Therapeutic Strategies to Combat Increasing Rates of Multidrug Resistant Pathogens.

The emergence of antimicrobic-resistant infectious pathogens and the consequent rising in the incidence and prevalence of demises caused by or associated to infections which are not sensitive to drug treatments is one of today's major global health challenges. Antimicrobial resistance (AMR) can bring to therapeutic failure, infection's persistence and risk of serious illness, in particular in vulnerable populations such as the elderly, patients with neoplastic diseases or the immunocompromised. It is assessed that AMR will induce until 10 million deaths per year by 2050, becoming the leading cause of disease-related deaths. The World Health Organisation (WHO) and the United Nations General Assembly urgently call for new measures to combat the phenomenon. Research and development of new antimicrobial agents has decreased due to market failure. However, promising results are coming from new alternative therapeutic strategies such as monoclonal antibodies, microbiome modulators, nanomaterial-based therapeutics, vaccines, and phages. This narrative review aimed to analyse the benefits and weaknesses of alternative therapeutic strategies to antibiotics which treat multidrug-resistant bacterial infections.

Dietary management and access to treatment for patients with glucose deficiency syndrome type 1: an overview review with focus on the European regulatory framework.

BACKGROUND: Glut-1 deficiency Syndrome (GLUT-1 DS) is a rare disease caused by a mutation in the SLC2A1 gene that codes for the glucose transporter protein GLUT-1 DS. Currently, there is no indicated drug therapy for this condition and ketogenic diet (KD) is the most effective remedy to treat it. OBJECTIVE: The objective of this study was to review the published literature that evaluated the effectiveness of KD in the dietary management of GLUT-1 DS syndrome, describing the state-of-the-art the treatment pathway for patients with GLUT-1 DS syndrome in light of the current European regulatory framework within the National Health Services. METHODS: The literature search was carried out on September 10, 2023, and all studies conducted in humans diagnosed with GLUT-1 deficiency syndrome and treated with KD were included. RESULTS: A total of 156 scientific papers have been extracted. Applying the exclusion criteria, 38 articles have been considered eligible. In 29 out of 38 studies, the main outcome for determining the efficacy of KD was the measurement of the number of epileptic seizures, demonstrating that patients treated with KD experienced improvements with a clear reduction in the number of epileptic attacks. Currently, in the European Union, only one country provides full reimbursement by the national health system for KD. DISCUSSION: Although they are crucial for the treatment of GLUT-1 DS, according with current food regulations, KD are not evaluated on the basis of an unambiguous efficacy result, but only on the basis of safety. As a result, it is desirable to carry out clinical studies in the coming years based on the determination of efficacy in target populations, also in view of the marketing of these products on the European market.

Should SARS-CoV-2 serological testing be used in the decision to deliver a COVID-19 vaccine booster? A pro-con assessment.

Anti-SARS-CoV-2 vaccination has saved millions of lives in the past few years. To maintain a high level of protection, particularly in at-risk populations, booster doses are recommended to counter the waning of circulating antibody levels over time and the continuous emergence of immune escape variants of concern (VOCs). As anti-spike serology is now widely available, it may be considered a useful tool to identify individuals needing an additional vaccine dose, i.e., to screen certain populations to identify those whose plasma antibody levels are too low to provide protection. However, no recommendations are currently available on this topic. We reviewed the relevant supporting and opposing arguments, including areas of uncertainty, and concluded that in most populations, spike serology should not be used to decide about the administration of a booster dose. The main counterarguments are as follows: correlates of protection are imperfectly characterised, essentially owing to the emergence of VOCs; spike serology has an intrinsic inability to comprehensively reflect the whole immune memory; and booster vaccines are now VOC-adapted, while the commonly available commercial serological assays explore antibodies against the original virus.

The importance of antibiotic treatment duration in antimicrobial resistance.

Antimicrobial resistance (AMR) poses a significant threat to global health, leading to increased deaths from drug-resistant infections and escalates healthcare costs. Often termed a "silent pandemic," AMR occurs when pathogens become resistant to antimicrobial drugs, enabling their proliferation and spread. Inappropriate antibiotic usage is a major contributor to this phenomenon, which also extends to fungal infections. In particular, the duration of antibiotic therapy is a crucial aspect, with evidence suggesting that prolonged use can heighten bacterial resistance and harm the human microbiota. In fact, studies comparing short-term versus long-term antibiotic therapies show no significant difference in traditional treatments. In addition, therapeutic drug monitoring allows personalized antibiotic regimens, optimizing dosage and duration to minimize resistance and adverse effects. As a result, clinicians should regularly reassess treatment effectiveness, utilizing techniques like antibiotic timeout and de-escalation therapy to avoid prolonged antibiotic use and mitigate resistance. All these strategies are crucial to prevent and counter the phenomenon of antimicrobial resistance.

