Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines.

This study explores the impact of antiretroviral administration on the expression of human endogenous retroviruses (HERVs), cell growth, and invasive capability of human melanoma cell lines in culture. We investigated three antiretrovirals-lamivudine, doravirine, and cabotegravir-in A375, FO-1, and SK-Mel-28, BRAF-mutated, and in MeWo, P53-mutated, melanoma cell lines. The findings indicate a general capability of these drugs to downregulate the expression of HERV-K Pol and Env genes and hinder cell viability, mobility, and colony formation capacity of melanoma cells. The antiretroviral drugs also demonstrate selectivity against malignant cells, sparing normal human epithelial melanocytes. The study reveals that the integrase inhibitor cabotegravir is particularly effective in inhibiting cell growth and invasion across different cell lines in comparison with lamivudine and doravirine, which are inhibitors of the viral reverse transcriptase enzyme. The investigation further delves into the molecular mechanisms underlying the observed effects, highlighting the potential induction of ferroptosis, apoptosis, and alterations in cell cycle regulatory proteins. Our findings showed cytostatic effects principally revealed in A375, and SK-Mel-28 cell lines through a downregulation of retinoblastoma protein phosphorylation and/or cyclin D1 expression. Signs of ferroptosis were detected in both A375 cells and FO-1 cells by a decrease in glutathione peroxidase 4 and ferritin expression, as well as by an increase in transferrin protein levels. Apoptosis was also detected in FO-1 and SK-Mel-28, but only with cabotegravir treatment. Moreover, we explored the expression and activity of the stimulator of interferon genes (STING) protein and its correlation with programmed death-ligand 1 (PD-L1) expression. Both the STING activity and PD-L1 expression were decreased, suggesting that the antiretroviral treatments may counteract the detrimental effects of PD-L1 expression activation through the STING/interferon pathway triggered by HERV-K. Finally, this study underscores the potential therapeutic significance of cabotegravir in melanoma treatment. The findings also raise the prospect of using antiretroviral drugs to downregulate PD-L1 expression, potentially enhancing the therapeutic responses of immune checkpoint inhibitors.

Clostridioides difficile infection: history, epidemiology, risk factors, prevention, clinical manifestations, treatment, and future options.

SUMMARYClostridioides difficile infection (CDI) is one of the major issues in nosocomial infections. This bacterium is constantly evolving and poses complex challenges for clinicians, often encountered in real-life scenarios. In the face of CDI, we are increasingly equipped with new therapeutic strategies, such as monoclonal antibodies and live biotherapeutic products, which need to be thoroughly understood to fully harness their benefits. Moreover, interesting options are currently under study for the future, including bacteriophages, vaccines, and antibiotic inhibitors. Surveillance and prevention strategies continue to play a pivotal role in limiting the spread of the infection. In this review, we aim to provide the reader with a comprehensive overview of epidemiological aspects, predisposing factors, clinical manifestations, diagnostic tools, and current and future prophylactic and therapeutic options for C. difficile infection.

Vancomycin-resistant enterococcus bloodstream infection successfully managed with oritavancin and fosfomycin as sequential treatment.

Bloodstream infections caused by vancomycin-resistant enterococci are increasingly reported and a consensus therapy does not exist. Oritavancin has shown good antimicrobial activity against VRE, but its use is mainly limited to skin, soft tissue, and/or bone infections. Fosfomycin is increasingly used for enterococcal infections (including bloodstream infections and endocarditis) as a partner drug given its anti-biofilm and synergistic properties. Recently in vitro and in vivo synergism between oritavancin and fosfomycin against VRE isolates has been demonstrated. Herein we report the case of a hematologic patient with a VRE bloodstream infection successfully treated with oritavancin and fosfomycin as sequential treatment.

Outcome of SARS CoV-2 inpatients treated with convalescent plasma: One-year of data from the Veneto region (Italy) Registry.

