis after Herpes Zoster Ophthalmicus: A Case Report and a Narrative Review of the Literature.

Herpes zoster ophthalmicus results from the reactivation of the latent varicella zoster virus, affecting the first branch of the trigeminal nerve. In 20-70% of cases, Zoster Ophthalmicus can lead to ocular involvement, affecting various orbital structures. Orbital myositis is a rare but severe complication of herpes zoster ophthalmicus. We present a case of a 52-year-old man with no significant medical history who developed zoster-associated right ocular myositis and dacryocystitis. He was treated with intravenous acyclovir and oral steroids. A review of the literature identified 29 patients across 19 studies. The median age was 61 years, with a slight female predominance. In 55% of cases, the patients had no notable medical history. The most common presentation of myositis involved all oculomotor muscles. There were 22 cases who were treated with intravenous antiviral therapy and 19 received steroids. A full resolution of symptoms was achieved in 51.7% of patients. Zoster-related orbital myositis is a rare complication that should be considered even in immunocompetent individuals. It may occur either before or after the appearance of a vesicular rash. Magnetic resonance imaging is the preferred radiological exam for assessing orbital involvement. Intravenous antiviral therapy should be started within 72 h of symptom onset, and its combination with systemic corticosteroids appears to be an effective treatment for zoster-related ocular myositis.

Impact of adequate empirical combination therapy on mortality in septic shock due to Pseudomonas aeruginosa bloodstream infections: a multicentre retrospective cohort study.

OBJECTIVES: To determine the association of adequate empirical combination therapy (AECT) with 30-day all-cause mortality in patients with septic shock due to Pseudomonas aeruginosa bloodstream infections (BSI). METHODS: This multicentre, retrospective cohort study analysed data from 14 public hospitals in Italy, including all consecutive adult patients admitted during 2021-2022 with septic shock due to P. aeruginosa BSI. We compared the outcomes of patients receiving AECT to those on adequate empirical monotherapy (AEMT) using Cox regression analyses. RESULTS: Of the 98 patients who received adequate empirical antibiotic treatment for septic shock due to P. aeruginosa BSI, 24 underwent AECT and 74 were given AEMT. AECT was associated with a lower 30-day all-cause mortality (25%, six out of 24) compared to AEMT (56.8%, 42 out of 74; P = 0.007). Multivariate Cox regression analysis indicated AECT as the only factor significantly associated with improved survival (aHR 0.30; 95% CI 0.12-0.71; P = 0.006). By contrast, the use of monotherapy or combination therapy in the definitive regimen did not influence mortality (aHR 0.73; 95% CI 0.25-2.14; P = 0.568). CONCLUSIONS: AECT may be associated with reduced mortality compared to monotherapy in septic shock patients due to P. aeruginosa BSI. However, the administration of definitive adequate monotherapy or combination therapy yields similar outcomes, suggesting that once susceptibility is documented, switching to a single active in vitro drug is safe and feasible. Further studies are recommended to validate these findings.

BrainAgeNeXt: Advancing Brain Age Modeling for Individuals with Multiple Sclerosis.

Aging is associated with structural brain changes, cognitive decline, and neurodegenerative diseases. Brain age, an imaging biomarker sensitive to deviations from healthy aging, offers insights into structural aging variations and is a potential prognostic biomarker in neurodegenerative conditions. This study introduces BrainAgeNeXt, a novel convolutional neural network inspired by the MedNeXt framework, designed to predict brain age from T1-weighted magnetic resonance imaging (MRI) scans. BrainAgeNeXt was trained and validated on 11,574 MRI scans from 33 private and publicly available datasets of healthy volunteers, aged 5 to 95 years, imaged with 3T and 7T MRI. Performance was compared against three state-of-the-art brain age prediction methods. BrainAgeNeXt achieved a mean absolute error (MAE) of 2.78 ± 3.64 years, lower than the compared methods (MAE = 3.55, 3.59, and 4.16 years, respectively). We tested all methods also across different levels of image quality, and BrainAgeNeXt performed well even with motion artifacts and less common 7T MRI data. In three longitudinal multiple sclerosis (MS) cohorts (273 individuals), brain age was, on average, 4.21 ± 6.51 years greater than chronological age. Longitudinal analysis indicated that brain age increased by 1.15 years per chronological year in individuals with MS (95% CI = [1.05, 1.26]). Moreover, in early MS, individuals with worsening disability had a higher annual increase in brain age compared to those with stable clinical assessments (1.24 vs. 0.75, p < 0.01). These findings suggest that brain age is a promising prognostic biomarker for MS progression and potentially a valuable endpoint for clinical trials.