Tracking progress on antimicrobial resistance by the quadripartite country self-assessment survey (TrACSS) in G7 countries, 2017-2023: opportunities and gaps.

Antimicrobial resistance (AMR) poses serious challenges to the healthcare systems worldwide. Multiple factors and activities contribute to the development and spread of antimicrobial-resistant microorganisms. Monitoring progress in combating AMR is fundamental at both global and national levels to drive multisectoral actions, identify priorities, and coordinate strategies. Since 2017, the World Health Organization (WHO) has collected data through the Tracking AMR Country Self-Assessment Survey (TrACSS). TrACSS data are published in a publicly-available database. In 2023, 71 (59.9%) out of 177 responding countries reported the existence of a monitoring and evaluation plan for their National Action Plan (NAP) on AMR, and just 20 countries (11.3%) the allocation of funding to support NAP implementation. Countries reported challenges including limited financial and human resources, lack of technical capacity, and variable political commitment. Even across the Group of Seven (G7) countries, which represent some of the world's most advanced economies, many areas still need improvement, such as full implementation of infection prevention and control measures, adoption of WHO access/watch/reserve (AWaRe) classification of antibiotics, effective integration of laboratories in AMR surveillance in the animal health and food safety sectors, training and education, good manufacturing and hygiene practices in food processing, optimising pesticides use and environmental residues of antimicrobial drugs. Continuous and coordinated efforts are needed to strengthen multisectoral engagement to fight AMR.

Advances in Therapeutic Strategies for the Management of Clostridioides difficile Infection.

The infection caused by Clostridioides difficile represents one of the bacterial infections with the greatest increase in incidence among nosocomial infections in recent years. C. difficile is a Gram-positive bacterium able to produce toxins and spores. In some cases, infection results in severe diarrhoea and fulminant colitis, which cause prolonged hospitalisation and can be fatal, with repercussions also in terms of health economics. C. difficile is the most common cause of antibiotic-associated diarrhoea in the healthcare setting. The problem of bacterial forms that are increasingly resistant to common antibiotic treatments is also reflected in C. difficile infection (CDI). One of the causes of CDI is intestinal dysmicrobialism induced by prolonged antibiotic therapy. Moreover, in recent years, the emergence of increasingly virulent strains resistant to antibiotic treatment has made the picture even more complex. Evidence on preventive treatments to avoid recurrence is unclear. Current guidelines indicate the following antibiotics for the treatment of CDI: metronidazole, vancomycin, and fidaxomycin. This short narrative review provides an overview of CDI, antibiotic resistance, and emerging treatments.

Antimicrobial Resistance in Gonorrhea.

Antimicrobial resistance is a global public health emergency. The World Health Organization recently highlighted the growing number of new sexually transmitted infections such as gonorrhea, syphilis, and Chlamydia, which are resistant to common antibiotics. The phenomenon is also on the rise due to increasing intercontinental travel. Emerging antibiotic-resistant strains of gonorrhea are particularly associated with international spread from Southeast Asian travelers. Infection with Neisseria gonorrhoeae can cause a wide spectrum of associated diseases such as dermatitis, arthritis and septic arthritis, and pelvic inflammatory disease, and can even lead to serious health consequences for the individual. Natural infection confers no immunity, and vaccination is not available currently, although in several countries, it has been reported that the antimeningococcal vaccine may protect against gonorrhea. Implementing all necessary preventive measures is crucial, as well as appropriate and timely diagnostic methods and effective antimicrobial therapeutic treatments in the correct modalities to avoid the increase of forms of gonorrhea that are resistant to common antibiotics and difficult to eradicate.

The Impact of Antimicrobial Resistance in Cystic Fibrosis.