OBJECTIVES AND BACKGROUND: Convalescent plasma (CP) has been used worldwide to contrast SARS-CoV-2 infection. Since April 2020, it has also been used in the treatment of patients with COVID-19 in the Veneto region (Italy), along with all the other available drugs and therapeutic tools. Here we report data analysis and clinical results in 1,517 COVID-19 inpatients treated with CP containing high-titre neutralizing anti-SARS-CoV-2 antibodies (CCP). Mortality after 30 days of hospitalization has been considered primary outcome, by comparing patients treated with CCP vs all COVID-19 patients admitted to hospitals of the Veneto region in a one-year period (from April 2020 to April 2021). PATIENTS AND METHODS: Adult inpatients with a severe form of COVID-19 have been enrolled, with at least one of the following inclusion criteria: 1) tachypnea with respiratory rate (RR) ≥ 30 breaths/min; 2) oxygen saturation (SpO2) ≤ 93% at rest and in room air; 3) partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≤ 200 mmHg, 4) radiological picture and/or chest CT scan showing signs of interstitial disease and/or rapid progression of lung involvement. Patients received a maximum of three therapeutic fractions (TFs) of CCP with a neutralizing antibody titre of ≥ 1:160, administered over a period of 3-5 days. If TFs of CCP with titre ≥ 1:160 were unavailable, 2 with antibody titre of ≥ 1:80 have been administered. RESULTS: Of the 1,517 patients treated with CCP, 209 deceased at the 30-day follow-up (14%). Death was significantly associated with an older age (p<0.001), a longer time of hospitalization before CCP infusion (p<0.001), a greater number of inclusion criteria (p<0.001) and associated comorbidities (p<0.001). Conditions significantly associated with an increased frequency of death were PaO2/FiO2 ≤ 200 (p<0.001) and tachypnea with RR>30 (p<0.05) at entry, concurrent arterial hypertension (p<0.001), cardiovascular disease (p<0.001), chronic kidney disease (p<0.001), dyslipidemia (p<0.05) and cancer (p<0.05). Moreover, factors leading to an unfavorable prognosis were a life-threatening disease (p<0.001), admission to Intensive Care Unit (p<0.001), high flow oxygen therapy or mechanical ventilation (p<0.05) and a chest X-ray showing consolidation area (p<0.001). By analyzing the regional report of hospitalized patients, a comparison of mortality by age group, with respect to our series of patients treated with CCP, has been made. Mortality was altogether lower in patients treated with CCP (14% v. 25%), especially in the group of the elderly patients (23% vs 40%,), with a strong significance (p<0.001). As regards the safety of CCP administration, 16 adverse events were recorded out of a total of 3,937 transfused TFs (0,4%). CONCLUSIONS: To overcome the difficulties of setting up a randomized controlled study in an emergency period, a data collection from a large series of patients with severe COVID-19 admitted to CCP therapy with well-defined inclusion criteria has been implemented in the Veneto region. Our results have shown that in patients with severe COVID-19 early treatment with CCP might contribute to a favourable outcome, with a reduced mortality, in absence of relevant adverse events.

The impact of the SARS-CoV-2 epidemic outbreak on the vascular access team operations after conversion to COVID-19 dedicated hospital.

BACKGROUND: On February 21 2020, in Schiavonia Hospital occurred the first death by COVID-19 in Italy and since this date SARS-CoV-2 caused more than 100,000 deaths in our country. Our hospital was immediately closed and re-opened after 15 days as a reference Covid Hospital. Among services involved in a process of destruction and rebirth there was also the Vascular Access Team. METHODS: We analyzed our Vascular Access Team activity comparing data from the first month (March) in which basically it did not work and data from the following month (April) in which we began to re-build the Team adapting it to the new reality. RESULTS: In all patients admitted to Intensive Care Unit a Centrally Inserted Central Catheter multilumen was placed, but in March only 5.5% of patients admitted to Medicine-Sub-intensive Unit had a catheter different from the short peripheral cannula while in April it was possible to guarantee a more suitable catheter 31.7% of patients admitted to Medicine-Sub-intensive Unit (p < 0.000). In April, compared to March, a significant higher number of Midline were implanted in Medicine-Sub-intensive Unit (36/139 vs 12/238 p < 0.000) where also a higher number of Centrally Inserted Central Catheter and Femoral Inserted Central Catheter were implanted (8/139 vs 1/238 p = 0.003). This change allowed us to implant more vascular accesses in Medicine-Sub-intensive Unit favoring Midline with a longer average duration. Only one patient with Midline developed a catheter vein thrombosis, and in only one patient the device was removed for suspected infection. CONCLUSIONS: The experience we gained will allow us to be more prepared in the future and our experience has highlighted that a structured Vascular Access Team is necessary to respond adequately to COVID-19 patients' needs, to ensure the effectiveness of the maneuver, to reduce complications and to avoid the waste of resources, always working in safe condition.