Maribavir treatment for resistant cytomegalovirus disseminated disease in kidney transplant recipients: A case-based scoping review of real life data in literature.

The treatment of refractory CMV is often associated with high toxicity. Maribavir (MBV) is a novel oral antiviral, known for its favourable safety profile in fragile patients. We describe a case of CMV disease with end organ damage following kidney transplantation at high risk, for recipient-donor serological mismatch. A 54-year-old female with history of obesity, hypertension, and chronic kidney disease, on prednisone and tacrolimus after kidney transplantation in November 2022, soon after developed primary CMV infection, treated with Valganciclovir and CMV Ig. In January 2023 the patient presented with fever and dyspnea. Pulmonary miliary opacities and right-upper lobe consolidation were found at CT-scan along with CMV-DNA positivity on BAL and serum. Lung biopsy confirmed CMV infection. Antiviral was switched to Ganciclovir. Despite initial benefit, fever and respiratory failure happened 8 days later, leading to intubation at day 15. Due to slow decrease serum CMV-DNA and detection of UL97 mutation, conferring resistance to valganciclovir and ganciclovir, the patient was started on foscarnet and letermovir. She was extubated after a gradual respiratory improvement and discharged from ICU to rehabilitation department with HFNC; reduction in serum CMV-DNA, but persistently elevated CMV-DNA on BAL were documented. At week 8, MBV was started and letermovir continued, for a 8 weeks course, without notable adverse effects. Respiratory function improved but soon after septic shock occurred. A bone marrow biopsy resulted in lymphoma, without indications for treatment: the patient developed coma and died 6 months after admission. MBV has recently been approved in Europe for treatment of R/R CMV in HSCT and SOT recipients. MBV showed superior rates of viraemia clearance after 8 weeks compared to SOC, demonstrating also a favourable safety profile with fewer patients discontinuing treatment and being affected by nephrotoxicity and neutropenia. Its main side effects are taste impairment, gastro-intestinal symptoms and asthenia. Based on actual promising perspectives regarding antiviral stewardship, more data are required to corroborate benefit of MBV in terms of toxicity and impact on mortality in highly fragile populations as SOT recipients. MBV received approval for the treatment of refractory or resistant CMV infections to other antiviral agents. Nevertheless, real-life data on efficacy and safety of MBV are still lacking. We conducted a narrative review of the current literature on MBV as treatment for CMV infection in kidney transplant recipients to understand clinical characteristics, safety and outcomes of MBV in this population. A search was run on the main scientific databases. 194 papers were identified, of which 188 were excluded by title and abstract evaluation. Subsequently, 6 papers were included. We performed descriptive statistics on the entire study population. The studies included in our analysis showed a higher prevalence of male subjects. The median age was 57 year. CKD was the most frequently reported comorbidity. Seven patients reported a donor/recipient mismatch (D+/R-). The case report and the cohort of patients collected from the literature show that MBV was used as an option in R/R CMV, notably for the presence or suspicion of CMV resistance to previous treatment. The clinical presentation of CMV in kidney SOT was heterogenous and varied from isolated reactivation of CMV-DNAemia, isolated fever or gastrointestinal involvement. For mild to moderate CMV disease, as with the cases reported in our review, or for proven ganciclovir, foscarnet or cidofovir resistance, MBV could be a valuable option. Outcomes of the patients treated with MBV were not reported in all the studies; however, where reported, 45.4% of the cases developed virological failure during MBV treatment with the development of specific resistance to MBV. MBV was generally well-tolerated, with low rates of toxicity, normally reversible. The introduction of new oral antivirals, such as MBV, could improve treatment, prophylaxis and preemptive treatment strategies, especially in anti-CMV treatment experienced patients.

First step results from a phase II study of a dendritic cell vaccine in glioblastoma patients (CombiG-vax).

Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test). Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT).

Risk factors for mortality in Acinetobacter baumannii bloodstream infections and development of a predictive mortality model.

OBJECTIVES: Acinetobacter baumannii (A. baumannii) nosocomial infections represent a serious hazard to public health, given high mortality rates and rapid spread of multidrug-resistance. The primary outcome of this study was to evaluate predictors of 14- and 30-d mortality in bloodstream infections (BSIs) due to both carbapenem-resistant and carbapenem-sensitive Acinetobacter. Secondary end points were to identify risk factors for BSIs due to carbapenem-resistant A. baumannii (CRAB) and to develop a predictive model for mortality in CRAB-related BSIs. METHODS: Between 2019 and 2023, all consecutive hospitalized adult patients with bacteraemia due to A. baumannii were retrospectively enrolled at a single-centre. RESULTS: One hundred twenty-six episodes of BSI caused by A. baumannii were recorded, 89.7% of which were due to CRAB. Recent burn injuries, older age, previous CRAB colonization, and antibiotics exposure were identified as risk factors for acquiring CRAB BSI. Overall, 14-d mortality was observed in 26.1% of the patients and 30-d mortality in 30.9% of the patients. On multivariate analysis, the Sequential Organ Failure Assessment (SOFA) score was associated with both 14- and 30-d mortality, whereas burn injuries correlated with 30-d survival. Concurrent coronavirus disease (COVID) was associated with mortality, although not reaching statistical figures. No major impact of receiving appropriate treatment was observed. Based on these findings, a multivariable model to predict mortality among patients with CRAB BSI was built and internally validated. CONCLUSIONS: A. baumannii BSIs are characterized by poor outcomes and limited therapeutic options. This study aimed to assist physicians in prompt identification of patients who are at greater risk of death, contributing to more informed clinical decision making.

Use of Cefiderocol in Adult Patients: Descriptive Analysis from a Prospective, Multicenter, Cohort Study.

INTRODUCTION: Cefiderocol is a siderophore cephalosporin showing activity against various carbapenem-resistant Gram-negative bacteria (CR-GNB). No data currently exist about real-world use of cefiderocol in terms of types of therapy (e.g., empirical or targeted, monotherapy or combined regimens), indications, and patient characteristics. METHODS: In this multicenter, prospective study, we aimed at describing the use of cefiderocol in terms of types of therapy, indications, and patient characteristics. RESULTS: Cefiderocol was administered as empirical and targeted therapy in 27.5% (55/200) and 72.5% (145/200) of cases, respectively. Overall, it was administered as monotherapy in 101/200 cases (50.5%) and as part of a combined regimen for CR-GNB infections in the remaining 99/200 cases (49.5%). In multivariable analysis, previous isolation of carbapenem-resistant Acinetobacter baumannii odds ratio (OR) 2.56, with 95% confidence interval (95% CI) 1.01-6.46, p = 0.047] and previous hematopoietic stem cell transplantation (OR 8.73, 95% CI 1.05-72.54, p = 0.045) were associated with administration of cefiderocol as part of a combined regimen, whereas chronic kidney disease was associated with cefiderocol monotherapy (OR 0.38 for combined regimen, 95% CI 0.16-0.91, p = 0.029). Cumulative 30-day mortality was 19.8%, 45.0%, 20.7%, and 22.7% in patients receiving targeted cefiderocol for infections by Enterobacterales, A. baumannii, Pseudomonas aeruginosa, and any metallo-ß-lactamase producers, respectively. CONCLUSIONS: Cefiderocol is mainly used for targeted treatment, although empirical therapies account for more than 25% of prescriptions, thus requiring dedicated standardization and guidance. The almost equal distribution of cefiderocol monotherapy and cefiderocol-based combination therapies underlines the need for further study to ascertain possible differences in efficacy between the two approaches.

Management of Clostridioides difficile infection: an Italian Delphi consensus.