The phenomenon of antimicrobial resistance (AMR) is a critical global health challenge, with prospects indicating its potential to become the leading cause of death worldwide in the coming years. Individuals with pre-existing conditions, such as neoplastic disease undergoing chemotherapy, those on immunosuppressive therapy, and individuals with rare diseases like cystic fibrosis (CF), face heightened challenges due to AMR. CF is a rare disease caused by a deficiency in the synthesis of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel protein, resulting in multi-organ clinical symptoms, particularly in the respiratory system. PwCF experience recurrent pulmonary exacerbations triggered by bacterial or viral infections, making them particularly vulnerable to the impact of AMR. This review delves into the complex relationship between AMR and climate dynamics, focusing on the unique challenges faced by individuals with CF. It discusses the methods employed to measure AMR, its global impact on antibiotic resistance, and the specific microbial communities present in the CF airway. The review also explores the intricacies of antimicrobial resistance within the context of cystic fibrosis, emphasizing the urgent need for research in this field.

Anti-CGRP mAbs for the Preventive Treatment of Migraine: An Overview Review and a Cost Saving Analysis in the Global Scenario.

Objectives: Migraine is a neurological disease with a high frequency of incidence. The new monoclonal antibodies selective for the calcitonin gene-related peptide and its ligand (anti-CGRP mAbs) have been marketed both in the USA and EU based on the positive efficacy results in the prevention of migraine. This search has been carried out with the aim of collecting real-world evidence on the effectiveness of anti-CGRP mAbs, performing a cost-savings analysis, and comparing performances among anti-CGRP mAbs medicines marketed in the American and European market. Methods: The literature review has been performed in PubMed database on 31 December 2022; the cost of the unitary dose of anti-CGRP mAbs has been extracted consulting an American national database. Results: The results confirm efficacy and good tolerability of anti-CGRP mAbs, determining a difference in the purchase price. In fact, all extracted studies showed a protective risk factor exposure in monthly migraine days reduction for all the anti-CGRP mAbs, whereas the cost analysis showed that using eptinezumab, in a quarter there is a cost saving of at least $425 per patient, compared with the other anti-CGRP mAbs. Conclusions: With equal efficacy and equal safety, anti-CGRP mAbs should be prescribed also regard to the cost established at the negotiation, making sure to guarantee the best treatment to the patients, but at the same time impacting as little as possible to the healthcare services resources.

Estimates of antibiotic resistance in Italy and Western Europe in 2019: a MICROBE-based comparative analysis.

BACKGROUND: antimicrobial resistance (AMR) will cause 10 million deaths per year worldwide by 2050, with economic costs of up to 100 trillion dollars. Antibiotic resistance (ABR) constitutes the majority of this health threat. Globally, 1.27 million people died in 2019 as a direct result of ABR. One in 5 deaths occurred in children under five, and 6 bacterial pathogens accounted for more than 70% of ABR-associated deaths. OBJECTIVES: to compare ABR estimates in terms of death and disability-adjusted life-years (DALYs) in 2019 in Italy and in Western Europe (WE) by grading the infectious syndromes and the bacterial pathogens involved, with the aim to identify the most urgent healthcare needs in Italy. DESIGN: the estimates of the burden of ABR in 2019 in WE and Italy, extracted from the Measuring Infectious Causes and Resistance Outcomes for Burden Estimation (MICROBE) tool by the Institute for Health Metrics and Evaluation (IHME; Seattle, USA), reported deaths and DALYs associated with 33 bacterial pathogens across 12 infectious syndromes, as well as deaths and DALYs associated with and attributable to ABR for 23 bacteria and 86 pathogen-drug combinations. The comparison between WE and Italy was performed in steps. First, among the 12 groups of infectious syndromes from the Global Burden of Diseases (GBD) study 2019, the most impacting in terms of deaths and DALYs were ranked based on the magnitude of rates, and the corresponding ABR-associated burden was reported. Then, the burden of the leading pathogens (bacteria, viruses, fungi, and polymicrobial infections) for all infectious syndromes was compared between the two areas. Death and DALY rates associated with ABR were reported for each bacterium, together with the percentage of ABR-attributable burden. Although it is known that Italy is one of the WE countries with the largest share of elderly, crude rates were reported instead of age-standardized rates, in order to quantify the actual burden of ABR in the two areas. SETTING AND PARTICIPANTS: Italy and Western Europe. MAIN OUTCOMES MEASURES: death and DALYs rates per 100,000 inhabitants. RESULTS: the largest difference between ABR-associated death rates in the two areas was found for bloodstream infections (25.2 and 18.8 per 100,000 in Italy and WE, respectively), followed by peritoneal and abdominal infections (15.1 and 12.2 in Italy and WE, respectively). However, the percentages of deaths and DALYs attributable to ABR were always higher in Italy for all the infections considered. Regarding pathogens, Escherichia coli accounted for the greatest burden associated to ABR, in terms of both deaths and DALYs, in both areas. The highest ABR-attributable percentage of deaths was found for Acinetobacter baumannii (28.4% in WE and 31.9% in Italy), accounting also for the highest percentage of ABR-attributable DALYs (28.4% in WE and 31.7% in Italy). The pathogen-drug combination with the highest burden associated with AMR was Escherichia coli-Aminopenicillin, while the greatest AMR-attributable burden was found for Staphylococcus aureus-Methicillin (MRSA). On average, 55.4% of Escherichia coli was resistant to Aminopenicillin in WE, with Italy ranking third (67.6%). Nordic countries showed smaller values, with Sweden in last place (32.8%). The average percentage of MRSA in WE was 16%, with Italy exceeding it by more than 13 pointsConclusions: despite similar sepsis mortality rates in Italy and other WE countries, the proportion of ABR-associated and attributable deaths was higher in Italy. Targeted strategies aimed at reducing the circulation of bacteria and resistant microorganisms together with other interventions could lead to an overall reduction in deaths associated with ABR.