Pacemaker implantation in a COVID-19 patient. Balancing the patient's needs and the team's risk of exposure.

COVID-19 patients may have cardiovascular complications requiring invasive treatment. Pacemaker implantation procedure may be challenging because of the necessity of personal protective equipment use. We report pacemaker implantation in a 78-year-old man with severe bilateral COVID-19 interstitial pneumonia, a second degree 2:1 atrioventricular block, and concomitant aortic stenosis.

Therapeutic Options for Infections due to vanB Genotype Vancomycin-Resistant Enterococci.

Enterococci are ubiquitous, facultative, anaerobic Gram-positive bacteria that mainly reside, as part of the normal microbiota, in the gastrointestinal tracts of several animal species, including humans. These bacteria have the capability to turn from a normal gut commensal organism to an invasive pathogen in patients debilitated by prolonged hospitalization, concurrent illnesses, and/or exposed to broad-spectrum antibiotics. The majority of vancomycin-resistant enterococcus (VRE) infections are linked to the vanA genotype; however, outbreaks caused by vanB-type VREs have been increasingly reported, representing a new challenge for effective antimicrobial treatment. Teicoplanin, daptomycin, fosfomycin, and linezolid are useful antimicrobials for infections due to vanB enterococci. In addition, new drugs have been developed (e.g., dalbavancin, telavancin, and tedizolid), new molecules will soon be available (e.g., eravacycline, omadacycline, and oritavancin), and new treatment strategies are progressively being used in clinical practice (e.g., combination therapies and bacteriophages). The aim of this article is to discuss the pathogenesis of infections due to enterococci harboring the vanB operon (vanBVRE) and their therapeutic, state-of-the-art, and future treatment options and provide a comprehensive and easy to use review for clinical purposes.

Trends in the Incidence and Antibiotic Resistance of Enterococcal Bloodstream Isolates: A 7-Year Retrospective Multicenter Epidemiological Study in Italy.

The spread of resistance to vancomycin and other last-resort drugs in Enterococcus spp. remains of concern. In Italy, surveillance data for enterococcal bloodstream isolates in humans are scant. The aim of our study was to assess the incidence trends of bacteremias due to Enterococcus species and their prevalence trends of antimicrobial resistance. We retrospectively included all consecutive not-duplicate Enterococcus species isolated from blood cultures, in patients from 11 Italian hospitals (2011-2017). Incidence was defined as the number of isolates per 10,000 patient-days, while resistance prevalence was defined as the number of resistant strains divided by the number of tested strains. We included 4,858 isolates (59%, 36%, and 5% due to Enterococcus faecalis, E. faecium, and other Enterococcus spp., respectively). Over the study period, the incidence of bacteremias due to E. faecalis (incidence rate ratio [IRR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.008) and E. faecium increased (IRR: 1.03, 95% CI: 1.01-1.05, p < 0.001) alongside with the whole enterococcal bacteremias trend (IRR: 1.02, 95% CIs: 1.01-1.04, p = 0.002). A progressive increase in vancomycin-resistant E. faecium (VREfm) bacteremias was observed. Resistance to tigecycline and linezolid was rarely reported. The incidence of enterococcal bloodstream isolates is increasing in Italy, together with the prevalence of VREfm. Resistance to linezolid, a cornerstone drug used in the treatment of VRE bloodstream infection, remains negligible.

Schiavonia Hospital response to COVID-19 outbreak: a first single-center experience.

