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.

The Early Access and the Potential Cost Savings by the Compassionate Use of Onco-haematological Drugs: Results from the Italian Study Compass-O.

BACKGROUND: Compassionate drug use (CDU) provides early access to not yet authorised medicines and is funded by pharmaceutical companies. The observational retrospective study Compass-O monitored the CDU of onco-haematological drugs, managed by seven Italian units for cytotoxic drug preparations (Unità Farmaci Antiblastici [UFA]), between 1 January, 2016 and 31 December, 2021. OBJECTIVE: We aimed to evaluate the CDU of onco-haematological drugs managed by seven Italian UFA, between 2016 and 2021. METHODS: The seven UFA provided anonymised data concerning CDU approved in the study period. The early access and potential cost savings for the National Health System (Servizio Sanitario Nazionale [SSN]) were analysed for CDU concerning drug-therapeutic indication combinations with complete data and reimbursed by SSN up to December 2023 (date of study execution), according to the executive decision of the Italian Medicines Agency (Agenzia Italiana del Farmaco [AIFA]). Both analyses distinguished solid/liquid tumours and categorised the combinations as innovative (fully/conditionally) or non-innovative based on AIFA assessments. RESULTS: Compass-O collected 783 CDU authorisations, with 572 (73.1%) analysable in terms of early access and cost savings. On average, early access amounted to 514 days and the total cost savings was €376,115,801. Compassionate drug use approvals involved mainly solid tumours (93.7% vs 6.3% for liquid tumours), and the combination of trastuzumab emtansine-breast cancer was the most dispensed (n = 73; early access = 426 days; potential cost savings: €610,388). Out of 572 CDU approvals, 200 (35%) were innovative drug-therapeutic indication combinations, with 598 days of early access and a total potential saving of €113,124,069. CONCLUSIONS: The study Compass-O showed a significant economic burden of CDU and a relevant need for early access, particularly for innovative drugs. However, there is currently no structured monitoring of CDU in Italy, suggesting the need for a national observatory, of which Compass-O can be the pilot phase.

The role of the hospital pharmacist to guarantee access and continuity of care for the management of epilepsy.

In this article the pivotal role of hospital pharmacists in the multidisciplinary management of epilepsy is discussed. Hospital pharmacists are members of national and local ethics committees, oversee clinical trials, and ensure adherence to regulations for patient access to novel therapeutic treatments. They actively contribute to regulatory processes and the definition of prescribing centers. In the post-launch phase, hospital pharmacists are a key member in the multidisciplinary team, they are involved in decisions relating to the local introduction of drugs, in the management of the drug within the hospital structure and with the direct distribution, and to ensure proper and timely treatment. The pharmacovigilance network, including hospital and community pharmacists, monitors and prevents adverse effects related to epilepsy medications and enhances a collaborative approach with specialists to promote prescription appropriateness, targeting therapy for better patient outcomes. Finally, the potential benefits of deprescribing are briefly discussed, underscoring the importance of a multidisciplinary approach involving doctors and clinical pharmacists to gather comprehensive data and enhance patient care in epilepsy management.

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.

European Association of Hospital Pharmacists (EAHP) guidance on the pharmacy handling of in vivo gene therapy medicinal products.

Gene therapy is becoming increasingly prevalent, with new gene therapy medicinal products (GTMPs) being approved for use every year. Hospital pharmacists are expected to prepare and dispense these products, but there is substantial heterogeneity in the availability of up-to-date, practical guidance at a national level in Europe. Many institutions have no or very limited experience in handling GTMPs. As such, there is a need for updated, practical guidance to aid hospital pharmacy teams in developing institutional standard operating procedures (SOPs) for the safe handling of GTMPs across the entire workflow. Here, we present the European Association of Hospital Pharmacists' updated guidance on the handling of GTMPs, developed by a team of recognised experts from around Europe. Each aspect of the GTMP handling process is addressed, including receipt and storage, dispensing and reconstitution, transportation, administration, waste disposal, decontamination of spills and accidental exposure. A series of figures are provided to aid the development of practical workflows. This guidance document is intended as a framework to help develop institutional SOPs and should always be used in conjunction with local regulations.

A real-world multicentre evaluation of atezolizumab plus platinum-etoposide chemotherapy as first-line treatment in patients with extensive-stage small cell lung cancer in Italy.