BACKGROUND: Clostridioides difficile infection (CDI), a leading cause of nosocomial deaths, is a microbiota-mediated disease. As such, the use of broader spectrum antibiotics, such as vancomycin and metronidazole, can prime the gastrointestinal tract to become more prone to CDI recurrences. Fidaxomicin, a narrow-spectrum antibiotic, has been demonstrated to be superior in preventing recurrence and in preserving the intestinal microbiota; however, widespread employment worldwide has been hindered due to high acquisition costs. OBJECTIVES: To integrate the currently available guidelines on the management of CDI and to shed light on the timeliest employment of fidaxomicin. METHODS: An expert panel was gathered to obtain consensus using Delphi methodology on a series of statements regarding the management of CDI and on appropriate antibiotic use. RESULTS: Consensus was reached on 21 of the 25 statements addressing the management of CDI. CONCLUSIONS: Delphi methodology was used to achieve consensus on the management of CDI, on the identification of patients at risk of recurrences or severe infection, and on the most appropriate use of fidaxomicin, with the final aim of fostering clinical practice application of treatment algorithms proposed by previous guidelines, in absolute synergy. It could be an important tool to promote more appropriate and cost-effective CDI treatments in European settings with limited resources, like Italy.

Clinical and microbiological features of positive blood culture episodes caused by non-fermenting gram-negative bacilli other than Pseudomonas and Acinetobacter species (2020-2023).

INTRODUCTION: Non-fermenting Gram-negative bacilli (NFGNB) other than Pseudomonas aeruginosa and Acinetobacter baumannii complex are pathogens of interest due to their ability to cause health-care associated infections and display complex drug resistance phenotypes. However, their clinical and microbiological landscape is still poorly characterized. METHODS: Observational retrospective study including all hospitalized patients presenting with a positive positive blood culture (BC) episode caused by less common NFGNB over a four-year period (January 2020-December 2023). Clinical-microbiological features and factors associated with mortality were investigated. RESULTS: Sixty-six less common NFGNB isolates other than Pseudomonas and Acinetobacter species causing 63 positive BC episodes were recovered from 60 patients. Positive BC episodes were predominantly sustained by Stenotrophomonas maltophilia (49.2%) followed by Achromobacter species (15.9%) that exhibited the most complex resistance phenotype. Positive BC episodes had bloodstream infection criteria in 95.2% of cases (60 out 63), being intravascular device (30.2%) and respiratory tract (19.1%) the main sources of infection. Fourteen-day, 30-day, and in-hospital mortality rates were 6.4%, 9.5%, and 15.9%, respectively. The longer time from admission to the positive BC episode, older age, diabetes, admission due to sepsis, and higher Charlson Comorbidity Index were identified as the main predictors of in-hospital mortality. CONCLUSIONS: Positive BC episodes sustained by NFGNB other than Pseudomonas and Acinetobacter species were predominantly sustained by Stenotrophomonas maltophilia and Achromobacter species, having bloodstream infection criteria in the vast majority of cases. Factors that have emerged to be associated with mortality highlighted how these species may have more room in prolonged hospitalisation and at the end of life for patients with chronic organ diseases.

Dendritic cell vaccines as cancer treatment: focus on 13 years of manufacturing and quality control experience in advanced therapy medicinal products.

BACKGROUND AIMS: Dendritic cells (DCs) are professional antigen-presenting cells of the mammalian immune system. Ex vivo differentiated DCs represent a unique Advanced Therapy Medicinal Product (ATMP), used in several clinical trials as personalized cancer immunotherapy. The therapy's reliability depends on its capacity to produce high-quality mature DCs (mDCs) in compliance with Good Manufacturing Practices. AIMS: From March 2010 to December 2023, 103 patients were enrolled in multiple clinical trials at the Immuno-Gene Therapy Factory at IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori". Six hundred forty-two doses were produced, and the manufacturing process was implemented to optimize production. Our study is a retrospective analysis focusing on the quality control results. METHODS: We retrospectively analyzed the results of the quality control tests carried out on each produced batch, evaluating viability, purity and phenotype of mDCs and their quality in terms of microbiological safety. The data obtained are given with median and interquartile range. RESULTS: The batches were found to be microbiologically safe in terms of sterility, mycoplasma, and endotoxins. An increase in DC maturation markers was found. The release criteria checks showed a high percentage of viability and purity was maintained during the production process. CONCLUSIONS: Our findings have confirmed that the measures implemented have ensured the safety of the products and have contributed to the establishing a robust "Pharmaceutical Quality System." This has enabled many safe mDCs to be produced for clinical trials.