INTRODUCTION: On 21 February 2020, Schiavonia Hospital (SH) detected the first 2 cases of COVID-19 in Veneto Region. As a result of the underlying concomitant spread of infection, SH had to rearrange the clinical services in terms of structural changes to the building, management of spaces, human resources and supplies, in order to continue providing optimal care to the patients and staff safety. The aim of this article is to describe how SH was able to adjust its services coping with the epidemiological stages of the pandemic. MATERIAL AND METHODS: Three periods can be identified; in each one the most important organizational modifications are analyzed (hospital activities, logistical changes, communication, surveillance on HCW). RESULTS: The first period, after initial cases' identification, was characterized by the hospital isolation. In the second period the hospital reopened and it was divided into two completely separated areas, named COVID-19 and COVID-free, to prevent intra-hospital contamination. The last period was characterized by the re-organization of the facility as the largest COVID Hospital in Veneto, catching exclusively COVID-19 patients from the surrounding areas. CONCLUSIONS: SH changed its organization three times in less than two months. From the point of view of the Medical Direction of the Hospital the challenges had been many but it allowed to consolidate an organizational model which could answer to health needs during the emergency situation.

The hazard of (sub)therapeutic doses of anticoagulants in non-critically ill patients with Covid-19: The Padua province experience.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is responsible for a worldwide pandemic, with a high rate of morbidity and mortality. The increasing evidence of an associated relevant prothrombotic coagulopathy has resulted in an increasing use of antithrombotic doses higher than usual in COVID-19 patients. Information on the benefit/risk ratio of this approach is still lacking. OBJECTIVE: To assess the incidence of relevant bleeding complications in association with the antithrombotic strategy and its relationship with the amount of drug. METHODS: Consecutive COVID-19 patients admitted between February and April 2020 were included in a retrospective analysis. Major bleedings (MB) and clinically relevant non-major bleeding (CRNMB) were obtained from patient medical records and were adjudicated by an independent committee. RESULTS: Of the 324 patients who were recruited, 240 had been treated with prophylactic doses and 84 with higher doses of anticoagulants. The rate of the composite endpoint of MB or CRNMB was 6.9 per 100-person/months in patients who had been given prophylactic doses, and 26.4 per 100-person/months in those who had been prescribed higher doses (hazard ratio, 3.89; 95% confidence interval, 1.90-7.97). The corresponding rates for overall mortality were 12.2 and 20.1 per 100-person/months, respectively. CONCLUSIONS: The rate of relevant bleeding events was high in patients treated with (sub)therapeutic doses of anticoagulants. In the latter group, overall mortality did not differ from that of patients treated with standard prophylactic doses and was even higher. Our result does not support a strategy of giving (sub)therapeutic doses of anticoagulants in non-critically ill patients with COVID-19.

Mycobacterium chimaera infections: An update.

Mycobacterium chimaera is a non-tuberculous mycobacterium belonging to the Mycobacterium avium complex, described for the first time in 2004. It acts as an opportunistic pathogen, with infections, usually respiratory illnesses, occurring more frequently in immunocompromised patients or in patients with underlying respiratory diseases. During the last decade Mycobacterium chimaera disseminated infections following cardiothoracic surgery, especially open-heart surgery, have been increasingly reported worldwide. From a pathogenic standpoint, Mycobacterium chimaera is acquired during cardiopulmonary bypass via bioaerosols emitted from contaminated heater-cooler units water systems. Due to non-specific symptoms and long latency, postoperative Mycobacterium chimaera infections may not be promptly diagnosed and treated, and may become life-threatening. The indication for revision surgery needs to be carefully evaluated on a case-by-case basis, and antibiotic therapy should be based on drug susceptibility testing results. Our review aims to provide an updated account of microbiological characteristics, clinical presentation, diagnosis, and management of Mycobacterium chimaera infections, with a special focus on those developing after cardiothoracic surgery.

Cellulosimicrobium cellulans aortic prosthetic valve endocarditis.