INTRODUCTION: The aim of this study was to analyze real-life data from a cohort of adult patients receiving atezolizumab in combination with carboplatin and etoposide for first-line treatment of ES-SCLC, in order to assess relative dose intensity (RDI), time-to-treatment discontinuation (TTD), time-to-treatment failure (TTF), progression-free survival (PFS), overall survival (OS) of treatments as well as the correlation between these outcomes. METHODS: An observational retrospective study was conducted. All patients treated with atezolizumab combined with carboplatin and etoposide for first-line treatment of ES-SCLC were included. Median TTD, TTF, PFS and OS were calculated in our cohort of patient by the Kaplan Meier method. RESULTS: The curves obtained with the Kaplan Meier method of TTF and TTD are substantially similar, indicating a good concordance of the information extracted by the two different data sources. This tendency was confirmed also when the TTD versus PFS curves were compared. The median OS registered was 11.8 months. Patients with no liver metastases showed a longer median time of OS than patients with liver metastases. The mean value of RDI for the entire cohort was 87.4%. CONCLUSIONS: Our study showed that TTD, calculated from the administration data is a useful proxy of TTF as registered in the clinical chart. TTD is a real-world outcome that can be used to demonstrate the efficacy of drugs used for administered therapies. It can be used as an end point for RWE studies, where the evaluation is less structured and standardized.

Onasemnogene Abeparvovec: Post-infusion Efficacy and Safety in Patients With Spinal Muscular Atrophy (SMA)-A Fondazione Policlinico Gemelli IRCCS Experience.

Objective: The term Spinal Muscular Atrophy (SMA) identifies a group of genetic disorders affecting spinal motor neurons. It is caused by the loss of the SMN1 gene, resulting in degeneration of spinal alpha motor neurons and muscle atrophy. This study is focused on innovative gene therapies with onasemnogene abeparvovec approved in Italy in March 2021 with full reimbursement by the National Health Service. The objective pursued is verify, by means of the CHOP-INTEND scores obtained, whether therapy with onasemnogene abeparvovec led to an improvement in the clinical picture of the treated subjects and any adverse reactions that occurred. Methods: this study was conducted by evaluating the scores in the different re-evaluations of individual patients treated in our hospital (Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Rome) and comparing them with the results of the CL-303 study described in SPC (Summary of Product Characteristics). The data were extracted from the patients' clinical records on the AIFA (Agenzia Italiana del Farmaco - Italian Medicines Agency) registries, also collecting information on any post-infusion ADRs. Everything was then represented graphically to have a clear comparison with the data from the study registered for drug approval. Results: from the data obtained, 7 out of 8 patients improved their health status post infusion with, in some cases, a significant increase in score. Conclusions: this result allows us to understand how crucial it is to start treatment as soon as possible after the diagnosis of the condition as the greatest improvements were seen in subjects who received treatment within 2 months of birth.

Combined treatment of nerve growth factor and transcranical direct current stimulations to improve outcome in children with vegetative state after out-of-hospital cardiac arrest.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is one of the most dramatic events in pediatric age and, despite advanced neurointensive care, the survival rate remains low. Currently, no effective treatments can restore neuronal loss or produce significant improvement in these patients. Nerve Growth Factor (NGF) is a neurotrophin potentially able to counteract many of the deleterious effects triggered by OHCA. Transcranial Direct Current Stimulation (tDCS) has been reported to be neuroprotective in many neurological diseases, such as motor deficit and cognitive impairment. Children with the diagnosis of chronic vegetative state after OHCA were enrolled. These patients underwent a combined treatment of intranasal administration of human recombinant NGF (hr-NGF), at a total dose of 50 gamma/kg, and tDCS, in which current intensity was increased from zero to 2 mA from the first 5 s of stimulation and maintained constant for 20 min. The treatment schedule was performed twice, at one month distance each. Neuroradiogical evaluation with Positron Emission Tomography scan (PET), Single Photon Emission Computed Tomography (SPECT), Electroencephalography (EEG) and Power Spectral Density of the brain (PSD) was determined before the treatment and one month after the end. Neurological assessment was deepened by using modified Ashworth Scale, Gross Motor Function Measure, and Disability Rating Scale. RESULTS: Three children with a chronic vegetative state secondary to OHCA were treated. The combined treatment with hr-NGF and tDCS improved functional (PET and SPECT) and electrophysiological (EEG and PSD) assessment. Also clinical conditions improved, mainly for the reduction of spasticity and with the acquisition of voluntary finger movements, improved facial mimicry and reaction to painful stimuli. No side effects were reported. CONCLUSIONS: These promising preliminary results and the ease of administration of this treatment make it worthwhile to be investigated further, mainly in the early stages from OHCA and in patients with better baseline neurological conditions, in order to explore more thoroughly the benefits of this new approach on neuronal function recovery after OHCA.