Risk of Infection in Patients With Multiple Myeloma Treated With T-Cell Redirecting Approaches: A Call Out for Clinicians.

T-cell redirecting therapies such as chimeric antigen receptor T-cells and bispecific antibodies, are emerging as a novel class of immunotherapeutic agents for treatment of relapsed refractory multiple myeloma (MM). Their use is associated with an increased risk of infectious adverse events, fostered by cytopenias, hypogammaglobulinemia and T-cell exhaustion. Multiple ongoing clinical trials and real-world studies are investigating safety of T-cell therapy, highlighting the need for strategies to prevent and monitor the risk of infection. Recommended measures for risk mitigation include intravenous immunoglobulin supplementation, adequate prophylaxis therapy, vaccination and careful assessment for early diagnosis and treatment of infection. Here, we summarize available data on the risk of infections with approved and under development T-cell redirecting therapies for the treatment of MM.

Outcomes and Predictors of Mortality in Patients With KPC-Kp Infections Treated With Meropenem Vaborbactam: An Observational Multicenter Study.

Background: Meropenem-vaborbactam is a recent and promising option for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, including those resistant to ceftazidime-avibactam. Methods: We conducted a retrospective analysis of observational data from 19 Italian hospitals on use and outcomes of patients treated with meropenem-vaborbactam for at least ≥24 hours for KPC-Kp infections. Crude and propensity-weighted multiple Cox regression models were performed to ascertain risk factors independently associated with 30-day mortality. Results: The cohort included 342 adults with bloodstream infections (n = 172) and nonbacteremic infections (n = 170), of which 107 were lower respiratory tract infections, 30 were complicated urinary tract infections, and 33 were infections involving other sites. Most infections (62.3%) were managed with meropenem-vaborbactam monotherapy, or in combination with at least 1 other active drug (usually fosfomycin, tigecycline, or gentamicin) (37.7%). The 30-day mortality rate was 31.6% (108/342). In multiple Cox regression model, 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index ≥ 3, dialysis, concomitant COVID-19, and INCREMENT score ≥ 8. Administration of meropenem-vaborbactam within 48 hours from infection onset was a negative predictor of mortality. All predictors, except administration of meropenem-vaborbactam within 48 hours, remained significant when the multiple Cox regression model was repeated after adjustment for the propensity score for receipt of combination therapy. Conclusions: Despite the limits of a retrospective study, the data derived from this multicenter cohort provide additional evidence on the efficacy of meropenem-vaborbactam in treating severe KPC-Kp infections, even when used as monotherapy.

Management of intra-abdominal infections: recommendations by the Italian council for the optimization of antimicrobial use.

Intra-abdominal infections (IAIs) are common surgical emergencies and are an important cause of morbidity and mortality in hospital settings, particularly if poorly managed. The cornerstones of effective IAIs management include early diagnosis, adequate source control, appropriate antimicrobial therapy, and early physiologic stabilization using intravenous fluids and vasopressor agents in critically ill patients. Adequate empiric antimicrobial therapy in patients with IAIs is of paramount importance because inappropriate antimicrobial therapy is associated with poor outcomes. Optimizing antimicrobial prescriptions improves treatment effectiveness, increases patients' safety, and minimizes the risk of opportunistic infections (such as Clostridioides difficile) and antimicrobial resistance selection. The growing emergence of multi-drug resistant organisms has caused an impending crisis with alarming implications, especially regarding Gram-negative bacteria. The Multidisciplinary and Intersociety Italian Council for the Optimization of Antimicrobial Use promoted a consensus conference on the antimicrobial management of IAIs, including emergency medicine specialists, radiologists, surgeons, intensivists, infectious disease specialists, clinical pharmacologists, hospital pharmacists, microbiologists and public health specialists. Relevant clinical questions were constructed by the Organizational Committee in order to investigate the topic. The expert panel produced recommendation statements based on the best scientific evidence from PubMed and EMBASE Library and experts' opinions. The statements were planned and graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence. On November 10, 2023, the experts met in Mestre (Italy) to debate the statements. After the approval of the statements, the expert panel met via email and virtual meetings to prepare and revise the definitive document. This document represents the executive summary of the consensus conference and comprises three sections. The first section focuses on the general principles of diagnosis and treatment of IAIs. The second section provides twenty-three evidence-based recommendations for the antimicrobial therapy of IAIs. The third section presents eight clinical diagnostic-therapeutic pathways for the most common IAIs. The document has been endorsed by the Italian Society of Surgery.