INTRODUCTION: Invasive infections due to Cellulosimicrobium spp. (a Gram-positive coryneform) are extremely rare. Only a few cases of bloodstream infections and endocarditis have been described, as bacteraemia due to coryneforms is usually discarded as blood culture contamination. CASE PRESENTATION: A 66-year-old female, with a history of aortic valve replacement, presented with fever, left leg purpura and acute kidney injury. Multiple repeated blood cultures were positive for Cellulosimicrobium cellulans , and targeted therapy was started. At first, endocarditis was excluded by echocardiograms, and the acute nephritis was interpreted as an atypical presentation of Henoch-Shönlein purpura. High-dose prednisone was started, and after 10 weeks the patient presented again with fever, mental confusion and acute left arm ischaemia. A subsequent echocardiogram and radiolabelled leukocyte scintigraphic evaluation revealed aortic prosthetic valve endocarditis with periprosthetic abscess and arterial brachial thrombosis. The patient deceased, and the autoptic examination confirmed an aortic valve periprosthetic abscess and revealed multiple arterial thromboses and septic embolisms in the kidneys, brain, spleen and myocardium. CONCLUSION: Isolation of coryneform bacteria on blood culture should not always be discarded as blood culture contamination. In the case of endocarditis due to Cellulosimicrobium spp., the removal of any prosthetic material, along with prolonged in vitro active antimicrobial therapy, should be pursued in order to reduce persistence or relapses of infection.

Role of fecal microbiota transplantation in inflammatory bowel disease.

There is increasing evidence of the key role played by altered intestinal microbiota in the pathogenesis of inflammatory bowel disease (IBD). Management strategies involving immune modulation are effective and widely used, but treatment failures and side effects occur. Fecal microbiota transplantation (FMT) provides a novel, perhaps complementary, strategy to restore the normal gut microbiota in patients with IBD. This review summarizes the available efficacy and safety data on the use of FMT in patients with IBD. Several aspects remain to be clarified about the clinical predictors of the response to FMT, its most appropriate route of administration, and the most appropriate quantity and quality of microbiota to be transplanted. Further studies focusing on long-term outcomes and safety are also warranted.

Clinical management of non-faecium non-faecalis vancomycin-resistant enterococci infection. Focus on Enterococcus gallinarum and Enterococcus casseliflavus/flavescens.

Enterococcus gallinarum and Enterococcus casseliflavus/flavescens are enterococci intrinsically resistant to vancomycin belonging to the E. gallinarum group. They are responsible mainly for healthcare-associated infections, in particular bloodstream, urinary tract and surgical wound infections. Diseases due to these bacteria are significantly increasing worldwide, as they are prone to cause infection in patients with concurrent hepatobiliary or oncohematological disorders. Along with their distinguishing vancomycin resistance, due to a chromosomally-encoded VanC operon, their additional intrinsic resistance to many antibiotics other than glycopeptides limits the therapeutic choices. In addition, their intrinsic vancomycin resistance, unlike the vancomycin resistance of Enterococcus faecalis and Enterococcus faecium caused by transmissible plasmids, poses different infection control issues. We focused on the therapeutic and infection control issues of clinical syndromes caused by E. gallinarum and E. casseliflavus/flavescens. We propose therapeutic algorithms on bloodstream infections, endocarditis, central nervous system infections, endophthalmitis and urinary tract infections. The implementation of infection control measures in cases of E. gallinarum and E. casseliflavus/flavescens infection or colonization should be evaluated on a case-by-case basis, especially for epidemic outbreaks or for isolates supposed to harbor a potential transmissible vancomycin-resistance phenotype.

Aseptic central nervous system infections in adults: what predictor for unknown etiological diagnosis?

Despite the availability of nucleic acid amplification tests (NAATs), most of aseptic acute meningitides, encephalitides, and meningoencephalitides (AAMEMs) in adults remain of unknown etiology so far. To shed light on such topic, we aimed to evaluate potential predictors for AAMEMs of unknown origin. We collected retrospectively data from all consecutive cases of AAMEMs in adults discharged from an Italian referral hospital, from January 2004 to December 2016. Laboratory analysis included common immunometric methods and NAATs. Potential predictors for unknown etiology (age, seasonality, serum C-reactive protein value, antibiotic use before lumbar puncture, immunodeficiency conditions, clinical symptoms and signs) were evaluated by a logistic regression analysis model. A p value ≤ 0.05 was considered to indicate statistical significance. The study included 92 patients (median age 39 years; 54.3% males) affected by meningitis (n = 57), encephalitis (n = 25), and meningoencephalitis (n = 10). The identified agents that cause AAMEMs were herpesviruses (20.7%), enteroviruses (5.4%), tick-borne encephalitis virus (3.3%), influenza virus A (2.2%), West Nile virus (1.1%), and parvovirus B19 (1.1%), while 66.3% of cases were of unknown etiology. No predictor was found to be significantly associated with AAMEMs of unknown etiology. We suggest that potential infectious agents causing undiagnosed cases should be investigated among non-bacterial, non-opportunistic, and non-seasonal organisms.