A Short Update on the Use of Monoclonal Antibodies in COVID-19.

Monoclonal antibodies in the prophylaxis and treatment of COVID-19 have been crucial in reducing severe infections when vaccines were unavailable. However, as the virus and its variants have changed over time, the effectiveness of monoclonal antibodies has been questioned. This technical note highlights the need to assess the antiviral activity of these antibodies against new variants and adapt treatment strategies accordingly. On the one hand, in vitro studies have suggested reduced susceptibility of the latest variants to monoclonal antibodies, whereas clinical data still show benefits in reducing severe illness and mortality, indicating that laboratory results do not always mirror real-world outcomes. As a result, although resistance to monoclonal antibodies can develop over time, they could still have an important role in COVID-19 treatment, especially when used in combination, and ongoing research aims to identify effective antibodies against new variants.

Multicenter study on the prevalence of colonization due to carbapenem-resistant Enterobacterales strains before and during the first year of COVID-19, Italy 2018-2020.

Background: Among multidrug-resistant (MDR) bacteria able to threaten human health, carbapenem-resistant Enterobacterales (CRE) have become a major public health threat globally. National and international guidelines point out the importance of active routine surveillance policies to prevent CRE transmission. Therefore, defining lines of intervention and strategies capable of containing and controlling the spread of CRE is considered determinant. CRE screening is one of the main actions to curb transmission and control outbreaks, outlining the presence and also the prevalence and types of carbapenemase enzymes circulating locally. Objective: The purpose of this study was to outline the epidemiology of CRE colonization in Italy, detecting CRE-colonized patients at admission and during hospitalization, before and during the first year of COVID-19. Materials and methods: A total of 11,063 patients admitted to seven different hospitals (Bologna, Catania, Florence, Genoa, Naples, Palermo, and Turin) in Intensive Care Units (ICU) and other wards (non-ICU) located in the North, Center, and South of Italy were enrolled and screened for CRE carriage at admission (T0) and during the first 3 weeks of hospitalization (T1-T3). The study spanned two periods, before (September 2018-Septemeber 2019, I observational period) and during the COVID-19 pandemic (October 2019-September 2020, II observational period). Results: Overall, the prevalence of CRE-colonized patients at admission in ICU or in other ward, ranged from 3.9 to 11.5%, while a percentage from 5.1 to 15.5% of patients acquired CRE during hospital stay. There were large differences between the I and II period of study according to the different geographical areas and enrolling centers. Overall, comparison of prevalence of CRE-positive patients showed a significant increased trend between I and II observational periods both in ICU and non-ICU wards, mostly in the Southern participating centers. KPC-producing Klebsiella pneumoniae was the most frequent CRE species-carbapenemase combination reported in this study. In particular, the presence of KPC-producing K. pneumoniae was reported in period I during hospitalization in all the CRE-positive patients enrolled in ICU in Turin (North Italy), while in period II at admission in all the CRE-positive patients enrolled in ICU in Catania and in 58.3% of non-ICU CRE-positive patients in Naples (both centers in South Italy). Conclusion: The prevalence of CRE in Italy highly increased during the COVID-19 pandemic, mostly in the Southern hospital centers. KPC-producing K. pneumoniae was the most frequent colonizing CRE species reported. The results of our study confirmed the crucial value of active surveillance as well as the importance of multicenter studies representing diverse geographical areas even in endemic countries. Differences in CRE colonization prevalence among centers suggest the need for diversified and center-specific interventions as well as for strengthening efforts in infection prevention and control practices and policies.