Risk of SARS-CoV-2 infection and severe COVID-19 in hematological patients who received or not pre-exposure prophylaxis with tixagevimab/cilgavimab: a target trial emulation.

We emulated a hypothetical target trial in which hematological subjects cared at the University Hospital of Pisa (Italy) received or not SARS-CoV-2 prophylaxis with tixagevimab/cilgavimab. Subjects who received prophylaxis (cases) were compared to those who did not (controls). The main outcome was SARS-CoV-2 infection in the subsequent 6 months. Inverse probability weighting (IPW) was used to adjust for confounders. A multivariable analysis was performed to identify variables associated with SARS-CoV-2 infection. We recruited 462 patients: 228 received prophylaxis, 234 were controls. COVID-19 was lower in cases compared to controls (16.7% vs 24.8%, p = 0.03, after IPW 14.3% vs 24.6%, p = 0.01). On multivariable analysis, B-cell depleting therapies (HR 2.09, 95%CI 1.05-4.18, p = 0.037) were associated with increased risk of COVID-19, while tixagevimab/cilgavimab prophylaxis (HR 0.45, 95%CI 0.27-0.73, p = 0.001) and previous SARS-CoV-2 infection (HR 0.27, 95%CI 0.14-0.51, p < 0.001) were protective. In conclusion, prophylaxis with monoclonal antibodies may reduce the risk of COVID-19 in hematological patients.

A rare case of primary cutaneous Nocardia vinacea in an immunocompetent patient: A case report and a review of the literature.

The nocardiae are a complex group of bacteria belonging to the aerobic saprophytes actinomycetes. Although nocardiosis typically occurs in immunocompromised patients, infection may occasionally develop in immunocompetent patients as well. Here we describe a rare case of primary cutaneous nocardiosis due to Nocardia vinacea in an immunocompetent 79-year-old patient. Since cutaneous nocardiosis presents variably and mimics other cutaneous infections, acid-fast and Gram stainings on clinical samples are significant to obtain a rapid and presumptive diagnosis.

How We Treat Drug-Susceptible Pulmonary Tuberculosis: A Practical Guide for Clinicians.

Tuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide and pulmonary TB (PTB) is the main variant responsible for fueling transmission of the infection. Effective treatment of drug-susceptible (DS) TB is crucial to avoid the emergence of Mycobacterium tuberculosis-resistant strains. In this narrative review, through a fictional suggestive case of DS PTB, we guide the reader in a step-by-step commentary to provide an updated review of current evidence in the management of TB, from diagnosis to post-treatment follow-up. World Health Organization and Centre for Diseases Control (CDC) guidelines for TB, as well as the updated literature, were used to support this manuscript.

Uncommon Haemorrhagic Cystitis of Infectious Origin: A Narrative Review for Urologists.

Purpose: Haemorrhagic cystitis may be due to different etiologies with infectious diseases representing an insidious cause to diagnose. The aim of this narrative review is to provide a comprehensive overview of less common but difficult-to-diagnose causes of infectious haemorrhagic cystitis of bacterial, mycobacterial, and parasitic origin, Moreover, we highlight possible diagnostic tools and currently available treatment options in order to give an updated tool for urologists to use in daily practice. Patients and Methods: The search engine PubMed was used to select peer-reviewed articles published from 1/Jan/2010 to 31/Aug/2022. Results: Bacteria, fungal, TB and schistosomiasis are uncommon causes of haemorrhagic cystitis burdened by high morbidity, especially if not promptly diagnosed. Conclusion: Because haemorrhagic cystitis ranges in severity from mild dysuria associated with pelvic discomfort to severe life-threatening haemorrhage, punctual diagnosis, and immediate treatment are essential to avoid further complications.

Treatment of latent tuberculosis infection in incarcerated people: a systematic review.

BACKGROUND: The estimated number of people deprived of liberty is increasing, with 11.55 million incarcerated globally in 2021. Transmission of Mycobacterium tuberculosis strains is facilitated in over-crowded, poorly ventilated settings, such as jails and penitentiaries. Moreover, inmates may show individual risk factors for the development of tuberculosis disease. Treatment regimens for latent tuberculosis infection (LTBI) may require up to 9 months of drug exposure and are characterized by adverse events (AE) and low completion rates. OBJECTIVES: To describe current scientific evidence on feasibility, acceptability, and completion rate of LTBI treatment in prison or correctional institutes. DATA SOURCES: Articles were retrieved from MEDLINE/PubMed, no time restriction was applied. STUDY ELIGIBILITY CRITERIA: Human retrospective and prospective studies published on LTBI treatment in incarcerated populations were included. ASSESSMENT OF RISK OF BIAS: Bias assessment plots and Egger weighted regression test were used to determine the risk of bias. METHODS OF DATA SYNTHESIS: Absolute and relative frequencies were assessed for qualitative data. Pooled proportion of included study groups and 95% confidence interval estimates, weighted for sample sizes, were illustrated in forest plots. I2 indicator association were used for true variability and overall variation. Fixed and random-effects models were chosen depending on the estimated between-study heterogeneity. RESULTS: Of the 11 selected studies, only 1 was conducted in a high tuberculosis incidence country. Overall, completion rates ranged from 26% to 100% across the included studies. Reason for the discontinuation of treatment were transfer to other facilities, release, or loss to follow-up (range, 0-74%), incidence of AEs (range, 0-18%), and refusal or withdrawal from treatment (range, 0-16%). CONCLUSIONS: Implementation of short-course regimens in prisons should be considered given the low incidence of AEs observed; however, inmates consistently refused to complete LTBI treatment, thus underlining the need for improvement in retention in care.