Spread of Vancomycin-Resistant Enterococcus faecium Isolates Despite Validated Infection Control Measures in an Italian Hospital: Antibiotic Resistance and Genotypic Characterization of the Endemic Strain.

An alarming increase of vancomycin-resistant Enterococcus faecium (VREfm) isolates was detected in an Italian referral hospital subjected to policies of infection control validated by the Joint Commission International. Analysis of the population structure of 122 consecutive, nonreplicate VREfm isolates collected over an 18-month period identified a single major clone that spread around the whole hospital, rapidly establishing an endemic state. It belonged to sequence type (ST) 17 and showed a highly multidrug-resistant phenotype, being resistant to all antimicrobial classes for the carriage of several resistance determinants. Furthermore, some strains with decreased susceptibility to daptomycin were detected. Eighteen out of the 122 isolates did not group in the major clone. They showed a low spreading potential inside the hospital wards, even if most of them displayed a multidrug-resistant phenotype and belonged to a hospital-adapted lineage. Causes that led to the VREfm endemic state have not been fully elucidated. However, it is conceivable that the increase in systemic antibiotic consumption and the use of selective digestive tract decontamination, including vancomycin in critically ill patients during the period before 2014, may have played a role in the ST17 clone dissemination, but additional traits conferring high fitness in hospital environment cannot be excluded.

Correlation between antibiotic consumption and resistance of bloodstream bacteria in a University Hospital in North Eastern Italy, 2008-2014.

PURPOSE: The spread of multidrug-resistant bacteria is a worrisome problem worldwide. This study investigated the correlation between antibiotic consumption and antimicrobial resistance trends of the most important bacteria causing bacteremia at the University hospital of Trieste, Italy, from 2008 to 2014. METHODS: Antibiotic consumption (Defined Daily Dose-DDD-per 100 patient/days) and antibiotic resistance (percentage of antibiotic intermediate o resistant isolates) were analyzed independently with linear correlation by year. Potential correlations between antibiotic consumption and bacteria resistance rates were investigated through the Pearson's correlation. RESULTS: The overall consumption of antibiotic grew from 80 to 97 DDD 100 patient/days (p = 0.005) during the study period. The increased consumption of amoxicillin/clavulanate and piperacillin/tazobactam was associated with the reduction of MRSA rate from 48.5 to 25.9% (p = 0.007 and p = 0.04, respectively). The increased consumption of piperacillin/tazobactam was associated with the reduction of ESBL-positive Enterobacteriaceae rate from 28.9 to 20.9% (p = 0.01). The increased consumption of carbapenems was associated with the increased rate of carbapenem-resistant Acinetobacter baumannii from 0 to 96.4% (p = 0.03). No carbapenem-resistant Enterobacteriaceae isolates were reported. The consumption of vancomycin grew significantly (p = 0.005). A dramatic spread of vancomycin-resistant Enterococcus faecium occurred in 2014. The consumption of fluoroquinolones and extended-spectrum cephalosporins remained stable. CONCLUSIONS: An antibiotic stewardship program targeted to limit the consumption of extended-spectrum cephalosporins and fluoroquinolones in favor of amoxicillin/clavulanate and piperacillin/tazobactam correlates with a decreasing rate of MRSA and ESBL-positive Enterobacteriaceae. The analysis of correlations between antibiotic consumption and bacterial resistance rates is a useful tool to orient antimicrobial stewardship policies at local level.

Candida albicans Osteomyelitis Pubis: The Possible Pathogenic Role of Pelvic Irradiation.

Radiation to the pelvis, mainly directed against either prostatic or gynecologic cancers, is burdened by a lot of complications. The genitourinary tract is most frequently involved, presenting with bladder irritation, incontinence, and fertility disorders. However, side effects of radiation can also affect the bone, usually causing an osteolytic process which deteriorates the bone structure and leads to fractures, avascular necrosis, and other pathological insults. Here, we describe a case of Candida albicans osteomyelitis of the pubic symphysis as late complication of pelvic radiotherapy performed against prostate cancer.