Different profiles of acute graft pyelonephritis among kidney recipients from standard or elderly donors.

Background: Acute graft pyelonephritis (AGPN) is a relatively common complication in kidney transplants (KTs); however, the effects on allograft function, diagnostic criteria, and risk factors are not well established. Methods: Retrospective analysis of all consecutive adult KTs was performed between 01 January 2011 and 31 December 2018 (follow-up ended on 31 December 2019) to examine the association between the diagnosis of AGPN (confirmed with magnetic resonance imaging [MRI]) during the first post-transplantation year and graft outcomes. Results: Among the 939 consecutive KTs (≈50% with donors ≥60 years), we identified 130 MRI-confirmed AGPN episodes, with a documented association with recurrent and multidrug-resistant bacterial urinary tract infections (UTIs) (p < 0.005). Ureteral stenosis was the only risk factor associated with AGPN (OR 2.9 [95% CI, 1.6 to 5.2]). KTs with AGPN had a decreased allograft function at the first year (ΔeGFR 6 mL/min/1.73 m2 [-2-15] in non-AGPN vs. -0.2 [-6.5-8.5] in AGPN, p < 0.001), with similar and negative profiles in KTs from standard or elderly donors. However, only KTs with AGPN and a donor <60 years showed reduced death-censored graft survival (p = 0.015); most of this subgroup received anti-thymocyte globulin (ATG) induction (40.4% vs. 17.7%), and their MRI presented either a multifocal AGPN pattern (73.9% vs. 56.7%) or abscedation (28.3% vs. 11.7%). No difference was noted in death-censored graft survival between early (<3 months post-KT) or late (3-12 months) AGPN, solitary/recurrent forms, or types of multidrug-resistant pathogens. Linear regression confirmed the independent role of multifocal pattern, abscedation, ATG induction, and donor age on the eGFR at the first year. Conclusion: AGPN, influenced by multifocal presentation, ATG induction, donor age, and abscedation, affects kidney function and significantly impacts allograft survival in KTs with donors <60 years.

Impact of COVID-19 on antimicrobial stewardship activities in Italy: a region-wide assessment.

BACKGROUND: In the region of Piedmont, in Northern Italy, formal monitoring of antimicrobial stewardship (AMS) programs has been in place since 2012. The objective of our study was to provide an updated assessment of AMS programs operating in our region, and to assess the impact of the COVID-19 pandemic on stewardship activities. METHODS: A retrospective observational study was conducted to investigate AMS programs implemented in acute-care trusts participating in a broader healthcare-associated infections and antimicrobial resistance (AMR) prevention and control program, promoted by the regional health department. Within this program, structure, process, and outcome indicators of AMS programs were investigated, using a previously developed scoring system. Differences between scores prior to (2019) and during the pandemic (2021) were assessed. Linear regression was used to assess whether the 5-year trends (2017-2021) in outcome measures in relation to structure and process scores were statistically significant. Compound annual growth rates (CAGR) for each outcome were calculated to illustrate changes in outcome rates over time. RESULTS: All public trusts in the Region (20) and a small number of private institutions (3) provided data for this study. A modest, non-significant improvement was found for 2021 structure, process, and total scores compared to respective 2019 scores. A significant improvement was found concerning the definition of a formal mission statement, whereas significantly less trusts included monitoring adherence to antimicrobial policy or treatment guidelines in their programs. Overall consumption of antibiotics for systemic use saw an increase in 2021, with 2021 recording the highest median overall consumption compared to all previous years considered in this study. Methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant enterobacteria (CRE) rates decreased over the 5-year period. Significant downwards trends in MRSA rates were identified for high-outlier structure and process groups. CONCLUSIONS: Results of this study suggest AMS programs in Piedmont were not set back following the pandemic. This outcome was possible thanks to well-established programs, coordinated within a regional framework. Continued efforts should be dedicated to supporting AMS programs and contrasting AMR, even when the focus is shifted towards other public health emergencies.