Efficacy and Safety of Nirmatrelvir/Ritonavir, Molnupiravir, and Remdesivir in a Real-World Cohort of Outpatients with COVID-19 at High Risk of Progression: The PISA Outpatient Clinic Experience.

INTRODUCTION: Different antivirals are available for the treatment of outpatients with COVID-19. Our aim was to describe a real-world experience of outpatient management of COVID-19 subjects at high risk of progression. METHODS: This prospective observational study conducted in the University Hospital of Pisa (January 2022-July 2022) included consecutive COVID-19 outpatients with at least one risk factor for disease progression. Patients received nirmatrelvir/ritonavir, molnupiravir, or 3-day remdesivir, according to the Italian Medicines Agency (AIFA) indications. All patients were followed up until 30 days from the first positive nasopharyngeal swab. The primary endpoint was a composite of death or hospitalization. Secondary endpoints were occurrence of adverse events and a negative test within 10 days from the first positive test. Multivariable analysis was performed to identify factors associated with death or hospitalization. RESULTS: Overall, 562 outpatients were included: 114 (20.3%) received molnupiravir, 252 (44.8%) nirmatrelvir/ritonavir, and 196 (34.9%) 3-day remdesivir. The composite endpoint occurred in 2.5% of patients and was more frequent in patients treated with remdesivir (5.1%) compared with molnupiravir (1.8%) or nirmatrelvir/ritonavir (0.8%, ANOVA among groups p = 0.012). On multivariable Cox regression analysis, presence of ≥ 3 comorbidities, hematological disease, gastrointestinal symptoms, and each-day increment from symptoms onset were factors associated with death or hospitalization, while antiviral treatment was not a predictor. Adverse events occurred more frequently in the nirmatrelvir/ritonavir group (49.2%). Nirmatrelvir/ritonavir compared with remdesivir was associated with a higher probability of having a negative test within 10 days from the first positive one. CONCLUSION: Death or hospitalization did not differ among high-risk COVID-19 outpatients treated with currently available antivirals. Safety and time to a negative test differed among the three drugs.

Pretomanid for tuberculosis treatment: an update for clinical purposes.

Coronavirus disease (COVID-19) pandemic determined a 10 years-set back in tuberculosis (TB) control programs. Recent advances in available therapies may help recover the time lost. While Linezolid (LZD) and Bedaquiline (BDQ), previously Group D second line drugs (SLDs) for TB, have been relocated to Group A, other drugs are currently being studied in regimens for drug resistant TB (DR-TB). Among these, Pretomanid (PA), a recently introduced antimycobacterial drug derived from nitroimidazole with both solid bactericidal and bacteriostatic effect, and with an excellent effectiveness and tolerability profile, is in the spotlight. Following promising data obtained from recently published and ongoing randomized controlled trials (RCTs), the World Health Organization (WHO) determined to include PA in its guidelines for the treatment of rifampicin-resistant (RR), multi drug resistant (MDR) and pre-extensively drug resistant TB (pre-XDR-TB) with BDQ, LZD and Moxifloxacine (MFX) in a 6-month regimen. Although further studies on the subject are needed, PA may also represent a treatment option for drug-susceptible TB (DS-TB), latent TB infection (LTBI) and non tuberculous mycobacteria (NTM). This narrative review aims to examine current implementation options and future possibilities for PA in the never-ending fight against TB.

Superinfections caused by carbapenem-resistant Enterobacterales in hospitalized patients with COVID-19: a multicentre observational study from Italy (CREVID Study).

Objectives: To describe clinical characteristics and outcomes of COVID-19 patients who developed secondary infections due to carbapenem-resistant Enterobacterales (CRE). Methods: Retrospective observational study including COVID-19 patients admitted to 12 Italian hospitals from March to December 2020 who developed a superinfection by CRE. Superinfection was defined as the occurrence of documented bacterial infection >48 h from admission. Patients with polymicrobial infections were excluded. Demographic, clinical characteristics and outcome were collected. Isolates were classified as KPC, metallo-ß-lactamase (MBL) and OXA-48-producing CRE. A Cox regression analysis was performed to identify factors independently associated with 30 day mortality. Results: Overall, 123 patients (median age 66 years, IQR 59-75) were included. The majority of infections occurred in the ICU (81, 65.9%), while 42 (34.1%) in medical wards. The most common types of infection were bloodstream infections (BSI) (n = 64, 52%), followed by urinary-tract infections (UTI) (n = 28, 22.8%), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) (n = 28, 22.8%), intra-abdominal infections (n = 2, 1.6%) and skin infections (n = 1, 0.8%). Sixty-three (51.2%) infections were caused by KPC-, 54 (43.9%) by MBL-, and 6 (4.8%) by OXA-48-producing CRE. Thirty-day mortality was 33.3% (41/123). On Cox regression analysis, HAP/VAP compared with UTI (HR 7.23, 95% CI 2.09-24.97, P = 0.004), BSI compared with UTI (HR 3.96, 95% CI, 1.33-11.77, P = 0.004), lymphopenia on admission (HR 3, 95% CI 1.44-6.26, P = 0.003) and age (HR 1.05, 95% CI 1.02-1.08, P = 0.002) were predictors of 30 day mortality. Conclusions: Superinfections by CRE were associated with high risk of 30 day mortality in patients with COVID-19. HAP/VAP was the strongest predictor of death in these patients.

Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease.

Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE inhibitor (IC50 = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu = 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did not show significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 µM) in a MTT assay.

Risk factors and outcomes of fungal superinfections in patients with severe COVID-19: an observational study from Pisa academic hospital.

Background: Superinfections acquired during the hospital course represent common complications in COVID-19 patients. Several studies reported an increasing incidence of COVID-19 associated pulmonary aspergillosis (CAPA) and candidaemia. The aim of this study is to describe fungal superinfections in a large cohort of hospitalized patients with COVID-19 and identify factors independently associated with the risk of fungal superinfections. Methods: Observational study including patients with COVID-19 admitted to the tertiary-care, University Hospital of Pisa, Italy from April 2020 to May 2021. Patients with pneumonia and laboratory confirmed SARS-CoV-2 infection with a RT-PCR test on a nasopharyngeal swab, were eligible for the study. Patients who died within 24 hours from admission and those with missing data were excluded. Data about fungal superinfections were collected. To identify factors independently associated with the development of fungal superinfections, a multivariate regression analysis was performed. Results: Among 983 patients with COVID-19, 52 (5.3%) fungal superinfections were detected. Fungal superinfections included: 24/52 (46%) CAPA, 27/52 (51.9%) episodes of candidaemia and 1 case of pulmonary pneumocystosis in a haematological patient. All patients with CAPA were cared for in intensive care unit (ICU). The majority of patients received liposomal amphotericin B as antifungal treatment (83.3%). In-hospital mortality was 41.7%. Among 27 episodes of candidaemia, 16 (59.3%) occurred in ICU while 11 (40.7%) in medical wards. In-hospital mortality was 14.8%. Overall, patients with fungal superinfections had a median age of 73 (IQRs 59-77) years and a median length of ICU stay of 40 (17-50) days. In-hospital mortality among all patients with superinfections was 28.8%. On multivariable analysis, ICU stay (OR 17.63, 95% CI 8.3-37.41, p<0.001), high-dose steroids (OR 13.48, 95% CI 6.68-27.26, p<0.001), and diabetes mellitus (OR 2.14, 95% CI 1.09-4.17, p=0.026) were factors independently associated with the risk of developing a fungal superinfection. Conclusions: Fungal superinfections may complicate the hospital course of COVID-19 patients, especially of those admitted to ICU. Surveillance with detection of galactomannan on bronchoalveolar lavage in patients with clinical deterioration should be performed. A rational use of steroids is essential to avoid the risk of developing a fungal superinfection.

Efficacy of Bamlanivimab/Etesevimab and Casirivimab/Imdevimab in Preventing Progression to Severe COVID-19 and Role of Variants of Concern.

INTRODUCTION: The aim of this study was to evaluate the risk of hospitalization or death in patients infected by SARS-CoV2 variants of concern (VOCs) receiving combinations of monoclonal antibodies (mAbs), bamlanivimab/etesevimab or casirivimab/imdevimab. METHODS: Observational prospective study conducted in two Italian hospitals (University Hospital of Pisa and San Donato Hospital, Arezzo) including consecutive outpatients with COVID-19 who received bamlanivimab/etesevimab or casirivimab/imdevimab from March 20th to May 10th 2021. All patients were at high risk of COVID-19 progression according to FDA/AIFA recommendations. Patients were divided into two study groups according to the infecting viral strain (VOCs): Alpha and Gamma group. The primary endpoint was a composite of hospitalization or death within 30 days from mAbs infusion. A Cox regression multivariate analysis was performed to identify factors associated with the primary outcome in the overall population. RESULTS: The study included 165 patients: 105 were infected by the VOC Alpha and 43 by the VOC Gamma. In the Alpha group, no differences in the primary endpoint were observed between patients treated with bamlanivimab/etesevimab or casirivimab/imdevimab. Conversely, in the Gamma group, a higher proportion of patients treated with bamlanivimab/etesevimab met the primary endpoint compared to those receiving casirivimab/imdevimab (55% vs. 17.4%, p = 0.013). On multivariate Cox-regression analysis, the Gamma variant and days from symptoms onset to mAbs infusion were factors independently associated with higher risk of hospitalization or death, while casirivimab/imdevimab was protective (HR 0.33, 95% CI 0.13-0.83, p = 0.019). CONCLUSIONS: In patients infected by the SARS-CoV-2 Gamma variant, bamlanivimab/etesevimab should be used with caution because of the high risk of disease progression.