Long-Term Spasticity Management in Post-Stroke Patients: Issues and Possible Actions-A Systematic Review with an Italian Expert Opinion.

Spasticity is a well-known motor dysfunction occurring after a stroke. A group of Italian physicians' experts in treating post-stroke spasticity (PSS) reviewed the current scientific evidence concerning the state-of-the-art clinical management of PSS management and the appropriate use of botulinum toxin, aiming to identify issues, possible actions, and effective management of the patient affected by spasticity. The participants were clinicians specifically selected to cover the range of multidisciplinary clinical and research expertise needed to diagnose and manage PSS. When evidence was not available, the panel discussed and agreed on the best way to manage and treat PSS. To address the barriers identified, the panel provides a series of consensus recommendations. This systematic review provides a focused guide in the evaluation and management of patients with PSS and its complications. The recommendations reached by this panel of experts should be used by less-experienced doctors in real life and should be used as a guide on how to best use botulinum toxin injection in treating spasticity after a stroke.

CAR T-Cell Therapies in Italy: Patient Access Barriers and Recommendations for Health System Solutions.

CAR T-cell therapy has emerged as a potentially transformative immunotherapy for certain B-cell malignancies including relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Unhindered and appropriate access for eligible patients is essential to enable optimal outcomes and depends on effective interplay of stakeholders and processes along the patient's therapeutic journey. In Italy, CAR T-cell therapies have been awarded innovation status by the Italian Medicines Agency (AIFA) and were integrated into routine patient care under specific criteria. However, our analysis indicates that fewer than one in five DLBCL patients eligible under the EMA authorization, or around one in three DLBCL patients eligible under the AIFA criteria, received treatment with a licensed CAR T-cell therapy product in 2020. This publication describes key patient access barriers to CAR T-cell therapies in Italy and provides recommendations on potential solutions at the health system level.

Is COVID-19 a Real Incentive for Flu Vaccination? Let the Numbers Speak for Themselves.

Seasonal flu vaccination is one of the most important strategies for preventing influenza. The attitude towards flu vaccination in light of the COVID-19 pandemic has so far been studied in the literature mostly with the help of surveys and questionnaires. Whether a person chooses to be vaccinated or not during the COVID-19 pandemic, however, speaks louder than any declaration of intention. In our teaching hospital, we registered a statistically significant increase in flu vaccination coverage across all professional categories between the 2019/2020 and the 2020/2021 campaign (24.19% vs. 54.56%, p < 0.0001). A linear regression model, based on data from four previous campaigns, predicted for the 2020/2021 campaign a total flu vaccination coverage of 30.35%. A coverage of 54.46% was, instead, observed, with a statistically significant difference from the predicted value (p < 0.0001). The COVID-19 pandemic can, therefore, be considered as an incentive that significantly and dramatically increased adherence to flu vaccination among our healthcare workers.

Price and reimbursement for orphan medicines and managed entry agreements: does Italy need a framework?

This article illustrates a consensus opinion of an expert panel on the need and usefulness of a framework for price and reimbursement (P&R) process and managed entry agreements (MEAs) for orphan medicines in Italy. This opinion was gathered in three rounds: an introductory document was sent to the panel and discussed during a recorded online meeting. A second document was sent to the panel for their review. In the third step the final document was validated. Members of the expert panel are the authors of the article. The panel agreed that Italy does not need a specific value framework for orphan medicines, driving the P&R process. Rather, a more structured value framework for all medicines tailored to the specific drugs can be useful. For orphan drugs, the panel advocated for a multidisciplinary approach and the contribution of different stakeholders to value assessment, and acknowledged the importance of addressing, more than for other drugs, unmet needs, equity issues and societal value. The panel raised the need of increasing the importance of patient-reported outcomes. Experts, acknowledging the growing criticisms in implementation of outcome-based agreements in Italy, expressed their position against their abandonment in favour of discounts only and supported orphan medicines as natural candidates for these agreements. Finally, the panel made some recommendations on the appraisal process for orphan medicines, including an early discussion on the uncertainty of the evidence generated and the adoption of a structured approach to identify the agreement, which better responds to the uncertainty.