Real-World Experience of Ceftobiprole for Community- and Hospital-Acquired Pneumonia from a Stewardship Perspective.

Ceftobiprole is a fifth-generation cephalosporin approved by European and American regulatory agencies for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). Ceftobiprole administration is useful in severe CAP as well as HAP where the potential is to save other ß-lactams including carbapenems or linezolid/vancomycin in clinical practice. The aim of this study was to report the real-world evidence of ceftobiprole in patients with CAP and HAP in a single center. In this retrospective study, we included 159 patients with CAP or HAP: 105 (66%) had CAP and 54 (34%) had HAP. The median age was 70 years (IQR 60-77), the median Charlson Comorbidity Index was 5 (IQR 3-7.5) and baseline INCREMENT ESBL score was 8 (IQR 6-11). Ceftobiprole was mostly given as a combination treatment (77%) or as a carbapenem-sparing strategy (44%). There were no differences in mortality between shorter and longer duration of treatment (<7 days compared with ≥7 days (HR 1.02, C.I. 0.58-1.77, p = 0.93) or between first-line (HR 1.00, C.I. 0.46-2.17, p = 0.989) and second-line therapy. Ceftobiprole use in CAP or HAP in the real world is effective as a first- and second-line treatment as well as a carbapenem-sparing strategy. Further studies are needed to explore the full potential of ceftobiprole, including its real-world use in antimicrobial stewardship programs.

Adjunctive immunotherapeutic agents in patients with sepsis and septic shock: a multidisciplinary consensus of 23.

BACKGROUND: In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. METHODS: A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. RESULTS: The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. CONCLUSIONS: Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

Multidrug-resistant pathogens and ventilator-associated pneumonia in critically ill COVID-19 and non-COVID-19 patients: a prospective observational monocentric comparative study.

BACKGROUND: The COVID-19 pandemic has increased the incidence of ventilator-associated pneumonia (VAP) among critically ill patients. However, a comparison of VAP incidence in COVID-19 and non-COVID-19 cohorts, particularly in a context with a high prevalence of multidrug-resistant (MDR) organisms, is lacking. MATERIAL AND METHODS: We conducted a single-center, mixed prospective and retrospective cohort study comparing COVID-19 patients admitted to the intensive care unit (ICU) of the "Città della Salute e della Scienza" University Hospital in Turin, Italy, between March 2020 and December 2021 (COVID-19 group), with a historical cohort of ICU patients admitted between June 2016 and March 2018 (NON-COVID-19 group). The primary objective was to define the incidence of VAP in both cohorts. Secondary objectives were to evaluate the microbial cause, resistance patters, risk factors and impact on 28 days, ICU and in-hospital mortality, duration of ICU stay, and duration of hospitalization). RESULTS: We found a significantly higher incidence of VAP (51.9% - n = 125) among the 241 COVID-19 patients compared to that observed (31.2% - n = 78) among the 252 NON-COVID-19 patients. The median SOFA score was significantly lower in the COVID-19 group (9, Interquartile range, IQR: 7-11 vs. 10, IQR: 8-13, p < 0.001). The COVID-19 group had a higher prevalence of Gram-positive bacteria-related VAP (30% vs. 9%, p < 0.001), but no significant difference was observed in the prevalence of difficult-to-treat (DTR) or MDR bacteria. ICU and in-hospital mortality in the COVID-19 and NON-COVID-19 groups were 71% and 74%, vs. 33% and 43%, respectively. The presence of COVID-19 was significantly associated with an increased risk of 28-day all-cause hospital mortality (Hazard ratio, HR: 7.95, 95% Confidence Intervals, 95% CI: 3.10-20.36, p < 0.001). Tracheostomy and a shorter duration of mechanical ventilation were protective against 28-day mortality, while dialysis and a high SOFA score were associated with a higher risk of 28-day mortality. CONCLUSION: COVID-19 patients with VAP appear to have a significantly higher ICU and in-hospital mortality risk regardless of the presence of MDR and DTR pathogens. Tracheostomy and a shorter duration of mechanical ventilation appear to be associated with better outcomes.

Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM.

PURPOSE: The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs). METHODS: After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method. RESULTS: Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.